Notes & Notes 
For MRCP part I & 11 
 
By 
 
Dr. Yousif Abdallah Ham ad 
 
1

gmail.com@ dryousif23  
https://www.facebook.com/dryousif23 
 
2

The main Sources of this Notes & Notes  
 
4

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah  Hamad                      
  
 The contents 
Section  Page  
Neurology 5 
Endocrinology  180 
Cardiology  464 
Respiratory  608 
Gastroenterology  794 
Renal  925 
Rheumatology  1035 
Haematology  1134 
Infectious  1245 
Minor  
Dermatology  1354 
Ophthalmology  1427 
Psychiatry  1479 
Basics  
Cell biology   1517 
Biochemistry and metabolism  1543 
Immunology  1581

Immunology  1581 
Genetics  1635 
Statistics  1665 
Pharmacology  1694 
 5

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              1 
  
Notes & Notes
For MRCP part 1 & 11
 
By
 
Dr. Yousif Abdallah Hamad
 
Neurology
 
Updated 
 
2017
 
Contains: 
1/ Passmedicine 2017  
2/ On examination 2017  
3/ Pastest 2017  
4/ Red fonts --> previous exams  
5/ Other updated UK sources 
 
6

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              2 
  
CNS anatomy 
 
7

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              3 
 Foramina of the skull 
Questions asking about foramina of the skull have come up in the exam in previous years. B elow is a 
brief summary of the major foramina: 
 
Foramen Bone Vessels Nerves 
Optic canal Sphenoid Ophthalmic artery Optic nerve (II) 
Superior 
orbital 
fissure Sphenoid Superior ophthalmic vein

fissure Sphenoid Superior ophthalmic vein 
Inferior ophthalmic vein Oculomotor nerve (III) 
Trochlear nerve (IV) 
lacrimal, frontal and nasociliary 
branches of ophthalmic nerve (V: V1)  
Abducent nerve (VI) 
Inferior 
orbital 
fissure Sphenoid 
and maxilla Inferior ophthalmic veins 
Infraorbital artery 
Infraorbital vein Zygomatic nerve and infraorbital 
nerve of maxillary nerve (V2) 
Orbital branches of pterygopalatine 
ganglion 
Foramen 
rotundum Sphenoid - Maxillary nerve (V2) 
Foramen

Foramen 
ovale Sphenoid Accessory meningeal artery Mandibular nerve (V3) 
Jugular 
foramen  Occipital and 
temporal Posterior meningeal artery 
Ascending pharyngeal artery  
Inferior petrosal sinus 
Sigmoid sinus 
Internal jugular vein Glossopharyngeal nerve (IX)  
Vagus nerve (X)  
Accessory nerve (XI)  
 Right jugular foramen lesion:  
 palatal weakness and swallowing difficulties ( IX/X),  
 shoulder and sternocleidomastoid weakness (due to accessory nerve ( XI) involvement. 
 
Anatomy

Anatomy   
 hindbrain comprises: 
 myel encephalon (medulla oblongata and lower part of the fourth ventricle) 
 medulla oblongata opens into the fourth ventricle. 
 met encephalon  (pons, cerebellum and intermediate part of fourth ventricle), and 
 Isthmus rhomb encephalon . 
 Cranial nerve nucleus 
 All the nuclei except that of the trochlear nerve (CN IV) supply nerves of the same side  of 
the body. 
 nucleus ambiguous

the body. 
 nucleus ambiguous  
 gives rise to fibres of the glossopharyngeal (IX), vagus (X), and accessory (XI) 
nerves. 
 Solitary nucleus 
 embedded in the medulla oblongata ,  
 purely sensory nuclei 
 receives inputs from cranial nerves : facial ( VII), glossopharyngeal (IX) and vagus  (X).  
 involved in the reflexes initiated through the vagus or glossopharyngeal nerves 
(e.g., carotid sinus reflex, gag reflex, etc.). 
 specifically receives:

 specifically receives: 
 Taste  information from the facial nerve (anterior 2/3 of the tongue), 
glossopharyngeal nerve (posterior 1/3) and  vagus nerve (small area on the 
epiglottis)  
 general visceral sensory inputs from the chemoreceptors in the carotid body  (via 
glossopharyngeal nerve) and aortic body  (via vagus nerve) and baroreceptors in 
the carotid sinus (via glossopharyngeal nerve) 
 general visceral sensory inputs from mechanoreceptors and chemoreceptors

located in the heart, lungs and gastrointestinal tract (via vagus nerve).  8

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              4 
  Nucleus locus coeruleus  
 located in the  pons  
 involved with the physiological responses to stress and panic . 
 the principal site for brain synthesis of norepinephrine  (noradrenaline). 
 Norepinephrine also released from the adrenal medulla. 
 Melanin granules  inside the neurons contribute to its blue colour .

 In opiate withdrawal: 
 Opioids inhibit the firing of neurons in the locus coeruleus.  
 opiate withdrawal  increased activity of the locus coeruleus withdrawal 
symptoms .  
 clonidine  (alpha2 adrenoceptor  agonist ) is used to counteract this 
withdrawal  effect by decreasing adrenergic neurotransmission from the 
locus coeruleus  
 
Brain lesions 
The following neurological disorders/features may allow localisation of a brain lesion: 
Frontal lobes lesions

 Difficulties with task sequencing and executive skills 
 Expressive (Broca's) aphasia:  
 located on the posterior aspect of the frontal lobe, in the inferior frontal gyrus.  
 Speech is non-fluent, laboured, and halting  
 Disinhibition  
 Perseveration  
 Anosmia  
 primitive reflexes (positive grasp, pout and palmomental reflexes)  
 inability to generate a list  
 Changes in personality.  
  
 Parietal lobes lesions

Parietal lobes lesions
 sensory inattention (contralateral hemihypesthesia) 
 apraxias 
 astereognosis (tactile agnosia) 
 inferior homonymous quadrantanopia 
 Neglect 
 mild hemiparesis   
 parietal ataxia 
 Acalculia (inability to perform mental arithmetic). 
 Gerstmann's syndrome  (lesion of dominant parietal):  
 Alexia (inability to read), acalculia, finger agnosia and right-left disorientation 
 unilateral impairment of optokinetic nystagmus.

 Optokinetic nystagmus  is a nystagmus  that occurs in response to a rotation movement. 
It is present normally. 
 
9

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              5 
   
 Temporal lobes lesions
 Homonymous quadrantanopias 
 
PITS  
 
(Parietal- Inferior, Temporal- Superior) 
 
 Wernicke's aphasia:  
 this area 'forms' the speech before 'sending it' to Broca ’s area.  
 Lesions result in word substitution, neologisms but speech remains fluent 
 superior homonymous quadrantanopia

 superior homonymous quadrantanopia 
 auditory agnosia 
 prosopagnosia (difficulty recognising faces) 
 Memory impairment. 
  
 Occipital lobes lesions
 homonymous hemianopia (with macula sparing)    
 may present as Anton syndrome  where there is blindness but the patient is unaware or 
denies blindness.  
 cortical blindness 
 visual agnosia 
 visual illusions and elementary visual hallucinations.

May 2010 exam: A patient diagnosed with a glioma in the parietal lobe. Which feature is 
most likely to develop?  Acalculia  
  
 Cerebellum lesions
 midline lesions:  
 gait and truncal ataxia 
 hemisphere lesions:  
 intention tremor,  
 past pointing,  
 dysdiadokinesis (inability to perform rapid, alternating movements) ,  
 nystagmus 
 
10

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              6 
   
 More specific areas
Area Associated conditions 
Medial thalamus  and 
mammillary bodies  of the 
hypothalamus Wernicke and Korsakoff ’s syndrome 
Subthalamic nucleus of the basal 
ganglia  Hemiballism  
Striatum ( caudate nucleus ) of the 
basal ganglia Huntington  chorea  
Substantia nigra of the basal

Substantia nigra of the basal 
ganglia Parkinson's disease 
Amygdala Kluver-Bucy syndrome: 
 hypersexuality,  
 hyperorality (insertion of inappropriate objects in the mouth) 
 hyperphagia,  
increased activation  to the amygdala is associated with depression  
Hippocampus  pathology  Short term  memory impairment  (for example, Alzheimer's 
disease).  
Lateral geniculate nucleus 
pathology   visual field defect.

pathology   visual field defect. 
Red nucleus   tremor , which is present both at rest and during action (for 
example, multiple sclerosis tremor). 
Prefrontal cortex damage disinhibition  and problems with social interaction  and 
judgement and has been implicated in schizophrenia . 
Left prefrontal cortex  Depression  
 
11

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              7 
 Transient ischaemic attack (TIA)  
Definition  
 temporary, focal cerebral ischemia that results in brief neurologic deficits lasting < 24 hours   
Stroke risk assessment 
 ABCD2 prognostic score  
 ABCD2 score  is used to determine the risk for stroke  in the days following a (TIA)  
 This gives a total score ranging from 0 to 7.

 This gives a total score ranging from 0 to 7. 
Criteria Points 
A Age >= 60 years 1 
B Blood pressure >= 140/90 mmHg 1 
C Clinical features   
- Unilateral weakness 
- Speech disturbance, no weakness  
2 
1 
D Duration of symptoms 
- > 60 minutes  
- 10-59 minutes  
2 
1 
 Patient has diabetes 1 
 Interpretation of ABCD2 risk score 
 If the ABCD2 risk score is 4 or above  high risk of stroke 
 should have: 
 aspirin (300 mg daily) started immediately

 aspirin (300 mg daily) started immediately 
 specialist assessment and investigation within 24 hours  of onset of 
symptoms 
 measures for secondary prevention introduced as soon as the 
diagnosis is confirmed, including discussion of individual risk factors 
 If the ABCD2 risk score is 3 or below  low risk of stroke 
 specialist assessment within 1 week  of symptom onset, including decision on brain 
imaging 
 if vascular territory or pathology is uncertain, refer for brain imaging

 People with crescendo TIAs (two or more episodes in a week) should be treated as being  
at high risk of stroke, even though they may have an ABCD2 score of 3 or below. 
 The risk for stroke can be estimated from the ABCD2 score as follows: 
 
 2 day risk 7 day risk  
Score 1-3 (low) 1.0% 1.2% 
Score 4-5 (moderate) 4.1% 5.9% 
Score 6 –7 (high)  8.1% 11.7%  
 
The Risk of future ischemic stroke after a TIA  
 overall annual  risk is 3 –4%, 
 over the next 7 days is 11%

 over the next 7 days is 11%  
 over the following 5 years   is 24 –29%. 
 
Ref: emedicine.medscape.com Updated: Sep 11, 2017 
https://emedicine.medscape.com/article/1910519-overview  
 
12

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              8 
 A 77-year-old man presented after a single episode of unilateral weakness of the  left arm that lasted 
for 2 hours.  170/100 mmHg. What is his chance of having a stroke in the first week?   11% 
Ref: www.mrcpuk.org/ Acute Medicine Specialty Certificate Examination/ sample questions

Investigations (NICE guidelines. Last updated: March 2017 ) 
 Most specific and sensitive for TIA  
 MRI is superior to CT  in detecting the small ischemic lesions occurring after TIA and 
minor stroke.   
 Identifies ischemia earlier than CT (within 3 –30 minutes after onset) 
 Non-contrast cranial CT (gold standard and most important initial imaging  in 
stroke ):  
 detects acute hemorrhage but cannot reliably identify early 
ischemia

ischemia 
 CT scanning should only be used if  MRI is contraindicated 
 Although the definition of TIA is "a transient episode of neurological dysfunction caused 
by focal brain, spinal cord, or retinal ischemia, without acute infarction," up to 50% of TIA 
show ischemic changes in imaging.  
 MRI findings of ischemia  
 T1: hypointense 
 T2: hyperintense 
 Time of image: 
 ABCD2 score ≥ 4  urgent brain imaging  within 24 hours (preferably diffusion-
weighted MRI)

weighted MRI) 
 the most appropriate next step  Admit for MRI neuroimaging, 
initiate anti-platelet therapy 
 ABCD2 score ≤ 4   brain imaging (preferably diffusion-weighted MRI) within 1 
week  
 Duplex ultrasound  of carotid stenosis 
   the most appropriate next step if bruits in the neck are heard upon auscultation.  
 If ultrasound is not available, a CTA or MRA may be used. 
Treatment 
 Antithrombotic therapy  (2012 Royal College guideline)

 clopidogrel is recommended first-line (as for patients who've had a stroke)  
 aspirin + dipyridamole should be given to patients who cannot tolerate clopido grel 
 
2016 Royal College guideline 
 Patients with a confirmed diagnosis of TIA should receive clopidogrel (300 mg loading dose 
and 75 mg daily thereafter) and high intensity statin therapy (e.g. atorvastatin  20-80 mg daily) 
started immediately.

started immediately. 
 
January 2013 exam: Which factor is most associated with an increased risk of going on to 
have a stroke in a patient presented with TIA?   Duration of his TIA  
 
 Stroke  
Etiology 
 35% - atherosclerosis of the extracranial vessels (carotid atheroma) 
 30% - cardiac and fat emboli, endocarditis 
 15% - lacunar 
 10% - parenchymal hemorrhage 
 10% - subarachnoid hemorrhage 
Presentation 
 Edema occurs 2-4 days post-infarct.  
 Watch for symptoms

 Watch for symptoms 
 decorticate (cortical lesion): flexion of arms 
 decerebrate (midbrain or lower lesion): extension of arms  
 cerebellar: ataxia, nystagmus, abnormal finger-nose and heel-shin 13

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              9 
  Other stroke syndromes 
 lateral medullary infarct (Wallenburg syndrome) 
 loss of pain and temp on ipsilateral face and contralateral body, vestibulocerebella r 
impairment, Horner's syndrome 
 
Imaging 
 CT without contrast  for acute presentation  
 the next best step in the management of stroke  
 to rule out hemorrhage

 to rule out hemorrhage 
 Contrast head CT is not used in the diagnosis of acute stroke.  
 if the CT is negative  MRI, specifically diffusion-weighted imaging and others, is the most 
widely used.  
 MR studies may show which brain regions are already infarcted and which are at risk of 
infarction if perfusion is not restored.  
 An acute ischemic stroke is diagnosed by diffusion weighted MRI or by using the clinical

history (i.e. don't delay tPA just to get an MRI if there is strong clinical suspicion and no 
evidence of bleed). 
Management 
 If an ischemic stroke suspected clinically and CT is negative for evidence of a hemorrhagic 
stroke, the recommended treatment is to give IV tPA if the presentation is within 3-4 .5 hours.  
 Of note, a contraindication to tPA is systolic BP > 185 or diastolic BP > 110 mm Hg.  
 For embolic disease and hypercoagulable states give warfarin or aspirin only once the

hemorrhagic stroke has been ruled out.  
 
14

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              10 
 ___________________________________________________ _______________
Stroke by anatomy  
Site of the lesion Associated effects 
Anterior cerebral artery Contralateral hemiparesis and sensory loss, lower 
extremity > upper  
Middle cerebral artery Contralateral hemiparesis and sensory loss, upper 
extremity > lower

extremity > lower  
Contralateral homonymous hemianopia  
Aphasia (global aphasia)  
Posterior cerebral artery Contralateral homonymous hemianopia with macular 
sparing  
Visual agnosia 
Other possible findings:  
 Cortical blindness 
 Visual hallucinations 
 Thalamic syndrome, and 
 Claude's and Weber's syndromes.  
Weber's syndrome  (branches of the posterior 
cerebral artery that supply the midbrain ) 
Or branches of the basilar artery  Ipsilateral CN III palsy 
Contralateral weakness

Contralateral weakness 
Posterior inferior cerebellar artery  
(PICA )(lateral medullary syndrome, 
Wallenberg syndrome ) 
lesion to dorsolateral medulla  Ipsilateral : facial pain and temperature loss 
Contralateral : limb/torso pain and temperature loss. 
 Ataxia, nystagmus 
Anterior inferior cerebellar artery ( lateral 
pontine syndrome ) Symptoms are similar to Wallenberg's (see above), but: 
Ipsilateral : facial paralysis  and deafness  
Retinal/ophthalmic artery Amaurosis fugax

Retinal/ophthalmic artery Amaurosis fugax 
Basilar artery 'Locked-in' syndrome 
 
___________________________________________________ _______________
Middle cerebral artery (MCA) occlusion  
For individuals aged up to 60 years who suffer an acute MCA territory ischaemic stroke 
complicated by massive cerebral oedema , surgical decompression by hemicraniectomy  
should be offered within 48 hours of stroke onset. 
 
 Divisions 
 Superior division

 Superior division 
 Occlusion of the superior division of the MCA results in: 
 contralateral hemiparesis that affects the face, hand and arm, but spares the 
leg 
 contralateral hemisensory deficit in the same distribution 
 no homonymous hemianopia 
 If the dominant hemisphere is involved, there is also expressive aphasia  
 Inferior division 
 Occlusion of the inferior division of the middle cerebral artery results in: 
 contralateral homonymous hemianopia

 contralateral homonymous hemianopia 
 marked impairment of cortical sensory functions, such as graphaesthesia 
and stereognosis on the contralateral side of the body 
 disorders of spatial thought, including 
 lack of awareness that a deficit exists (anosognosia) 
 neglect of and failure to recognise the contralateral limbs 
 neglect of the contralateral side of external space 15

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              11 
  dressing apraxia 
 constructional apraxia 
 Involvement of the dominant hemisphere also causes receptive aphasia  
 acute confusional state may occur if the non-dominant hemisphere is affected   
 Neurosurgery in treatment of MCA (decompressive hemicraniectomy)

 Current clinical guidelines recommend that patients who are under 60 years  of age with 
large  cerebral infarctions arising in the MCA territory should be considered for  
decompressive hemicraniectomy.  
 Decompressive hemicraniectomy  involves removing part of the skull in order to reduce 
intracranial pressure and should be carried out within 48 hours of the index event. 
 Eligibility is based on 
1. Clinical and radiological evidence of a stroke affecting this territory,

2. Radiological evidence that more than 50% or 145 cm3 of the MCA territory is 
involved  and 
3. Being classified as having a moderate to severe stroke according to the National 
Institute of Health stroke scale. 
September 2010 exam: Right sided sensory loss affecting arms more than the legs + right 
sided homonymous hemianopia. What area is the stroke most likely to have affected? 
Middle cerebral artery  
Lacunar strokes

Lacunar strokes  
 Lacunar strokes is defined by one of:  
 Unilateral weakness (and/or sensory deficit) of face and arm, arm and leg or all three. 
 Pure sensory stroke. 
 Ataxic hemiparesis 
 The term 'lacune' refers to a small deep infarct resulting from occlusion of a penetrating bran ch 
 Lacunar infarcts occur in areas supplied by small perforating vessels and result from: 
 atherosclerosis 
 hypertension  
 diabetes

 diabetes 
 present with either isolated hemiparesis, hemisensory loss or hemiparesis with limb ataxia 
 strong association with hypertension 
 common sites include the basal ganglia, thalamus and internal capsule 
 The putamen  is the commonest site for hypertensive intracerebral haemorrhage  
Lateral medullary syndrome 
 
 also known as Wallenberg's syndrome ,

 also known as Wallenberg's syndrome ,  
 occurs following occlusion of the Posterior Inferior Cerebellar Artery  lesion to 
dorsolateral medulla  
 Features  
 Cerebellar features  
 ataxia 
 nystagmus 
 Brainstem features 
 ipsilateral: dysphagia, facial numbness, cranial nerve palsy e.g. Horner's 
 contralateral: limb sensory loss   
 Damage to: 
 vestibular nucleus  nystagmus and vomiting 
 inferior cerebellar peduncle  ipsilateral limb ataxia

 spinothalamic tract  contralateral loss of pain and temperature sensation 
 IXth and Xth nerve nuclei  ipsilateral palatal, pharyngeal and vocal cord paralysis 
 nucleus and tract of the Vth nerve  ipsilateral loss of facial pain and temperature 
sensation 
 descending sympathetic fibres  ipsilateral Horner syndrome 
 Diagnosis 
16

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              12 
  MRI will be better able to visualise cerebellar infarction.  
 
September 2009 exam: Lateral medullary syndrome is caused by occlusion of which vessel? 
 
May 2012 exam: H/O unsteady feet, right-sided Horner's syndrome and horizontal

nystagmus, sensory loss on the left side. Where is the lesion most likely to be? Posterior 
inferior cerebellar artery  
Pontine stroke 
Diplopia + hemiparesis + lower motor neurone facial nerve lesion  pontine stroke 
 
 Rapidly deteriorating level of consciousness, impaired extraocular movement and extensive  
sensorimotor deficits are clinical clues to pontine haemorrhage.

 Decerebrate state is most likely a pontine lesion.  
 
 Millard-Gubler syndrome ; a pontine lesion  that produces: 
 ipsilateral Vlth and Vllth nerve palsy 
 contralateral  hemiparesis  
 
Crossed neurological signs  (ipsilateral motor and sensory cranial nerve signs  and contralateral 
hemiplegia )  localise to the brainstem (midbrain, pons or medulla).  
 Pons  (ipsilateral abducens and facial nerves palsy, contralateral hemiplegia)

 Midbrain  (ipsilateral oculomotor nerve palsy , contralateral hemiplegia)  
 
Weber's syndrome    
 ipsilateral III palsy 
 contralateral weakness 
Cerebellar haemorrhage 
 The most common symptoms are of severe nausea, vomiting and ataxia.  
 Headache may be severe.

 Headache may be severe. 
  Patients with cerebellar haemorrhage can rapidly become comatose within hours after th e onset 
from herniation, because of its limited space in the posterior fossa. 
Hypoperfusion strokes  
 Hypoperfusion tends to cause brain injuries at 'watershed' areas that are border zones betw een 
the major cerebral arteries. 

Arteries aneurysms  
anterior communicating artery aneurysms  The most common aneurysm in circle of 
Willis  
 Most anterior artery communicating aneurysms are asymptomatic unless they rupture, 
and so they are usually found either incidentally or when a patient presents w ith SAH.  
 
Posterior communicating artery aneurysm  will cause  compression of the third nerve, 
and therefore :  isolated ipsilateral  painfu l third nerve palsy

 Pupillary involvement (pupil dilation) from compression of the parasympatheti c fibres 
that run on the outside of the third nerve  
  Other features of a third nerve palsy include ptosis, and a ‘down and out ’ eye. 
 Cerebral aneurysms may be associated with polycystic kidney disease. 
 
 17

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              13 
Stroke: types  
 The Oxford Stroke Classification  (also known as the Bamford Classification) classifies strokes 
based on the initial symptoms 
 The following criteria should be assessed: 
1. unilateral hemiparesis and/or hemisensory loss of the face, arm & leg

2. homonymous hemianopia 
3. higher cognitive dysfunction e.g. dysphasia 
 Total anterior circulation infarcts  (TACI, c. 15%) 
 involves middle and anterior cerebral arteries 
 all 3 of the above criteria are present 
 Partial anterior circulation infarcts  (PACI, c. 25%) 
 involves smaller arteries of anterior circulation e.g. upper or lower division of middle 
cerebral artery 
 2 of the above criteria are present 
 Lacunar infarcts  (LACI, c. 25%)

 Lacunar infarcts  (LACI, c. 25%) 
 involves perforating arteries around the internal capsule, thalamus and basal 
ganglia 
 presents with 1 of the following: 
 unilateral weakness (and/or sensory deficit) of face and arm, arm and leg or 
all three. 
 pure sensory stroke. 
 ataxic hemiparesis 
 Posterior circulation infarcts  (POCI, c. 25%) 
 involves vertebrobasilar arteries 
 cerebellar or brainstem syndromes 
 loss of consciousness

 loss of consciousness 
 isolated homonymous hemianopia 
Stroke: assessment 
 FAST screening tool  (Face/Arms/Speech/ Time):  
 widely known by the general public following a publicity campaign.  
 It has a positive predictive value of 78%. 
 
 ROSIER score   
 useful for medical professionals.  
 It is validated tool recommended by the Royal College of Physicians.

 Exclude hypoglycaemia first, then assess the following: 
Assessment Scoring 
Loss of consciousness or syncope - 1 point 
Seizure activity - 1 point 
New, acute onset of:  
• asymmetric facial weakness  + 1 point 
• asymmetric arm weakness  + 1 point 
• asymmetric leg weakness  + 1 point 
• speech disturbance  + 1 point 
• visual field defect  + 1 point 
 stroke is likely if > 0  18

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              14 
  
 Scores ad scales used in stroke   
score Used in  
“ABCD2 ” score predicts the risk of stroke following a 
transient ischaemic attack 
Barthel Index   measures a person ’s daily functioning, e.g 
ability to bath, feed 
“CHADS2-Vasc ” assesses stroke risk in patients with non-
valvular atrial fibrillation

valvular atrial fibrillation 
 Modified Rankin Scale measures the degree of disability, after a 
stroke 
NIHSS Score (National 
Institute of Health Stroke 
Scale)   is a tool used acutely to assess the degree 
of stroke-related neurologic deficit and 
hence determine appropriate treatment e.g. 
thrombolysis 
 
 Barthel index  
 used to assess disability following a stroke  
 The Barthel index correlates well with other prognostic scales.

 It has very good concurrent and predictive validity. 
 It is very sensitive and it only takes 10 minutes to perform. 
 The most limitation of the Barthel index is floor and ceiling effects .  
 It basically means that a disabled person can score a maximum score of 100 
and still not be independent. 
 It is poor at differentiating disability in patients who function at a higher level.  
 It also has floor effects as it may incorrectly score patients low who are

initially bed bound following a stroke. 
 WHO International Classification of Functioning, Disability and Health (ICF)  
 The NICE guidelines on stroke suggest that we use terminology to describe the type of 
impairment  in accordance with the WHO International Classification of Functioning, 
Disability and Health.  
 'impairment of body function' 
 Symptoms and signs like hemiparesis  are classified as. 
 'activity limitation'

 'activity limitation'   
 difficulties in executing certain activities, for example communication 
impairment in patients with aphasia following a stroke or the inability to pick 
up a cup in the affected hand. 
 'participation restriction'   
 problems in social roles - for example as a spouse or parent. 
 'pathology'   
 the diagnosis/disease. 
Stroke: management  
 
 Initial management

 Initial management 
 blood glucose, hydration, oxygen saturation and temperature should be maintained within 
normal limits  
 Blood pressure   
 should not be lowered in the acute phase unless there are complications e.g. 
Hypertensive encephalopathy.  
 Aspirin   
19

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              15 
  300mg orally or rectally should be given as soon as possible if a haemorrhagic 
stroke has been excluded 
 Thrombolysis   
 Thrombolysis should only be given if: 
 administered within 4.5 hours of onset of stroke symptoms  
 haemorrhage has been definitively excluded (i.e. Imaging has been performe d)

 Alteplase is currently recommended by NICE.  
 blood pressure should be reduced to below 185/110  mmHg before alteplase 
treatment 
 Patients treated with thrombolysis should be started on an antiplatelet agent after 24 
hours once significant haemorrhage has been excluded. 
 Contraindications to thrombolysis:   
Absolute Relative 
 Previous intracranial haemorrhage 
 Seizure at onset of stroke 
 Intracranial neoplasm 
 Suspected subarachnoid haemorrhage

 Suspected subarachnoid haemorrhage 
 Stroke or traumatic brain injury in preceding 
3 months 
 Gastrointestinal haemorrhage in preceding 3 
weeks 
 Lumbar puncture in preceding 7 days 
 Active bleeding 
 Oesophageal varices 
 Uncontrolled hypertension >200/120mmHg   Concurrent anticoagulation 
(INR >1.7) 
 Haemorrhagic diathesis 
 Active diabetic haemorrhagic 
retinopathy 
 Suspected intracardiac 
thrombus 
 Major surgery / trauma in 
preceding 2 weeks 
 Pregnancy

 Pregnancy 
 Active pancreatitis.  
 patients with severe strokes only have an 8% likelihood of achieving clinically significant 
improvement with tPA alone.  
 Intra-arterial clot retrieval (Mechanical thrombectomy)  
 Advantages  
 safe and effective  
 Mechanical thrombolytic devices can remove a clot in a matter of minutes, whereas 
pharmaceutical thrombolytics, even those delivered intra-arterially, may take as 
long as 2 hours to dissolve a thrombus.

long as 2 hours to dissolve a thrombus.  
 patients should undergo the procedure within 6 hours  of symptom onset.  
 Indications  
 large vessel occlusion (usually in addition to IV thrombolytic therapy)  
 proximal MCA  or  
 distal internal carotid artery  or  
 basilar artery  occlusion.  
 Patients who are ineligible for IV thrombolysis  who present within the 
appropriate time-frame with large vessel occlusion.  
 Surgical treatment  decompressive hemicraniectomy

 Indications   
 Patient with middle cerebral artery infarction who meet all of the criteria below: 
1. Aged 60 years or under. 
2. Clinical deficits suggestive of infarction in the territory of the middle cerebral 
artery, with a score on the National Institutes of Health Stroke Scale  
(NIHSS) of above 15 . 
3. Decrease in the level of consciousness to give a score of 1 or more  on 
item 1a of the NIHSS.  
4. Signs on CT of an infarct of at least 50% of the middle cerebral artery

territory 
 
 Secondary prevention  
 clopidogrel  is now recommended by NICE  20

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              16 
  aspirin plus MR dipyridamole is now recommended after an ischaemic stroke only if 
clopidogrel is contraindicated or not tolerated, but treatment is no longer limited to 2 
years' duration 
 MR dipyridamole alone is recommended after an ischaemic stroke only if aspirin or

clopidogrel are contraindicated or not tolerated, again with no limit on duration of 
treatment 
 Aspirin  
 Start aspirin after excluding  intracerebral haemorrhage by brain imaging 
 aspirin 300 mg orally if they are not dysphagic or if they are dysphagic  aspirin 
300 mg rectally or by enteral tube. 
 aspirin 300 mg should be continued until 2 weeks after the onset of stroke, at w hich 
time definitive long-term antithrombotic treatment should be initiated.

 Anticoagulation treatment for other comorbidities (e.g: atrial fibrillation):  
 should not be started until brain imaging has excluded haemorrhage,  
 usually after 14 days  from the onset of an ischaemic stroke. 
 ischaemic stroke + atrial fibrillation  aspirin 300 mg for the first 2 weeks 
before considering anticoagulation treatment. 
 cerebral infarction in patient  with prosthetic valves and who are at significant risk of

haemorrhagic transformation,  anticoagulation treatment should be stopped 
for 1 week and aspirin 300 mg substituted.  
 ischaemic stroke and symptomatic proximal DVT or PE  should receive 
anticoagulation treatment in preference to treatment with aspirin 
 haemorrhagic stroke and symptomatic DVT or PE  prevent further PE using 
either anticoagulation or a caval filter.  
 Statin treatment 
 Immediate initiation of statin is not recommended in  acute stroke

 Many physicians will delay treatment until after at least 48 hours due to the 
risk of haemorrhagic transformation 
 If already on statins should continue their statin  
 all patients who are diagnosed with stroke or TIA should be commenced on 
statin therapy irrespective of the cholesterol level .(passmedicine 2017 part 2)  
 
 Glycaemic management during the inpatient enteral feeding of stroke patients with 
diabetes:

diabetes: 
 The Joint British Diabetes Society 2012 guidelines recommend a target BM of 
between 6 and 12 mmol/l for hyperglycaemic patients on NG feed with insulin to be 
started when BM over 12 mmol/l.  
 The insulin regime of choice is a biphasic insulin such as humulin  M3, with a 
mixture of intermediate and short acting insulin, prescribed twice daily, at the start 
and middle of the NG feed. 
 the optimal management of hyperglycaemia  Prescribe biphasic 
insulin twice daily

insulin twice daily 
 Patients with hyperglycaemia should never be prescribes PRN actrapid nor should 
the NG feed be stopped 
___________________________________________________ _____________________________ 
Spontaneous intracerebral haemorrhage  
Current management of spontaneous intracerebral haemorrhage  (bmj.com 2017) 
http://svn.bmj.com/content/2/1/21  
 
 The most common locations of hypertensive ICH are  the putamen, thalamus, subcortical 
white matter, pons and cerebellum

white matter, pons and cerebellum   
 Common risk factors   
 HTN, ( the most common risk factor ) 
 age,  
 history of heavy alcohol,  
 methamphetamine or cocaine use,  
 education at less than a high school level and  
 genetic alleles associated with cerebral amyloid. 21

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              17 
  Classification by location 
 lobar versus non-lobar and supratentorial versus infratentorial. 
 Lobar ICH 
 commonly due to cerebral amyloid angiopathy  (CAA).  
 Amyloid deposition  in small-sized to medium-sized cortical perforators may 
lead to the rupture of these vessels, 
 Non-lobar ICH

 Non-lobar ICH 
 commonly due to long-standing high blood pressure  resulting in lipohyalinosis 
of small perforating arteries  of the basal ganglia, thalamus, pons and cerebellum, 
leading to deep haemorrhages, often with extension into the ventricles.  
 Feature 
 ICH should be suspected in any patient with severe headache, vomiting, elevated systoli c 
blood pressures or decreased level of consciousness.  
 Fever is common

 Fever is common  
 Sustained fever after ICH is an independent prognostic factor for worse outcome. 
 non-contrast head CT  is highly sensitive and specific  
 Treatment 
 Stabilisation of airway, breathing and circulation (ABCs)   
 Intubation  for airway protection is indicated in patient with GCS ≤8  or significant 
respiratory distress.  
 Patient with a decreased level of consciousness from intraventricular haemorrhage with

hydrocephalus , mass effect or brainstem herniation should receive: 
 ventriculostomy ,  
 hyperosmolar therapy with mannitol  0.5–1 g/kg or hypertonic saline  (HTS) 
infusion.   
 In patients with an intracerebral haemorrhage, intervention to control the blood 
pressure is required only when the systolic  BP exceeds 170 mmHg .  
 Intensive lowering of systolic blood pressure to <140 mm Hg is proven safe by two 
recent randomised trials .

recent randomised trials . 
 the 2015 update to the AHA/ASA Guidelines for the Management of Spon taneous 
ICH recommend that for patients presenting with SBP between 150 and 200, acute 
lowering of SBP to 140 mm Hg is safe and may be effective for improving 
functional outcome. 
 aggressive blood pressure reduction with continuous antihypertensive drug 
intravenous infusion and frequent monitoring 
 Intravenous calcium channel blockers (eg, nicardipine ) and β -blockers (eg,

labetalol ) are the treatment of choice  for early BP reduction, given their short 
half-life and ease of titration. 
 During acute phase , patients may have resistant HTN  due to sympathetic 
surge . A few weeks later, they may require fewer medications and be at risk of 
hypotension unless the doses of medications are adjusted promptly 
 
 In patients with small  haematoma without significant mass effect , there is no indication for

routine use of mannitol or hypertonic saline (HTS)  Observe  
  However, for patients with large ICH (volume > 30 cbic centmetre) or symptomatic 
perihaematoma oedema, it may be beneficial to keep serum sodium level at 14 0–150 mEq/L for 
7–10 days to minimise oedema expansion and mass effect.  
 Mannitol and  hypertonic saline (HTS) can be used emergently for worsening cerebr al oedema, 
elevated intracranial pressure (ICP) or pending herniation.

 Ventriculostomy is indicated for patients with severe intraventricular haemorrhage, 
hydrocephalus or elevated ICP. 
 Reversal of coagulopathies 
 12–20% of patients presenting with ICH are taking oral anticoagulants.  
 For all patients taking vitamin K antagonists (eg, warfarin)  
 for patients with INR ≥1.4:  
  vitamin K 10 mg and  3-factor or 4-factor prothrombin complex 
concentrates (PCCs)  22

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              18 
  PCC is an inactivated concentrate of factors II, IX and X, with variable 
amounts of factor VII.  
 Variation in factor VII concentrations in PCC has led to their 
classification as either 3- or 4-factor. 
 PCC is preferred over FFP  
 Recombinant Factor VIIa (rFVIIa)  has been associated with relatively high

thrombosis rates and should only be considered in patients who will not 
accept blood products (eg, Jehovah's witness).  
 Direct thrombin inhibitors  (DTIs; eg, dabigatran , argatroban  and bivalirudin )  
 reversal of coagulopathy is indicated if patient presents within 3 –5 half-lives  (or 
beyond in patient with renal insufficiency).  
 haemorrhage associated with dabigatran    Idarucizumab  (5 g intravenous 
divided into two doses)

divided into two doses) 
 If idarucizumab is not available, or if the haemorrhage is associated with a DTI 
other than dabigatran , PCC  is recommended. 
 Haemodialysis can also be considered in patients with dabigatran-associated ICH 
and renal insufficiency, especially if continued haemorrhage despite first-lin e 
therapies. 
 For patients taking Factor Xa inhibitors (eg, rivaro xaban, apixaban and edo xaban):

 PCC  is recommended if the haemorrhage occurred within 3 –5 half-lives of drug 
exposure (or in context of liver failure).  
 If presenting within 2 hours of drug exposure, activated charcoal can be 
administrated to prevent further drug absorption.  
 Laboratory testing is unlikely to be helpful in guiding treatment; therefore, reversal 
should be guided by bleeding (major or intracranial) instead. 
 low-molecular-weight heparin  (low molecular weight heparin (LMWH); eg, enoxaparin,

dalteparin, nadroparin and tinzaparin) 
  protamine  should be administered.  
 For thrombolytic  (eg, recombinant tissue plasminogen activator (rtPA)) reversal: 
 1st line  cryoprecipitate  administration.  
 2nd line (If cryoprecipitate is contraindicated or unavailable) ,  tranexamic acid ( 
anti-fibrinolytic agent)  
 For patients taking antiplatelet agents (eg, aspirin, clopidogrel and abciximab):

 platelet transfusion is not recommended routinely, regardless of antiplatelet agent, 
platelet function testing, haemorrhage volume or neurological examination. 
 Platelet transfusion seems inferior to standard care  for patients taking antiplatelet 
therapy before ICH 
 Platelet transfusion should be considered for patients with aspirin- or adenosine 
diphosphate receptor (ADP) inhibitor-associated ICH who will undergo a  
neurosurgical procedure.

neurosurgical procedure.  
 Platelet function testing prior to platelet transfusion should be performed if 
possible and timely results available. If platelet function is within normal 
limits or patient has documented antiplatelet resistance, platelet transfusion 
should be avoided. 
 Management of intraventricular haemorrhage (IVH) and hydrocephalus 
 (IVH) occurs in up to 45% of patients with ICH.  
 External ventricular drain (EVD) placement should be considered in:

 any patient with GCS ≤ 8,  
 significant IVH,  
 hydrocephalus or 
 evidence of transtentorial herniation 
 Elevated ICP (>20 mm Hg) should be treated with hyperosmolar therapy (HTS and/or 
mannitol), cerebrospinal fluid drainage or sedation, though none of these the rapies has 
been shown to improve outcomes 
 Surgical intervention 
 no benefit for early haematoma evacuation in patients with supratentorial ICH  23

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              19 
  Unlike supratentorial ICH, cerebellar ICH  is considered a neurosurgical emergency and 
evacuation is recommended  per current guidelines given the high morbidity from rapid 
development of brainstem compression  
 Surgical indications include: 
 haematoma size >3 cm in diameter,  
 brainstem compression or  
 hydrocephalus.

 hydrocephalus. 
 Management of peri-haematoma oedema (PHE) 
 (PHE) develops within the first few days after ICH and may cause elevated ICP, mass 
effect, midline shift and brain herniation 
 asymptomatic PHE  require no specific treatment  except maintaining a normal sodium 
goal.  
 symptomatic cerebral oedema and elevated ICP  mannitol and hypertonic saline (HTS)  
are the first-line

are the first-line  
 Mannitol is an osmotic diuretic.  It increases water excretion by the kidneys and 
reduces cerebral oedema and ICP. 
 HTS increases plasma osmolarity  and the flow of excess water from cerebral 
tissue to the blood via the osmotic gradient . 
 HTS vs mannitol: 
 A meta-analysis performed in 2011 showed that HTS is slightly more 
effective than mannitol  for the treatment of elevated ICP. 
 A recent analysis of the INTERACT2 data showed that mannitol  seems

safe, but might not improve outcome  in patients with acute ICH 
  According to patient's medical history: 
 patients with congestive heart failure  should receive a bolus of 
mannitol  or 23.4% of HTS ,  
 whereas continuous infusion of 3% of HTS  can be used for patients 
with dehydration or decreased urine output . 
 Patients with DVT or PE + ICH: 
 consider anticoagulation depending on stability of the haematoma, cause of h aemorrhage 
and time since presentation.

and time since presentation.  
 If systemic anticoagulation is contraindicated, inferior vena cava filter  placement should 
be considered 
 Prophylactic management 
 prophylaxis of venous thromboembolism (VTE): 
 risk of (DVT) is 1–5%.  
 Start mechanical VTE prophylaxis at the time of admission  
 preferably with  intermittent pneumatic compression (IPC) devices  
 cuffs around the legs that fill with air and squeeze legs  Ĺblood flow 
through the  leg veins  prevent blood clots.

through the  leg veins  prevent blood clots. 
 If (IPC) devices are unavailable, graduated compression stockings (GCS)  
can be utilised.  
 Early aggressive comprehensive care may improve survival  and functional 
recovery. 
 Prophylactic doses of subcutaneous unfractionated heparin or LMWH should be 
started in patients with stable haematomas within 48 hours of admission . 
 Mechanical VTE prophylaxis should be continued after initiation of 
pharmacological prophylaxis.

pharmacological prophylaxis. 
 There is no benefit for seizure prophylaxis or aggressive management of fever or 
hyperglycaemia.  
 
 24

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              20 
  
Intracerebral haemorrhage in association with anticoagulants (royal college guidelines 2016):  
intracerebral haemorrhage in association with  reversed with 
vitamin K antagonist treatment combination of prothrombin complex concentrate 
and intravenous vitamin K. 
dabigatran idarucizumab

dabigatran idarucizumab 
factor Xa inhibitor prothrombin complex concentrate 
 
The 2016 RCP stroke guidelines state: Patients with primary intracerebral haemorrhage  who present 
within 6 hours of onset with a systolic blood pressure above 150mmHg should be treated urgen tly using 
a locally agreed protocol for blood pressure lowering to a systolic blood pressure of 140 mmHg  for 
at least 7 days, unless: 
 the Glasgow Coma Scale score is 5 or less

 the Glasgow Coma Scale score is 5 or less 
 the haematoma is very large and death is expected 
 a structural cause for the haematoma is identified 
 immediate surgery to evacuate the haematoma is planned. 
 
January 2013 exam:  Which medications should be given following an ischaemic stroke (i.e. 
after 14 days)? Clopidogrel + statin  
 
25

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              21 
  
September 2009 exam: A 62-year-old man admitted 5 hours after left hemiplegia. ECG 
confirms atrial fibrillation. A CT head is normal. What is the most appropriate initial 
management? Aspirin (He is outside the thrombolysis window so alteplase is not an option. anticoagulation

should be commenced 14 days after an ischaemic stroke.)  
Paradoxical embolisation 
 For a right-sided thrombus (e.g. DVT) to cause a left-sided embolism (e.g. stroke) it must 
obviously pass from the right- to-left side of the heart.  
 The following cardiac lesions may cause such events 
 patent foramen ovale  
 present in around 20% of the population

 present in around 20% of the population 
 Transoesophageal echocardiography (TOE) is the investigation of  choice  to 
investigate for a patent foramen ovale,  
 transthoracic echocardiography with contrast may be an alternative.  
 TOE offers better views of the anatomical area. 
 atrial septal defect - a much less common cause 
Cerebral venous thrombosis  (CVT)

Cerebral venous thrombosis  (CVT) 
Patients with a hypercoagulable state (e.g pregnancy) and papilloedema with neurological 
signs should be investigated for cerebral venous thrombosis . 
Basics 
 Structure 
 reflections in dura matter where meningeal and periosteal layers split 
 Function 
 return blood from cerebral veins to internal jugular vein 
 veins contains NO valves 
Epidemiology 
 more common in young women  
 Sex: ♀ > ♂, 3:1 
 Age of onset: ≤ 40 years  
Pathophysiology

Pathophysiology 
 The underlying problem is a thrombosis and the petechial haemorrhages are caused by 
venous outflow blockage .  
 Thrombogenesis occurs in the cerebral venous system, ĺ Ļ cerebral drainage ĺ Ĺ intracranial 
pressure ĺ cl inical features (see below) 
 Additionally, thrombus formation ĺ congestion within the venous system of the brain ĺ bloo d 
stasis ĺ Ļ oxygenated blood in brain tissue ĺ cerebral  edema and/or infarcts/stroke. 
Types

Types 
 The dural sinuses are grouped into: 
 sagittal,  
 lateral (including the transverse, sigmoid, and petrosal sinuses), and  
 cavernous sinuses. 
 Because of its complex neurovascular anatomic relationship, it is the most 
important of any intracranial septic thrombosis.  
 50% of patients have isolated sagittal sinus thromboses  
 the remainder have coexistent lateral sinus thromboses and cavernous sinus thrombosis 
Risk factors and etiology 
 local infection

 local infection  
 Staphylococcus aureus  is the most common 
 sinusitis  
 Frontal sinuses are the most common source of infection 
 local infection midface infection  
 most commonly a furuncle  
 diabetes mellitus   
 hypercoagulable states:    26

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              22 
  pregnancy, post-partum period , 
 It typically presents with headache, seizures and focal neurological deficit 
two to three weeks postpartum (but is also seen earlier. 
 Malignancy  
 clotting disorders (e.g., factor V Leiden, protein C and S deficiencies, antiphospho lipid 
syndrome) 
 polycythemia

syndrome) 
 polycythemia 
 intracranial hypotension  
 lumbar puncture 
 Minor head trauma 
 medications  
 Oral contraceptive pill , including the third-generation formulations  
 Corticosteroids 
 Epsilon-aminocaproic acid 
 Thalidomide 
 Tamoxifen 
 Erythropoietin 
 Phytoestrogens 
 L-asparaginase 
 Heparin - Heparin therapy has been reported to produce thrombotic thrombocytopen ia 
with associated venous sinus thrombosis 
Features 
 Raised intracranial pressure (ICP):

Features 
 Raised intracranial pressure (ICP):  
 headache  
 The most common presenting symptom  
 nausea & vomiting 
 Vomiting in the morning is characteristic of raised ICP as it follows a period of lying 
flat. 
 Bending over, coughing or straining causes a transient increase in already raised ICP  
↑optic nerve compression  visual disturbance.  
 Papilloedema 
 Cranial nerve symptoms  
 (e.g., diplopia, tinnitus, unilateral deafness, facial palsy)

 Cranial nerves III, IV and VI palsies 
 Ocular chemosis  
 Proptosis   
 Seizures 
 Focal or generalized seizures are frequent, occurring in up to 40% of patients.  
 rare cause of stroke, 
Investigations 
 If CVT is suspected, D-dimer levels and imaging studies are first steps of diagnosis 
 D-dimers: > 500 μg/L  
 Imaging: 
 CT/MRI (with or without venography): tests of choice to confirm the diagnosis

 Plain CT/MRI help detect only edema and/or infarcts, but the thrombus itself can 
be visualized by means of venography . 
 CT 
 Hypodense structures indicate ischemic event 
 Thrombus can appear as a hyperdense vein or sinus 
 CT venography shows a filling defect  in a vein or sinus  
 MRI 
 Thrombus is isointense on T1 and hypointense on T2 early in the disease 
 Cerebral edema can be identified 
 MR venography demonstrates a lack of flow 
 Evaluation for possible causes

 Evaluation for possible causes 
 Ĺ ESR and antibody studies  27

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              23 
  CBC, CRP  
 Tests for clotting disorders (e.g., Leiden factor V mutation)  
 Thrombophilia screen should be performed.  
 
Treatment of cerebral venous thrombosis  
 If primary  anticoagulants (full-dose heparin then warfarin). 
 Secondary thrombosis (usually secondary to infection)   should be treated or drained if

possible.  
 Dexamethasone can be used to reduce cerebral oedema.  
 Surgical therapy 
 Indications 
 Progressive neurologic worsening (despite adequate anticoagulation) 
 Acute rise in intracranial pressure 
 Impending herniation 
 Surgical options 
 Blood clot removal 
 Vessel recanalization 
 Shunt placement 
 
Sagittal sinus thrombosis   
 the most frequently affected sinus 
 Superior sagittal sinus thrombosis (SSST) is the most common type of dural 
venous sinus thrombosis

venous sinus thrombosis  
 Features  
 Anterior occlusion is usually asymptomatic,  
 posterior occlusion can present with:  
 raised intracranial pressure (headache, vomiting), and papilloedema  
 involvement of the upper hemispheres (paraplegia).  
 may present with seizures and hemiplegia   
 disorder of the oculomotor nerve by affecting the oculomotor (Edinger-Westphal) 
nuclei.  
 parasagittal biparietal or bifrontal haemorrhagic infarctions are sometimes seen

 The territory of the affected sinus usually shows congestive oedema, which can 
progress to haemorrhagic venous infarction. 
 on contrast CT empty delta sign (is a specific to the superior sagittal sinus) 
 Empty delta sign   superior sagittal 
sinus thrombosis  
 
 CT with contrast demonstating a  superior sagittal 
sinus thrombosis showing the typical empty delta 
sign.  
 Look at the 'bottom' of the scan for the triangular 
shaped dural sinus.

shaped dural sinus.  
 This should normally be white due to it being filled 
with contrast.  
 The empty delta sign occurs when the thrombus 
fails to enhance within the dural sinus and is 
outlined by enhanced collateral channels in the 
falx.  
 This sign is seen in only about 25%-30% of cases 
but is highly diagnostic for sagittal 
 
 28

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              24 
  
Cavernous sinus thrombosis  ( CST) 
 Cavernous sinus contents 
 
Structures passes through the cavernous sinus: 
 internal carotid artery with its surrounding sympathetic plexus  
 third, fourth, and sixth cranial nerves are attached to the lateral wall of the sinus.

 Ophthalmic (V1) and maxillary (V2) divisions of the fifth cranial nerve are emb edded in the wall 
 The mandibular branch of the trigeminal nerve (V3) does not travel in the 
cavernous sinus and would therefore not be affected.  
 V3 innervates the lower face. ( NO lower face symptoms ) 
Other features of cavernous sinus syndrome 
 peri-orbital oedema (Chemosis, oedema and cyanosis of the upper face occur due t o obstruction 
of the ophthalmic vein)

of the ophthalmic vein) 
 Eye swelling begins as a unilateral process  and spreads to the other eye within 24-
48 hours via the intercavernous sinuses . This is pathognomonic for CST . 
 Periorbital edema may be the earliest  physical finding. 
 ophthalmoplegia:  
 6th nerve damage typically occurs before 3rd & 4th 
 Lateral gaze palsy (patient cannot abduct eye) (isolated cranial nerve VI) is usually  
seen first

seen first  
 since CN VI lies freely within the sinus in contrast to CN III and IV, which lie within 
the lateral walls of the sinus. 
 Ptosis, mydriasis, and eye muscle weakness from cranial nerve III dysfunction 
 Patients typically have double vision on looking upward  
 trigeminal nerve involvement may lead to hyperaesthesia of upper face and eye pain  
 central retinal vein thrombosis 
 Signs of increased intraocular pressure (IOP) may be observed.

 Pupillary responses are sluggish. 
 Decreased visual acuity is common 
 
Which group of nerves run through the cavernous sinus? 
 III, IV, (V-1, V-2), and VI  
 
 September 2012 exam: Left-sided eye pain & diplopia for the past 2 days + 6th & 3rd cranial 
nerve palsy on the left side + hyperaesthesia of the upper face on the left side. Where is the 
likely lesion? Cavernous sinus  
 
superior orbital fissure syndrome

superior orbital fissure syndrome 
 is similar to the cavernous sinus syndrome except for the presence of proptosis.  29

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              25 
 Lateral sinus thrombosis  
 6th and 7th cranial nerve palsies 
Lesions at the jugular foramen 
Causes of jugular foramen syndromes 
 Nasopharyngeal carcinoma is the commonest cause.

 Other are  neurofibromas, metastatic tumours, jugular vein thrombosis, Paget ’s disease of the 
bone, and basal skull fractures. 
 
Affected CN  9,10,11 
 CN IX (Glossopharyngeal nerve) & CN X (Vagus nerve)  palatal weakness and swallowing 
difficulties , Laryngeal muscle paralysis would result in bovine cough and husky voice . 
 CN XI (Accesory nerve)   shoulder and sternocleidomastoid weakness 
___________________________________________________ _____________________________

Cervical vascular dissection  
Stroke provoked by minimal trauma (e.g: exercise) is likely due to Cervical vascular dissection  
until proven otherwise   
 Mechanism of ischaemia   
 Most ischaemic symptoms (85-95%) of cases are caused by emboli from the site of the 
dissection. 
 (5-15%) due to vessel narrowing (subintimal tears  intramural haematomas  protrude 
inward and narrow the vessel lumen) 
 
 Feature    
 sudden-onset weakness and numbness provoked by exercise

 When an ischaemic event occurs in the context of exercise, the possibility of a 
Valsalva manoeuvre precipitating embolism from a patent foramen ovale should 
also be considered.However, an arterial dissection should be considered most 
likely until proven otherwise  
 Horner's sign may be present 
 two-thirds of patients have head or neck pain, the remainder present painlessly 
 
 Investigation   (magnetic resonance angiography)

___________________________________________________ _______________  
Carotid artery stenosis  
 Epidemiology 
 Carotid artery stenosis causes 10% to 15% of all ischaemic strokes. 
 the annual risk of stroke in patients with asymptomatic carotid disease is between 1% and 
2% 
 Pathophysiology 
 Atherosclerotic plaque in the cervical carotid artery is the most common cause.  
 Plaque disruption and athero-embolisation into the intracranial circulation is the most

common mechanism for stroke. 
 The most common site of carotid Atherosclerosis: 
 usually at the fork where the common carotid artery divides into the internal and 
external carotid artery.  
 Features 
Carotid artery atherosclerosis is an important cause of ipsilateral amaurosis fugax.  
 
 The majority of carotid artery stenosis are asymptomatic. 
 cervical bruit 
 plaques rupture  embolism to : 
 intracranial arteries  (TIA or stroke) or

 intracranial arteries  (TIA or stroke) or  
 retinal arteries  (amaurosis fugax or retinal strokes). 
 Duplex ultrasonography  is the preferred mode of diagnosis;  
 sensitivity of 99%, specificity of 86%  
 stepwise diagnostic work- up:  
 carotid duplex for screening purposes.  30

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              26 
 
 If the stenosis is less than 50%,  no further imaging is needed.  
 If the stenosis > 50%, CTA or MRA should be considered for more 
detailed plaque characterization. 
 CT or magnetic resonance angiography  helps to define the anatomy if intervention is 
indicated. 
 computed tomography angiography (CTA)

 computed tomography angiography (CTA) 
 sensitivity is 85% and specificity 93%  
 requires exposure to ionising radiation, and the iodinated contrast is a 
hazard in patients with renal insufficiency. 
 faster and less expensive than MRA. 
 less susceptible than (MRA) to overestimate the stenosis 
 magnetic resonance angiography (MRA) 
 Less commonly performed than CTA 
 sensitivity 88% and specificity 84%  
 has a tendency to overestimate stenosis severity.

 does not require ionising radiation. 
 NICE guidelines state that a patient with a TIA should receive a CT/MRI head and carotid 
duplex  within a week.   
 cervical angiography 
 The definitive test  for identifying and quantifying the degree of stenosis in the 
carotid artery 
 however, it is infrequently ordered as it is invasive  (requiring catheterisation of the 
aortic arch and carotid artery) and carries a risk of atheroembolic stroke .

 Generally ordered when non-invasive tests show a suspicion of a string sign (i.e., 
≥95% sten osis). 
 Management 
 Initial management  antiplatelet therapy, and risk factor modification. 
 endarterectomy  
 Indications 
 if carotid stenosis  > 70% according ECST criteria (European Carotid Surgery 
Trial' Collaborative Group)  
 or > 50% according to NASCET  (North American Symptomatic Carotid 
Endarterectomy Trial)  criteria .

Endarterectomy Trial)  criteria . 
 2016 Royal College guideline  recommend that : The degree of 
carotid artery stenosis should be reported using the (NASCET)  
method . 
 If carotid endarterectomy is deemed necessary then surgery should be 
performed within two weeks . ("urgent" endarterectomy within 2 weeks) 
 It reduces the risk of disabling stroke or death by 48%  in a person with severe 
symptomatic carotid stenosis (>70%) who has had a TIA.

 The peri-operative risk of disabling stroke or death is approximately 3%.  
 The benefit of endarterectomy is prevention of future stroke. 
 Surgery will be appropriate  if there is a TIA or resolving stroke. 
 with dense strokes, if there is no recovery, the benefits are greatly 
reduced due to end-organ damage. 
 Contraindications: 
 100% carotid stenosis  
 usually requires a bypass  procedure, as risk of endarterectomy 
outweighs benefit.

outweighs benefit. 
 previous stroke with persistent neurological symptoms 
 Carotid stenting   
 used as an alternative to endarterectomy.  
 less invasive revascularisation strategy, and uses an embolic protection device.  
 There seems to be a similar early risk of death or stroke, and similar long-term 
benefits. 
 Restenosis . 31

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              27 
  Previous radiotherapy to the neck  may make endarterectomy difficult, and 
stenting may be preferred. 
 Revascularisation would have the risk of reperfusion haemorrhage. 
 Risk is higher in elderly patients, possibly due to vascular tortuosity and 
calcification.  
 Question

 Question 
left-sided hemiparesis of more than 8 hours ’ duration. carotid ultrasound scan, shows 80% stenosis of 
the left carotid artery, 50% stenosis of the right  carotid artery. What is the most appropriate treatment  
for long-term stroke prevention? 
 Clopidogrel 
 endarterectomy is not recommended in: 
 significant stenosis but asymptomatic side (left carotid in this case) 
 symptomatic side but there is less than 70% (right carotid in his case) .

Carotid artery stenosis management 
 Symptomatic (TIA, stroke, and amaurosis fugax) 
 ipsilateral carotid stenosis ≥ 50% (NASCET criteria)  carotid endarterectomy + 
antiplatelet therapy and cardiovascular risk reduction 
  ipsilateral carotid stenosis < 50%  antiplatelet therapy and cardiovascular risk reduction 
 Asymptomatic 
 asymptomatic carotid stenosis <70%  antiplatelet therapy and cardiovascular risk 
reduction 
 asymptomatic carotid stenosis ≥ 70% :

 asymptomatic carotid stenosis ≥ 70% :  
 1st line  antiplatelet therapy and cardiovascular risk reduction 
 the best course of action?  Discharge and outpatient follow up  
 Adjunct  carotid endarterectomy   
 Bilateral carotid stenosis: 
 asymptomatic bilateral stenoses ≥ 70% (NASCET criteria) 
 the higher-grade stenosis is addressed surgically first. 
 In the case of equal degrees of stenosis, handedness is considered. (eg, the left

carotid would be surgically treated first in a right-handed person). 
 symptomatic found to have carotid stenosis in a contralateral carotid artery, the 
asymptomatic carotid stenosis is treated 
 Carotid restenosis:    antiplatelet therapy ± revascularisation 
 The causes of restenosis: 
 within 30 days of the carotid intervention  Residual stenosis. 
 within the first 2 years after surgery  neointimal hyperplasia  
 2 years after surgery  new atherosclerotic plaque

 perform carotid artery re- stenting when the stenosis reaches ≥ 70% (NASCET criteria) in 
asymptomatic patients and  ≥ 50% (in symptomatic patients). 
Ref: bestpractice.bmj.com 2017  
 
Carotid artery dissection  
The classic triad of symptoms of carotid dissection are:  
1. unilateral (ipsilateral) headache 
2. ipsilateral Horner's syndrome  and 
3. contralateral  hemisphere signs (aphasia, neglect, visual disturbance, hemiparesis ).

 The two commonest causes of young onset stroke  (less than 40 years) are: 
 cardio-embolism and  
 carotid artery dissection. 
 Dissection of the internal carotid artery can occur intracranially or extracranially 
 Extracranially is more common  
 75% of carotid dissections affect the internal carotid artery (that is, extracranially) 
 Causes 
 mechanical forces (eg, trauma, blunt injury, and stretching)

 arteriopathies (eg, Ehlers-Danlos syndrome IV and other connective tissue disorders)  
 Features 32

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              28 
  Pain  is the initial symptom   
 Headache (including neck and facial pain) 
 ipsilateral to the dissected artery. 
 It usually precedes a cerebral ischemic event, unlike headache associated with 
stroke, which usually follows or accompanies the ischemic event.  
 25% of patients have isolated ipsilateral neck pain.

 Ischaemic neurological features (transient or completed strokes ) are found in 30-80%  
 Pulsatile tinnitus  is common, ( 25%)  
 syncope  
 partial Horner  syndrome (Ptosis with miosis) 
 usually painful  when caused by internal carotid artery dissections 
 The term partial Horner syndrome is used for the oculosympathetic palsy because 
anhydrosis is absent .  
 Because t he sympathetic fibers innervating the facial sweat glands  are

anatomically located on the external  rather than the internal carotid artery  
 amaurosis fugax . 
 Transient episodic blindness 
 caused by decreased blood flow to the retina 
 Decreased taste sensation ( hypogeusia ) 
 
 The current gold standard  for diagnosis of carotid artery dissection, contrast 
arteriography  (the single best investigation of choice ) should be strongly considered, 
if there is: 
 mono or hemiparesis with normal mental state,

 mono or hemiparesis with normal mental state,  
 signs or history of major cervical trauma with abnormal neurology,  
 or basilar skull fracture in a patient with altered mental status. 
 Magnetic resonance angiography (MRA)  replaced conventional angiography 
 MRA may fail to detect intramural hematoma within the first 24-48 hours after the  
occurrence of carotid artery dissection. 
 Helical computed tomography angiography (CTA) 
 100% sensitivity and specificity

 100% sensitivity and specificity   
 (CTA) is rapidly replacing conventional angiography and possibly MRA as the 
diagnostic modality of choice.  
 Helical CTA is fast and noninvasive 
 CTA may be the first (or even the only) modality used for screening and 
diagnosis for carotid artery dissection in trauma patients  
 The hallmark of injury to the internal carotid artery on CTA is a  change in the 
caliber of the vessel.

caliber of the vessel.   
 Non-contrast CT is not an adequate screening or diagnostic test for internal carotid 
artery dissection. 
 Conventional angiography  
 It was the standard diagnostic modality 
 Now it is no longer considered the diagnostic modality of choice  
 it is invasive, resource-intensive, and costly;  
 it may miss dissections when the false lumen does not opacify with contrast 
medium. 
 should be reserved for high suspicion negative results with other imaging

 The pathognomonic finding for a carotid artery dissection is an intimal flap and 
double lumen, secondary to an intramural hematoma.  This finding is rarely 
detected.  
 The most common angiographic finding  is termed the string sign , which is a 
long, tapered, narrowing column of contrast material in the distal segment of the 
internal carotid artery. 
 Doppler ultrasonography (DUS) 
 With its improving resolution, ready applicability, speed, and ease of use, DUS ca n

now be used for the initial assessment of patients  with suspected carotid artery 
 In trauma cases, it usually is already at the bedside for focused assessment 
with sonography for trauma (FAST). 
 DUS has the lowest cost and the highest safety profile.  
 sensitivity is high as 96% 33

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              29 
  The pathognomonic  DUS finding  for carotid artery dissection is the 
demonstration of a membrane in the longitudinal and axial view . 
 The most common DUS finding in carotid artery dissection is a high-resistance 
flow pattern  or the absence of signal in a totally occluded artery .

 Unlike angiography, DUS is able to demonstrate a false lumen even if it is 
thrombosed. 
 have a 31% false-negative  rate in patients with carotid artery dissection who 
presented with Horner syndrome . 
 Whenever abnormalities are found by DUS, follow-up with another imaging 
modality is always indicated. 
 in practice many trusts will require a CT head first.  
 in the absence of arteriography , duplex scanning or MRI with MRA may be considered 
the next best tests.  
 Management

 antithrombotic treatment provides the best outcome. 
 Do not initiate anticoagulation in trauma patients without first ruling out intracranial 
hemorrhage 
 Surgery has a limited role  
 Prognosis 
 When the condition is diagnosed early, the prognosis is usually good. 
 Healing usually takes 3-6 months 
 75% of patients making a good recovery. 
 mortality is less than 5%.  
Carotid dissection 
 Younger age group <50 years. 
 Neck pain.

 Neck pain. 
 Associated with vigorous exercise or event that sustains severe neck movement (e.g., roller 
coaster ride, motor vehicle accident). 
 May have Horner's syndrome or history of genetic collagen abnormality. 
____________________________________________________________ 
Carotico-cavernous fistula  
 Caroticocavernous fistula is a high pressure shunt of blood between the intracavernous carotid 
artery and the cavernous sinus.

artery and the cavernous sinus. 
 It is usually traumatic and may occur secondary to open or closed head trauma.  
 Feature 
 Patients usually complain of pain in the eye . 
 The most striking sign is pulsatile  proptosis.  
 Patients also have palsies of the IIIrd, IVth and Vth nerve  palsies,  
 injection and chemosis  due to raised episcleral venous pressure. 
 orbital bruit  can be heard . 

Vertebral artery dissection 
The typical presentation of vertebral artery dissection is a young person  (average age 40 years) with 
severe occipital headache and neck pain  following a recent head or neck injury . The trauma is often 
trivial, but is usually associated with some form of cervical distortion. 
 About 85% of patients develop focal neurological signs due to ischaemia of the brain stem or 
cerebellum.

cerebellum.  
 The commonest neurological manifestations are symptoms attributable to lateral medullary 
dysfunction (that is, Wallenberg's syndrome). 
 Common symptoms and signs  include: 
 ipsilateral facial pain and/or numbness (the most common symptom) 
 vertigo (very common) 
 dysarthria or hoarseness (CN IX and X) 
 ipsilateral loss of taste (nucleus and tractus solitarius) 
 hiccups 
 nausea and vomiting

 hiccups 
 nausea and vomiting 
 diplopia or oscillopsia (image movement experienced with head motion), and 
 dysphagia (CN IX and X). 
 Depending upon which areas of the brain stem or cerebellum are affected, clinical signs may  
include: 34

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              30 
  limb or truncal ataxia 
 ipsilateral Horner syndrome (up to 1/3 patients affected) 
 ipsilateral impairment of fine touch and proprioception 
 contralateral impairment of pain and thermal sensation in the extremities (that is, 
spinothalamic tract) 
 contralateral hemiparesis 
 lateral medullary syndrome

 lateral medullary syndrome 
 tongue deviation to the side of the lesion (impairment of CN XII), and 
 internuclear ophthalmoplegia (lesion of the medial longitudinal fasciculus). 
 Risk factors  associated with the development of vertebral artery dissection include: 
 judo 
 yoga 
 ceiling painting 
 nose blowing 
 minor neck trauma 
 chiropractor manipulation 
 hypertension 
 oral contraceptive use, and 
 female sex. 
____________________________________________________________

Localisation of speech problems  
 The speech area is in the left, dominant side of the brain in about 99% of right -handed people 
 Thus, impairment of the speech area with a stroke, causing left-sided weakness, is rare. It will 
occur in virtually no right-handers and in only 30% of left-handers.  
 As a general rule, a lesion of the left hemisphere will cause dysphasia whilst, in the right 
hemisphere, it will cause neglect, visuo-spatial and cognitive problems

 Wernicke's aphasia and pure aphasia (that is, without alexia) are middle cerebral artery.  
 
Comprehension, fluency and repetition are the three main variables that allow for localisation of 
speech problems 
The three, general, areas are: 
1. Wernicke's area (posterior, superior temporal lobe) - lesions produce normal fluency, 
impaired comprehension, impaired repetition 
35

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              31 
  receptive aphasia  
 They are unaware of their language difficulties  
2. conduction (arcuate fasciculus) - lesions produce normal fluency, normal comprehension , 
diminished repetition 
3. Broca's area (inferior frontal lobe)  
 lesions produce impaired fluency, intact comprehension, impaired repetition.

 Unlike Wernicke's aphasia, Broca's patients are aware of their language difficulties.  
Mixed aphasia  
 Mixed aphasia  (or transcortical mixed aphasia) is not a complete 'global aphasia'. 
 In global aphasia there is receptive and expressive dysphasia.  
 With mixed aphasia, patients can often repeat words but not understand commands , name 
objects or have intelligible spontaneous speech. 'Mixed aphasia' is not specific for stroke , 
although it can be caused by it.

although it can be caused by it. 
 It may be caused by  the following: 
 Alzheimer's disease 
 Bilateral cerebral damage 
 Tumours, and 
 Thalamic lesions. 
 
Transcortical sensory aphasia  
Transcortical sensory aphasia involves poor comprehension with fluent speec h and repetition. 
 
 The main problem lies within the brain in a region known as the  temporal-occipital-parietal 
junction , located behind Wernicke's area.

junction , located behind Wernicke's area.  
 The patient has intact repetition but is unable to follow verbal commands . He has fluent 
grammatical speech.   
 It is characterised by impaired auditory comprehension with intact repetition and fluent spe ech, 
and is caused by damage to the temporal lobes.  
  It differs from Wernicke's aphasia in that patients still have intact repetition , and exhibit cholalia 
(the compulsive repetition of words)  
 
Nomic aphasia or nominal aphasia

Nomic aphasia or nominal aphasia  
 Anomic aphasia or nominal aphasia results in word finding difficulties.  
  On closer examination there may also be repetition problems and comprehension prob lems but 
these are typically mild compared to other aphasia syndromes.  
 
Aphemia  
 Aphemia is a type of aphasia in which there is severe dysarthria and impairment of verbal 
output.   
 There is intact comprehension.

output.   
 There is intact comprehension. 
  It is believed to be the result of pars opercularis, inferior pre-Rolandic gyrus or subcortical 
lesions. 
January 2008 exam:  H/O difficulty in finding the right words whilst speaking. With normal 
comprehension. Where is the likely lesion? Posterior frontal lobe  (expressive aphasia due to a 
lesion in Broca's area, located on the posterior aspect of the frontal lobe, in the in ferior frontal gyrus)

Pupil conditions 
Basic principle 
 oculomotor nerve carries  parasympathetic efferents to the sphincter pupillae muscle. 
 optic nerve carries sympathetic postganglionic fibres to the dilator pupillae muscle. 
 parasympathetic fibers lead to pupillary constriction (miosis) 
 light enters the eye  retinal ganglion  optic nerve ĺ optic chiasm ĺ optic tract 

pretectal nucleus  Edinger-Westphal nucleus   ciliary ganglion  pupillary 
constrictor muscles  causing uniform bilateral miosis 
 sympathetic fibers lead to pupillary dilation (mydriasis) 36

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              32 
  hypothalamic nuclei  T1 and T2 spinal cord levels  paravertebral sympathetic chain 
(via the white ramus)  superior cervical ganglion  pupillary dilator muscle 
 Causes of small pupils include: 
 Horner's syndrome 
 Old age 
 Pontine haemorrhage  
 Argyll Robertson pupil 
 Drugs, and

 Drugs, and 
 Poisons (opiates, organophosphates). 
 Causes of dilated pupils include: 
 Holmes-Adie (myotonic) pupil 
 Third nerve palsy 
 Poisons (atropine, CO, ethylene glycol ). 
  
Hippus   
 Hippus is papillary athetosis.  
 athetosis  abnormal muscle contraction causes involuntary writhing movements. 
 It is typically a benign finding. 
  It is a spasmodic rhythmical dilation and contraction of the pupil.

 It is particularly noticeable when pupils are tested with a light, but is independent of eye 
movements or light.  
 Pathological hippus is rare but is recognised with aconite poisoning, trauma, cirrhosis and renal 
disease (possibly due to frontal lobe dysfunction).  
Tonic pupil (Holmes-A die pupil) (HAS) 
 
Holmes-A die  dilated pupil 
Overview

Overview 
 tonic pupil or Holmes-Adie pupil is a dilated pupil caused by parasympathetic damage. 
 characteristically seen in young women 
 degeneration of parasympathetic nerves in the cilliary ganglion which leads to de nervation of the 
pupil and hence hypersensitvity to dilute pilocarpine drops.  
 usually occurs after a herpes zoster infection  
Features 
37

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              33 
  At the beginning of the condition the pupil is large, (abnormally large pupil po orly reactive to light 
with a normal near reflex), but over time (years) it gradually diminishes in size to be  smaller than 
the non-affected pupil. becomes small and poorly reactive.

 absence of deep tendon reflexes, usually in the Achilles tendon.  
Association 
 Ross ’s syndrome: triad of:  
1. abnormal pupil size,  
2. loss of deep tendon reflexes, and  
3. excessive sweating 
 Sjogren ’s syndrome  
 migraine. 
Diagnosis 
 Slit lamp examination may reveal small worm like contractions of the iris, but  the usual 
diagnostic test is to use weak pilocarpine eye drops , which induce vigorous pupil contraction

on the affected side, but only weak contraction of the pupil on the unaffecte d side. 
Treatment 
 In adults it tends to be a benign condition and is simply observed , however infants are usually 
referred because of an association with familial dystonias. 
 The loss of deep tendon reflexes is permanent 
 For impaired vision in the affected eye  
 reading glasses to compensate, and pilocarpine drops to be applied 3 times daily t o 
constrict the dilated pupil.

constrict the dilated pupil.     
 For most individuals, pilocarpine drops and glasses will improve vision.  
 Thoracic sympathectomy is the definitive treatment for excessive sweating.  
 
The combination of these 3 symptoms – abnormal pupil size, loss of deep tendon reflexes, and 
excessive sweating – is usually called Ross ’s syndrome , although some doctors will still diagnose the 
condition as a variant of HAS .

condition as a variant of HAS .  
 
___________________________________________________ _____________________________  
Argyll  Robertson  Pupil (ARP ) 
Argyll-Robertson: small irregular pupils that do not react to light but react to accommodation. 
Referred to as the "Whore's Eye" because of the association with tertiary syphilis and  because of 
the convenient mnemonic that, like a prostitute, they “accommodate but do not react ” 
 
Causes: neurosyphilis , Multiple Sclerosis, Sarcoidosis, DM

Accommodation  Reflex Present  
 
ARP  
 
Pupillary  Reflex  Absent   bilateral small pupils 
 "prostitute's pupils"  that 
reduce in size on a near object 
(they “accommodate ”), but 
do not constrict when exposed 
to bright light (they do not 
“react ” to light).  
 They are a highly specific sign 
of neurosyphilis, and might also 
be a sign of diabetic neuropathy. 
 
38

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              34 
  
Pupillary Defect Comments 
Argyll 
Robertson pupil  A type of light-near dissociation where 
 the eye does not constrict in response to light as much as it does 
with accomodation 
 pupil has an  absent light reflex 
 Associated with neurosyphilis  
Adie's myotonic 
pupil  A type of light-near dissociation where

pupil  A type of light-near dissociation where 
  light reflex is merely reduced  
 Secondary to 
 degeneration of the 
 ciliary ganglion 
 postganglionic parasympathetic neurons 
 
___________________________________________________ _______________________________ 
Visual field defects 
 
The main points for the exam are:

The main points for the exam are: 
 left homonymous hemianopia means visual field defect to the left, i.e. Lesion o f right optic tract 
 homonymous quadrantanopias: PITS (Parietal-Inferior, Temporal-Superior)  
 incongruous defects = optic tract lesion; congruous defects = optic radiation lesion or occipital 
cortex 
A congruous defect simply means complete or symmetrical visual field loss and conversely an

incongruous defect is incomplete or asymmetric. Please see the link for an excellent diagram. 
 
Homonymous hemianopia  
 incongruous defects: lesion of optic tract 
 congruous defects: lesion of optic radiation or occipital cortex 
 macula sparing: lesion of occipital cortex 
Homonymous quadrantanopias* 
 superior: lesion of temporal lobe 
 inferior: lesion of parietal lobe 
 mnemonic = PITS (Parietal-Inferior, Temporal-Superior) 
Bitemporal hemianopia 
 lesion of optic chiasm

 lesion of optic chiasm 
 upper quadrant defect > lower quadrant defect = inferior chiasmal compression, com monly a 
pituitary tumour 
39

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              35 
  lower quadrant defect > upper quadrant defect = superior chiasmal compression, commonly  a 
craniopharyngioma 
 
Bilateral internal carotid artery displacement can cause binasal incongruous hemianopia if 
the optic nerves are compressed.

the optic nerves are compressed. 
 
September 2012 exam: What sort of visual field defect is expected following an operation to 
remove a meningioma in left temporal lobe? Right superior homonymous quadrantanopia  
 
January 2009 exam:  In a left congruous homonymous hemianopia. Where is the lesion most 
likely to be? Right occipital cortex  
 ___________________________________________________ _________________________ 
Cortical blindness

Cortical blindness  
 The visual cortex is located in the occipital lobes, receiving its blood supply from the posterior 
cerebral arteries. 
 The area for macular vision is in a small area adjacent to the calcarine sulcus. 
 Bilateral occlusion or infarction of the vessels supplying this area results in cortical blindness:  
 the visual pathways as far as the cortex are normal and as a result pupillary reactions and 
fundoscopy are normal.

fundoscopy are normal. 
 Patients with cortical blindness frequently have visual hallucinations and occasionally 
deny that they are blind. 
 
40

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              36 
  
___________________________________________________ _________________________ 
Drop attacks  
 Drop attacks describes the sudden falling to one's knees without loss of consciousness and 
without warning. Recovery is immediate. 
 Often the attacks spontaneously stop after a year or two.

 The aetiology of drop attacks is uncertain. 
 Over 90% of drop attacks occur in women although men can develop the problem.  
 The average age of onset is between 45 and 55 
 textbooks suggest that vertebrobasilar ischaemia is the cause  
Features 
 sudden fall to the ground while standing or walking 
 Patients with functional drop attacks normally can ’t remember the fall itself but are aware of the

impact on the ground (or within seconds of falling). This is different to a mechanical f all when 
people often do remember the fall (often in detail). Its also different to a dissociative a ttack (non-
epileptic attack) where there is an actual ‘blackout ’. 
 Unlike an epileptic seizure or a faint, people with drop attacks can usually get up again q uite 
quickly 
 Injury is a common consequence 
___________________________________________________ _________________________

Klüver –Bucy syndrome 
 
 Klüver –Bucy syndrome is a syndrome resulting from bilateral lesions of the medial temporal lob e 
(including amygdaloid  nucleus).  
 Herpes simplex virus-1 can cause bilateral amygdala lesions leading to Klüver –Bucy syndrome. 
 may present with  
 compulsive eating, 
  hypersexuality ,  
 insertion of inappropriate objects in the mouth (hyperorality),  
 visual agnosia, and docility. 
 
 41

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              37 
  
Cranial nerves 
 
Brain stem (Mid brain, Pons, Medulla Oblongata) lesions are typically characterized by ipsila teral cranial

nerve involvement and contralateral body involvement.  
 
 Lesions of the cerebellopontine angle  causes compression of cranial nerves  V (trigeminal),  VII 
(facial)  and VIII (vestibulocochlear).   
 The  cavernous sinus syndrome consists of variable involvement of 
 Oculomotor (III) 
 Trochlear (IV) 
 Abducens (VI) 
 Trigeminal (ophthalmic and maxillary division) (V) and 
 Oculo-sympathetic nerves.

 Oculo-sympathetic nerves. 
 The superior orbital fissure  syndrome is similar to the cavernous sinus syndrome except for 
the presence of proptosis . 
 petrous apex lesion 
 features 
 abducens nerve palsy  
 horizontal diplopia 
 ipsilateral Facial pain  or sensory disturbance ( numbness ) in the trigeminal nerve 
distribution 
  occurs secondary to involvement of the trigeminal nerve at the Meckel 
cave.    
 causes 
 meningioma or nasopharyngeal carcinoma of the petrous apex.

 The most common cause now  
 petrous osteitis (Gradenigo syndrome) 
42

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              38 
  In the pre-antibiotic era 
 
___________________________________________________ _____________________________ __ 
Optic nerve  
 The optic and olfactory nerves lie entirely within the supra-tentorial fossa , unlike the rest of the 
cranial nerves.

cranial nerves.  
 The optic nerve is part of the central nervous system, hence its myelin sheaths are 
derived from oligodendrocytes , not Schwann cells.  
 Accordingly, diseases of the peripheral nervous system and radiculopathies don ’t target the optic 
nerve.  
 The physiological blind spot results from absence of photoreceptors in the area of the retin a 
where the optic nerve leaves the eye.

where the optic nerve leaves the eye.  
 It leaves the eye through the optic canal. It forms the afferent pathway of the d irect and 
consensual pupillary reflexes. 
Oculomotor Third (III) nerve palsy 
Features 
 divergent squint - affected eye deviated 'down and out' . 
 ptosis 
 dilated pupil (sometimes called a 'surgical' third nerve palsy) 
 Unreactive pupil to light 
Causes 
 diabetes mellitus

Causes 
 diabetes mellitus 
 vasculitis e.g. temporal arteritis, SLE 
 false localizing sign due to uncal herniation through tentorium if raised ICP 
 posterior communicating artery aneurysm (pupil dilated) 
 cavernous sinus thrombosis 
 Weber's syndrome: ipsilateral third nerve palsy with contralateral hemiplegia -caused by  midbrain 
strokes 
 other possible causes: amyloid, multiple sclerosis 
Ipsilateral 3rd CN palsy  + contralateral hemiplegia  Weber's syndrome

Ipsilateral 3rd CN palsy  + contralateral hemiataxia  Benedikt syndrome 
Ipsilateral 3rd CN palsy  + ipsilateral hemiparesis + Contralateral homonymous hemianopsia   
Uncal herniation  
 
Fourth nerve (IVth) palsy  
Overview 
 supplies superior oblique (depresses eye, moves inward) 
 Head trauma (including minor head injuries) can result in a trochlear nerve palsy as it is

compressed against the tentorial edge or along another part of the pathway. 
 The fourth cranial nerve palsy  superior oblique palsy vertical diplopia  (eg: missing 
steps when walking down the stairs, bumping head when trying to get out of a car)  
Features 
 vertical diplopia 
 classically noticed when reading book or going down stairs 
 The trochlear nerve would lead to nystagmus on looking down and out .

Trigeminal neuralgia 
 
 Sensation over the face is supplied by the trigeminal nerve 
 Trigeminal neuralgia is a pain syndrome characterised by severe unilateral pain.  
43

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              39 
  Causes  
 idiopathic  (The vast majority)  
 compression of the trigeminal roots by tumours or vascular problems 
 The International Headache Society defines trigeminal neuralgia as: 
 unilateral disorder characterised by brief electric shock-like pains , abrupt in onset and

termination, limited to one or more divisions of the trigeminal nerve 
 the pain is commonly evoked by light touch, including washing, shaving, smoking, talkin g, 
and brushing the teeth ( trigger factors ), and frequently occurs spontaneously 
 small areas in the nasolabial fold or chin may be particularly susceptible to the 
precipitation of pain ( trigger areas ) 
 the pains usually remit for variable periods 
 Management  
 carbamazepine is first-line

 carbamazepine is first-line 
 failure to respond to treatment or atypical features (e.g. < 50 years old) should prompt 
referral to neurology 
 
January 2015 exam: History of electric shock like pains on the right side of the face. around 
10-20 episodes a day which, each lasting for around 30-60 seconds. What is the most 
suitable first-line management? Carbamazepine  
 
What is the nerve supply to the angle of the jaw?

The angle of the jaw is supplied by nerve roots C2/C3 and not the trigeminal nerve.  
 In patients with non-organic sensory loss, that loss usually extends to the edge of th e jaw. 
 
abducens (VIth) nerve palsy  
 The VIth nerve is motor to the lateral rectus muscle. 
 It is responsible for abduction of the ipsilateral eye.

 In the neutral position the affected eye is deviated medially due to unopposed action  of the 
medial rectus. 
 In patients with diplopia the 'cover test' can be used to determine the eye that has the 
problem.  
 On covering the affected eye the outermost image disappears. 
 Eg : diplopia on right horizontal gaze , improved on covering the right eye  the 
right abducens is affected  
 After finding a VIth nerve palsy the cause should always be looked for, it is not a d iagnosis in

itself. 
 Due to the long course and anatomy of the VIth nerve it can be damaged in any co ndition 
causing raised intracranial pressure. It can therefore be a 'false localising sign'. 
 
 44

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              40 
 ___________________________________________________ _______________________________ 
Facial (VII) nerve  
Facial nerve branches (mnemonic)  
(superior to inferior) as they exit the anterior border of 
the parotid gland: To Zanzibar By Motor Car 
1. T: temporal 
2. Z: zygomatic 
3. B: buccal 
4. M: mandibular 
5. C: cervical

5. C: cervical  
 
Facial Palsy + convergent squint  
                     Ļ 
    lesion in Pons  
   as VI th is encircled by VII th 
 
Supply - 'face, ear, taste, tear' 
 face: muscles of facial expression 
 ear: nerve to stapedius   (Hyperacusis is due to paralysis of stapedius)  
 taste: supplies anterior two-thirds of tongue 
 tear: parasympathetic fibres to lacrimal glands, also salivary glands

 Orbicularis oculi  is affected causing inability to blink/close eyelids. 
Causes of bilateral facial nerve palsy 
1. sarcoidosis 
2. Guillain-Barre syndrome 
3. polio,  
4. Lyme disease 
Causes of unilateral facial nerve palsy - as above plus 
Lower motor neuron  Upper motor neuron 
 Bell's palsy 
 Ramsay-Hunt syndrome (due to 
herpes zoster) 
 acoustic neuroma 
 parotid tumours 
 HIV 
 multiple sclerosis* 
 may also cause an UMN palsy  
 diabetes mellitus  stroke 
 
LMN vs. UMN

LMN vs. UMN 
 upper motor neuron lesion 'spares' upper face i.e. forehead 
 lower motor neuron lesion affects all facial muscles 
 
45

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              41 
 ___________________________________________________ ________________  
Bell's palsy 
Definition 
  acute, unilateral, idiopathic, facial nerve paralysis.  
Causes 
 unknown  
 although the role of the herpes simplex virus has been investigated previously.  
 The peak incidence is 20-40 years

 The peak incidence is 20-40 years  
 more common in pregnant women. 
Features  
 lower motor neuron facial nerve palsy - forehead affected 
 other features 
 post-auricular pain (may precede paralysis),  
 altered taste,  
 dry eyes,  
 hyperacusis (seen in around a third of patients) 
 prednisolone 1mg/kg for 10 days should be prescribed for patients within 72 hours of 
onset of Bell's palsy .  
 Adding in aciclovir gives no additional benefit

 eye care is important - prescription of artificial tears and eye lubricants should be con sidered 
Prognosis 
 if untreated around 15% of patients have permanent moderate to severe wea kness 
 
January 2012 exam:  Which features would be most consistent with a diagnosis of Bell's 
palsy?  Hyperacusis  
 
May 2010 exam: What is the current evidenced base approach to the management of Bell's 
palsy? Prednisolone

palsy? Prednisolone  
 
Ramsay Hunt syndrome  
Aetiology 
 Ramsay Hunt syndrome (herpes zoster oticus) is caused by the reactivation  of the varicella 
zoster virus in the geniculate ganglion  of the seventh cranial nerve. 
Features  
 auricular pain  is often the first feature  
 facial nerve palsy 
 vesicular rash around the ear 
 other features include vertigo and tinnitus 
Management

 oral aciclovir and corticosteroids are usually given 
Acoustic neuroma 
 
 Acoustic neuromas (more correctly called vestibular schwannomas)  
 account for 5% of intracranial tumours and 90 % of cerebellopontine angle  
 Features can be predicted by the affected cranial nerves 
 cranial nerve V: absent corneal reflex 
 cranial nerve VII: facial palsy

 cranial nerve VII: facial palsy 
 cranial nerve VIII: hearing loss , vertigo, tinnitus  
 Bilateral acoustic neuromas are seen in neurofibromatosis type 2  
 MRI of the cerebellopontine angle is the investigation of choice 
 
46

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              42 
 Other notes 
 The lacrimal gland is supplied by the facial nerve. 
 The glossopharyngeal nerve supplies the parotid salivary gland controlling salivary se cretions. 
 The trochlear nerve supplies the superior oblique muscle. 
 The oculomotor nerve innervates the superior rectus. 
 The vagus nerve supplies the palatal muscles.

 The vagus nerve supplies the palatal muscles.  
Holmes tremor 
Holmes tremor  lesion in the  red nucleus  
 Holmes tremor is caused by a lesion in the red nucleus. 
 This is most commonly due to a previous stroke of this area. 
  It is classically an irregular low frequency tremor which is a combination of resting, postural and 
action tremor.

action tremor. 
  It may also arise from any underlying structural disorders including multiple sclerosis, tumors, 
haemorrhage, trauma, neuroleptic agents, radiation.  
 Treatments include: 
 medical therapy such as levodopa  
 however thalamotomy or chronic thalamic stimulation have also shown to play a role in 
managing this condition. 
 
Movement disorders  
Movement disorders in order of least speed to fastest (DACB)  
 Dystonia - fixated position

 Dystonia - fixated position 
 Athetosis - Snake-like writhing (slow) 
 Choreiform - Like a dance choreographer 
 Ballistic/Ballismus/Hemiballismus - Fast flinging movements, can injure themselves or oth ers 'like 
a ballistic missile' (memorisation method) 
 
Chorea  
 
 Chorea describes involuntary, rapid, jerky movements which often move from one part of th e 
body to another ('dance-like') .  
 Slower, sinuous movement of the limbs is termed athetosis.

 Chorea is caused by  damage to the basal ganglia, especially the caudate nucleus.  
Causes of chorea  
 Inherited causes  such as: 
  Huntington's chorea  
  Wilson's disease 
 ataxic telangiectasia 
 Acquired causes  include: 
 Drugs - antipsychotics, anticonvulsants, amphetamines, oral contraceptive pill, L-dopa, 
dopamine agonists in patients with Parkinson's disease 
 Toxins - carbon monoxide, cyanide, opiates, mercury

 Immune - post-streptococcal (rheumatic fever) (Syndenham's chorea), SLE,  anti-
phospholipid syndrome, vasculitis (PAN, Behcet's disease) 
 Infectious - meningitis, encephalitis, cerebral toxoplasmosis, new variant Creutzfeldt-
Jakob disease 
 Vascular - stroke, polycythaemia, moyamoya 
 Hormonal - hypoparathyroidism, pregnancy, OCP, HRT, hyperthyroidism 
 Metabolic - hyper/hyponatraemia, hypo/hyperglycaemia, hypomagne saemia, 
hypocalcaemia, B1 and B12 deficiency. thyrotoxicosis

 Paraneoplastic - small cell lung carcinoma, renal cell carcinoma, ovarian carcinoma, 
lymphoma  polycythaemia rubra vera  
 CNS - trauma, tumours, senile chorea.  neuroacanthocytosis 
47

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              43 
  pregnancy: chorea gravidarum  
 often in patients who have had rheumatic fever.  
 usually begins in 1st trimester and resolves spontaneously after delivery.  
 If treatment before delivery is necessary because chorea is severe, barbiturates 
are indicated because they have fewer fetal risks than other drugs used to manage

chorea.  
 Rarely, a similar disorder occurs in women taking oral contraceptives. 
 
September 2012 exam: (SLE) presents with continuous jerky, irregular movements, which 
move from one limb to another. Where is the lesion most likely to be? Caudate nucleus  
Cerebellar syndrome  
Unilateral cerebellar lesions cause ipsilateral signs 
 
Causes 
 Friedreich's ataxia, ataxic telangiectasia 
 neoplastic: cerebellar haemangioma

 neoplastic: cerebellar haemangioma 
 stroke 
 alcohol 
 multiple sclerosis 
 hypothyroidism 
 drugs: phenytoin, lead poisoning 
 paraneoplastic e.g. secondary to lung cancer 
A history of vertigo, nystagmus, Slurred speech, intention tremor and past p ointing, as well as 
ataxia, suggest the cerebellum as the site of injury. 
Oppenheim's sign  is seen when scratching of the inner side of leg leads to extension of the 
toes. It is a sign of cerebral irritation

toes. It is a sign of cerebral irritation 
___________________________________________________________ 
Inferior cerebellar vermis lesion 
A patient has: 1. A staggering gait 2. Truncal instability 3. Normal arm and leg coordinatio n 4. 
Spontaneous nystagmus 5. A rotated head posture  
In children the commonest cause is a medulloblastoma.  
 
Abnormal gait  
 lesions of cerebellar vermis cause  truncal ataxia and tendency to fall backwards.

 Basal ganglia disease causes   extrapyramidal signs with Parkinsonism (festinant gait, marche 
à petits pas). 
 Proximal myopathy causes   a waddling gait. 
 Phenytoin toxicity  broad-based ataxic gait  
Gait disturbance may occur for a variety of reasons: 
 Sensory ataxia in B 12 deficiency and tabes dorsalis 
 Pyramidal signs in B 12 deficiency and SLE 
 Cerebellar ataxia in cerebrotendinous xanthomatosis. 
Nystagmus

Nystagmus  
Upbeat nystagmus  cerebellar vermis lesions  
Downbeat nystagmus  foramen magnum lesions (Arnold-Chiari malformation)  
 Nystagmus is defined as involuntary oscillations of the eyes. 
 This may be pendular when the oscillations are equal in rate and amplitude, o r jerking when 
there are quick and slow phases. (The quicker phase is used to define the direction.) 
 Nystagmus may be caused by: 
 Visual disturbances 
 Lesions of the labyrinth

 Lesions of the labyrinth 
 The central vestibular connections 
 Brain stem or cerebellar lesions. 
 Pendular nystagmus is due to: 
 usually due to loss of macular vision,  48

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              44 
  may be seen in diffuse brain stem lesions. 
 Jerking nystagmus  which is of constant direction regardless of the direction of gaze , 
suggests   a labyrinthine or cerebellar lesion. 
 Nystagmus which changes with the direction of  gaze  suggests widespread central 
involvement of vestibular nuclei.

involvement of vestibular nuclei.  
 Jerking nystagmus presents only on lateral gaze , the fast component of which is in the 
direction of gaze and indicates a lesion of the brain stem or cerebellum.  
 Nystagmus confined to one eye suggests:  
 a peripheral lesion of the nerve or muscle,  
 or a lesion of the medial longitudinal bundle. 
 Nystagmus restricted to the abducting eye on lateral gaze (ataxic nystagmus) is due to a  lesion

of the medial longitudinal bundle  between the pons and mid-brain as in multiple sclerosis 
(MS). 
 Nystagmus occurring on upward gaze with the fast component upwards (upbeat nystag mus) may 
be due to a lesion in the mid-brain  at the level of the superior colliculus. 
 Downbeat nystagmus (fast phase downwards) suggests a lesion in the lower part of the 
medulla. It is therefore typical of the Arnold-Chiari malformation (Chiari type I 
malformation ).

malformation ).  
 Wernicke's encephalopathy is another rare cause. 
 Horizontal nystagmus occurs in unilateral disease of the cerebral hemisphere, with the f ast 
phase directed to the side of the lesion. 
  Lateral cerebellar lesions classically cause pronounced nystagmus, whereas this is rarer and 
much more subtle with midline lesions. 
May 2007 exam:  Which one of the following is most associated with downbeat nystagmus? Arnold-
Chiari malformation

Chiari malformation  
Spinocerebellar ataxia 
 Spinocerebellar ataxias are a group of autosomal dominant disorders which are associated with 
the progressive development of ataxic features such as gait disturbance, nystagmus and tr emor.  
 The majority of affected patients develop symptoms within the 3rd and 4th decade. 
Hemiballism

Hemiballism 
 
The presence of severe flinging movements affecting proximal muscles and following no 
particular pattern is typical for hemiballism. 
 
 damage to the subthalamic nucleus  of the basal ganglia  Hemiballism  decreased 
suppression of involuntary movements.  
 Ballisic movements are involuntary, sudden, jerking movements which occur contralateral to th e 
side of the lesion.  
 The ballisic movements primarily affect the proximal limb musculature whilst the distal muscles

may display more choreiform-like movements  
 It is always unilateral, but it is common for arms and legs to move together.  
 Bilateral ballismus is rare and implicates a metabolic cause, usually non-ketotic hyperosmolar 
coma. 
 Symptoms may decrease whilst the patient is asleep.  
  The movements worsens with activity, and decrease with relaxation.  
Causes   
 vascular events (stroke). infarction being the commonest cause . 
 traumatic brain activity 
 amyotrophic lateral sclerosis

 amyotrophic lateral sclerosis 
 hypergylcaemia 
 malignancy 
49

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              45 
  vascular malformations 
 tuberculomas, and 
 demyelinating plaques. 
 
Treatment  
 Anti-dopaminergic agents (e.g. Haloperidol) are the mainstay of treatment . 
 Topiramate can be used, as can intrathecal baclofen, botulinum toxin and  tetrabenazine .

  Functional neurosurgery can be used for cases which have failed to respond to other tre atment.  
Prognosis 
 Usually the flinging movements stop spontaneously in the next four to eight w eeks 
 
 September 2012 exam: H/O involuntary, jerking movements of arms, resolved during 
asleep. Damage to which structure may lead to hemiballism? Subthalamic nucleus  
 
Epilepsy

Epilepsy 
Epilepsy classification 
Basics 
 two main categories are generalised and partial seizur es 
 partial seizures may progress to general seizures 
 other types: myoclonic, atypical absence, atonic and tonic seizures are usually seen in childh ood 
Generalised - no focal features, consciousness lost immediately 
 grand mal (tonic-clonic) 
 petit mal (absence seizures)

 petit mal (absence seizures) 
 myoclonic: brief, rapid muscle jerks 
 Lennox-Gastaut syndrome 
 Occurs in 1 – 5 in every 100 children with epilepsy.  
 The most common cause of intractable (difficult to treat) childhood epilepsy.  
 The most common time for it to start is between three and five years of age.  
 The most common type of seizures is atonic seizures or ‘drop attacks ’.  
 partial seizures progressing to generalised seizures 
Partial - focal features depending on location

Partial - focal features depending on location 
 simple (no disturbance of consciousness or awareness) 
 complex (consciousness is disturbed) 
  jacksonian seizure   
 also known as a focal (partial) motor seizure.  
 In this condition an uncontrolled, spontaneous discharge of electricity from one motor 
cortex presents with contralateral motor signs.  
 The patient has preserved consciousness as it is a partial seizure

 after the seizure it is common to have a Todd's paralysis where the limb is weak. 
 Temporal lobe epilepsy  presents with the sensation of déjà vu or an unreal feeling and can 
progress to hallucinations and altered conscious level. 
 Rolandic epilepsy  is a benign partial epilepsy associated with centro-temporal spikes. There is 
an excellent prognosis. 
 aversive seizures  are a form of simple partial seizure, consisting of head turning and conjugate 
eye movements. 
 
 50

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              46 
 Complex partial seizures   
 Temporal lobe epilepsy  can take the form of automatisms such as chewing and 
swallowing repeatedly, scratching the head   or searching for an object.    
 Some   people   may even    undress.     
 Spread of the seizure activity to the contralateral temporal lobe impairs memory of the even t

in the complex partial form of temporal lobe epilepsy. 
 They    can occur  as  a  result  of  seizure activity  in  any  part  of  the brain   bu t   most  
commonly arise in the temporal lobes . 
 The commonest finding is hippocampal sclerosis   
 MRI is an appropriate investigation  
 
Epilepsy: treatment 
 
Most neurologists now start antiepileptics following a second epileptic seizure. NICE guidelines sug gest

starting antiepileptics after the first seizure if any of the following are present: 
 the patient has a neurological deficit 
 brain imaging shows a structural abnormality 
 the EEG shows unequivocal epileptic activity 
 the patient or their family or carers consider the risk of having a further seizure unacceptable 
Sodium valproate is considered the first line treatment for patients with generalised seiz ures with 
carbamazepine used for partial seizures

carbamazepine used for partial seizures 
 
Generalised tonic-clonic seizures  
 sodium valproate 
 second line: lamotrigine, carbamazepine 
Absence seizures* (Petit mal) 
 sodium valproate or ethosuximide  
 sodium valproate particularly effective if co-existent tonic-clonic seizures in primary generalised  
epilepsy 
 *carbamazepine may actually exacerbate absence seizure  
Myoclonic seizures 
 second line: clonazepam, lamotrigine

 second line: clonazepam, lamotrigine 
 (carbamazepine and phenytoin may worsen  myoclonic seizures). 
Partial seizures 
 carbamazepine 
 second line: lamotrigine**, sodium valproate 
 **the 2007 SANAD study indicated that lamotrigine may be a more suitable f irst-line drug for 
partial seizures although this has yet to work its way through to guidelines  
Stopping of anti-epileptic drugs (AED) (2004 NICE guidelines)

 Can be considered if seizure free for > 2 years, with AEDs being stopped over 2-3 months 
 Benzodiazepines should be withdrawn over a longer period.  
AED cessation can be considered if seizure free for > 2 years – Stop AEDs over 2-3 months  
 
January 2015 exam: Which one of the antiepileptic drugs is most associated with weight 
gain? Sodium valproate  
 
51

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              47 
 September 2012 exam:  What is the most appropriate first-line antiepileptic for myoclonic 
seizures? Sodium valproate  
 
Absence seizures 
 
 Absence seizures (petit mal) are a form of generalised epilepsy that is mostly seen in childr en.

  The typical age of onset of 3-10 years old and girls are affected twice as commonly a s boys. 
 
Features 
Absence seizure (petit mal) presents with a blank stare, 3 Hz brain waves and do 
not show postictal confusion. 
 
 absences last a few seconds and are associated with a quick recovery 
 seizures may be provoked by hyperventilation or stress 
 the child is usually unaware of the seizure 
 they may occur many times a day 
 EEG: bilateral, symmetrical 3Hz spike and wave pattern

 sodium valproate and ethosuximide are first-line treatment 
 Absence seizures  are best treated by drugs that specifically target  T-
type calcium currents , which are believed to be involved in providing the pacemaker 
current for thalamic neurons , which then generate the generalized rhythmic discharge in 
the cortex during absence attacks. 
 The only two drugs listed that target the T-type calcium current  
are ethosuximide and valproic acid .

are ethosuximide and valproic acid .  
 Ethosuximide has much better safety profile than valproic acid, and thus is 
considered first-line treatment  
Prognosis 
 good prognosis - 90-95% become seizure free in adolescence 
Juvenile myoclonic epilepsy 
Juvenile myoclonic epilepsy is the most common  primary generalised epilepsy, but is 
underdiagnosed due to lack awareness of the condition by doctors

 is a common form of idiopathic generalised epilepsy, representing 10% of all patients with 
epilepsy.   
 typically first manifests itself between the ages of 10 and 18  with brief episodes of  involuntary 
muscle twitching occurring early in the morning .  
 Genetic 
 The condition is genetically linked to the short arm of chromosome 6. 
 Presentation  
 Absence seizures in childhood (which may be remain undiagnosed)

 Myoclonic jerks, especially of the upper limbs, which predominantly occur in the mornings 
shortly after waking (and may be so subtle as to be interpreted as 'clumsiness' when 
eating breakfast) 
 Generalised ton ic-clonic seizures, which often present for the first time between the ages 
of 13 and 18 years (usually provoked by sleep deprivation and/or excessive alcoho l 
intake) 
 There may be a positive family history 
 Precipitating factors include:  
 alcohol,  
 menstruation and

 alcohol,  
 menstruation and  
 sleep deprivation. 
 Investigations   
52

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              48 
  Interictal EEG is diagnostic showing  generalised spike- and polyspike-wave activity; a 
photosensitive response may also be present 
 Management   
 responds extremely well to sodium valproate   
 other options include, lamotrigine and topiramate.

 but may be exacerbated by some other antiepileptic drugs including carbamazepine 
 Lifelong drug treatment is usually necessary to avoid relapses in patients who achieve 
seizure-free status on medication. 
 Prognosis  
 Prognosis is extremely favourable if the condition is treated correctly, with many patients 
becoming seizure-free. 
Epilepsy in children: syndromes 
Infantile spasms (West's syndrome)

Infantile spasms (West's syndrome) 
 brief spasms beginning in first few (4-6) months of life; M>F 
 1. Flexion of head, trunk, limbs ĺ extension of arms (Salaam attack); last 1 -2 secs, repeat up to 
50 times 
 2. Progressive mental handicap 
 3. EEG: hypsarrhythmia 
 usually 2nd to serious neurological abnormality (e.g. TS, encephalitis, birth asph yxia) or may be 
cryptogenic 
 poor prognosis 
 vigabatrin/steroids 
Typical (petit mal) absence seizures 
 onset 4-8 yrs

 onset 4-8 yrs 
 duration few-30 secs; no warning, quick recovery; often many per day 
 EEG: 3Hz generalized, symmetrical 
 sodium valproate, ethosuximide 
 good prognosis: 90-95% become seizure free in adolescence 
 
Lennox-Gastaut syndrome 
 may be extension of infantile spasms (50% have hx) 
 onset 1-5 yrs 
 atypical absences, falls, jerks 
 90% moderate-severe mental handicap 
 EEG: slow spike 
 ketogenic diet may help 
Benign rolandic epilepsy 
 most common in childhood, M>F

 most common in childhood, M>F 
 paraesthesia (e.g. unilateral face), usually on waking up 
Juvenile myoclonic epilepsy (Janz syndrome) 
 onset: teens; F:M = 2:1 
 1. Infrequent generalized seizures, often in morning 
 2. Daytime absences 
 3. Sudden, shock like myoclonic seizure 
 usually good response to sodium valproate 
Neonatal period - try vitamin B6 
 2nd: hypoglycaemia, meningitis, head trauma 
 pyridoxine dependency (AR, IV B6) 
 benign familial neonatal seizures (AD)

 benign familial neonatal seizures (AD) 
 benign neonatal convulsions (5th day) 
Gelastic seizures  
 Gelastic seizures should be suspected in cases of erratic laughing or crying .   
 The term Gelastic originates from the Greek word "Gelos" which means laughter  
 typically arise from hypothalamic  hamartomas

 typically arise from hypothalamic  hamartomas  
 It can be hard to identify in young children but there is usually associated automatisms su ch as 
fidgeting or lip smacking or change in sensorium.  
Status epilepticus 53

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              49 
  Status epilepticus is traditionally defined as continuous convulsion lasting longer than 30 
minutes , or the occurrence of serial convulsions between which there is no return of 
consciousness. 
 It may be generalised (tonic clonic, absent) or partial (simple, complex, or with secondary

generalisation). Generalised tonic clonic seizures predominate. 
 This is a medical emergency. The priority is termination of seizure activity, which if prolon ged will 
lead to irreversible brain damage. 
 Approximately 20 minutes of status epilepticus produces regional oxygen sufficiency 
deficiency promoting cell damage and necrosis. This is, therefore, used as the t hreshold in 
children. 
 Cell death thus results in increased metabolic demands from continually discharging

neurones. Vulnerable areas include the hippocampus, the mid to low cerebellum, middle 
cortical areas, and thalamus. 
 The relationship between neurological outcome and duration of status epilepticus is unkno wn 
 The most common cause in a child less than 3 years is a prolonged febrile seizure. Slee p 
deprivation and drug withdrawal can also precipitate it. 
 There are three major sub-types: 
1. prolonged febrile seizures.

1. prolonged febrile seizures. 
2. idiopathic status epilepticus (no underlying central nervous system [CNS] lesion or insult). 
3. symptomatic (longstanding neurological disorder or metabolic abnormality). 
 General treatment  
 Initial management begins with ABC.  Maintain airway and circulation with intubation    
 Remember "DEFG" (Don't Ever Forget Glucose): Hypoglycaemia should be excluded as it

is easily and rapidly treatable (if present 3-5 ml/kg of 10% dextrose is given by IV 
infusion), 
 blood obtained for full blood count, electrolytes including calcium and magnesium, 
glucose, creatinine, anticonvulsant levels. Blood and urine may be obtained for toxicolo gy. 
Arterial blood gases should be done, and consideration given to lumbar puncture. 
 Anticonvulsant therapy  
 First-line  drugs are benzodiazepines such as diazepam or lorazepam.

 Lorazepam is preferred because of long duration of anti-epileptic effect. 
 This is effective in ~80% cases. 
 If the patient does not respond, the regime may be repeated after 5-10 minu tes 
using the same or a different benzodiazepine. 
 If ineffective within 10 minutes it is appropriate to start a second-line  agent 
 Second-line   
 If seizures recur or fail to respond after 30 minutes a parenteral anti-epileptic agent 
should be started.

should be started. 
 such as phenytoin , sodium valproate, levetiracetam, or phenobarbital.  
 phenytoin may be given as a loading dose followed by an infusion. 
 Fosphenytoin :  
 Fosphenytoin is a pro-drug of phenytoin - metabolised in the body to 
phenytoin and endogenous phosphates. 
 has several advantages over phenytoin: 
 it can be given IV or IM (phenytoin can only be given IV)  
 can be given at infusion rates three times faster than phenytoin

 therapeutic levels are achieved within 10 minutes, 
 it has a lower incidence of adverse events than phenytoin. 
 If the patient is already taking phenytoin, either IV phenytoin or 
fosphenytoin should still be given: it is likely that plasma levels are 
subtherapeutic. 
 Third-line   
 If no response within 30 minutes from onset, then the best way to achieve rapid 
control of seizure activity is induction of general anaesthesia .

 The anaesthetic agents thiopental  and propofol  may be effective 
(unlicensed indication) but should only be done with full intensive care 
support. 54

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              50 
  
If a patient in generalised status epilepticus does not respond to lorazepam and adequate doses 
of intravenous phenytoin, what is the next step in their management? 
 Transfer to an Intensive Therapy Unit 
 
The use of phenytoin is not recommended in patients with underlying liver impairment therefore

not used in status epilepticus secondary to alcohol withdrawal. 
Drug therapy  
 Only start after a minimum of two fits.  
 Only use one drug at a time, and begin with a small dose, and gradually increase it, until 
control is achieved, toxic affects occur, or the maximum dose is reached.   
Drug  Mechanism  Side effects  Clinical uses  
Phenobarbital  Inhibits sodium  channels , 
thus reducing action 
potential 
propagation. Does not 
lower the seizure

lower the seizure 
threshold.  Sedation, impairment of motor and cognition 
systems after long term use, 
megaloblastic anaemia  Rarely used 
due to 
sedation – 
been 
superceeded 
byphenytoin  
Phenytoin  Inhibits sodium  channels , 
potential propagation. Acts 
on voltage dependent 
channels, and selectively 
binds when they are in the 
open state. Vertigo , nystagmus, headaches , 
megaloblastic anaemia ,

megaloblastic anaemia , 
hypersensitivity, confusion  and cognition 
problems (high dose). Teratogenic, gum 
hypertrophy, arrythmias Partial and 
generalised 
attacks, 
but not in 
absence. High 
doses my 
precipitate 
attacks 
Carbamazepine  Inhibits sodium  channels , 
open state. Ataxia, drowsyness, dizziness , GI disturbance, 
cardio effects, water rention (and

cardio effects, water rention (and 
subsequent hyponatraemia ), alter metabolism  of 
other drugs, skin rash  First line 
for partial 
seizures  
Also often 
tried as a 2ndor 
third line drug, 
when other 
treatments 
have been 
unsuccessful. 
Lamotrigine  Inhibits sodium  channels , 
potential propagation. Nausea, dizziness , ataxia Generalised 
seizures –
2nd line 
treatment 
Ethosuximide  Calcium  channel inhibitor 
–inhibits calcium  channels

–inhibits calcium  channels 
of the T-type – thought to 
be involved in the 3Hz 
rhythmic discharge seen in 
absence seizures Dizziness , nausea, anorexia , lethargy. Can 
precipitate tonic/clinic attacks Useful 
for absence 
seizures  
Sodium valproate  -          Increases GABA 
concentration  
-          Inhibits sodium channels  
-          Inhibits glutamate 
decarboxylase  Very few side effects.  
Highly teratogenic  
10% will have hair loss

10% will have hair loss 
Reduces efficacy of contraceptive pill  First line 
treatment for:  
-          Absence 
seizures  
-          Generalised 
seizures  
second line 
treatment 
seizures  
 55

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              51 
  
Which antiepileptic drugs does not have interactions with warfarin? 
 Lamotrigine has no effect on liver enzymes and is the treatment of choice for patient 
taking warfarin 
 Phenytoin, carbamazepine, primidone and phenobarbital are liver enzyme inducers  
 Sodium valproate is a liver enzyme inhibitor

What is the likelihood of being seizure-free after a second or third antiepileptic is added?  
 A study of patients with previously untreated epilepsy demonstrated that 47% achi eved control of 
seizures with the use of their first single drug. 
 14 % became seizure-free during treatment with a second or third drug. 
 
September 2008 exam:  H/O complex partial seizures, not able to tolerate either carbamazepine or

sodium valproate. What is the most appropriate next line drug?   Lamotrigine  
 
What is the likelihood of controlling seizures in a patient never previously on anti-epileptic 
medication? 
A study of patients with previously untreated epilepsy demonstrated that:  
 With a single first-line anti-convulsant agent    47% achieved control of seizures  
 Fourteen per cent became seizure-free during treatment with a second or third drug.

 An additional 3% became seizure-free with the use of two drugs simultaneously. 
 
Epilepsy: pregnancy and breast feeding 
 
 The risks of uncontrolled epilepsy during pregnancy generally outweigh the risks of m edication to 
the fetus.  
 All women thinking about becoming pregnant should be advised to take folic acid 5m g per day 
well before pregnancy to minimise the risk of neural tube defects.

  Around 1-2% of newborns born to non-epileptic mothers have congenital defects. This rise s to 3-
4% if the mother takes antiepileptic medication. 
 
Other points  
 aim for monotherapy 
 there is no indication to monitor antiepileptic drug levels 
 Sodium valproate  (November 2013 Drug Safety Update) 
 Sodium valproate should not be used during pregnancy and in women of 
childbearing age unless clearly necessary .  
 associated with neural tube defects

 associated with neural tube defects  
 New evidence showing a significant risk of neurodevelopmental delay in children following 
maternal use of sodium valproate. 
 Women of childbearing age should not start treatment without specialist neu rological or 
psychiatric advice. 
 Because of relatively short half-life, it should be taken 2-3 times per day .  
 It can result in pancreatitis (and severe abdominal pain).

 carbamazepine : often considered the least teratogenic of the older antiepileptics 
 phenytoin :  
 associated with cleft palate 
 It is advised that pregnant women taking phenytoin are given vitamin K in the last 
month of pregnancy to prevent clotting disorders in the newborn.  
 Lamotrigine :  
 the rate of congenital malformations may be low.  
 The dose of lamotrigine may need to be increased in pregnancy

 Breast feeding  is generally considered safe for mothers taking antiepileptics with the possible 
exception of the barbiturates 
 
56

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              52 
 Prescribing in patients with epilepsy 
 The following drugs may worsen seizure control in patients with epilepsy: 
 alcohol, cocaine, amphetamines 
 ciprofloxacin, levofloxacin 
 aminophylline, theophylline 
 buproprion 
 methylphenidate (used in ADHD) 
 mefenmic acid

 mefenmic acid 
 Some medications such as benzodiazipines, baclofen and hydroxyzine may provoke seizures 
whilst they are being withdrawn.  
 P450 enzyme inducers  will decrease the drug level and therefore increase the failure rate  of 
oestrogen and progesterone containing contraceptives.  
 Carbamazepine 
 Oxcarbazepine 
 Phenytoin 
 Phenobarbitone 
 Primidone 
 Topiramate 
 Other medications may worsen seizure control by  interfering with the metabolism of anti-

epileptic drugs (i.e. P450 inducers/inhibitors). 
 Lamotrigine 
  is not a P450 inducer.  
 Levels of lamotrigine are reduced by oral contraceptives containing ethinylestradiol, 
increased seizure frequency may therefore occur.  
 There is no evidence that progestogen-only methods affect lamotrigine levels. 
_________________________________________________________________________________________  
Pseudoseizures 
Suspected psychogenic non-epileptic seizures  do Video-EEG recording

 Pseudoseizures are commonly misdiagnosed as true seizures and treated inappropria tely with 
anti-epileptic drugs. 
Factors favouring pseudoseizures  
 pelvic thrusting 
 family member with epilepsy 
 more common in females 
 crying after seizure 
 don't occur when alone 
 gradual onset 
 prolonged nature of the attacks (15-30 minutes)  
 Violent shaking,  
 resistance to passive eye opening 
 normal vital signs

 normal vital signs  
 
Urinary incontinence can also occur in pseudoseizures but tongue biting is rare. 
 
Factors favouring true epileptic seizures 
 tongue biting 
 raised serum prolactin* 
 *why prolactin is raised following seizures is not fully understood. It is hypothesised t hat there is spread 
of electrical activity to the ventromedial hypothalamus, leading to release of  a specific prolactin 
regulator into the hypophyseal portal system  
Diagnosis

Diagnosis 
 Video telemetry is useful for differentiating  
Treatment 
 Simple observation  is the appropriate management.  
 
 57

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              53 
 _________________________________________________________________________________________  
Somatosensory seizures 
 Spread of symptoms ('marching') in seconds   
 Example   tingling sensation starts in fingers and spreads in seconds to affect the whole arm 
and leg

and leg  
 The usual source of somatosensory seizures is the  parietal lobe . 
 
 Positive symptoms  (jerking, tingling) usually signify  epilepsy . 
 Negative symptoms  (weakness, numbness) are usually caused by transient focal 
ischaemia . 
 Spread of symptoms  ('marching') indicates migraine (in 5-20 minutes ) or seizures 
(in seconds).  
Rett syndrome

Rett syndrome  
 Rett syndrome is a neurodevelopmental disorder of the grey matter  
 mostly affecting girls.  
 related to the MECP2 gene on the X chromosome 
 Feature 
 Small hands and feet with deceleration of head growth.  
 Epileptic   repetitive hand movements  such as hand wringing . 
 GI problems, such as constipation. 
Tourette syndrome  
 Definition

 Definition 
 a chronic neurologic disorder that manifests with motor and vocal tics 
 Epidemiology  
 Tourette syndrome presents before 18 years of age and many children grow out of it. 
 more common in males (4:1) 
 Pathogenesis 
 due to genetic, environmental, and social factors resulting in an abnormality in the 
mesolimbic spinal system  
 the condition is familial in most cases 
 Features

 Features 
 The motor tics often have a build up that the patient is aware of, like an itch.  
 Commonly they involve blinking, throat clearing or shoulder shrugging.   
 Shouting of swear words is a typical vocal tic of Tourette's. 
 Associated conditions:  
 90% of patients have a comorbid psychiatric disorder such as:  
 attention deficit hyperactivity disorder (~60% of cases) 
 obsessive compulsive disorder (~27% of cases) 
 Diagnosis

 The criteria for diagnosis require multiple motor and one or more vocal tics, showing 
themselves over a year, with not more than three consecutive months tic free.  
 MRI and EEG are typically normal  
 tics typically decline during adolescence and may resolve around 18 years of age (~50% 
of children) 
 management 
 Cognitive behavioural approaches (e.g., comprehensive behavioural intervention for tics

[CBIT], which includes habit reversal therapy) are considered first-line  interventions for 
patients with mild to moderate tics. 
 Medication should be recommended only when behavioural intervention has not  been 
effective or is not available. 
 First-line pharmacotherapy is generally an alpha-2 agonist  (e.g., clonidine and 
guanfacine). 
 
 58

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              54 
Huntington's disease 
 
Genetics  
 autosomal dominant, neurodegenerative genetic disorder 
 trinucleotide repeat disorder: repeat expansion of CAG 
 results in degeneration of cholinergic and GABAergic neurons in the striatum of the basal

ganglia  
 due to defect in huntingtin gene on short arm of chromosome 4 
 The disease may develop earlier in life in each successive generation  
Features: typically appear between 30 and 50 years of age. 
 chorea 
 personality changes (e.g. irritability, apathy, depression) and intellectual impairment (The earliest 
symptom ) 
 lack of coordination and an unsteady gait   
 dystonia 
 saccadic eye movements 
 The disease leads eventually to dementia and premature death. 
Diagnosis

Diagnosis 
 DNA analysis is the most useful diagnostic test  
 (e.g., via PCR)  
 trinucleotide CAG repeat expansion in the Huntington gene is diagnostic 
 MRI  caudate nucleus atrophy 
 Atrophy of the caudate nucleus, putamen, and deep cerebral cortex are the hall mark 
features of Huntington's disease.  
 The role of neuroimaging is primarily to rule out other intracranial causes of a patie nt's 
symptoms, rather than to diagnose HD.  
Treatment

Treatment  
 Tetrabenazine  works as a VMAT-inhibitor (vesicular monoamine transporter 2),  involved in 
transportation of monoamines. It is indicated for Huntington's chorea to reduce hyperkinetic 
movements. 
Prognosis 
 progressive and incurable condition 
 typically results in death 20 years after the initial symptoms develop. 
 Average life span after clinical onset is about 15 years. 
_________________________________________________________________________________________

Subclavian Steal Syndrome 
 is associated with retrograde flow in the vertebral artery due to proximal subclavian artery 
stenosis.  
 Neurological symptoms are precipitated by vigorous exercise with the arm above the head, such 
as painting a wall. 
 Diagnosis is often confused with transient ischemic attacks or epilepsy. 
 Duplex ultrasound and MRA are the investigations of choice. 
 Endarterectomy and stenting are common surgical methods involved in relieving symptoms

associated with this condition. 
Headache  
__________________________________________________________________________________________  
Trigeminal autonomic cephalalgias (TAC) 
 Trigeminal autonomic cephalalgias (TACs) 
 cluster headache 
 attacks have a frequency between one every other day and 8 per day an d last 15-
180 minutes. 
 paroxysmal hemicranias

 paroxysmal hemicranias 
 attacks have a frequency above five per day and last 2-30 min. The cond ition 
responds absolutely to indomethacin 
 hemicrania continua 59

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              55 
  a constant form of paroxysmal hemicrania (no headache-free periods). Also 
responds absolutely to indomethacin. 
 short-lasting unilateral neuralgiform headache attacks with conjunctival injection and 
tearing (SUNCT syndrome) 
 short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms 
(SUNA)

(SUNA) 
 could get 20 attacks in a day, each last around 1600 seconds. 
 hemicrania continua and paroxysmal hemicrania clearly are the two that completely  resolve with 
indomethacin. 
 Notice the differences between how long each lasts and how many attacks there can b e per day. 
The rest of the features are quite similar to each other between the headaches, so  learn the 
general features of a TAC then memorise how long each should last and its frequency  to help 
you differentiate them.

you differentiate them. 
the most likely to aid  in making a diagnosis a trial of indomethacin 
 
___________________________________________________________________________________________  
Cluster headache 
 
 Cluster headaches are more common in men (5:1) and smokers. 
 more common in younger males below the age of 40 
Features  
 pain typical occurs once or twice a day, each episode lasting 15 mins - 2 hours  
 clusters typically last 4-12 weeks

 clusters typically last 4-12 weeks 
 intense pain around one eye (recurrent attacks 'always' affect same side) 
 The attacks are often nocturnal and are associated with parasympathetic overactivity. 
 patient is restless during an attack 
 accompanied by redness, lacrimation, lid swelling 
 nasal stuffiness 
 miosis and ptosis in a minority 
 Acute : 100% oxygen, subcutaneous or a nasal triptan

 the use of 100% oxygen at least 12 litres per minute via a non-rebreathable mask   
 It is not recommended to offer paracetamol, NSAIDS, opioids, ergots or oral triptans for 
the acute treatment of a cluster headache. 
 prophylaxis:  First line  verapamil , prednisolone  , with other options including lithium, sodium 
valproate and gabapentin 
 NICE recommend seeking specialist advice from a neurologist if a patient develops cluster 
headaches with respect to neuroimaging 
 
60

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              56 
  
Differential diagnosis 
 The main differential is between cluster headaches and chronic paroxysmal hemicrania  (CPH; 
which is treated with indomethacin). 
 Features that distinguish CPH are 
 Shorter duration of attacks (2-45 mins) 
 Increased frequency of attacks 
 Female preponderance and

 Female preponderance and 
 Selective response to treatment with indomethacin. 
 
Distinguishing cluster headaches and Chronic Paroxysmal Hemicrania 
Cluster headache Chronic Paroxysmal Hemicrania 
more common in males more common in females 
frequency of 1-4 (maximum 8) in 24 hours. the frequency of attacks is higher , usually more 
than 15 in 24 hours 
The duration of headaches is (15-60 min). The duration  of headaches is shorter  (2-25 min)

Not responds to indomethacin responds very well to indomethacin  
 
Distinguishing cluster headaches and SUNCT  (short lasting unilateral neuralgiform 
headache with conjunctival injection or tearing) : 
cluster headaches SUNCT 
more prevalent in younger males below the 
age of 40  more common in older patients above the age 
of 40. 
typically onset at night can occur at any time of day 
last from 15 minutes to 3 hours typically lasts for seconds to minutes.

rarely onset more than 3 times per day has been described in up to 75 times per day. 
A transient Horners syndrome is typical  Horners may be lacking in SUNCT 
classically, but not always, triggered by 
alcohol not triggered by alcohol 
Migraine 
Diagnostic criteria 
The International Headache Society has produced the following diagnostic criteria for migraine without 
aura: 
Point Criteria

aura: 
Point Criteria 
A At least 5 attacks fulfilling criteria B-D 
B Headache attacks lasting 4-72 hours * (untreated or unsuccessfully treated) 
C Headache has at least two of the following characteristics: 
 1. unilateral location 
 2. pulsating quality (i.e., varying with the heartbeat) 
 3. moderate or severe pain intensity 
 4. aggravation by or causing avoidance of routine physical activity (e.g., walking or climbing 
stairs) 
D During headache at least one of the following:

D During headache at least one of the following: 
 1. nausea and/or vomiting 
 2. photophobia and phonophobia 
E Not attributed to another disorder (history and examination do not suggest a secondary headache 
disorder or, if they do, it is ruled out by appropriate investigations or headache attacks do not occur 
for the first time in close temporal relation to the other disorder) 
 NICE suggests migraines may be unilateral or bilateral 61

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              57 
  
Migraine with aura 
 seen in around 25% of migraine patients 
 tends to be easier to diagnose with a typical aura being progressive in nature  
 may occur hours prior to the headache.  
 Typical aura include: 
 transient hemianopic disturbance or a spreading scintillating scotoma ('jagged crescent').

 Spreading (over minutes) sensory and motor symptoms  
 Word-finding difficulties are also a common migraine aura symptom. 
 autonomic symptoms such as a Horner syndrome 
 
 may occur with or without headache  
 NICE also give more detail about typical auras : 
 are fully reversible 
 develop over at least 5 minutes 
 last 5-60 minutes 
 The following aura symptoms are atypical and may prompt further investigation/referral; 
 motor weakness 
 double vision

 double vision 
 visual symptoms affecting only one eye 
 poor balance 
 decreased level of consciousness. 
 
 Complicated migraine   
 Complicated migraine  is one which results in hemi sensory or hemi motor findings 
associated with a typical migraine presentation.  
 Confusional migraine  involves alteration in sensorium rather than limb involvement. 
 
Other features: 
 family history of similar headaches is common  
 Bilateral fortification spectra

 Bilateral fortification spectra 
 Fortification spectra (jagged lines resembling battlements) and teichopsia (flashes) are 
common features of migraine. 
 Precipitation by oral contraceptives (contraindicated in migraine with aura) 
 Frequency reduced by tricyclic antidepressants (can be useful in the prophylaxis of m igrain) 
 Third nerve palsy 
 seen in ophthalmoplegic migraine 
 ophthalmoplegic migraine was reclassified as a cranial neuralgia  in the most recent

International Headache Society classification. 
 most commonly affects the third nerve,  
 the deficits can be permanent.  
 A subset of these patients will have gadolinium enhancement of the cisternal seg ment of 
the cranial nerve  
 it is thought some of these patients actually have a demyelinating neuropathy .  
Migraine: management 
 
acute  5-HT agonists  
prophylaxis: β -blocker, 5-HT2 antagonist 
 
 5-HT receptor agonists are used in the acute treatment of migraine

 5-HT receptor antagonists are used in prophylaxis.  
Acute treatment  
62

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              58 
  first-line: 
 combination of oral triptan and NSAID, OR oral triptan and paracetamol 
 for young people aged 12-17 years:  nasal triptan  is preferred than oral triptan 
 if the above measures are not effective or not tolerated offer a non-oral preparation of

metoclopramide* or prochlorperazine and consider adding a non-oral NSAID or triptan 
 *caution should be exercised with young patients as acute dystonic reactions may 
develop with metoclopramide. 
Prophylaxis (NICE 2015)  
 prophylaxis should be given if patients are experiencing 2 or more attacks per month.  
 Modern treatment is effective in about 60% of patients. 
 NICE advise either topiramate  or propranolol  or  amitriptyline   'according to the person's

preference, comorbidities and risk of adverse events'.  
 Propranolol should be used in preference to topiramate  in women of child bearing 
age as it may be teratogenic  and it can reduce the effectiveness of hormonal 
contraceptives  
 if these measures fail NICE recommend 'a course of up to 10 sessions of acupunctu re over 5- 8 
weeks' 
 gabapentin are not recommended now because evidence shows that it is not effective  in 
preventing migraine.  (NICE 2015)

preventing migraine.  (NICE 2015)  
 NICE recommend: 'Advise people with migraine that riboflavin (400 mg once a day) may be 
effective in reducing migraine frequency and intensity for some people' 
 riboflavin also known as vitamin B 2 
 safe during pregnancy. 
 for women with predictable menstrual migraine  treatment: 
  NICE recommend either frova triptan  (2.5 mg twice a day) or zolmi triptan  (2.5 mg twice 
or three times a day) as a type of 'mini-prophylaxis'

 pizotifen is no longer recommend.  
 Adverse effects such as weight gain & drowsiness are common 
 
Efficacy of Paracetamol in migraine  
 Migraine  ↓ gastric empting  ↓Paracetamol absorption  ↓Paracetamol effects 
 Metoclopramide may be useful in accelerating gastric emptying. 
 paracetamol absorption technique is used to study gastric emptying.  
 
January 2006 exam: Which type of medication would be most appropriate to reduce the

frequency of migraine attacks?  Beta-blocker (Topiramate is also recommended by NICE as first-line 
prophylaxis against migraine. However, a beta-blocker is a better choice in a female of child-bearing  age) 
Migraine: pregnancy, contraception and other hormonal factors 
Migraine during pregnancy  
 paracetamol 1g is first-line 
 aspirin 300mg or ibuprofen 400mg can be used second-line in the first and  second trimester

Migraine and the combined oral contraceptive (COC) pill  
 if patients have migraine with aura then the COC is absolutely contraindicated due to an 
increased risk of stroke (relative risk 8.72) 
 
Migraine and menstruation 
 many women find that the frequency and severity of migraines increase around  the time of 
menstruation 
 SIGN recommends that women are treated with mefanamic acid or a combination of as pirin,

paracetamol and caffeine. Triptans are also recommended in the acute situation 
Migraine and hormone replacement therapy (HRT) 
 safe to prescribe HRT for patients with a history of migraine but it may make migraines worse 
Triptans 
 Triptans are specific 5-HT1 agonists  used in the acute treatment of migraine.  
 They are generally used first-line in combination therapy with an NSAID or paracetamol.  
Prescribing points  63

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              59 
  should be taken as soon as possible after the onset of headache, rather than a t onset of aura 
 oral, orodispersible, nasal spray and subcutaneous injections are available 
Adverse effects 
 'triptan sensations' - tingling, heat, tightness (e.g. throat and chest), heaviness, pre ssure 
Contraindications

Contraindications 
 patients with a history of, or significant risk factors for, ischaemic heart disease or 
cerebrovascular disease 
Epilepsy is not a contraindication to the use of triptans 
Idiopathic intracranial hypertension(IIH) 
 
Suspected  Idiopathic intracranial hypertension  lumbar puncture to confirm the diagnosis 
is the next step

is the next step  
 
 also known as pseudotumour cerebri and formerly benign intracranial hypertension  
 classically seen in young, overweight females. 
 
Features  
 headache 
 blurred vision ,  
 Diplopia is common due to sixth nerve palsy.  
 papilloedema (usually present) 
 enlarged blind spot 
 Reduction in colour vision is common  
 sixth nerve palsy may be present 
 normal appearances of the magnetic resonance imaging (MRI). Normal ventricular size, anatom y

and position. Normal CSF cell count and protein content. 
 plantars are flexor  
 Extensor plantars suggest alternative diagnosis. 
 Absence of retinal venous pulsations 
Risk factors 
 obesity 
 female sex 
 pregnancy 
 drugs*: oral contraceptive pill (eg:  Dianette ) , steroids , tetracycline , vitamin A , Nalidixic acid  
 *if intracranial hypertension is thought to occur secondary to a known causes (e.g. 
Medication) then it is of course not idiopathic 
Diagnosis

Diagnosis 
 the diagnosis is confirmed by finding an elevated CSF opening pressure  (more than 20 cm 
H2O). CSF protein, glucose and cell count will be normal. 
 CT and MRI scans are often normal  
Management  
 weight loss 
 diuretics e.g. acetazolamide 
 topiramate is also used, and has the added benefit of causing weight loss in m ost patients 
 repeated lumbar puncture 
 surgery:  
 A lumboperitoneal or ventriculoperitoneal shunt may also be performed to reduce

intracranial pressure 
 optic nerve sheath decompression and fenestration may be needed to preven t damage to 
the optic nerve.  
 In progressive visual loss  Lumbo-peritoneal (LP) shunt  is the treatment of 
choice.  
64

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              60 
  Optic nerve fenestration is an alternative. 
 There are no comparative studies between the two interventions. 
Complication 
 Progressive visual loss and optic atrophy  
 
 September 2008 exam: Sudden loss of vision in left eye + headaches + bilateral

papilloedema. Which drug is most likely to be responsible? Prednisolone  intracranial 
hypertension  
Spontaneous intracranial hypotension (SIH) 
 
Strong postural relationship with the headache generally much worse when upright. Pa tients may 
therefore be bed-bound  
 Low (CSF) pressure headache, that is seen most frequent following lumbar pu ncture, but may

also occur either following an episode of possible minor trauma to meninges (eg sports injury  to 
neck or back) or without apparent cause (SIH).  
 The lower limit of the normal range for CSF pressure is 10 cm H2O 
 Mechanism : CSF leak leads to  low CSF pressure  orthostatic headache in association with 
one or more of the following symptoms: 
 nausea, vomiting 
 horizontal diplopia 
 unsteadiness or vertigo 
 altered hearing 
  neck pain/stiffness 
 interscapular pain

 interscapular pain  
 visual field abnormalities 
 Diagnosis   
 may be confirmed by measuring CSF opening pressure  at lumbar puncture: by very 
definition, the opening CSF pressure is low, below 60 mm H 2O, and often a 'dry' tap is 
encountered 
 However, the pressure may be normal 
 CSF fluid analysis is normal 
 MRI studies typically reveal diffuse pachymeningeal enhancement, frequently in

association with 'sagging' of the brain, tonsilar descent and posterior fossa crowding 
 Treatment  
 conservative measures are often undertaken  first  (bed rest, analgesia, increased fluid 
intake)  
 epidural blood patch is the treatment of choice 
Medication overuse headache 
 
 Medication overuse headache is one of the most common causes of chronic daily head ache.  
 may affect up to 1 in 50 people 
Features

Features  
 present for 15 days or more per month 
 developed or worsened whilst taking regular symptomatic medication 
 patients using opioids and triptans are at most risk 
 may be psychiatric co-morbidity 
Management  (from 2008 SIGN guidelines) 
 simple analgesics and triptans should be withdrawn abruptly (may initially worsen headaches) 
 opioid analgesics should be gradually withdrawn 
65

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              61 
  Withdrawal symptoms are likely to occur, including worsening headache, nausea, agitation an d 
sleep disturbance. These usually settle within seven days, and headaches should stop w ithin 
approximately three weeks. 
Thunderclap headache

Thunderclap headache 
 Thunderclap headache describes a sudden (reaches maximum severity within seco nds to 
minutes of onset) and severe headache. 
Causes  
 subarachnoid hemorrhage 
 cerebral venous sinus thrombosis 
 internal carotid artery dissection 
 pituitary apoplexy 
 reversible cerebral vasoconstriction syndrome 
 primary sexual headache 
 posterior reversible leucoencephalopathy syndrome 
___________________________________________________ ________________  
Parkinsonism

Parkinsonism 
Causes: 
 Parkinson's disease 
 drug-induced e.g. antipsychotics, metoclopramide  
 progressive supra-nuclear palsy 
 multiple system atrophy 
 Wilson's disease 
 post-encephalitis 
 dementia pugilistica (secondary to chronic head trauma e.g. boxing) 
 toxins: carbon monoxide, MPTP 
Drugs causing Parkinsonism 
 phenothiazines: e.g. chlorpromazine, prochlorperazine 
 butyrophenones: haloperidol, droperidol 
 metoclopramide

 metoclopramide 
 Domperidone does not cross the blood-brain barrier and therefore does not cause e xtra-
pyramidal side-effects 
Parkinson's disease 
 
 Parkinson's disease is a progressive neurodegenerative condition caused by degeneration of 
dopaminergic neurons in the substantia nigra. 
 After approximately 50% of the dopamine neurons, and 75-80% of striatal d opamine is lost

patients start to exhibit the classical signs of bradykinesia, resting tremor and rigidity.  
 The characteristic microscopic finding in Parkinson's disease is the Lewy body  
 
Epidemiology  
 around twice as common in men 
 mean age of diagnosis is 65 years 
 Decreased dopamine impairs movement by which mechanisms? 
 Decreased activation of the D1 and D2 receptors 
 pathway involved in conscious motion, and how that pathway becomes interrupted in

Parkinsonian patients: 
 There are two pathways in the brain that promote motion:  
 the direct, stimulatory pathway and 
 the indirect, inhibitory pathway.  
66

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              62 
  In normal circumstances, the stimulatory pathway is activated while the inhibitory path way 
is deactivated, allowing for smooth motion.  
 The substantia nigra produces dopamine, which binds the D1 receptors in the striatum, 
inhibiting the globuspallidus, leading to activation of the thalamus and allowing movemen t.

 Also, dopamine binds the D2 receptor, inhibiting the inhibitory pathway. This allows for 
activation of the subthalamic nucleus, inhibition of the globus pallidus internus and 
activation of the thalamus, leading to movement.  
 Inhibition of the globus pallidus is necessary to promote thalamic function. In Parkinso nian 
patients, decreased dopamine leads to increased globus pallidus internus outpu t and 
decreased motion.

decreased motion. 
 Parkinson  Ļ dopamine  Ĺ globus pallidus internus  output  Ļthalamic function  
Ļmotion. 
 Parkinson  Ļ dopamine  Ļactivity at the D1 receptor  Ļexcitatory  pathway,  
 Parkinson  Ļ dopamine  Ļ activity at the D2 receptor  disinhibiting the inhibitory  
pathway  Ĺ globus pallidus internus  output  Ļthalamic function  Ļmotion. 
 Which mechanism underlying the neurodegeneration seen in Parkinson's? 
 Impaired protein degradation

 Impaired protein degradation  
 Mutations in either the parkin gene or UCHL1  lead to impaired protein 
degradation. 
 Alpha-synuclein  is a synaptic protein accumulates in Lewy body dementia and 
Parkinson's disease, 
  
Features 
The classic triad of features: bradykinesia, tremor and rigidity.  
 
The symptoms of Parkinson's disease are characteristically asymmetrical . 
 
 Bradykinesia 
 poverty of movement also seen, sometimes referred to as hypokinesia

 short, shuffling steps with reduced arm swinging 
 difficulty in initiating movement 
 Tremor 
 most marked at rest, 3-5 Hz 
 worse when stressed or tired 
 typically 'pill-rolling', i.e. in the thumb and index finger 
 The tremor of parkinsonism only disappears during REM sleep. 
 Rigidity 
 lead pipe 
 cogwheel: due to superimposed tremor 
 Other characteristic features 
 mask-like facies 
 flexed posture 
 micrographia 
 drooling of saliva 
 psychiatric features:

 psychiatric features:  
 depression is the most common feature (affects about 40%);   
 dementia, psychosis and sleep disturbances may also occur 
 impaired olfaction 
 REM sleep behaviour disorder 
 The most early feature  
 Imperfect abolition of muscle tone during REM sleep. 
 Caused by lesion in the area of the pons responsible for REM  sleep atonia. 
 Patient may seen to kick, laugh, punch or fight invisible enemies during REM sleep.

 Interestingly, the side most affected by Parkinson ’s appear to adopt near normal 
movement during REM sleep.  
 Intestinal pseudo-obstruction 
 common feature of advanced Parkinson ’s  67

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              63 
  results in symptoms of intermittent abdominal bloating and vomiting .  
 
Drug-induced parkinsonism has slightly different features to Parkinson's disease: 
 motor symptoms are generally rapid onset and bilateral 
 rigidity and rest tremor are uncommon  
 
A Lewy body  (stained brown) in a brain cell of the

substantia nigra in Parkinson's disease. The brown 
colour is positive immunohistochemistry staining for 
alpha-synuclein.  
Discoloration of the substantia nigra due to  loss of 
pigmented nerve cells . 
 
Diagnosis 
Parkinson ’s Disease Society Brain Bank diagnostic criteria  for Parkinson ’s disease 
 Step 1. Diagnosis of a parkinsonian syndrome 
 Bradykinesia and at least one of the following: 
 Muscular rigidity 
 Rest tremor (4-6 Hz)

 Rest tremor (4-6 Hz) 
 Postural instability unrelated to primary visual, cerebellar, vestibular, or 
proprioceptive dysfunction 
 Step 2. Exclusion criteria for Parkinson ’s disease 
 History of: 
 Repeated strokes with stepwise progression 
 Repeated head injury 
 Antipsychotic or dopamine-depleting drugs 
 Definite encephalitis or oculogyric crises on no drug treatment 
 More than one affected relative 
 Sustained remission

 Sustained remission 
 Negative response to large doses of levodopa (if malabsorption excluded) 
 Strictly unilateral features after 3 years 
 Other neurological features: supranuclear gaze palsy, cerebellar signs, early 
severe autonomic involvement, Babinski sign, early severe dementia with 
disturbances of language, memory, or praxis 
 Exposure to known neurotoxin 
 Presence of cerebral tumour or communicating hydrocephalus on neuroimaging

 Step 3. Supportive criteria for Parkinson ’s disease 
 Three or more required for diagnosis of definite Parkinson ’s disease: 
68

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              64 
  Unilateral onset 
 Excellent response to levodopa 
 Rest tremor present 
 Severe levodopa-induced chorea 
 Progressive disorder 
 Levodopa response for over 5 years 
 Persistent asymmetry affecting the side of onset most 
 Clinical course of over 10 years. 
  
Investigations

 Single photon Emission Computed Tomography (SPECT) 
 The investigation of choice  
 for people with tremor if essential tremor cannot be clinically differentiated from 
parkinsonism.  
 
Feature most strongly suggest idiopathic Parkinson's disease  The asymmetry of tremor  
 
Parkinson's disease: management  (NICE guidelines 2017)  
 there is no proven neuroprotective or disease-modifying therapy. 
 First-line treatment:

 First-line treatment:  
 if the motor symptoms are affecting the patient's quality of life  levodopa  
 if the motor symptoms are not affecting the patient's quality of life  dopamine agonist 
(non-ergot derived), levodopa or monoamine oxidase B (MAO-B) inhibitor 
 Do not offer  ergot-derived dopamine  agonists as first-line  treatment for Parkinson's disease. 
 second line  
 Adjuvant treatment of motor symptoms (dyskinesia and/or motor fluctuations)   if not

responded despite optimal levodopa therapy  Add non-ergot-derived dopamine 
agonists, MAO-B inhibitors or catechol-O-methyl transferase (COMT) inhibitors  
 Third line  : 
 If dyskinesia is not adequately managed by modifying existing therapy, consider 
amantadine  
 for advanced Parkinson ’s disease, whose symptoms are not adequately controlled by best 
medical therapy  deep brain stimulation.

medical therapy  deep brain stimulation.  
 Whilst all drugs used to treat Parkinson's can cause a wide variety of side-effects NICE produ ced 
tables to help with decision making: 
 
Levodopa Dopamine agonists MAO-B inhibitors 
Motor 
symptoms  More improvement in motor 
symptoms Less improvement in 
motor symptoms Less improvement in motor 
symptoms 
Activities of 
daily living  More improvement in activities 
of daily living Less improvement in

of daily living Less improvement in 
activities of daily living Less improvement in activities 
of daily living 
Motor 
complications  More motor complications Fewer motor 
complications Fewer motor complications 
Adverse 
events  Fewer specified adverse events* More specified adverse 
events* Fewer specified adverse 
events* 
* excessive sleepiness, hallucinations and impulse control disorders 
 
 If a patient continues to have symptoms despite optimal levodopa treatment or has dev eloped

dyskinesia then NICE recommend the addition of a dopamine agonist, MAO-B inhibitor or 
catechol-O-methyl transferase (COMT) inhibitor as an adjunct.  
 
 69

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              65 
  
 NICE summarise the main points in terms of decision making : 
Dopamine 
agonists MAO- B 
inhibitors COMT 
inhibitors Amantadine 
Motor 
symptoms  Improvement in 
motor symptoms Improvement in 
motor symptoms No evidence of improvement 
in motor symptoms 
daily living  Improvement in

daily living  Improvement in 
activities of daily 
living Improvement in 
living No evidence of improvement 
in activities of daily living 
Off time  More off-time 
reduction Off-time reduction Off-time 
reduction No studies reporting this 
outcome 
Adverse events  Intermediate risk 
of adverse events Fewer adverse 
events More adverse 
events No studies reporting this 
outcome 
Hallucinations  More risk of

outcome 
Hallucinations  More risk of 
hallucinations Lower risk of 
hallucinations No studies reporting this 
outcome 
 
Specific points regarding Parkinson's medication  
 Antiparkinsonian medicines should not be withdrawn abruptly  or allowed to fail suddenly due 
to poor absorption (for example, gastroenteritis, abdominal surgery) to avoid the poten tial for 
acute akinesia  or neuroleptic malignant syndrome .

 The practice of withdrawing people from their antiparkinsonian drugs (so called 'drug ho lidays') to 
reduce motor complications should not be undertaken because of the risk of neuroleptic 
malignant syndrome. 
 
 Management of non-motor symptoms of Parkinson ’s dis ease  (NICE 2017)  
 Excessive daytime sleepiness 
 Consider modafinil  
 Rapid eye movement sleep behaviour disorder 
 Consider clonazepam or melatonin 
 Nocturnal akinesia 
 Consider levodopa or oral dopamine agonists

 Consider levodopa or oral dopamine agonists  
 If neither is effective, consider rotigotine 
 Postural hypotension  
 review the person's existing medicines to address possible pharmacological causes, 
including: 
 antihypertensives (including diuretics) 
 dopaminergics 
 anticholinergics 
 antidepressants 
 first line   midodrine  
 alpha agonist   
 monitor for supine hypertension. 
 Second line  fludrocortisone

 Second line  fludrocortisone   
 If midodrine is contraindicated, not tolerated or not effective.  
 Psychotic symptoms (hallucinations and delusions) 
 Do not treat if they are well tolerated. 
 Reduce the dosage of any Parkinson's disease medicines  
 Consider quetiapine  in people without cognitive impairment. 
 If standard treatment is not effective, offer clozapine  
 Lower doses of quetiapine  and clozapine  are needed for people with Parkinson ’s

disease than in other indications 
 Do not  offer olanzapine 
 Dementia 70

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              66 
  cholinesterase inhibitor (rivastigmine, donepezil, or galantamine capsules or rivastigmine 
patches)  
 if cholinesterase inhibitors are not tolerated or contraindicated  Consider memantine  
 Drooling 
 Consider glycopyrronium bromide 
 Anticholinergic 
 reduce excessive saliva (sialorrhea)

 reduce excessive saliva (sialorrhea) 
 does not cross the blood –brain barrier  no central effects. 
 If glycopyrronium bromide is not effective, not tolerated or contraindicated, consider 
referral for botulinum toxin  
 Parkinsonian malignant syndrome  
 Triggered by abrupt withdrawal from anti-parkinsonian medication .  
 The presentation is similar of neuroleptic malignant syndrome  (pyrexia, rigidity, 
tachycardia) but without a history of neuroleptic drug use.

 Re-initiation of Parkinson's therapy is curative . 
 
Parkinson's medication   
 
Levodopa  
  precursor to dopamine , can penetrate the blood brain barrier  and be converted to dopamine 
by amino acid decarboxylase (or dopa decarboxylase) enzyme. 
 peripherally administered dopamine  cannot penetrate the blood brain barrier 
 usually combined with a decarboxylase inhibitor  (e.g. carbidopa or benserazide) to prevent 
peripheral metabolism of levodopa to dopamine

peripheral metabolism of levodopa to dopamine 
 levodopa alone peripheral conversion of levodopa to dopamine significant GI side 
effects such as nausea and vomiting . 
 Levodopa, coupled with carbidopa, remains the gold standard of symptomatic treatm ent for 
Parkinson disease.  
 reduced effectiveness with time (usually by 2 years) 
 side effects:  
 dyskinesia (involuntary writhing movements),  
 dry mouth,  
 anorexia,  
 cardiac arrhythmias  palpitations,

 cardiac arrhythmias  palpitations,  
 postural hypotension ,  
 drowsiness 
 reddish discolouration of urine upon standing 
 psychosis ,  
 hallucinations (usually visual).  
 usually appear late (more than two years after initiation of treatment). 
 The risk for developing psychiatric symptoms increases with:  
 age,  
 other psychiatric conditions,  
 long duration of levodopa treatment , and  
 high doses. 
 no use in neuroleptic induced parkinsonism 
 'on-off' effect,

 'on-off' effect,  
 On/off phenomena may be considerably improved either by the addition of cabergoline (a  
dopamine agonist) or a subcutaneous infusion of apomorphine.  
 Liquid forms of l-dopa may also be helpful as they allow closer titration  of dose, and 
splitting meals into smaller snacks and one larger evening meal also affects the 
pharmacokinetics (PK) of l-dopa positively.  
 
Dopamine receptor agonists 71

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              67 
  
 Non-ergot  
 Ropinirole 
 Apomorphine 
 Pramipexole 
 Rotigotine 
 Ergot-derived dopamine receptor agonists   
 eg: bromocriptine, cabergoline, pergolide  
 not recommended as first-line treatment for Parkinson's disease. 
 Side effects:  
 pulmonary , retroperitoneal and cardiac  fibrosis .

 echocardiogram, ESR, creatinine and chest x-ray should be obtained prior to 
treatment and patients should be closely monitored 
 pergolide was withdrawn from the US market in March 2007 due to 
increased incidence of valvular dysfunction 
 
 impulse control disorders  
 The different types of impulse control disorders (for example, compulsive 
gambling, hypersexuality, binge eating and obsessive shopping).  
 more common with: 
 dopamine agonist therapy

 dopamine agonist therapy 
 history of previous impulsive behaviours 
 history of alcohol consumption and/or smoking 
 can also develop while taking dopaminergic therapies other than dopamine 
agonists.  
 Treatment 
 gradually reducing any dopamine agonist.  
 Monitor for improvement and symptoms of dopamine agonist 
withdrawal.  
  if modifying dopaminergic therapy is not effective  cognitive 
behavioural therapy 
 excessive daytime somnolence

 excessive daytime somnolence 
 If excessive daytime sleepiness develops then:  
 patients should not drive.  
 Medication should be adjusted to control symptoms.  
 Modafinil  can be considered if alternative strategies fail. 
 Psychotic symptoms (hallucinations and delusions) (more likely than levodopa).  
 Nasal congestion 
 postural hypotension. 
 If orthostatic hypotension develops then: 
 medication review for potential causes should be done.

 If symptoms persist then midodrine  (acts on peripheral alpha-
adrenergic receptors to increase arterial resistance) can be 
considered. 
 
MAO-B (Monoamine Oxidase-B) inhibitors 
 e.g. Selegiline 
 inhibits the breakdown of dopamine secreted by the dopaminergic neurons 
Amantadine 
 mechanism 
 not fully understood, probably increases dopamine release and inhibits its uptake at 
dopaminergic synapses 
  Amantadine is a weak antagonist of the NMDA-type glutamate receptor , increases

dopamine release, and blocks dopamine reuptake  
 indications 
72

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              68 
  Amantadine is not a powerful anti-Parkinsonian medication. It is used only in idiopathic 
Parkinson ’s disease 
 if no clinical response is noted, the medication should be withdrawn gradually, not stop ped 
abruptly.  
 side-effects 
 ataxia,  
 slurred speech,  
 confusion, dizziness 
 livedo reticularis

 livedo reticularis 
 peripheral edema and weight 
 should be avoided in congestive heart failure  
COMT (Catechol-O-Methyl Transferase) inhibitors 
 e.g. Entacapone, tolcapone 
 COMT is an enzyme involved in the breakdown of dopamine, and hence may be  used as an 
adjunct to levodopa therapy 
 blocks conversion of dopamine to 3-methoxytyramine. 
 used in conjunction with levodopa in patients with established PD 
Antimuscarinics 
 block cholinergic receptors

 block cholinergic receptors 
 now used more to treat drug-induced parkinsonism rather than idiopathic Parkinson's disea se 
 help tremor and rigidity 
 e.g. procyclidine, benzotropine, trihexyphenidyl (benzhexol) 
 Do not offer anticholinergics to people with Parkinson's disease who have developed dyskinesia 
and/or motor fluctuations.  
 Anticholinergic drugs such as benzhexol  remain the treatment of choice in parkinsonian 
tremor.

tremor. 
 
January 2011 exam : H/O schizophrenia , developed parkinsonism secondary to his antipsychotic 
medication. Which drug is most useful in the management of tremor? Benzhexol  
 
January 2008 exam: What is the mechanism of action of selegiline in Parkinson's disease. ? Monoamine 
Oxidase-B inhibitor  
Progressive supranuclear palsy 
 
 The triad of parkinsonism, vertical gaze palsy and cognitive impairment 
 
Overview

Overview 
 aka Steele-Richardson-Olszewski syndrome  
 a 'Parkinson Plus' syndrome 
Features 
 impairment of vertical gaze (down gaze worse than up gaze - patients ma y complain of difficultly 
reading or descending stairs) 
 parkinsonism 
 falls 
 slurring of speech 
 cognitive impairment  
 also cause pyramidal signs, dementia or frontal lobe syndrome. 
Management  poor response to L-dopa  
Prognosis  Median survival is about seven years.  
 
73

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              69 
 __________________________________________________________________________________________ 
Multiple system atrophy 
 Shy-Drager syndrome is a type of multiple system atrophy. 
 The average age of onset is 50 years (earlier than in Parkinson's disease)  
 the median survival six to nine years.

 the median survival six to nine years. 
  It runs a briefer course than Parkinson's disease. 
 
 Multi-system atrophy includes three syndromes that usually overlap 
1. Strionigral degeneration leading to parkinsonism 
2. Autonomic failure 
3. Olivopontocerebellar degeneration. 
 
Features  
 autonomic disturbance (atonic bladder, postural hypotension) 
 cerebellar signs

 cerebellar signs 
 The unifying pathologic hallmark is  the presence of a-synuclein-positive inclusions  located 
in various brain regions.  
May 2012 exam: A 67-year- old increasing clumsiness + ataxic gait + ĹĹupper limb tone with 
cog-wheel rigidity. Blood pressure is 135/80 lying and 95/70 standing. What is the most 
likely diagnosis? Multiple system atrophy  
 
__________________________________________________________________________________________

Normal pressure hydrocephalus (NPH) 
 
 Normal pressure hydrocephalus is a reversible cause of dementia  seen in elderly patients.  
Mechanism   
 It is thought to be secondary to reduced CSF absorption at the arachnoid villi . 
Causes 
 These changes may be secondary to: 
  head injury,  
 subarachnoid haemorrhage or  
 meningitis 
The classical triad of features is  
1. urinary incontinence 
2. dementia and bradyphrenia 
3. gait abnormality (may be similar to Parkinson's disease)

What is the underlying cause of urinary incontinence in NPH? 
 Inability to suppress voiding 
 The symptoms of NPH are caused by an underlying compression of the 
periventricular white matter tracts  loss of central inhibition of the detrusor muscle 
 strong voiding reflex that cannot be suppressed ( urge incontinence ). 
 The urge incontinence is potentially exacerbated by the functional frontal lobe 
impairment that results from compression, which prevents recognition of the urinary

urge. 
 
Imaging 
 hydrocephalus with an enlarged fourth ventricle   
 the most likely helpful initial managements steps is CSF drainage via repeated lumbar 
puncture  
 ventriculo-peritoneal shunting 
74

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              70 
  
Acute confusional state 
 Acute confusional state is also known as delirium or acute organic brain syndrome.  
 It affects up to 30% of elderly patients admitted to hospital. 
Features  - wide variety of presentations 
 memory disturbances (loss of short term > long term) 
 may be very agitated or withdrawn 
 disorientation

 disorientation 
 mood change 
 visual hallucinations 
 disturbed sleep cycle 
 poor attention 
Diagnosis 
 The Confusion Assessment Method ( CAM ) is the most effective tool in identifying delirium. 
 treatment of underlying cause 
 modification of environment 
 the 2006 Royal College of Physicians publication 'The prevention, diagnosis and mana gement of 
delirium in older people: concise guidelines' recommended haloperidol 0.5 mg a s the first-line 
sedative

sedative 
 the 2010 NICE delirium guidelines advocate the use of haloperidol or olanzapin e 
 
January 2011 exam:  An elderly patient  admitted for UTI, became agitated and aggressive. 
What is the most appropriate management? Haloperidol 0.5 mg orally  
___________________________________________________ __________________________ 
Dementia 
Presence of the e4 allele of apo-lipoprotein E  Alzheimer's disease 
Loss of GABA is seen in  Parkinson's disease.

Loss of GABA is seen in  Parkinson's disease. 
Peri-vascular mononuclear inflammation is seen in  multiple sclerosis. 
Loss of Betz cells is seen in  motor neurone disease. 
 Dementia affect over 700,000 people in the UKT 
 DP43 is a protein that has recently been found to be involved in a multitude of 
neurodegenerative diseases  including dementia  and motor neuron disease.  
 
Common causes of dementia  
 Alzheimer's disease (the most common) ( 50-75% )

 cerebrovascular disease: multi-infarct dementia (c.  20-30% %) 
 Lewy body dementia (c. 10-20%) 
Rarer causes (c. 5% of cases)  
 Huntington's 
 CJD 
 Pick's disease (atrophy of frontal and temporal lobes) 
 HIV (50% of AIDS patients) 
Important differentials, potentially treatable 
 hypothyroidism, Addison's 
 B12/folate/thiamine deficiency 
 syphilis 
 brain tumour 
 normal pressure hydrocephalus 
 subdural haematoma 
 depression 
 chronic drug use e.g. Alcohol, barbiturates

 chronic drug use e.g. Alcohol, barbiturates 
Features  
 diagnosis can be difficult and is often delayed 
 the mini-mental state examination is widely used. A score of 24 or less out of 30 sug gests 
dementia 75

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              71 
  Short term memory impairment is the commonest clinical presentation of Alzheimer's  disease. 
The best way to test short term memory is to ask the patient to recall new information in 
the next few minutes.  
 Long term memory is usually intact. 
 Usually patients are fully orientated in time, person and place.

Distinguishing between normal aging and dementia   
 Memory impairment, occasional difficulties in word finding, and slower cognitive processing are 
normal effects of aging.  
 An important distinguishing factor between normal aging and forms of dementia is the degree to 
which independence with everyday activities is impaired. In normal aging, independence in 
daily activities  is preserved. 
 cognitive exams are within normal limits in aging.

  Alzheimer's disease is often accompanied by behavioral changes (such as aggression, 
depression, insomnia) 
 
 in the 2011 NICE guidelines structural imaging was said to be essential in the investigation of 
dementia 
 MRI to exclude other cerebral pathologies and to help establish the subtype diagnosis.(CT could 
be used, but MRI is better) 
 Perfusion hexamethylpropyleneamine oxime (HMPAO) single-photon emission compu ted

tomography (SPECT) should be used to differentiate Alzheimer's disease, vascular 
dementia and frontotemporal dementia if the diagnosis is in doubt.   
 Vascular dementia   
 typically occurs in those with widespread vascular disease .  
 The course is typically fluctuating with stepwise progression.  
 Differentiation from Alzheimer ’s disease can be difficult, although a history of 
strokes or the presence of focal neurological signs are very suggestive .

 CT or MRI will show  multiple lacunar infarcts 
 does not respond to acetylcholinesterase inhibitors such as donepezil. 
  Vascular dementia caused by lipohyalinosis or microatheroma formation and NOT 
thromboemboli. Therefore, anticoagulation is not indicated.  
 Memory therapy is the best next step in management for this patient's 
confirmed vascular dementia. 
 treatment specific to vascular dementia also includes reduction of

cardiovascular risk factors and, in some cases, anticoagulation.  
 
76

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              72 
 
Progressive impairment in an individual with 
cardiovascular disease, hypertension, 
hypercholesterolemia, and focal neurological 
deficits is suggestive of vascular dementia . 
 
The CT scan of the head confirms this diagnosis 
and shows lacunar infarcts in the frontal region as 
well as hypodense periventricular lesions.

well as hypodense periventricular lesions. 
 
subcortical arteriosclerotic encephalopathy 
(Binswanger's disease) with microangiopathic 
lesions, which are primarly hypodense 
perventricular lesions (shaded areas). The 
arrows point to two lacunar infarcts 
(marginated hypodense areas) in the frontal 
region. 
 
 People with Down's syndrome may show SPECT abnormalities throughout life th at resemble 
those in Alzheimer's disease, so this test is not helpful in this group.

 Cerebrospinal fluid examination should be used if Creutzfeldt –Jakob disease or other forms of 
rapidly progressive dementia are suspected. 
 
Assessing the severity of dementia 
 For people with learning disabilities, tools used: 
 Cambridge Cognitive Examination (CAMCOG)  
 Modified Cambridge Examination for Mental Disorders of the Elderly (CAMDEX)  
 DMR 
 Dementia Scale for Down Syndrome (DSDS), which can be useful in diagnosis of

dementia in people with learning disabilities who do not have Down's syndrome. 
 For others  cognition score 
 in primary care a blood screen is usually sent to exclude reversible causes (e.g. Hypothyroidism). 
NICE recommend the following tests: FBC, U&E, LFTs, calcium, glucose, TFTs, vitamin B12 a nd 
folate levels. Patients are now commonly referred on to old-age psychiatrists (sometimes workin g 
in 'memory clinics'). 77

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              73 
  in secondary care neuroimaging is performed* to exclude other reversible conditions (e.g . 
Subdural haematoma, normal pressure hydrocephalus) and help provide information on 
aetiology to guide prognosis and management 
  memory therapy  is an important component of treatment for all dementias,

 Memory therapy is individualized treatment for dementia that involves improving cognitiv e 
abilities through image recognition, solving math problems, and past memory recall. 
 For the management of Alzheimer's disease, behavioral and environmental regulation , such 
as adhering to a regular sleep schedule , should always be attempted prior to resorting to 
pharmacologic treatment. 
 Frequent travel has been shown to worsen the symptoms of Alzheimer's disease. Main taining a

consistent environment will help orient the patient. 
 
Pharmacological treatment 
 (1) acetylcholinesterase (AChE) inhibitors   
 The three acetylcholinesterase (AChE) inhibitors  donepezil , galantamine and rivastigmine 
are recommended for managing mild to moderate Alzheimer's  disease  
 The only role for cholinesterase inhibitors is to improve some cognitive function and 
improvement in activities of daily living .

improvement in activities of daily living .  
 There is no role for cholinesterase inhibitors in advanced Alzheimer's disease.  
 NICE guidelines recommend discontinuation of cholinesterase inhibitors once the mini men tal 
state examination has fallen below 12.  
 The best option would be to withdraw donepezil and possibly consider memantine, 
which is licensed for use in moderate to severe dementia.  
 Side-effects  of cholinesterase inhibitors  (donepezil)

 GIT: nausea, vomiting or diarrhea 
 Cardiac: bradycardia and, rarely, AV block 
 bladder outflow obstruction  
 rarely, hepatitis 
 
(2) N-methyl-D-aspartate (NMDA)-receptor antagonist  (Memantine)  
 Memantine , is a novel N-methyl-D-aspartate (NMDA)-receptor antagonist affects the 
transmission of glutamate   
 Memantine  is recommended for managing Alzheimer's disease for people with: 
 moderate Alzheimer's disease who are intolerant of or have a contraindication to AChE

inhibitors or 
 severe Alzheimer's  disease. 
 It has numerous drug interactions : 
 Other NMDA-receptor antagonists (eg ketamine, amantadine ): increased risk of 
psychosis 
 Dopamine agonists, L-dopa and anticholinergics: enhanced effects  
 Antispasmodics (eg baclofen): enhanced effects, as memantine has some antispasmo dic 
effects 
 Drugs excreted by cationic transporters in the kidney (eg quinine, cimetidine, ranitidine): 
reduced excretion, therefore higher plasma concentrations

(It inhibits renal excretion of ranitidine) 
 
Control of violence, aggression and extreme agitation  
 oral medication should be offered before parenteral medication  
 If parenteral treatment is necessary, (IM) route should be preferred because it is safe r than (IV).  
 (IM) lorazepam, haloperidol or olanzapine should be used.  
 
 Reversible causes of impaired memory : 
 Serum Vitamin B12 levels and  
 thyroid function tests 
 
 78

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              74 
  
Alzheimer's disease  
 Alzheimer's disease is a progressive degenerative disease of the brain  
 accounting for the majority of dementia seen in the UK 
 typically first affects the temporal and parietal lobes 
 Temporal lobe  degeneration results in memory loss (misplaced keys, leaving the stove

on) and language deficits (word-finding difficulties),  
 whereas parietal  lobe degeneration results in spatial navigation problems (getting lost 
during walks outside) 
Genetics  
 most cases are sporadic 
 5% of cases are inherited as an autosomal dominant trait 
 mutations in the (APP gene) Amyloid Precursor Protein (chromosome 21), presenilin 1 
(chromosome 14) and presenilin 2 (chromosome 1) genes are thought to cause the inheri ted 
form

form 
 apoprotein E allele E4 - encodes a cholesterol transport protein 
What is the primary anatomical target of Alzheimer ’s disease?  Cerebral cortex  
 Alzheimer's disease is a form of "cortical" type  of dementia that targets primarily the central 
cholinergic nuclei (e.g., the nucleus basalis of Myenert). 
  The “sub-cortical type ” of dementia occurs in Huntington's disease, advanced Wilson's 
disease, and advanced multiple sclerosis 
Pathological changes

Pathological changes 
 What kind of pathological deposits  are most likely to be present in the brain of 
Alzheimer's?  Amyloid plaques 
 macroscopic: widespread cerebral atrophy, particularly involving the cortex and hippocampus  
 microscopic: cortical plaques due to deposition of type A-Beta-amyloid protein and in traneuronal 
neurofibrillary tangles caused by abnormal aggregation of the tau protein

 biochemical: there is a deficit of acetylecholine from damage to an ascending for ebrain projection 
 Patients with Alzheimer disease have reduced production of choline acetyl transferase,  
leading to  a decrease in acetylcholine synthesis and impaired cortical cholinergic functioning. 
 evidence shows that excessive activation of the NMDA (N-methyl-D-aspartate) recepto r may play 
a role in the pathogenesis of AD.  
Neurofibrillary tangles

Neurofibrillary tangles 
 Neurofibrillary tangles are a pathological feature of Alzheimer's  
 paired helical filaments are partly made from a protein called tau 
 in AD are tau proteins are excessively phosphorylated 
Features 
 The amnestic presentation is the most common syndromic presentation of AD dementia.  
 The deficits should include:  
1. impairment in learning and recall of recently learned information,  
2. and a deficit from another domain, such as the visuospatial domain

(recognizing a family member). For example, he was unable to learn/recall a 
major family event.  
Investigation 
 MRI scan in Alzheimer   symmetrically increased size of the lateral ventricles  along with 
cerebral cortical atrophy  in a mainly frontal and parietal distribution. 
 
 NICE now recommend the three acetylcholinesterase inhibitors (donepezil, galantamine and 
rivastigmine) as options for managing mild to moderate Alzheimer's disease

  A well-known side effect of rivastigmine is AV block 
 memantine (a NMDA receptor antagonist) is reserved for patients with moderate - severe 
Alzheimer's 
Mild cognitive impairment (MCI)  is typically someone forgetting things and then remembering 
later in the day. Some patients may describe it as the 'ageing process', and th e complaints are 
typically vague. The presence of a second domain such as deficit of the visuospatial domain

suggest a diagnosis of Alzheimer's disease and rules out MCI. 
 79

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              75 
  
Aggression in Alzheimer's disease  
 Ideally, aggression in Alzheimer's disease should be managed with non-drug approa ches, aiming 
to identify and avoid triggers and finding behavioural techniques which manage the sympto ms. 
However, sometimes drug treatment is required.

However, sometimes drug treatment is required. 
 Atypical neuroleptics, such as quietapine, and haloperidol are not recommended as there is an 
increased risk of death or stroke. There is also concern that these agents may contribute to 
cognitive decline, and it is recognised that symptoms often relapse after cessation of haloperidol.  
 However, risperidone has been tested in this setting and is licensed for 6 weeks treatment

of persistent aggression in those with moderate to severe Alzheimer's disease , providing 
that non-pharmacological alternatives have been tried and there is a risk of harm.  
 Valproate has been widely used for its calming effects in this situation, but there is little  evidence 
of the efficacy of valproate. 
 Benzodiazepines are not recommended, as they can impair alertness and increase  daytime

sleepiness (thereby increasing the risk of falls), and are also associated with worsening cognitive 
decline.  
Lewy body dementia 
 
 Lewy body dementia is an increasingly recognised cause of dementia, accounting for up  to 20% 
of cases.  
 The characteristic pathological feature is alpha-synuclein cytoplasmic inclusions (Lewy bodies) in 
the substantia nigra, paralimbic and neocortical areas

 The relationship between Parkinson's disease and Lewy body dementia is complicated, 
particularly as dementia is often seen in Parkinson's disease. Also, up to 40% of patients with 
Alzheimer's have Lewy bodies 
 It should be distinguished from Parkinson's disease with dementia (PDD), which is diagnosed 
when the dementia onset is more than a year after the onset of Parkinson's. Lewy body 
dementia is diagnosed when the cognitive symptoms begin at the same time or within a

year of Parkinsonism.  
 Neuroleptics should be avoided in Lewy body dementia , as patients are extremely sensitive 
and may develop irreversible parkinsonism.  
 Questions may give a history of a patient who has deteriorated following the intro duction 
of an antipsychotic agent 
 The most appropriate therapeutic strategy with respect to maintaining his mobility is 
 Stop dopamine-blocking drugs (causing significant parkinsonism) eg: 
quetiapine   
Features

Features  
 progressive cognitive impairment 
 visual hallucinations (other features such as delusions and non-visual hallucinations may al so be 
seen) 
Other feature 
 Intermittent confusion 
 Myoclonus, and 
 Marked sensitivity to neuroleptic treatment. 
Diagnosis 
 usually clinical 
 single-photon emission computed tomography (SPECT) is increasingly used. It is currently

commercially known as a DaTscan. Dopaminergic iodine- 123-radiolabelled 2-carbomethoxy-3-
80

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              76 
 (4-iodo phenyl)-N- (3-fluoropropyl) nortropane (123-I FP-CIT) is used as the radioisotope. The 
sensitivity of SPECT in diagnosing Lewy body dementia is around 90% with a specificity of 100% 
Haloperidol   contra-indicated in Lewy body dementia 
Treatment

Treatment  
 The treatment of choice is rivastigmine, which improves both the visual hallucinations, an d 
cognitive impairment.  
 
September 2013 exam: A 78-year-old man with memory impairment, hallucinations,  resting tremor, 
festinating gait and an expressionless face. He scores 12 / 30 on the mini-mental state exam ination 
(MMSE). which test is most likely to confirm the diagnosis? SPECT scan (Lewy body dementia)

September 2006 exam:  H/O parkinsonian symptoms + agitation. deteriorated after 
prescribing haloperidol. What is the most likely underlying diagnosis? Lewy body dementia  
Frontotemporal lobar degeneration 
 Frontotemporal lobar degeneration (FTLD) is the third most common type of cortical demen tia 
after Alzheimer's and Lewy body dementia.

after Alzheimer's and Lewy body dementia.  
 Characterised by loss of 'executive' functions and multi-infarct state, usually has a step- wise 
history. 
 Although frontotemporal dementia is associated with chromosome 17 , when there is 
motor neurone disease (MND) associated the chromosome linked to the disorder is 9.   
 FTD-MND or FTS-ALS has been linked to chromosome 9. 
 C9ORF72 is associated with an autosomal dominant inheritance of motor neurone disease 
and frontotemporal dementia

and frontotemporal dementia 
 Frontotemporal dementia (FTD) start initially  in the orbitofrontal cortex and anterior 
cingulate regions of the frontal lobes  
 
 There are three recognised types of FTLD 
 Frontotemporal dementia (Pick's disease) 
 Progressive non fluent aphasia (chronic progressive aphasia, CPA) 
 Semantic dementia 
 
Common features of frontotemporal lobar dementias 
Onset before 65 
Insidious onset 
Relatively preserved memory and visuospatial skills

Personality change and social conduct problems 
 
Pick's disease   
 This is the most common type of frontotemporal dementia 
  characterised by personality change and impaired social conduct.  
 Other common features include hyperorality, disinhibition, increased appetite, and perseveratio n 
behaviours. 
 Focal gyral atrophy with a knife-blade appearance is characteristic of Pick's disease. 
 Macroscopic changes  seen in Pick's disease include:-

 Atrophy of the frontal and temporal lobes 
 Microscopic changes  include:- 
 Pick bodies - spherical aggregations of tau protein  (silver-staining) 
 Gliosis 
 Neurofibrillary tangles 
 Senile plaques 
CPA   
 Here the chief factor is non fluent speech. They make short utterances that are a grammatic. 81

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              77 
  Comprehension is relatively preserved. 
Semantic dementia   
 Here the patient has a fluent progressive aphasia. The speech is fluent but empty an d conveys 
little meaning.  
 Unlike in Alzheimer's memory is better for recent rather than remote events.  

Frontal lobe syndrome  
 Frontal lobe syndrome usually presents with 
 Personality changes 
 Urinary and faecal incontinence 
 Anosmia 
 Expressive dysphasia (dominant lobe) 
 Release of primitive reflexes (positive grasp, pout and palmomental reflexes) and 
 Epilepsy. 
 50% of patients presenting with status epilepticus (with no previous history of seizures) have 
frontal lobe tumour. 
 It can mimic dementia. 

Permanent vegetative state (PVS) 
 defined as a state of 'wakefulness without awareness'. 
 The condition typically occurs when there is irreversible damage to the cerebral hemisphe res but 
the brain stem remains intact. 
Causes  include 
 Head injury 
 Hypoxic injury (cardiac arrest, carbon monoxide poisoning) 
 Stroke 
 Hypoglycaemia 
 Intracranial infection 
 End-stage degenerative brain disease (for example, Alzheimer's). 
Features

Features 
 The patient breathes spontaneously without mechanical support, is haemodynam ically stable 
and has cycles of eye closure and opening that resemble a normal sleeping pattern but the 
patient is inattentive and unaware of his/her surroundings.  
 Patients may have spontaneous movements (moaning, grunting, teeth grinding, roving eye 
movements) and may also smile, laugh and cry without any apparent reason.

 Although there may be eye movement, the eyes do not track a moving object.  
 Patients may respond to painful stimuli and may have myoclonus in response to sta rtling stimuli.  
 Primitive reflexes may be present.  
 Posture may become decorticate  
 plantar responses are commonly extensor. 
_____________________________________________________________ 
Creutzfeldt-Jakob disease (CJD) 
 Creutzfeldt-Jakob disease (CJD) is rapidly progressive  neurological condition  caused

by prions that are resistant to degradation by proteases due to misfolding int o beta-pleated 
sheets. 
 prion is an incorrectly folded protein  that causes misfolding  of other proteins. 
 CJD is the most common prion disease in humans.  
Types 
1. Sporadic ( ∼ 85%): no identifiable cause 
2. Familial ( ∼ 10–15%): various mutations in the PRNP gene 
3. Acquired (< 1%) 
 Iatrogenic CJD : transmission during medical procedures (e.g., via organ transplantation,

blood transfusion) 
 Variant CJD (vCJD):  by ingestion of beef infected with bovine spongiform 
encephalopathy (BSE)  82

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              78 
  (BSE is a transmissible prion disease occurring in cattle. Infection leads to vCJD in 
humans.) 
 Caused by prion proteins.  
 These proteins induce the formation of amyloid folds resulting in tightly packed beta-
pleated sheets resistant to proteases. 
 Prions proteins lead to neurodegeneration

 Prions proteins lead to neurodegeneration 
 results from the conversion of an a-helix in a normal protein, termed prion 
protein (PrPc), to a ß-pleated form.  The new ß-pleated protein (PrPSc) resists 
degradation and facilitates conversion of normal proteins to the abnormal form.  
  accumulation of abnormal ß-pleated prion protein (PrPSc) results in "spongiform 
encephalopathy,"  
 the 'prion protein' is encoded on chromosome 20 - it's role is not fully understood

 methionine homozygosity at codon 129 of the prion protein is a risk factor for developing  
CJD - all patients who have so far died have had this  
  iatrogenic CJD cases in 1985 resulting from: 
  cadaveric tissue product ( cadaveric human growth hormones )  
 infected neurosurgical instrumentation  
 Change in practice has caused a fall in the numbers of iatrogenic CJD, although 
with possible incubation up to 30 years, cases may still present.

What is the agent responsible for variant Creutzfeldt-Jakob disease (CJD)? 
 Proteinaceous infectious particle (prion protein)  
 
Features 
Rapidly progressive dementia  and myoclonic  jerks  are the hallmarks of Creutzfeldt-Jakobdisease 
 
 progressive mental deterioration (100%); dementia (rapid onset) 
 myoclonus  or movement disorder (100%);  
 cerebellar signs (70%);  
 pyramidal weakness (62%); and  
 behavioural abnormality (55%).  
 
Differential diagnosis

 distinguished from other causes of dementia by its rapidly progressive course (patients usually 
die within one year of symptom onset), prominent myoclonus (especially provoked by  startle), 
and prominent gait disturbance. 
 
Investigation  
 CSF is usually normal 
 14-3-3 protein analysis may be useful in confirming a diagnosis of sporadic CJD. 
 elevation of IgG 
 EEG: biphasic, high amplitude sharp waves (only in sporadic CJD)

 EEG is usually normal in new variant CJD. 
 MRI: hyperintense signals  in the basal ganglia and thalamus 
 Brain biopsy 
 diagnostic for CJD, but the combination of MRI, EEG and lumbar puncture is usually 
sufficient to make the diagnosis in life. 
 the main histologic features are: 
 spongiform change,  
 neuronal loss without inflammation, 
 accumulation of the abnormal prion protein, 
 Amyloid plaques ( vCJD ) 83

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              79 
  Histologic features that distinguish vCJD  from CJD include the presence 
of amyloid plaques staining for PrPsc, which have eosinophilic centers and 
pale peripheries. 
 
Sporadic CJD 
The rapidly progressive neurological impairment, with myoclonus and hyper-reflexia coupled

with EEG abnormality and MRI changes in the caudate and putamen, is most consistent with 
sporadic CJD. 
 Sporadic CJD has an annual incidence of around 1 per million. 
 accounts for 85% of cases 
 10-15% of cases are familial 
 mean age of onset is 65 years  
 Presence of 14-3-3 protein in cerebrospinal fluid would support this diagnosis. 
 
New variant vCJD 
 younger patients (average age of onset = 25 years)

 psychological symptoms  such as anxiety, withdrawal and dysphonia are  the most common 
presenting features  
 Ataxia and involuntary movements (for example, myoclonus) usually appear at an interv al of 
about six months after the initial symptoms. 
 associated primarily with change in the posterior thalamus on MRI. 
 MRI brain typically shows bilateral pulvinar (posterior thalamic nuclei) high signals. 
 EEG is usually normal in new variant CJD.

 Testing for the 14-3-3 protein marker in (CSF) has a diagnostic sensitivity of around  80% 
 Sometimes, it is possible to isolate prion proteins from tonsillar tissue  
  produces a characteristic abnormality in brain tissue called " florid plaques " 
 median survival = 13 months 
 
Other prion diseases 
 kuru 
 fatal familial insomnia 
 Gerstmann Straussler-Scheinker disease

 Gerstmann Straussler-Scheinker disease 
 
The characteristic neuropathologic profile of variant CJD in both the cerebellum and cerebrum,  
by immunohistochemical analysis: 
 numerous kuru-type amyloid plaques surrounded by vacuoles and prion protein (PrP).  
 
Treatment 
 No curative therapy available 
 Symptomatic treatment and eventually palliative care 
Prognosis 
 Following disease manifestation, most patients die within 12 months, usually from comp lications 
such as pneumonia

such as pneumonia 
Cerebro-tendinous xanthomatosis  
 inherited conditio n, 
 associated with accumulation of cholesterol in tissues including brain, peripheral nerve and 
tendons  
 clinical picture : 
 Early onset dementia 
 Gait ataxia 
 Loss of vibration sense 
 Cataracts 
 Large tendon xanthomata. 84

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              80 
  Diagnosis 
 there is a deficiency in sterol storage, 
 diagnosis is based on high serum (and tendon) cholesTANOL .  
 cholestanol  is a derivative of cholesterol.  
 Serum cholesterol may be normal or low. 
 It is eminently treatable by the oral administration of chenodeoxycholic acid.

Transient global amnesia 
Overview 
 presents with transient loss of memory function 
 patients may appear anxious and repeatedly ask the same question 
 patients have no recall of events after the attack 
 aetiology is unknown, thought to be due to transient ischaemia to the thalamus  (in particular the 
amygdala and hippocampus) 
Risk factors  
 usually affects people over the age of 50 
 Migraine in younger patients (<55y)

 Migraine in younger patients (<55y) 
 Psychological and vascular risk factors  
 after a venous congestion in the context of insufficient jugular-vein valves. 
 Epilepsy can present with discreet episodes of amnesia. This syndrome is called transient 
epileptic amnesia.   
 Features that suggest epilepsy are;  
 shorter duration (should be less than 1 hour),  
 multiple attacks,  
 onset on waking from sleep

 onset on waking from sleep  
 accompanying epileptic features - e.g. motor automatism, stereotyped behaviours, 
limb shaking. 
Diagnostic criteria  are as follows; 
 discrete episode lasting for a few hours (always less than 24 hours) of anterograde am nesia, 
retrograde amnesia,  
 repetitive questioning  
 Normal perception  
 absence of other cognitive or neurological impairments. 
 absence of head trauma or loss of consciousness at the onset  
 preserved personal identity

 preserved personal identity  
 absence of epileptic features. 
 Patients are usually disoriented in time and place, but not usually person.  
 Attack is often associated with headache, nausea and dizziness.  
  Other associated features are chills, fear of death, paraesthesia, emotional u pset and chest 
pain. 
 Recurrence is unusual. 
 the best line of management    Admit for observation

 The great majority of patients recover within 24 hours and do not get further such episodes.  
 No treatment is needed except observation until recovery. 
 Imaging is considered if amnesia does not resolve after 24 hours. 
_____________________________________________________________
Restless legs syndrome  
 
 Restless legs syndrome (RLS) is a syndrome of spontaneous, continuous lower limb moveme nts 
that may be associated with paraesthesia.

that may be associated with paraesthesia. 
  It is extremely common, affecting between 2-10% of the general population. 
85

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              81 
   Males and females are equally affected and a family history may be present  
 
Clinical features  
 uncontrollable urge to move legs (akathisia). Symptoms initially occur at night but as conditio n 
progresses may occur during the day. Symptoms are worse at rest 
 paraesthesias e.g. 'crawling' or 'throbbing' sensations

 movements during sleep may be noted by the partner - periodic limb mov ements of sleeps 
(PLMS) 
Causes and associations 
 there is a positive family history in 50% of patients with idiopathic RLS 
 iron deficiency anaemia (a low serum ferritin is most likely to be a cause of secondary 
restless legs syndrome)  
 associated with nutritional deficiencies of folate, magnesium, iron 
 uraemia (end stage renal failure) ,  
 COPD,  
 gastric surgery,

 COPD,  
 gastric surgery,  
 chronic venous insufficiency,  
 hypothyroidism  
 drugs  such as beta-blockers, H2 antagonists or neuroleptics.  
 It can be exacerbated by diuretics, tricyclics, phenytoin and calcium antagonists. 
Diagnosis  is clinical although bloods to exclude iron deficiency anaemia may be appropriate 
 Although no specific tests exist for the diagnosis it is based on the international restless legs

syndrome study group four basic criteria for diagnosing RLS: 
1. A desire to move the limbs, often associated with paraesthesias or dysaesthesias 
2. Symptoms that are worse or present only during rest and are partially or temporarily 
relieved by activity 
3. Motor restlessness, and 
4. Nocturnal worsening of symptoms. 
 
 simple measures: walking, stretching, massaging affected limbs 
 treat any iron deficiency

 treat any iron deficiency 
 dopamine agonists  are first-line treatment (e.g. Pramipexole, ropinirole ) 
 Anti-convulsants such as sodium valproate being effective second line agents.   
 benzodiazepines 
 gabapentin 
 Pramipexole and rotigotine are also licensed for moderate to severe restless legs. 
Essential tremor  
Essential

Essential 
tremor (previously called benign essential tremor) is an autosomal dominant condition which u sually 
affects both upper limbs 
 
Features  
 postural tremor: worse if arms outstretched 
 improved by alcohol and rest 
 most common cause of titubation (head tremor) 
 propranolol is first-line 
 primidone is sometimes used 
 
86

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              82 
  
January 2013 exam: H/O involuntary movements of the head, worse on movement and during stress 
and relieved by alcohol and sleep. What is the most likely diagnosis?  Essential tremor (Essential 
tremor is the most common cause of titubation (head tremor).

January 2015 exam: H/O tremor of the arms, which is worse when arms are outstretched. His fathe r 
suffered from a similar complaint. What is the most suitable first-line treatment? Propranolol  
 
Friedreich's ataxia 
Genetics 
  autosomal recessive ,  
 trinucleotide repeat disorder   
 characterised by a GAA repeat in the  X25 gene  on chromosome 9  (frataxin ).  
 Friedreich's ataxia is unusual amongst trinucleotide repeat disorders in not demonstrating the

phenomenon of anticipation. 
 the most common early-onset hereditary ataxias. 
 The typical age of onset is 10-15 years old.  
 The posterior columns, corticospinal and spinocerebellar tracts are affected leading to 
cerebellum dysfunction, spastic paraparesis and absent reflexes in lower limbs. 
 Gait ataxia and kyphoscoliosis are the most common presenting features. 
 
Neurological features  
 absent ankle jerks/extensor plantars 
 cerebellar ataxia

 cerebellar ataxia 
 optic atrophy 
 spinocerebellar tract degeneration 
Other features 
 hypertrophic obstructive cardiomyopathy (90%, most common cause of death) 
 diabetes mellitus (10-20%) 
 high-arched palate 
 Bilateral pes cavus  
 kyphoscoliosis  
Diagnosis 
 definitive diagnosis  Genetic testing for expansion of the GAA triplet repeat  in the FXN gene 
  Other diagnostic tests suggestive of Friedreich ataxia include:

 nerve conduction studies showing absent or reduced sensory nerve action potentia ls, 
 MRI of the brain and spinal cord revealing cervical spine atrophy with minimal 
cerebellar atrophy. 
 
 87

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              83 
  
Ataxic telangiectasia 
 autosomal recessive disorder 
 caused by a defect in the ATM gene  which encodes for DNA repair enzymes . 
 It is one of the inherited combined immunodeficiency disorders. 
 It typical presents in early childhood with abnormal movements. oculomotor apraxia and 
choreoathetosis developing later.

choreoathetosis developing later.  
 
Features  
 telangiectasia (spider angiomas) 
 IgA deficiency  resulting in recurrent chest infections  bronchiectasis  
 10% risk of developing malignancy, lymphoma or leukaemia, but also non-lympho id tumours 
Diagnosis 
 Elevated serum alpha-fetoprotein , at least two standard deviations above the normal range, is 
diagnostic of ataxia-telangiectasia 
 confirmed by the identification of mutations on the ATM gene. 
Prognosis

Prognosis 
  Death in the late teens or 3rd decade from bronchiectasis  is typical.  
Sleep 
 
Sleep Stage  Description  EEG Waveform  
   Awake and alert  Beta 
   Awake and eyes closed  Alpha 
Stage N1  Light sleep  Theta 
Stage N2  Deeper sleep  Sleep spindles and K 
complexes 
Stage N3  Deepest non-REM sleep 
 Sleepwalking 
 Night terrors 
 Bedwetting   Delta  
REM  Dreaming  Beta

REM  Dreaming  Beta 
 
 Suprachiasmastic nucleus of the hypothalamus is involved in circadian rhythm regulation 
 GABA agonists (alcohol, benzodiazepines, and barbiturates) reduce REM and delta sleep 
 REM Sleep:  
 Physiology 
 rapid eye movement 
 same EEG pattern as when awake 
88

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              84 
  erection 
 Ĺ and variable pulse and blood pressure  
 loss of muscle tone 
 Timing 
 occurs every 90 min 
 duration Ĺ with every cycle  
 amount of REM sleep Ļ with age  
 acetylcholine is the principle neurotransmitter 
 norepinephrine, serotonin, and histamine suppress REM sleep

 therefore, certain antidepressants (eg, SSRI, SNRI) can pharmacologically 
suppress REM sleep 
 
Sleep paralysis 
 Mechanism is believed to involve a dysfunction in REM sleep. 
 Between 8% and 50% of people experience sleep paralysis at some time. 
 5% of people have regular episodes. 
 Males and females are affected equally.  
 Feature 
 aware but unable to move. 
 may include 
 hallucinations 
 fear. 
 Episodes generally last less than a couple of minutes.

 Associations 
 may occur in those who are otherwise healthy, 
 narcolepsy 
 familial 
 can be triggered by sleep deprivation, psychological stress, or abnormal sleep cycles 
 Diagnosis is based on a person's description. 
 Differential diagnosis 
 narcolepsy,  
 atonic seizure, and  
 hypokalemic periodic paralysis. 
 reassured that the condition is common and not serious. 
 Other options that may be tried include sleep hygiene, cognitive behavioral the rapy,

and antidepressants. 
Narcolepsy  
 Due to loss of orexin (hypocretin) neuropeptides  
 normally produced in the lateral hypothalamus. 
 associated with wakefulness  
 About one-third of all patients have a family history of the disorder.  
 There is a strong HLA association; about 95% of white people with narcolepsy are positive 
for the DRw16 subtype of DR2.

for the DRw16 subtype of DR2.  
 The MSLT will demonstrate rapid eye movement (REM) sleep at sleep onset, or sho rtly 
after the onset of sleep, in those with narcolepsy. 
 Triad of:  
1.  sleep paralysis,  
2. excessive daytime somnolence and  
3. cataplexy.  
 About 5% of patients with narcolepsy have cataplexy. 
 may include hallucinations 
 hypnagogic 
 just before sleep 
 hypnopompic 
 just before awakening 
 Diagnosis  89

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              85 
  Diagnosis is a clinical one, supported by an  overnight polysomnogram  and multi sleep 
latency test.  
 Non-amphetamine based stimulants, such modafinil,  are the treatment of choice. 
 
Cataplexy 
 Cataplexy describes the sudden and transient loss of muscular tone caused by strong em otion

(e.g. laughter, being frightened).  
 Features range from buckling knees to collapse.  
 Longer episodes can be associated with hallucinations.  
 Around two-thirds of patients with narcolepsy have cataplexy.  
 
Head injury 
Head injury: NICE guidance 
 
CT head immediately  (within the one hour  ) 
 GCS < 13 on initial assessment 
 GCS < 15 at 2 hours post-injury

 GCS < 15 at 2 hours post-injury 
 suspected open or depressed skull fracture. 
 any sign of basal skull fracture (haemotympanum, 'panda' eyes, cerebrospinal fluid lea kage from 
the ear or nose, Battle's sign). 
 post-traumatic seizure. 
 focal neurological deficit. 
 more than 1 episode of vomiting 
 
CT head scan within 8 hours of the head injury  - for adults with any of the following risk factors who 
have experienced some loss of consciousness or amnesia since the injury:

 age 65 years or older 
 any history of bleeding or clotting disorders 
 dangerous mechanism of injury (a pedestrian or cyclist struck by a motor vehicle, an occupant 
ejected from a motor vehicle or a fall from a height of greater than 1 metre or 5 s tairs) 
 more than 30 minutes' retrograde amnesia of events immediately before the head injury 
 If a patient is on warfarin perform a CT head scan within 8 hours of the injury  regardless

of whether he have risk factors for an intracranial injury. 
 
Battle's sign (mastoid ecchymosis) 
 bruising over the mastoid process, as a 
result of extravasation of blood along the 
path of the posterior auricular artery.  
 is an indication of fracture of middle cranial 
fossa of the skull,  
 take at least one day to appear after the 
initial traumatic basilar skull fracture  
 
Head injury: types of traumatic brain injury 
Basics

Basics 
 primary brain injury may be focal (contusion/haematoma) or diffuse (diffuse axonal injury) 
 diffuse axonal injury occurs as a result of mechanical shearing following deceleration, c ausing 
disruption and tearing of axons 
90

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              86 
  intra-cranial haematomas can be extradural, subdural or intracerebral, while contusions may 
occur adjacent to (coup) or contralateral (contre-coup) to the side of impact 
 secondary brain injury occurs when cerebral oedema, ischaemia, infection, tonsillar or tentorial 
herniation exacerbates the original injury.

herniation exacerbates the original injury.  
 The normal cerebral auto regulatory processes are disrupted following trauma rendering th e 
brain more susceptible to blood flow changes and hypoxia 
 the Cushings reflex (hypertension and bradycardia) often occurs late and is usually a pre 
terminal event 
 
Type of 
injury Notes 
Extradural 
(epidural) 
haematoma   Bleeding into the space between the dura mater and the skull.

  Often results from acceleration-deceleration trauma or a blow to 
the side of the head.  
 The majority of epidural haematomas occur in the temporal region 
where skull fractures cause a rupture of the middle meningeal 
artery . 
Features  
 
 features of raised intracranial pressure 
 some patients may exhibit a lucid interval (apparent recovery from 
the initial concussion, but deterioration is usually within 15- 30 
minutes). 
Subdural

minutes). 
Subdural 
haematoma  Bleeding into the outermost meningeal layer. Most commonly occur 
around the frontal and parietal lobes. 
 
Risk factors include old age, alcoholism and anticoagulation. 
 
Slower onset of symptoms than a epidural haematoma. 
Subarachnoid 
haemorrhage  Usually occurs spontaneously in the context of a ruptured cerebral 
aneurysm but may be seen in association with other injuries when a 
patient has sustained a traumatic brain injury 
 
91

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              87 
 Extradural (epidural) haematoma:   
Subdural haematoma  
 
92

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              88 
 Subarachnoid haemorrhage: 
 
Subdural haemorrhage 
  
The history of progressive 'confusion' and unsteadiness for some weeks followed by an acute 
exacerbation is a typical presentation of a subdural haematoma in the elderly population. 
Basics

Basics 
 most commonly secondary to trauma e.g. old person/alcohol falling over 
 initial injury may be minor and is often forgotten 
 caused by bleeding from damaged bridging veins between cortex and venous sinuse s 
 The phrase 'fluctuating conscious level' is common in questions and should always bring to m ind 
subdural haemorrhage 
 The combination of falls, alcohol excess, fluctuating episodes of confusion and focal n eurology 
points towards a diagnosis of subdural haemorrhage.

Features 
 headache ( The most common presenting symptom , seen in up to 80% of patients)  
 classically fluctuating conscious level 
 raised ICP   bilateral papilloedema  
Other common symptoms  are: 
 fatigue 
 memory impairment 
 confusion 
 nausea and vomiting 
 impaired vision, and 
 seizures. 
 Hemiparesis, or paralysis is also possible. 
Treatment 
 needs neurosurgical review ? burr hole 
 
93

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              89 
  
Acute subdural haematoma 
 usually results from acute head trauma 
 The haematoma accumulates between the surface of the brain and the dura m ater. 
 The mortality rate ranges between 50% and 90%.  
 A good outcome is most likely if surgical evacuation of the haematoma is prompt and 
secondary brain injury is prevented.

secondary brain injury is prevented.  
 Mortality is less likely in: 
 younger adults 
 patients with a GCS score above 6 or 7 
 those with pupil reactivity, and 
 those without cerebral contusions or uncontrolled rises in intracranial pressure. 
 
Subarachnoid haemorrhage (SAH) 
 Vascular malformations and aneurysms typically bleed in the subarachnoid space.  
Causes

Causes 
 85% are due to rupture of berry aneurysms (conditions associated with berry aneurysms includ e 
adult polycystic kidney disease, Ehlers-Danlos syndrome and coarctation of the aorta) 
 AV malformations (Cerebral aneurysms are associated with polycystic kidney disease ) 
 trauma 
 tumours 
 
 CT: negative in 5% 
 lumbar puncture: done after 12 hrs (allowing time for xanthochromia to develop)

 Lumbar puncture (LP) is not usually required unless the history is suggestive and the  CT is 
normal.  
 If CT image shows blood in the subarachnoid space, the most appropriate next 
investigation is  CT cerebral angiography  to look for an underlying aneurysm or vascular 
malformation which may be amenable to neurosurgical intervention.  
 
Intracranial hemorrhage  ECG changes: 
 deep  symmetrical T- wave inversion  
 prolonged QT interval 
Complications 
 rebleeding (in 30%)

 rebleeding (in 30%) 
 obstructive hydrocephalus (due to blood in ventricles) 
 vasospasm leading to cerebral ischaemia 
What is the most appropriate minimum interval between neurological observations in the first 
instance? Answer  30 min  
 neurosurgical opinion: no clear evidence over early surgical intervention against delayed 
intervention 
 Patients presenting following sub arachnoid haemorrhage may suffer from cerebral v asospasm.

Vasospasm occurs in approximately 30% of patients. it may result in further ischemia due to a 
reduction in distal blood flow. All patients are prescribed a calcium channel blocker (eg 
Nimodipine) to prophylactically prevent this.  
 post-operative nimodipine (e.g. 60mg / 4 hrly, if BP allows) has been shown to  reduce the 
severity of neurological deficits but doesn't reduce rebleeding* 
 *the way nimodipine  works in subarachnoid haemorrhage is not fully understood. It has

been previously postulated that it reduces cerebral vasospasm  (hence maintaining 
cerebral perfusion) but this has not been demonstrated in studies 
 94

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              90 
  
CT image shows diffuse subarachnoid 
haemorrhage in all basal cisterns, bilateral 
sylvian fissures and the inter-hemispheric 
fissure. This case demonstrates the typical 
distribution that takes the blood into the 
subarachnoid space in a subarachnoid 
hemorrhage. 
 
95

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              91 
  
Comparison of Intracranial Haemorrhage 
Feature  Subarachnoid  Subdural  Extradural  
Location  The inner most layer 
around the brain tissue  
  Between the dura mater and 
arachnoid mater  The outermost layer, between the 
skull  
and dura mater  
Mechanism  Usually due to rupture of 
a blood vessel (e.g. berry

a blood vessel (e.g. berry 
aneurysm or AVM ). 
Pain typically felt at the 
back of the head Usually due to trauma 
causing damage to one of 
the bridging veins. Trauma 
may be minor and could be 
many months ago. Can be 
acute or chronic. Due to direct moderate / severe head 
trauma. 
 Typically around the eye, 
causing fracture  
 of the temporal or parietal bone, 
resulting  
in laceration of the middle 
meningeal artery 
 and/or vein

 and/or vein 
Pain  Sudden onset, painful Possible dull headache  Likely, and often severe, but not 
sudden onset 
Consciousness  May become impaired 
quickly – if so, a very 
bad prognostic indicator Fluctuates, often over 
weeks or even months Classically, an initial lucid period, 
followed 
 by impaired consciousness 
Neurological 
signs  May be present; are a 
poor prognostic indicator Often insidious. May 
involve memory 
impairment, epilepsy ,

impairment, epilepsy , 
drowsiness, dizziness . Often 
occur weeks / months after 
injury  Typically after a lucid 
period, severe headache , 
 impaired consciousness . Vomiting, 
seizures, 
 drowsyness, confusion , and 
later, coma . 
Investigations  CT – should show 
irregular shaped bleed. If 
absent, and still 
suspicious, do LP to 
confirm (blood in CSF, 
CSF turn yellow when 
left to stand –
 xanthochromia)  CT / MRI – classically 
shows a crescent of blood

shows a crescent of blood 
around the brain tissue, and 
midline shift   CT / MRI – described as a lens 
 shaped lesion – meaning it 
is biconvex.  
LP is contraindicated!  
X-ray may show skull fracture  
Management  If few symptoms, 
surgical clipping of 
platinum coiling of 
aneursm, or 
if AVM  then balloon 
therapy and stening are 
beneficial. 
Give Nimodipine to 
reduce risk of vasospasm 
(and Ĺ survival) as long

(and Ĺ survival) as long 
as BP can be maintained. Burr hole or craniotomy Surgery to evacuate blood and ligate 
bleeding vessels 
Brain stem herniation  
The sudden onset of headache, ataxia and vomiting suggest  an intracranial haemorrhage, which 
leads to  mass effect and  subsequent brain stem herniation . 
 Brain herniation often causes false localising signs due to compression of various areas of th e 
brain.

brain.  
 it usually follows two patterns: 
1. uncal herniation  : presented with:  
 third nerve paresis  
 (ipsilateral dilated pupil, abnormal external ocular movements, including 
nystagmus) 96

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              92 
  The third nerve paresis occurs due to compression of the parasympathetic 
fibres around the third nerve, which results in unopposed sympathetic 
response. 
 contralateral hemiparesis  
 which can lead to ipsilateral hemiparesis. 
  Contralateral hemiparesis occurs with compression of the cerebral 
peduncle.

peduncle. 
  Ipsilateral hemiparesis and third nerve palsy occur late when the lateral 
translation is so great that it compresses the contralateral third nerve and 
peduncle. 
 
2. central herniation :presents with:  
 confusion and drowsiness,  
 followed by impaired vertical gaze, 
  small pupils, 
  impaired oculocephalic reflexes  
 Bilateral corticospinal tract signs including increased tone and Babinski signs. 
 signs of raised intracranial pressure:  
 bradycardia,

 bradycardia, 
 hypertension, 
 irregular breathing (Cushing response)  
 and a sixth-nerve palsy. 
 The sixth nerve is usually the first to be compressed due to its long extracerebral 
intracranial course. 
 Diplopia from either a third or sixth nerve palsy can cause nystagmus. 
 immediate intensive care support, with intubation and hyperventilation. 
 The case should be discussed urgently with neurosurgeons, and their advice sough t

regarding the possibility of operative intervention. 
 Intravenous mannitol and other hyperosmolar solutions are often indicated, and should b e 
  
Brain stem death  tests include:  
 Pupillary light response - CN II and III 
 Corneal reflex, response to supraorbital pressure - CN V and VII 
 Vestibulo-ocular reflex - CN III and VIII 
 Gag reflex - CN IX and X 
 Cough reflex - CN X 
 Absence of respiratory effort.

 Absence of respiratory effort.  
Post-concussion syndrome  
The most common symptoms are headache and neck discomfort; changes in memory, concentration, 
and attention; dizziness; irritability, depression or anxiety; and sleep disturbance, amo ng other 
symptoms. 
There is: 
 Disturbance of thought 
 Poor concentration span and 
 Subjects are easily distracted. 
 Anxiety is common

 Anxiety is common 
Encephalitis   
Encephalitis may be caused by: 
 Direct invasion  by a neurotoxic virus (encephalitis).  
 most commonly caused by enteral viruses, herpes simplex virus (HSV) 1 and 2, varicell a, 
cytomegalovirus (CMV), and Epstein-Barr virus (EBV).  
 occasionally caused by respiratory viruses, human herpes virus 6 (HHV6), rubella, or 
mumps. 97

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              93 
  Post-infectious  encephalopathy: delayed brain swelling because of an immunological response 
to the antigen, i.e. a neuroimmunological response.  
 caused by measles  or varicella zoster (cerebellar ataxia). 
 Slow virus infection , for example, human immunodeficiency virus (HIV) or subacute sclerosing 
panencephalitis (SSPE).

panencephalitis (SSPE). 
Herpes simplex encephalitis 
 
 Herpes simplex (HSV) encephalitis is a common topic in the exam. The virus characteristically 
affects the temporal lobes - questions may give the result of imaging or describe temporal lobe 
signs  e.g. aphasia. 
 Temporal lobe involvement is common (limbic encephalitis), in particular the anterior 
temporal lobes. These abnormalities are visible on CT or MRI.

 Winter is the peak incidence.  
 It has peaks of presentation in the young and old. 
 
Types 
Both herpes simplex virus type 1 and type 2 can cause encephalitis.  
 Herpes simplex type 1  is the virus associated with encephalitis in older children and adults.  
 Herpes simplex type 2  is characterised by generalised brain involvement, but is almost 
exclusively seen in neonates who acquire the virus during delivery.  
 
Herpes simplex encephalitis presents with:

Herpes simplex encephalitis presents with: 
 Behavioural changes or psychiatric disturbance 
 Focal seizures 
 Fever and 
 Alteration in consciousness. 
 
Features  
 fever, headache, psychiatric symptoms, seizures , vomiting 
 focal features e.g. aphasia 
 peripheral lesions (e.g. cold sores) have no relation to presence of HSV encephalitis 
 HSV-1 responsible for 95% of cases in adults 
 typically affects temporal and inferior frontal lobes 
Investigation

 CSF:  lymphocytosis , elevated protein, mildly raised red cells  and a normal or low glucose. 
 PCR for HSV on (CSF) is a highly specific test. 
 CT: medial temporal and inferior frontal changes (e.g. petechial haemorrhages) - n ormal in one-
third of patients 
 MRI is better 
 CT scan of the brain may be normal, but MRI may reveal the diagnosis. 
 EEG pattern: lateralised periodic discharges at 2 Hz 
Treatment 
 intravenous aciclovir

Treatment 
 intravenous aciclovir 
 Immediate treatment is required on clinical suspicion - do not wa it 
 continued until CSF PCR is negative, or for at least 14 days.  
 Intravenous fluids and aciclovir is the best option here.  
prognosis  
 The prognosis is dependent on whether aciclovir is commenced early.  
 If treatment is started promptly the mortality is 10-20%.  
98

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              94 
  Left untreated the mortality approaches 80% 
 
MRI of a patient with HSV encephalitis. 
There is hyperintensity of the affected 
white matter and cortex in the medial 
temporal lobes and insular cortex. 
 
January 2012 exam: H/O Confusion, headache and fever + seizure. MRI shows patchy haemorrhagic

changes in the temporal lobe. Given the likely diagnosis, what is the treatment of choice? Supportive 
treatment + intravenous acyclovir. (∆ Herpes simplex encephalitis)  
HIV: neurocomplications 
 
Focal neurological lesions  
Toxoplasmosis  
 
 the most common neurological infection seen in HIV,  
 occurring in up to 10% of patients 
 accounts for around 50% of cerebral lesions in patients with HIV

  occurring at CD4 counts of less than 100 cells/mm3. 
 constitutional symptoms , headache, confusion, drowsiness 
 CT: usually single or multiple ring enhancing lesions, mass effect may be seen 
 management: sulfadiazine and pyrimethamine  
99

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              95 
 
Cerebral toxoplasmosis: CT scan with contrast showing 
multiple ring enhancing lesions Cerebral toxoplasmosis: MRI (T1 C+) demonstrates multiple small 
peripherally enhancing nodules located predominantly in the basal 
ganglia as well as the central portions of the cerebellar hemispheres.

Only a small amount of surrounding oedema is present. 
 
The differential diagnosis of ring-enhancing lesions on CT in a patient with AIDS include: 
 Cerebral toxoplasmosis 
 Abscesses 
 Metastases 
 Atypical CNS lymphoma.  
Primary CNS lymphoma  
 accounts for around 30% of cerebral lesions 
 associated with the Epstein-Barr virus 
 CT: single or multiple homogenous enhancing lesions 
 treatment generally involves steroids (may significantly reduce tumour size), chemotherapy (e.g .

methotrexate) + with or without whole brain irradiation. Surgical may be considered for lower 
grade tumours 
 
100

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              96 
 
Primary CNS lymphoma: Non-contrast CT demonstrates a 
hyper-attenuating mass adjacent to the left lateral ventricle, 
with no calcification or haemorrhage. 
 Primary CNS lymphoma: MRI (T1 C+) demonstrates a large 
multilobulated mass in the right frontal lobe. It 
homogeneously enhances and extends to involve the

caudate and the periventricular area. There is significant 
mass effect. 
 
Differentiating between toxoplasmosis and lymphoma  is a common clinical scenario in HIV 
patients. The table below gives some general differences.  
 
Condition  CT finding  
Toxoplasmosis  Multiple  lesions  
 Ring or nodular enhancement  
 Thallium SPECT negative  
Lymphoma  Single  lesion 
 Solid (homogenous) enhancement 
 Thallium SPECT positive  
Tuberculosis  single enhancing lesion

Tuberculosis  single enhancing lesion  
Encephalitis  oedematous brain  
Cryptococcus  meningeal enhancement, cerebral oedema  
Progressive multifocal leukoencephalopathy 
(PML) single or multiple lesions, 
 no mass effect , 
 don't usually enhance  
AIDS dementia complex  cortical and subcortical atrophy  
 
 Given the more limited availablity of SPECT compared to CT many patients are trea ted empirically on

the basis of scoring systems , for example there is a 90% likelihood of toxoplasmosis if all of the 
following criteria are met:  
 toxoplasmosis IgG in the serum 
 CD4 < 100 and not receiving prophylaxis for toxoplasmosis 
 multiple ring enhancing lesions on CT or MRI 
Tuberculosis  
 much less common than toxoplasmosis or primary CNS lymphoma 
 CT: single enhancing lesion 
Generalised neurological disease  
Encephalitis  
 may be due to CMV or HIV itself

 may be due to CMV or HIV itself 
 HSV encephalitis but is relatively rare in the context of HIV 
 CT: oedematous brain 101

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              97 
  
Cryptococcus  
 most common fungal infection of CNS 
  typically there is a sub-acute onset of symptoms and the disease is associated with raised 
intracranial pressure (leading to the papiloedema and the falsely localising 6th nerve palsy).  
 headache, fever, malaise, nausea/vomiting, seizures, focal neurological deficit

 CSF: high opening pressure, India ink test positive 
 CT: meningeal enhancement, cerebral oedema 
 meningitis is typical presentation but may occasionally cause a space occupying lesion 
 raised intracranial pressure (ICP) is thought to be caused by the yeast cells and fungal 
polysaccharides forming microscopic plugs and blocking CSF resorption in the subarachnoid 
villi.  
 management  
 The best management would be intravenous anti-fungal agents, such as

amphotericin B and flucytosine.  
 Therapeutic lumber puncture is also advocated to reduce ICP.  
 Anti-retroviral (ARV) therapy should not be started immediately, as there is a very high 
risk of the patient developing IRIS (immune reconstitution inflammatory syndrome). 
Instead, ARVs should be delayed for several weeks or months after initiating treatment. 
Progressive multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) 
 widespread demyelination 
 rare and fatal opportunistic infection of the central nervous system caused by  (JC) virus .  
  seen in advanced HIV/AIDS  
 Associated with  infection of oligodendrocytes by JC virus (papova-virus) (a polyoma DNA  virus) , 
hence associated with high CD4 lymphocyte count 
 Natalizumab  has a black-box warning of increased risk of developing (PML ),

 Three risk factors have been clearly identified in patients with multiple sclerosis  which 
predispose them to the future developing PML:  
1. positive anti-JC viral serum antibodies,  
2. prior use of immunosuppressants, and  
3. increased duration of natalizumab treatment  and its number of infusions (25-49 infusions).  
Features  
 subacute onset :  
 Behavioural changes, speech, motor, visual impairment   
 Ataxia 
 Head tremor

 Ataxia 
 Head tremor 
 Focal neurology progressing over a period of months  to paresis and even coma. 
Diagnosis 
 CT: single or multiple lesions, no mass effect , don't usually enhance .  
 MRI is better - high-signal demyelinating white matter lesions are  seen 
 It can be diagnosed via CSF PCR for the JC virus.  
AIDS dementia complex 
 caused by HIV virus itself 
 symptoms: behavioural changes, motor impairment

 CT: cortical and subcortical atrophy 
 progresses over a longer time period than progressive multifocal leukoencephalopathy (PML).  
 Differential diagnosis  
 Patients with cryptococcal meningitis  present with headache, fever, vomiting and few 
neurological signs. 
 PML can present at any CD4 count with ataxia, behavioural changes and focal 
neurological signs, often progressing over a period of months  to paresis or even coma.

 Toxoplasmosis  presents with headache, fever and seizures. It has a typical CT head 
scan with ring enhancing lesions. 
 
 102

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              98 
 January 2010 exam:  H/O HIV positive, admitted following a seizure + headaches, night sw eats and 
poor appetite.  CD4=89 u/l.  CT head =Single homogenously-enhancing lesion in the right parietal lobe 
. What is the most likely diagnosis? Primary CNS lymphoma

January 2014 exam:  HIV positive, admitted with confusion, drowsiness and headache. temperature 
is 37.2ºC. CT brain (with contrast): Multiple hypodense regions predominantly in t he basal ganglia 
which show ring enhancement. Minimal surrounding oedema. No mass effect. What is the most 
likely diagnosis? Cerebral toxoplasmosis  (HIV - multiple ring enhancing lesions = toxoplasmosis)  
Motor neuron disease (MND)

Motor neuron disease (MND) 
Progressive motor weakness and pseudo-bulbar palsy + normal sensations  + normal brain 
imaging  always think of amyotrophic lateral sclerosis .  
Electromyography is the best investigation to carry out next.  
 Motor neuron disease is a neurological condition of unknown cause which can present with both  
upper and lower motor neuron signs.  
 the primary defect is in the anterior horn cells  
 Sex: ♂ > ♀  
 It rarely presents before 40 years

 It rarely presents before 40 years 
 
Types 
1. Amyotrophic lateral sclerosis  (50% of patients)  
 typically LMN signs in arms and UMN signs in legs 
 anterior motor horn degeneration  leads to  lower   motor neuron signs.  
 lateral corticospinal tract degeneration  leads to upper  motor neuron signs.  
 Causes 
 un known in 90 % (sporadic) 
  inherited (10%)  
 polygenic inheritance 
 A defect on  chromosome 21 , which codes for superoxide dismutase 1

(SOD1) , is associated with about 20% of familial cases of ALS, or about 2% 
of ALS cases overall.  
 characterized by stiff muscles, muscle twitching, and gradually worsening weakness due 
to muscles decreasing in size. This results in difficulty speaking, swallowing, and 
breathing. 
 20% of patients present with bulbar  onset.  
 most often a late clinical feature and suggests a poor  prognosis 
  Onuf nucleus  is preserved , thus the bladder and rectal sphincters remain normal

through the course of the disease. 
 Onuf nucleus is located  in the ventral part of laminae IX of the anterior horn of 
spinal cord segments S1- S4, and is composed of alpha motor neurons.  
2. Primary lateral sclerosis  
 UMN signs only 
3. Progressive muscular atrophy 
 LMN  signs only 
 affects distal  muscles before proximal 
 carries best prognosis 
4. Progressive bulbar palsy 
 Epidemiology 
 accounts for ∼ 0.2% of all motor neuron diseases  
 Age: 75 –80 years

 Age: 75 –80 years 
 palsy of the tongue, muscles of chewing/swallowing and facial muscles due to loss of 
function of brainstem motor nuclei 
 carries worst  prognosis 103

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              99 
  Most common cause of death is respiratory complications secondary to recurrent 
aspiration(e.g., pneumonia). 
 
Features 
 Clues, which point towards a diagnosis of motor neuron disease:  
 fasciculation 
 absence of sensory signs/symptoms*

 absence of sensory signs/symptoms* 
 *vague sensory symptoms may occur early in the disease (e.g. limb pain) but 'never' sensory 
signs 
 lower motor neuron signs in arms and upper motor neuron signs in legs 
 wasting of the small hand muscles/tibialis anterior is common 
 Other features 
 doesn't affect external ocular muscles 
 no cerebellar signs 
 abdominal reflexes are usually preserved and sphincter dysfunction if present is a late 
feature

feature 
 10 % of patients with MND have dementia ( fronto-temporal ). 
 Respiratory involvement  is thought to be present in up to 50% of MND  cases at 
presentation, although symptoms may be subtle.  
 bilateral diaphragmatic weakness causing orthopnea and exertional dyspnoea  
particularly during exertion, or on lying down, when the raised abdominal pressure 
causes lung compression. 
 Respiratory failure is the commonest cause of death in this condition.

Features NOT compatible with MND are: 
 sensory impairment  
 Optic atrophy and  
 bladder dysfunction. 
Diagnosis 
 The diagnosis of MND is clinical  
  Electromyography  shows:  
  reduced number of action potentials  
  increased amplitude.  
 Nerve conduction studies:  
 usually normal  
104

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              100 
  to exclude  a neuropathy.  
  MRI  
 to exclude  the differential diagnosis of cervical cord compression and myelopathy  
 creatine kinase  increased  
  
 Riluzole  
 prevents stimulation of glutamate receptors  decreasing

presynaptic glutamate release (thereby limiting cytotoxic effects of this neurotransmitter)  
 used mainly in amyotrophic lateral sclerosis 
 prolongs life by about 3 months  
 side effects: 
 Common side effects  are: 
 nausea,  
 asthenia,  
 abdominal pain,  
 dizziness,  
 asymptomatic elevation in liver enzymes.  
 Rare life-threatening side effects such as: 
 pancreatitis ,  
 hepatitis, and  
 neutropenia 
 Respiratory care

 Respiratory care 
 Non-Invasive Ventilation (NIV)(usually BIPAP) is used at night 
 have the greatest effect on survival 
 studies have shown a survival benefit of around 7 months  
Prognosis 
 poor: 50% of patients die within 3 years 
 The median survival time for motor neurone disease from onset of symptoms is th ree to five 
years.  
 Poor prognostic factors include: 
 low forced vital capacity (FVC) and  
 older age.

 older age. 
Bulbar palsy  
 Bulbar palsy results from bilateral impairment of function of the IXth, Xth and XIIth cran ial nerves.  
 This gives rise to dysarthria, dysphagia (often with choking episodes and nasal regurgitation o f 
fluids), dysphonia and poor cough, and susceptibility to aspiration pneumonia .  
 The lowermost part of VII may, infrequently, be involved.

 The disturbance is of the motor nuclei rather than of the corticobulbar tracts.  
 It is distinguished from pseudobulbar palsy by the presence of lower motor neurone signs.  
 Autonomic features are uncommon. 
Causes of bulbar palsy include: 
 motor neurone disease 
 Guillain Barre syndrome 
 syringobulbia 
 poliomyelitis 
 diphtheria 
 myasthenia gravis 
 neurosyphilis 
105

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              101 
  
Features  
 atrophy and fasciculations in bulbar muscles: 
 tongue appears wasted and folded; fasciculations are prominent and produce a writhing  
appearance 
 orbicularis oris is often affected at the same time as the tongue; orbicularis oculi a nd other facial 
muscles tend to be affected later and less severely

 the palate and the extrinsic muscles of the pharynx and larynx are affected after the ton gue 
 protrusion of the tongue is weakened and lost 
 dysarthria and dysphonia - from paresis of the lips, tongue and palate; nasal speec h is typical 
 dysphagia - food may regurgitate through the mouth; may be most noticeable with fluids  
 jaw jerk and gag reflex are absent 
 
Comparison of bulbar and pseudobulbar palsy  
 
Pseudobulbar Palsy  Bulbar Palsy  
degeneration of

degeneration of 
corticobulbar pathways 
to V,VII,X,XI,XII disturbance to X, XI, XII, 
sometimes VII, rather 
than the corticobulbar 
tracts 
lower motor neurone 
signs absent  lower motor neurone 
signs present  
gag reflex (+/n) gag reflex (-) 
spastic tongue wasted tongue, 
fasciculations 
jaw jerk (+) jaw jerk (n) 
spastic dysarthria nasal speech 
labile emotions normal emotions 
bilateral UMN signs in limbs 
+ = increased; - = reduced; n = normal

+ = increased; - = reduced; n = normal 
____________________________________________________________  
Benign fasciculation syndrome 
 benign fasciculation syndrome is a condition associated with a reduced threshold for a ction 
potentials at the neuromuscular junction and entirely benign. 
 Typically the patients are health professionals as they translate fasciculations to mean 
motor neurone disease. 
 The general public often do not pay any attention to muscle twitches particularly whe n

they feel well. 
 In the absence of clinical and electromyographic findings of neurogenic disease, the diag nosis of 
benign fasciculations is made.  
 the most effective approach to treatment is to treat any accompanying anxiet y. 
 No treatments have been found that completely control the symptoms.  
Opercular syndrome (OPS) 
 Opercular syndrome, also known as Foix-Chavany-Marie syndrome,

  is a paralysis of the facial, pharyngeal, masticatory, tongue, laryngeal, and brachial muscles.  
 It is a rare cortical form of pseudobulbar palsies caused by vascular insults to bilateral 
operculum.  
 caused by multiple strokes   
 Its clinical presentations include anarthria, weakness of voluntary muscles involving face, tongue, 
pharynx, larynx, and masticatory muscles.  
 However,  autonomic reflexes and emotional activities of these structures are preserved.

 presented with symptoms and signs limited to bulbar and masticatory muscles, especially for 
voluntary actions. Involuntary movement of these muscles, like yawning, are preserved .  106

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              102 
  Also, there are no long tract signs like extensor plantar or increased DTR.  
 Pseudobulbar paralysis in OPS is clinically distinguished from bulbar paralysis , disorders 
of the cranial nerves and neuromuscular junction (e.g., botulism  and myasthenia gravis ) 
by: 
 normal eye movements,

by: 
 normal eye movements,  
 preserved or hyperactive brainstem reflexes (e.g., jaw jerk),  
 the dissociation of automatic and volitional movements of the bulbar muscles with 
preservation of automatic movements,  
 absence of atrophy and fasciculations of the lower motor neuron-innervate d 
muscles  
 poor 
 Chewing, swallowing, and speech functions do not usually recover completely. 
 have a significant risk for aspiration pneumonia.

Cerebral palsy  
 Cerebral palsy is a disorder of movement and posture due to a non-progressive lesion of t he 
motor pathways in the developing brain. 
 clinical manifestations tend to evolve with age. 
 incidence is 2 per 1000 live births 
 the most common motor disability in children.  
Risk factors: 
 Preterm birth and low birth weight are the most important risk factors for cerebral palsy,

 Other risk factors include intrauterine infections, multiple pregnancies, kernicterus (very rare in 
developed countries), and/or structural brain abnormalities. 
Features: 
 Epilepsy in 40% 
 Squints in 30% 
 Hearing loss and visual impairment in 20%, and 
 Speech and language disorders. 
 behavioural problems. 
 Learning difficulties in cerebral palsy can be absent, mild, moderate or severe (45% incidence of 
learning impairment, with 25% classified as severe (IQ <50).

  cerebral palsy is primarily a clinical diagnosis, cranial ultrasound and/or MRI may help identi fy a 
causative lesion. 
 MRI of the head shows periventricular leukomalacia.  
Fasciculations   
are a lower  motor neurone finding  
Fasciculations may be seen in otherwise normal individuals with no muscular weakness/atrophy. If

pronounced and combined with muscle atrophy, they usually signify motor neurone diseas e. 
They may also be seen in diseases that involve: 
 Spinal cord grey matter 
 Lesions of anterior roots 
 Peripheral neuropathies. 
They may also be seen with: 
 Severe metabolic disturbance 
 Dehydration 
 Thyrotoxicosis. 
However, they are not seen in demyelinating disease of the central nervous system. 

Multifocal motor neuropathy with conduction block 
 It is a very important differential diagnosis of motor neurone disease because it is treatable  
 It is usually slowly progressive, sometimes mimicking mononeuritis multiplex 
 Sensation is normal 107

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              103 
  Nerve conduction studies support the diagnosis of multifocal motor neuropathy with   
conduction block  
 The treatment of choice is intravenous immunoglobulins  
Multiple sclerosis (MS)

Multiple sclerosis (MS)   
 Demyelinating CNS condition clinically defined by 2 episodes of neurological dysfunction (brain, 
spinal cord, or optic nerves) that are separated in space and time. 
 Classically presents in white women, aged between 20 to 40 years, with temporary visual or 
sensory loss. However, may affect either sex and any age or ethnic group 
 Associated with HLA- DR2  
Features 
• age  often under 50  
• non-specific features  
 eg: lethargy(75%). . 
 Visual

 Visual  
 optic neuritis: common presenting feature 
 loss or reduction of vision in 1 eye with painful eye movements 
 any patient with isolated optic neuritis  refer to a neurologist for further 
assessment 
 The cumulative probability of developing MS by 15 years after onset 
of optic neuritis was 50% 
 optic atrophy 
 Uhthoff's phenomenon: worsening of vision following rise in body temperature 
 internuclear ophthalmoplegia 
 Sensory 
 pins/needles

 Sensory 
 pins/needles 
 numbness 
 trigeminal neuralgia 
 Lhermitte's syndrome: paraesthesiae in limbs on neck flexion 
 classically associated with multiple sclerosis  
 suggests a lesion of the dorsal columns of the cervical cord or of the caudal 
medulla. 
 Other causes of Lhermitte's sign: 
 Radiation myelopathy 
 If following radiotherapy it usually resolves in two to three months. 
 Motor  
 upper  motor neurone findings only.

 Motor  
 upper  motor neurone findings only.  
 spastic weakness: most commonly seen in the legs 
 Cerebellar 
 ataxia: more often seen during an acute relapse than as a presenting symptom 
 tremor 
 Others 
 urinary incontinence 
 sexual dysfunction 
 intellectual deterioration   
Classification 
 
 Relapsing –remitting MS 
  lesions have developed at different times and are in different anatomical locations   
 Primary progressive MS.

 Primary progressive MS.  
 progressive neurological deterioration over 1 year or more  
 
Investigations   
 MRI : Do not diagnose MS on the basis of findings alone.  
 Visual evoked potentials (VEPs)  are averaged cerebral potentials evoked by visual stimuli (a 
flash or black-and white checkerboard pattern) and detected by scalp electrodes placed o ver the 
occiput 108

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              104 
  is highly sensitive for detecting demyelination of the optic nerve  and central visual 
pathways 
 In multiple sclerosis, VEPs may demonstrate abnormality when the MRI is normal , 
because the optic nerves are often involved early and may be asymptomatic 
Diagnosis

Diagnosis 
 the diagnosis of MS on the basis of established up- to-date criteria, such as the revised 2010 
McDonald criteria  
McDonald criteria (2010 revision) - MRI findings  
 Dissemination in space (DIS): 
 One or more T2 lesions in at least 2 of the 4 MS-typical regions of CNS (periventricular, 
juxtacortical, infratentorial, or spinal cord). 
 Dissemination in time (DIT): 
 Simultaneous presence of asymptomatic gadolinium(G d)-enhancing and non-enhancing 
lesions at any time, or

lesions at any time, or 
 New T2 and/or Gd-enhancing lesion on follow-up MRI, irrespective of timing with 
reference to baseline scan.   
 There is no cure.  
 Treatment of the condition can be divided into 3 parts:  
1. treatment of the acute attack;  
2. prevention of future attacks by reducing triggers and use of disease-modifying therapies;  
3. symptomatic treatments of neurological difficulties such as spasticity, pain, fatigue, and 
bladder dysfunction. 
Acute relapse

Acute relapse  
 High dose steroids (e.g. IV methylprednisolone) may be given for 3-5 days to shorten the le ngth 
of an acute relapse.  
 It should be noted that steroids shorten the duration of a relapse and do not alter the 
degree of recovery (i.e. whether a patient returns to baseline function)  
Disease modifying drugs  
 Beta-interferon  has been shown to reduce the relapse rate by up to 30%.  
 Certain criteria have to be met before it is used:

 relapsing-remitting disease + 2 relapses in past 2 years + able to walk 100m 
unaided 
 secondary progressive disease + 2 relapses in past 2 years + able to walk 10m 
(aided or unaided) 
 reduces number of relapses and MRI changes, however doesn't reduce overall disability 
 side effect  : The risk of thyroid disease  (both, hyper- and hypothyroidism) seems 
related to interferon beta-1b treatment during the first year only , particularly in patients

with pre-existing thyroiditis; the resulting thyroid dysfunction is generally transient, mild in 
degree, and needs no replacement therapy with L-thyroxine. 
 Keep thyroid function tests under review 
Other drugs  used in the management of multiple sclerosis  include: 
 glatiramer  acetate: immunomodulating drug - acts as an 'immune decoy' 
  generally regarded as safe in pregnancy  
 Beta interferon 1alpha and 1beta, fingolimod, natalizumab, and dimeth yl fumarate

are category C in pregnancy  
 natalizumab: a recombinant monoclonal antibody that antagonises Alpha-4 Beta -1-integrin found 
on the surface of leucocytes, thus inhibiting migration of leucocytes across the endothelium  
across the blood-brain barrier 
 Alemtuzumab is an anti-CD52 antibody used in the treatment of MS. 
 fingolimod :  
 the primary mode of action  sphingosine 1-phosphate receptor modulator,  
 additional actions of fingolimod:  
 Ceramide synthase inhibitor

 Ceramide synthase inhibitor  
 cannabinoid receptor antagonist 
 prevents lymphocytes from leaving lymph nodes.  It is an immunomodulator, which 
sequesters lymphocytes in lymph nodes.  109

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              105 
  It has been shown to reduce the rate of relapses in relapsing-remitting MS by over half.   
 An oral formulation is available 
Some specific problems  
Spasticity 
 Baclofen  and gabapentin are first-line.  
 Consider tizanidine or dantrolene as a second-line  
 Consider benzodiazepines as a third-line

 Consider benzodiazepines as a third-line  
 physiotherapy is important 
 cannabis and botox are undergoing evaluation 
Oscillopsia (loss of natural image stabilization)  
 Consider  gabapentin as a first-line  
 Consider memantine as the second-line  
Bladder dysfunction 
 may take the form of urgency, incontinence, overflow etc 
 guidelines stress the importance of getting an ultrasound first to assess bladder empty ing - 
anticholinergics may worsen symptoms in some patients

 if significant residual volume ĺ intermi ttent self-catheterisation 
 if no significant residual volume ĺ anticholinergics may improve urinary frequency  
MS-related fatigue  
• usually described as physical exhaustion that is unrelated to the amount of activity p erformed.  
•  seen in 78% of patients.  
• often aggravated by heat and humidity.  
• Offer  amantadine to treat fatigue in people with MS.  
• Consider mindfulness-based training, cognitive behavioural therapy

• exercises including yoga may be helpful.  
 Prognostic features 
Good prognosis features 
 young age of onset 
 relapsing-remitting disease 
 sensory symptoms 
 long interval between first two relapses 
Ways of remembering prognostic features 
 the typical patient carries a better prognosis than an atypical presentation 
Chances of developing MS in patient presented with acute isolated optic neuritis 
 Determined by presence or absence of demyelinating lesions on MRI

 with normal baseline MRI  the 10-year risk is 22% 
 with at least one MRI T2   > 3 white-matter lesion    the 10-year risk is 56 % 
pregnancy 
 relapse rates may reduce during pregnancy  and may increase 3 –6 months after childbirth  
before returning to pre-pregnancy rates  
 Only glatiramer acetate is thought to be safe in pregnancy.  
 Beta interferon 1alpha and 1beta, fingolimod, natalizumab, and dimeth yl fumarate are 
category C;

category C;  
 Mitoxantrone is category D; teriflunamide is category X.  
Internuclear ophthalmoplegia (INO) 
Overview 
 a cause of horizontal disconjugate eye movement 
 due to a lesion in the medial longitudinal fasciculus , which connects the IIIrd, IVth and VIth 
cranial nuclei in the pons 
 It is due to a lesion in the medial longitudinal fasciculus, which connects optic brainstem nuclei

on either side of the brainstem. Thus, conjugate movements, but not unilateral mov ement, is 
affected.  
 110

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              106 
 Features 
 impaired adduction of the eye on the same side as the lesion 
 horizontal nystagmus of the abducting eye on the contralateral side 
 When covering one eye, unilateral movements will be normal. But when tog ether, the adducting 
eye will not move past the midline. 
 the patient may complain of horizontal diplopia.

Causes 
 multiple sclerosis ( characteristic of MS ) 
 Tumour of the brainstem (glioma, for example) 
 Brainstem vascular lesions, or 
 Wernicke's encephalopathy. 
 
Chronic progressive external ophthalmoplegia (CPEO) 
 CPEO is an eye movement disorder characterized by slowly progressive inability to move the 
eyes and eyebrows.  which is often associated with mitochondrial disease.

 CPEO is the most common manifestation of mitochondrial myopathy (in two-thirds o f all cases).  
 It is associated with cytochrome deficiency.  
 typically presents in young adults, but may affect all ages.  
 Feature:  
 bilateral ptosis ( the initial sign), often unnoticed by the patient until the lid droops to the 
point of producing a visual field defect.  
 Fatigue  
 limitation to eye- movements in all directions. but downward gaze often less so.

 Ophthalmoplegia or the inability/difficulty to move the eye is usually symmetrical.   
 Weakness of extraocular muscle groups, such as orbicularis oculi and facial 
muscles, can be present in 25% of patients.  
 Visual acuity is affected in 95% of patients, but the deficit is usually mild.  
 Other diseases like Graves' disease, myasthenia gravis and glioma that may cause an  
external ophthalmoplegia must be ruled out.

external ophthalmoplegia must be ruled out.  
 It is important to have a dilated eye exam to determine if there is pigmentary retino pathy that may 
signify Kearns-Sayre syndrome which is associated with cardiac abnormalities.  
 muscle biopsy, which shows an accumulation of enlarged mitochrondria.  
 PCR can also determine a mutation of mitochondrial DNA.  
 Treatments  
 no specific treatment currently,  
 surgery can be used to correct ptosis

 surgery can be used to correct ptosis  
 prisms can be used to help with ophthalmoplegia. 
 
111

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              107 
 ____________________________________________________________ 
Miosis 
Ptosis + dilated pupil  third nerve palsy  Ptosis + constricted pupil  Horner's  
Causes of miosis (small pupil) 
 Horner's syndrome 
 Argyll-Robertson pupil 
 senile miosis 
 pontine haemorrhage   
 congenital 
Drugs causes 
 opiates

 opiates 
 parasympathomimetics: pilocarpine 
 organophosphate toxicity 
 
Causes of dilated pupils include: 
 Holmes-Adie (myotonic) pupil 
 Drugs, and 
 Poisons (atropine, CO, ethylene glycol). 
Ptosis 
Ptosis may be unilateral or bilateral 
 
Causes of bilateral ptosis : 
 myotonic dystrophy 
 myasthenia gravis* 
 syphilis 
 congenital

 syphilis 
Causes of unilateral ptosis , as above plus: 
 third nerve palsy 
 Horner's 
*ptosis is much less common in Lambert-Eaton syndrome than myasthenia gravis 
Horner's syndrome  
 
Horner's   ptosis, miosis and anhydrosis 
 
 Horner's syndrome develops following disruption of the sympathetic chain. 
Features 
 miosis (small pupil) 
 ptosis 
 enophthalmos* (sunken eye)

 ptosis 
 enophthalmos* (sunken eye) 
 *in reality the appearance is due to a narrow palpebral aperture rather than true enophthalmos  
 anhydrosis (loss of sweating one side) 
Distinguishing between causes 
 heterochromia ( difference  in iris colour ) is seen in congenital Horner's 
 anhydrosis: see below 
 
112

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              108 
 Types 
 There are three separate forms of Horner's syndrome, depending on what level the sym pathetic 
fibres are affected at: 
1. First-order sympathetic fibres  
 originate in the hypothalamus and descend through the brainstem to their syn apse 
with the preganglionic sympathetic fibres at C8-T2.

 First-order lesions can be caused by:  
 strokes,  
 multiple sclerosis and  
 basal meningitis. 
2. Second-order (preganglionic) fibres   
 leave the cord at T1 and ascend in the sympathetic chain over the lung apex. They 
synapse in the superior cervical ganglion at the level of C3-C4, at the bifurcation of 
the common carotid artery. 
 Lesions affecting these fibres can be caused by: 
 apical lung tumours,  
 lymphadenopathy an d  
 lower brachial plexus trauma.

 lower brachial plexus trauma. 
3. Third-order (postganglionic) fibres   
 pass along the internal carotid artery, with branches passing to the blood vessels and 
sweat glands of the face. They pass through the cavernous sinus and superior orbita l 
fissure, where they joint the long ciliary nerves to supply the iris dilator and Muller's 
muscle.  
 Because the sympathetic plexus accompanying the internal carotid artery

innervates sweat glands only to the medial forehead , facial anhydrosis is only 
partial when Horner's syndrome is caused postganglionic lesions.  
 These lesions can be caused by: 
 internal carotid artery dissection or  
 herpes zoster infection.  
 
Central lesions Pre-ganglionic 
lesions Post-ganglionic lesions 
Anhydrosis of the face, arm and 
trunk Anhydrosis of the 
face No anhydrosis 
Stroke 
Syringomyelia 
Multiple sclerosis 
Tumour 
Encephalitis Pancoast's tumour 
Thyroidectomy

Thyroidectomy 
Trauma 
Cervical rib Carotid artery dissection 
Carotid aneurysm 
Cavernous sinus thrombosis 
 
 Sweat glands are controlled by the sympathetic nervous system, for example, an hydrosis in 
Horner's syndrome. 
Myasthenia gravis  (MG) 
 Myasthenia gravis is an autoimmune disorder resulting in insufficient functioning acetylcholine 
receptors.

receptors.  
 Antibodies to acetylcholine receptors are seen in 85-90% of cases .  
 antibodies are less commonly seen in disease limited to the ocular muscles 
 more common in women (2:1) 
Feature  
 muscle fatigability (the key feature)  
 muscles become progressively weaker during periods of activity and slowly improve aft er 
periods of rest. 
 extraocular muscle weakness:  
 diplopia  
 ptosis  
 proximal muscle weakness: face, neck, limb girdle 113

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              109 
  dysphagia ( that is worse with liquids than solids  in contrast to achalasia which typically 
affects solids more than liquids, or solids and liquids equally ) 
 Acetyl choline receptors antibodies is the most appropriate investigation  
 No abnormality would be expected on chest x-ray, barium swallow or gastroscop y.

 Nasal regurgitation, coughing and choking episodes during meals, dysphagia that is 
worse with liquids than solids and dysarthria indicate neurogenic dysphagia (eg: 
myasthenia gravis and motor neuron disease). 
 Nasal regurgitation and dysarthria are not usually accompanying features of 
mechanical dysphagia. 
Associations 
 thymic hyperplasia in 50- 70% 
 thymomas in 15% 
 autoimmune disorders: pernicious anaemia, autoimmune thyroid disorders, rheumatoid, S LE 

 Single fibre electromyography (EMG) :  
 High sensitivity  (92-100%) 
 It simultaneously records the variability in potentials of two muscle fibres innervated by a n 
individual axon: jitter. 
 Electrical recordings of single motor unit activity commonly reveal variation in the 
latency of the various muscle fibre responses (jitter) 
 Although abnormal jitter  is not specific for MG and may occur in polymyositis and

amyotrophic lateral sclerosis (ALS), a large degree of jitter with minimal other 
abnormalities is suggestive of the diagnosis. 
  Jitter is the most sensitive EMG index in MG but is not specific of the condition. 
 The nerve conductions and EMG studies are usually normal in myasthenia gravis, b ut the 
repetitive stimulation of a nerve may demonstrate decrements of the muscle action 
potential (far less than 98%).

potential (far less than 98%). 
 An increase in decrement on stimulation at 3Hz is detectable in some patients. 
 CT thorax to exclude thymoma 
 CK normal 
 autoantibodies :  
 around 85-90% of patients have antibodies to acetylcholine receptors .  
 In the remaining patients, about 40% are positive for anti-muscle-specific tyrosine 
kinase (MuSK) antibodies 
 patients with (MuSK) antibodies are much less likely to have thymic hyperplasia 
or a thymoma,

or a thymoma,  
 may be less responsive to anticholinesterase drugs,  
 may require more aggressive early immunotherapy than patients who have AChR 
antibodies. 
 Tensilon test : IV edrophonium reduces muscle weakness temporarily - not commonly used 
anymore due to the risk of cardiac arrhythmia 
 Tensilon (edrophonium) challenge test can be used to diagnose MG, or distinguish it from 
cholinergic crisis.

cholinergic crisis. 
  Edrophonium given at increasing doses should produce improvement in muscle strength 
within a minute. 
 It does this by blocking the breakdown of acetylcholine by cholinesterase and temporari ly 
increases the level of acetylcholine at the neuromuscular junction.  
 However, a positive response is not specific and may occur in amyotrophic lateral 
sclerosis.  
 There is a risk of bradycardia, asystole and heart block and atropine should therefore be 
available.

available. 
  Airway support should be used as respiratory weakness can be exacerbated after the 
edrophonium wears off.  
 Although improved muscle strength after edrophonium is seen, it is not diagnostic but 
depends more on the clinical presentation and presence of AChR ab. 
 in mild cases  
 long-acting anticholinesterase e.g. pyridostigmine   114

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              110 
  Pyridostigmine  cholinesterase inhibitors increased ACh at neuromuscular 
junctions.  
 In more severe disease (with limb weakness or bulbar dysfunction) 
 immunosuppression:  
 prednisolone initially 
 addition of steroid-sparing agents such as mycophenolate mofetil, ciclosporin or 
azathioprine if necessary.

azathioprine if necessary. 
 In patients with congenital myasthenia , anticholinesterase drugs and immunomodulating 
treatments are not beneficial and should be avoided.  
 Thymectomy 
  improves symptoms in cases associated with thymoma, and may also be beneficial in 
young patients with recent onset of symptoms, but would not be used as an initial 
treatment option. 
 should also be considered in non-thymomatous generalised myasthenia in patients with

antibodies to acetylcholine receptor who are aged under 50.  
 Biopsy is not generally required prior to surgery. 
  thymectomy is not indicated if: 
1. patients have antibodies to MUSK (muscle specific tyrosine kinase) 
2. late onset disease or  
3. purely ocular disease 
Management of myasthenic crisis 
 intravenous immunoglobulins 
 plasmapheresis 
 Plasmapheresis usually works quicker but involves more expensive equipment

 Intubation and assisted ventilation: Elective intubation should be considered if the vital 
capacity show values are less than 20 mL/kg.   
 Ventilatory assistance should consist of endotracheal intubation with positive pressure 
mechanical ventilation.  
 endotracheal intubation can often be performed as an “elective ” procedure rather than 
as an emergency response to precipitous respiratory collapse.  (medical-masterclass.com. 
2017 part 2)  
 
Myasthenia gravis: exacerbating factors

Myasthenia gravis: exacerbating factors 
 The most common exacerbating factor is exertion resulting in fatigability, which is the h allmark 
feature of myasthenia gravis . Symptoms become more marked during the day 
The following drugs may exacerbate myasthenia:  
 Penicillamine 
 penicillamine toxicity  nephrotic syndrome and myasthenic syndrome. 
 quinidine, procainamide 
 beta-blockers , calcium channel blockers, verapamil, propafenone,.  
 lithium 
 phenytoin

 lithium 
 phenytoin 
 antibiotics: gentamicin , macrolides, quinolones, tetracyclines 
 Aminoglycoside-induced neuromuscular blockade  
 Aminoglycosides may impair neuromuscular transmission and should not be 
given to patients with myasthenia gravis;  
 large doses given during surgery have been responsible for a transient 
myaesthenic syndrome in patients with normal neuromuscular function. 
 
Cholinergic crisis due to overuse of pyridostigmine

 overuse of pyridostigmine  cholinergic crisis  (like organophosphate poisoning) 
 Excessive intake of pyridostigmine  potentiates cholinergic activity  bradycardia, 
hypotension, bronchospasm, abdominal cramping, diarrhea, and  flaccid paralysis of the 
extremities.  
 Differentiating a myasthenic crisis from a cholinergic crisis is difficult, but the edrophonium test 
is your clue.   
 Edrophonium is a short-acting acetylcholinesterase inhibitor.  115

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              111 
  In myasthenia gravis, this will lead to a temporary relief of symptoms.  
 In a cholinergic crisis, this will have no effect (or worsen the situation).  
 history of increased medication usage, worsening symptoms, and negative edroph onium test,  
cholinergic crisis precipitated by overuse of an acetylcholinesterase inhibitor.

 Atropine  would be indicated to antagonize cholinergic activity .  
 
Ref  Pastest – USMLE 2017 – step 1  
Lambert-Eaton syndrome 
 Myasthenia gravis  Lambert-Eaton  
muscle weakness  proximal muscle weakness: 
face, neck, limb girdle affects lower limbs first  
muscle power following 
exercise  becomes weaker  Temporary increase  
reflexes  normal or brisk  absence of reflexes or 
hyporeflexia

hyporeflexia  
Antibodies  Antibodies to acetylcholine 
receptors  antibody directed against pre-
synaptic voltage gated 
calcium channel  
Commonly associated tumor   thymomas or thymic 
hyperplasia  small cell lung cancer 
 
 Lambert-Eaton myasthenic syndrome is seen in association with small cell lung cancer, and to a  
lesser extent breast and ovarian cancer.  
 It may also occur independently as an autoimmune disorder.

  Lambert-Eaton myasthenic syndrome is caused by an antibody directed against p re-synaptic 
voltage gated calcium channel in the peripheral nervous system 
 
Features  
 repeated muscle contractions lead to increased muscle strength* (in contrast to 
myasthenia gravis) 
 limb girdle weakness (affects lower limbs first) .Proximal lower limb weakness is the most 
consistent neurological feature causing difficulty in standing from a seated position and 
climbing stairs.

climbing stairs.  
 hyporeflexia (but normalise with repetitive muscle contraction)  The weakness improves with 
exercise and the reflexes return. The absence of reflexes is characteristic, in contrast to 
myasthenia gravis where the reflexes are normal or brisk  
 autonomic symptoms: dry mouth, impotence, difficultly micturating 
 ophthalmoplegia and ptosis not commonly a feature (unlike in myasthenia gravis) 
Diagnosis

Diagnosis 
 the most likely to confirm the diagnosis  Voltage gated calcium channels antibodies  
 
EMG 
 incremental response to repetitive electrical stimulation 
 treatment of underlying cancer 
 immunosuppression, for example with prednisolone and/or azathioprine 
 3,4-diaminopyridine is currently being trialled** 
 intravenous immunoglobulin therapy and plasma exchange may be benefici al

May 2013 exam: A patient of small cell lung carcinoma presents with muscle weakness, 
spreading from legs to arms + hyporeflexia . C/O dry mouth & erectile dysfunction. 
Antibodies to which one are most likely to be responsible for these findings ? Voltage gated 
calcium channels  
 
*in reality this is seen in only 50% of patients and following prolonged muscle use m uscle strength will eventually 
decrease 116

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              112 
  
**works by blocking potassium channel efflux in the nerve terminal so that the actio n potential duration is 
increased. Calcium channels can then be open for a longer time and allow greater ace tylcholine release to the 
stimulate muscle at the end plate 

Neurofibromatosis 
 
NF1: chromosome 17 - as neurofibromatosis has 17 characters  
NF2: chromosome 22 - all the 2's  
Lisch nodules are seen in neurofibromatosis  
Genetics  
 autosomal dominant  
 In 50% of cases there will be no family history as there is a high incidence of new mu tations.  
 50% inherited and 50% sporadic mutations 
Types  
 There are two types of neurofibromatosis, NF1 and NF2.  
1. NF1  
 also known as von Recklinghausen's syndrome.

 also known as von Recklinghausen's syndrome.  
 caused by a gene mutation on chromosome 17 (NF1 gene ) which encodes 
neurofibromin  
 tumor suppressor that inhibits ras activity via stimulating GTPase 
 most common type of neurofibromatosis  
 affects around 1 in 4,000  
 half of all cases give no family history and are new mutations.  
 To be given the diagnosis of NF1 , an individual must have at least two of the 
following features: 
1) six or more café- au-lait spots

1) six or more café- au-lait spots 
 each over 5 mm in diameter in pre-pubertal individuals and  
 over 15 mm in post-pubertal individuals. 
2) two or more neurofibromas or a plexiform neurofibroma 
3) axillary freckling (can also be present in the groins) 
4) optic glioma 
5) lisch nodules (visible within the iris), or 
6) family history. 
2. NF2  
 caused by gene mutation on chromosome 22  
 affects around 1 in 100,000  

 Mutation of tumor suppressor gene ĺ loss of function ĺ  Ĺ risk  of cancer development 
 Neurofibromatosis I: neurofibromin 1 gene  (NF1) affected; encodes neurofibromin 
protein   on chromosome 17 
 Neurofibromatosis II: neurofibromin 2  gene ( NF2) affected; encodes Merlin 
protein  (tumor suppressor protein) on chromosome 22 
 
Features  
NF1 NF2 
 Cafȇ-au-lait spots ( ≥ 6, 15 mm in 
diameter) 
 Axillary/groin freckles

diameter) 
 Axillary/groin freckles 
 Peripheral neurofibromas 
 Iris harmatomas (Lisch nodules) 
in > 90%  
 Scoliosis 
 Pheochromocytomas  Bilateral acoustic neuromas ( the 
hallmark feature) 
 Multiple intracranial schwannomas, 
mengiomas and ependymomas 117

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              113 
  
 increased lifetime cancer risk 
Tuberous sclerosis (TS) 
 
 autosomal dominant  condition.  
 TS affects about 1 in 10,000 people in the general population

 It is the second most frequent neurocutaneous syndrome, with neurofibromatosis b eing the most 
common.  
 Like neurofibromatosis, the majority of features seen in TS are neuro-cutaneous  
 The responsible defects having been identified on both chromosome 9 and chromosome 
16. 
 caused by a mutation in the TSC1/TSC2 genes .  
 This gene produces the hamartin  and tuberin  proteins. 
 TSC1  (encodes  hamartin  on chromosome 9) and TSC2  (encodes tuberin  on 
chromosome 16)

chromosome 16)  
 These proteins are responsible for control of cell growth.  
 Most of the tumours which are produced in tuberous sclerosis are hamartomas  
 
Cigarettes and coffee with a rough stupid person with a butterfly on his nose while he is 
dancing 
 
Cutaneous features  
 Ash-leaf macules, which are discrete areas of hypopigmentation, often present at birth 
 fluoresce under UV light 
 Shagreen patches 
 roughened patches of skin over lumbar spine

 roughened patches of skin over lumbar spine 
 skin with a texture similar to shark (سمskin  
 adenoma sebaceum:  
 butterfly distribution over nose (angiofibromas of the face). 
 fibromata beneath nails (subungual fibromata) 
 dental pits  
 caf-au-lait spots* may be seen 
 *these of course are more commonly associated with neurofibromatosis but also found in 28% of 
patients. 
Neurological features 
 developmental delay 
 epilepsy (infantile spasms or partial)

 epilepsy (infantile spasms or partial) 
 infantile spasm is the most common type of seizure at initial diagnosis 
 hypsarrythmia on EEG 
118

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              114 
  vigabatrin, an irreversible GABA transaminase inhibitor, is particularly effective for 
infantile spasms 
 autism   
 intellectual impairment 
 Fibromas may also develop within the central nervous system, where they calcify typically in t he 
periventricular area. 
Also

Also 
 retinal hamartomas: dense white areas on retina (phakomata) 
 rhabdomyomas of the heart 
 Rhabdomyomas affect 50% to 60% of TS  
 generally regress during early childhood without the need for intervention.  
 gliomatous changes can occur in the brain lesions 
 polycystic kidneys, renal angiomyolipomata 
 lymphangioleiomyomatosis: multiple lung cysts 
 it is identified in females only  
  arises from metastases from renal angiomyolipomas.

Treatment (BMJ best practice 2017)  
 Angiofibromas or collagen plague  
 ≤ 2 mm  laser therapy  
 2 mm  dermabrasion or surgical resection  
 Ungula fibroma  clipping   
 Angiomyolipoma  
 3-6 cm  
 First line  surveillance  
 2nd line  mTOR inhibitor (Everolimus) 
 ≥ 3- 6 cm 
 First line  mTOR inhibitor (Everolimus) 
 2nd line  embolisation of the artery supplying a lesion + mTOR inhibitor 
(Everolimus)

(Everolimus) 
 3rd line  Partial renal-sparing nephrectomy may be performed if embolisation is 
unsuccessful 
 
January 2010 exam: Generalised seizure + patches of hypopigmented skin + fibromata 
under finger nails. What is the most likely diagnosis? Tuberous sclerosis  
 
May 2007 exam: H/O hypovolaemic shock. CT abdomen reveals a haemorrhagic lesion in the right 
kidney. biopsy shown it to be an angiomyolipomata. What is the most likely underl ying diagnosis? 
Tuberous sclerosis

Tuberous sclerosis  
Paraneoplastic syndromes affecting nervous system 
Lambert-Eaton myasthenic syndrome 
 associated with small cell lung cancer (also breast and ovarian) 
 antibody directed against pre-synaptic voltage gated calcium channel in the peripheral n ervous 
system 
 can also occur independently as autoimmune disorder 
Anti- Hu 
 associated with small cell lung carcinoma and neuroblastomas

 sensory neuropathy - may be painful 
 cerebellar syndrome 
 encephalomyelitis 
Anti- Yo 
 associated with ovarian and breast cancer 
Anti-GAD antibody 
 associated with breast, colorectal and small cell lung carcinoma 
 stiff person's syndrome or diffuse hypertonia 119

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              115 
 Anti- Ri 
 associated with breast and small cell lung carcinoma 
 ocular opsoclonus-myoclonus 
Anti-Purkinje cell antibodies 
 subacute cerebellar degeneration  
 peripheral neuropathy due to a remote (autoimmune) effect of gynecologic or breast carcinoma.

(GM1 antibodies)  (Glycolipid ganglioside-monosialic acid) associated with 
 Lower motor neuron syndromes 
 Amyotrophic lateral sclerosis 
 Multiple sclerosis 
 Other multifocal neuropathies and 
 Systemic lupus erythematosus (SLE) with central nervous system involvement. 
 
May 2009 exam: Ovarian cancer + unsteadiness, nystagmus and past-pointing. Which 
antibody is most likely to be present? Anti- Yo 
Kennedy's disease

Kennedy's disease 
Aetiology 
 The gene abnormality responsible for Kennedy's disease is an abnormal increase in t he 
trinucleotide CAG repeats in the region of the androgen-receptor gene 
 It is inherited in an X-linked recessive fashion, with the mother of an affected m ale patient being 
an obligate carrier 
 Characteristic symptoms include prominent muscle cramps, difficulty walking and lim b-girdle 
muscle weakness

muscle weakness 
 Dysarthria and dysphagia occur in less than half of patients 
 Reflexes are depressed or absent 
 Facial and particularly perioral fasciculations are highly characteristic of this condition 
 Gynaecomastia is present in up to 90% of cases 
 Endocrine abnormalities, such as infertility, testicular atrophy and diabetes mellitus, a re common  
Meningitis  (see infectious diseases)

Meningitis  (see infectious diseases) 
Brain tumours 
The majority of adult tumours are supratentorial, where as the majority of childhood tu mours are 
infratentorial. 
Type of tumour Features 
Glioblastoma 
multiforme  • The most common primary brain tumour in adults.  
• Histology: Pleomorphic tumour cells border necrotic areas  
Meningioma • The second most common primary brain tumour in adults

• Histology: Spindle cells in concentric whorls and calcified psammoma bodies  
Schwannoma • Often seen in the cerebellopontine angle: acoustic neuroma  
• Bilateral schwannoms are seen in neurofibromatosis  
• Histology: Antoni A or B patterns are seen. Verocay bodies (acellular areas 
surrounded by nuclear palisades) 
Pilocytic astrocytoma • The most common primary brain tumour in children  
• Histology: Rosenthal fibres (corkscrew eosinophilic bundle)

Medulloblastoma • More common in children  
• Found exclusively in the posterior fossa  
• Metatases through the CSF  
• Histology: Small, blue cells. Rosette pattern of cells with many mitotic figures 120

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              116 
 Type of tumour Features 
Ependymoma • Commonly seen in the 4th ventricle  
• May cause hydrocephalus  
• Histology: perivascular pseudorosettes  
Oligodendroma • Benign, slow -growing tumour common in the frontal lobes 
• Histology: Calcifications with 'fried -egg' appearance 
Haemangioblastoma • Vascular tumour of the cerebellum

• Associated with von Hippel -Lindau syndrome 
• Histology: foam cells and high vascularity  
Pituitary adenoma • Most common type is a prolactinoma 
• May present with bitemporal hemianopia  
Craniopharyngioma • Most common paediatric supratentorial tumour  
• Histology: Derived from remnants of Rathke pouch  
Metastases • Most common type of brain tumour  
 
Craniopharyngioma  
 slow-growing, calcified cystic tumour arising from the remnants of the craniopharyngeal du ct.

 It compromises 4.2% of all childhood tumours.  
 It is slightly more common in males than females.  
 The symptoms develop very slowly and usually become manifest once the t umour has attained a 
diameter of 3 cm.  
 The commonest presentation in young patients is growth failure and delayed puberty.  
 The radiological hallmark of a craniopharyngioma is the presence of a suprasellar calcified cyst, 
with calcification being more common in children than in adults.

 Using imaging studies, CTS is most useful in demonstrating the calcifications whereas MRI is 
essential for defining the local anatomy prior to surgical intervention.  
 Surgery is the management of choice and may attempt to resect the tumour in tot al, or to reduce 
the size followed by postoperative radiotherapy treatment. 
 
 121

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              117 
  
Meningioma  - MRI showing the typical well-circumscribed appearance. A dural tail can be wh ere the 
tumour 'connects' to the dura. It is seen in around 65% of meningiomas.  
 
 The CT shows a well defined 
spherical mass in the right posterior 
falx cerebri consistent with a 
meningioma .

meningioma .  
 
There is mild oedema and mass effect 
on the right lateral ventricle. The 
tumour is straddling the inferior 
surface of the falx. 
 
122

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              118 
  
Glioblastoma multiforme  - CT showing a peripherally enhancing lesion within the left frontal lobe. 
Note the contrast to the more homogenous  (مmeningioma above. 
A glioblastoma multifome would normally have a more heterogenous  (مappearance than   
Brain metastases

Brain metastases  
 Approximately 20% of people who die from cancer have brain metastases. These can be  solitary 
or multiple. 
 The most common sites that metastasise to the brain are: 
 lung (44%) 
 breast (10%) 
 kidney (7%) 
 gastrointestinal tract (6%), and 
 melanoma (skin 3%). 
 Therefore a chest x ray would be the initial investigation of choice , with the greatest chance 
of finding the primary. 
 Start dexamethasone immediately

 Start dexamethasone immediately  
 Surgical resection is usually only recommended if a single cerebral lesion is found. 
 Anticonvulsant prophylaxis is unnecessary if seizures are not a problem and are not 
effective in preventing first seizures in patients with newly diagnosed brain tumours. 
Spinal cord conditions 
Cerebro spinal fluid

Cerebro spinal fluid 
 What type of cells produce cerebrospinal fluid? 
 Ependymal cells 
 lines the ventricles and other CSF-filled spaces 
 Approximately 500ml of cerebrospinal fluid is produced each day. 
 It is absorbed into the circulation via the arachnoid villi.  
 CSF is largely similar to plasma in composition, but has much lower levels of protein. 
123

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              119 
  
Normal values  of cerebrospinal fluid (CSF) are as follows: 
 pressure = 60-150 mm (patient recumbent) 
 protein = 0.2-0.4 g/l 
 glucose = > 2/3 blood glucose 
 cells: red cells = 0, white cells < 5/mm³ 
The following conditions are associated with raised lymphocytes  
 viral meningitis/encephalitis 
 TB meningitis

 TB meningitis 
 partially treated bacterial meningitis 
 Lyme disease 
 Behcet's, SLE 
 lymphoma, leukaemia 
The following conditions are associated with raised protein levels 
 Guillain-Barre syndrome 
 tuberculous, fungal and bacterial meningitis 
 spinal block (Froin's syndrome*) 
 *describes an increase in CSF protein below a spinal canal blockage (e.g. tumour, disc, infection) 
 viral encephalitis

 viral encephalitis  
Vertebral level and corresponding structure  
 The aortic  opening is at T12. 
 Hyoid bone  C4 
 Bifurcation of common carotid  C4 
 Thyroid cartilage  C5 
 Carotid pulse palpated  C5 
 Cricoid cartilage C6 
 Beginning of trachea  C6 
 Beginning of esophagus  C6 
 Sternal notch T2 
 Arch of aorta  T2 
 Sternal angle T4 
 Junction of superior and inferior mediastinum T4

 Bifurcation of trachea T4 
 Inferior vena caval hiatus (opening in the diaphragm)  T8 
 Xiphisternal joint T9 
 Esophageal hiatus (opening in the diaphragm)    T10 
 Upper pole of left kidney T11 
 Upper pole of right kidney T12 
 Aortic hiatus (opening in the diaphragm)   T12 
 Umbilicus  L3 
 Iliac crest  L4 
 Bifurcation of aorta  L4 
 Beginning of sigmoid colon   S1 
 End of dural sac (and CSF )  S2 
 End of sigmoid colon  S3

 End of sigmoid colon  S3 
 
The spinal cord terminates at lower border of L1 vertebra 
Post-lumbar puncture headache 
 Epidemiology   
 Headache following lumbar puncture (LP) occurs in approximately one-third  of patients.  
 more common in young females  with a low body mass index  
 Pathophysiology  
 Leaking of cerebrospinal fluid from the dura  is the most likely explanation.   
 124

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              120 
 Typical features  
 usually develops within 24-48 hours following LP but may occur up to one week late r 
 may last several days 
 worsens with upright position 
 improves with recumbent position 
 
Factors which may contribute to 
headache Factors which do not contribute to 
headache 
Increased needle size

headache 
Increased needle size 
Direction of bevel 
Not replacing the stylet 
Increased number of LP attempts 
Use of a Quincke (sharp) needle  Increased volume of CSF removed 
Bed rest following procedure 
Increased fluid intake post procedure 
Opening pressure of CSF 
Position of patient 
 
What is the most appropriate type of needle to use in lumbar puncture? 
 20G Sprotte® (atraumatic) needle 
 Studies show that smaller atraumatic needles reduce the risk of post-lumbar puncture

headache. 
 supportive initially (analgesia, rest) 
 if pain continues for more than 72 hours then specific treatment is indicated, to  prevent subdural 
haematoma 
 treatment options include: blood patch, epidural saline  and intravenous caffeine 
Spinal cord lesions 
The diagram below shows cross-section view of the spinal cord:  
 
125

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              121 
  
Disorder Tracts affected Clinical notes 
Brown-Sequard syndrome 
(spinal cord hemisection) 1. Lateral corticospinal tract 
2. Dorsal columns 
3. Lateral spinothalamic tract 1. Ipsilateral  spastic paresis  below 
lesion 
2. Ipsilateral  loss of proprioception 
and vibration sensation  
3. Contralateral loss of pain and

3. Contralateral loss of pain and 
temperature sensation  
Subacute combined 
degeneration of the spinal cord 
(vitamin B12 & E deficiency) 1. Lateral corticospinal tracts 
3. Spinocerebellar tracts 1. Bilateral spastic paresis 
2. Bilateral loss of proprioception and 
vibration sensation 
3. Bilateral limb ataxia 
Friedrich's ataxia Same as subacute combined 
(see above) Same as subacute combined 
degeneration of the spinal cord (see 
above)

above) 
Anterior spinal artery occlusion 1. Lateral corticospinal tracts 
2. Lateral spinothalamic tracts 1. Bilateral spastic paresis 
2. Bilateral loss of pain and temperature 
sensation 
Syringomyelia 1. Ventral horns 
2. Lateral spinothalamic tract 1. Flacid paresis (typically affecting the 
intrinsic hand muscles) 
2. Loss of pain and temperature 
sensation 
Multiple sclerosis Asymmetrical, varying spinal

Multiple sclerosis Asymmetrical, varying spinal 
tracts involved Combination of motor, sensory and 
ataxia symptoms 
 
Sensory lesions 
Neurosyphilis (tabes dorsalis) 1. Dorsal columns 1. Loss of proprioception and vibration sensation 
Spinal lesion localisation 
 A lesion at left side of C5 will cause weakness of the left leg

 At the pyramidal decussation (lower medulla), 85% fibres cross over forming the lateral 
corticospinal tract, the remaining forming the ventral corticospinal tract, the fibres of which 
eventually cross the cord. Hence, a lesion at left side of C5 will cause weakness of the 
left leg.  
 Central spinal cord lesions  destroy: 
 Contiguous structures like the anterior horn cells (lower motor neurone signs) 
 Decussating sensory fibres (pain and temperature) and

 The lateral corticospinal tracts (upper motor neurone signs). 
 Conus medullaris lesion  causes: 
 Wasting and weakness of leg muscles with fasiculations (lower motor neurone signs) 
 Hyper-reflexia especially distally (upper motor neurone signs) supplied by the lower sacral 
segments (glutei) .  
 sensory loss of buttocks and perineum. 
Spinal cord compression 
Epidemiology

 Spinal cord compression is an oncological emergency and affects up to 5% of cancer patients .  
Causes 
 Extradural compression accounts for the majority of cases, usually due to vertebral body  
metastases.  126

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              122 
  It is more common in patients with lung, breast and prostate cancer 
Features  
 back pain 
 the earliest and most common symptom 
 may be worse on lying down and coughing 
 lower limb weakness 
 sensory changes: sensory loss and numbness 
 neurological signs depend on the level of the lesion.

 Lesions above L1  usually result in upper motor neuron signs in the legs and a sensory 
level.  
 Lesions below L1  usually cause lower motor neuron signs in the legs and perianal 
numbness. Tendon reflexes tend to be increased below the level of the lesio n and absent 
at the level of the lesion 
 
Diagnosis 
 The definitive investigation in this case is an MRI  of the vertebral column to look for vertebral 
collapse or other vertebral disease.  

 high-dose oral dexamethasone  
 Corticosteroids should be started immediately , even before the diagnosis is confirmed 
radiologically,  
 usually with dexamethasone 16mg STAT followed by 8mg BD (either oral or IV is 
acceptable).  
 temporarily reduce oedema related to the underlying tumour and thus have a positiv e 
impact on neurological deficit, 
 the response to steroids predicts neurological response to subsequent definitive

treatment which should be started within 24 hours.  
 urgent oncological assessment for consideration of radiotherapy or surgery 
 Urgent radiotherapy is the definitive treatment , although neurosurgical opinion should 
be sought in order to ensure that surgical decompression is not required.  
 Treatment is effective in 90% of patients if the diagnosis is made early. 
Prognosis 
 Pre-treatment ambulatory function is the best determinant of post treatment gait function

  80% of patients will maintain mobility if ambulatory function is good at presentation.  
 
 127

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              123 
  
This table demonstrates the expected features according to the level of compression 
 
Level of compression  
features 
L3 nerve root compression  Sensory loss  from anterior thigh to medial aspect of lower leg   
 Weak quadriceps 
 Ļ knee reflex  
 Positive femoral stretch test

 Positive femoral stretch test 
  
L4 nerve root compression  Caused by L3/4 disc prolapse  
 Sensory loss  over the thigh and anterior aspect of knee   
 Ļ knee reflex 
 
L5 nerve root compression  Caused by L4/5 disc prolapse  
 Sensory loss  dorsum of foot  and lateral aspect of leg 
 Weakness in foot and big toe dorsiflexion ('foot drop') 
 Reflexes intact 
 Positive sciatic nerve stretch test

 Positive sciatic nerve stretch test 
 
S1 nerve root compression   Caused by L5/S1 disc prolapse  
 Sensory loss  posterolateral aspect of leg (posterior calf and the plantar 
surface of the foot)  and lateral aspect of foot  
 Weakness in plantar flexion of foot 
 Ļ ankle reflex  
 
 L5/S1 disc prolapse  S1 nerve root 
compression causing : 
 Sensory loss to the posterior calf and the 
plantar surface of the foot

plantar surface of the foot 
 Motor loss to gastrocnemius  and 
soleus  
 Loss of ankle jerk. 
gastrocnemius muscle  meaning "stomach of 
leg" (referring to the bulging shape of the calf)  
gastrocnemius  and soleus  forms the 
calcaneal tendon or Achilles Tendon  and 
inserts onto the posterior surface of 
the calcaneus, or heel bone.  
 
Disc prolapse

Disc prolapse 
 Loss of sensation in the upper outer thigh is consistent with nerve root compression 
caused by a prolapsed vertebral disc.  
 
 'Disc prolapse' actually refers to herniation of the nucleus pulposus, which is usually contain ed by 
the annulus fibrosus.  128

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              124 
  The herniation of the nucleus pulposus is most commonly in the posterolateral direction  as it is 
the weakest part  of the surrounding annulus fibrosus. 
 commonly secondary to disc degeneration , but can also be traumatic.  
 most often occurs in the lumbar spine , especially L5/S1  which results in sciatica.

 usually occurs on one side, rather than bilaterally  
 Symptoms: 
 unilateral leg pain in the distribution of the affected nerve (which is often mor e severe 
than the back pain)  
 Pain is typically better with rest (although prolonged sitting can worsen it) –  
 if it is unremitting or worse on resting  you should consider other causes such 
as bony metastases  or infection. 
 numbness 
 paraesthesia 
 weakness and/or loss of tendon reflexes in the same distribution.

Cauda equina syndrome (CES)  
 cauda equina syndrome (CES), the lumbosacral roots, from L1 down to S5  are bilaterally 
damaged, symmetrically or asymmetrically, depending on the underline cause 
 Causes   
 herniation of a lumbar disc (at L4/L5 and L5/S1) 
 tumour (metastases, lymphoma, primary spinal tumours) 
  trauma  
 infection (epidural abscess).

  trauma  
 infection (epidural abscess).  
 Others: ankylosing spondylitis, Paget ’s disease, and congenital spinal stenosis.  
 Features: CES is a form of radiculopathy and is a lower motor neuron lesion,  hence it 
presents with:  
 flaccid paraplegia 
  unilateral or bilateral lower limb motor and/or sensory abnormality 
 areflexia 
 low back pain 
 Whilst classically patients present with a sensory level, this is variable in clinical practice. 
 flexor plantar reflexes

 flexor plantar reflexes 
  bladder retention and overflow incontinence (bowel and/or bladder dysfunction with 
saddle and perineal anaesthesia) 
 saddle anesthesia. 
 Patients usually describe numbness and/or "pins- and-needles" sensations of the 
groin and inner thighs which would contact a saddle when riding a horse. This 
reflects involvement of the S3-S5 roots. 
 Diagnosis: 
 MRI is the investigation of choice

 MRI is the investigation of choice  
 Determining the presence of bowel dysfunction (with reduced anal tone and sensation ) can be 
helpful prognostically, but does not assist with the differential diagnosis. 
Conus medularis syndrome 
Conus medullaris syndrome is caused by compression of the T12-L2 cord and nerve roots, and 
therefore results in a mix of upper and lower motor neuron signs.

 Conus medularis syndrome presents with mixed upper and lower motor neurone signs .  
 These include bilateral distal weakness with increased tone and hyper-reflexia, 
fasciculation.  
 Because of the anatomy of the spinal cord if there is compression at the level of the co nus 
medullaris some of the cord is compressed to cause upper motor (UMN) signs and some 
of the nerves are compressed to give lower motor signs.

 Cauda equina would give just LMN signs, and so would not have positive Babinski 
sign and clonus. 
 Sensory loss is most marked in the perianal region .  129

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              125 
  In Amyotrophic lateral sclerosis (the commonest form of motor neurone disease), There 
would be a mixture of UMN and LMN signs; however they do not have any sensory signs 
or incontinence.  
 It is much rarer than cauda equina syndrome.  
 
Autonomic dysreflexia

Autonomic dysreflexia 
 This clinical syndrome occurs in patients who have had a spinal cord injury at, or above T6 
spinal level.  
 poorly understood condition associated with abnormal control of the autonomic ne rvous system 
in quadriplegic patients. 
 It affects approximately 85% of patients with a lesion above C6 and may be triggered b y cystitis, 
retention of urine or a blocked catheter as in this case, or constipation.

 Briefly, afferent signals, most commonly triggered by faecal impaction or urinary retentio n (but 
many other triggers have been reported) cause a sympathetic spinal reflex via thoracolumba r 
outflow.  
 The increased sympathetic activity results in vasoconstriction and hypertension with stimulation 
of the carotid and aortic baroreceptors. These in turn respond via the vasomotor centre with  
increased vagal tone resulting in a bradycardia but reduced sympathetic tone with

vasodilatati on not possible due to the cord damage. 
 The usual, centrally mediated, parasympathetic response however is prevented by the cord 
lesion.  
 The result is  an unbalanced physiological response, characterised by : 
 extreme hypertension , may leads to complications  
  flushing and sweating above the level of the cord lesion 
 Agitation 
 recognition and removal of the noxious stimulus.

 Vasodilators such as calcium antagonists may be used to treat the hypertension. 
Spastic paraparesis 
Spastic paraparesis describes a upper motor neuron pattern of weakness in the lower limb s 
Causes  
130

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              126 
  demyelination e.g. multiple sclerosis 
 cord compression: trauma, tumour 
 parasagittal meningioma 
 tropical spastic paraparesis 
 classic presentation   HTLV-1 positive patient presenting with paraparesis and 
urinary retention due to Adult T-cell lymphoma (ATL) caused by human T-
lymphotropic virus type 1 (HTLV- I)

lymphotropic virus type 1 (HTLV- I) 
 transverse myelitis e.g. HIV 
 syringomyelia 
 hereditary spastic paraplegia 
 osteoarthritis of the cervical spine 
 
Absent ankle jerks, extensor plantars 
Typically caused by lesion producing both upper motor neuron (extensor plantars) and lower moto r 
neuron (absent ankle jerk) signs 
Causes  
 Absent ankle jerks may occur in conditions associated with neuropathy (B 12 deficiency, systemic

lupus erythematosus [SLE], cerebrotendinous xanthomatosis) and dorsal root disease (ta bes 
dorsalis).  
 subacute combined degeneration of the cord 
 motor neuron disease 
 Friedreich's ataxia (usually presents by age 30) 
 Syringomyelia 
 taboparesis (syphilis) 
 HIV 
 Spinal AVM 
 conus medullaris lesion 
Which neurological finding is most helpful in differentiating subacute combined degeneration of 
the cord from multiple sclerosis? 
 Absent ankle jerk

 Absent ankle jerk 
Subacute combined degeneration of spinal cord 
Basics 
 due to vitamin B12 deficiency 
 dorsal + lateral columns affected 
 joint position and vibration sense lost first  then distal paraesthesia 
 upper motor neuron signs typically develop in the legs, classically extensor plantars, brisk knee 
reflexes, absent ankle jerks  (Knee reflexes in SACDC may be increased, normal or absent)

 Lhermitte's phenomenon is typically present in multiple sclerosis, but may also occur in sub-
acute combined degeneration of the cord. 
 MRI typically shows increased signal on T2~weighted imaging  in the dorsal columns   
 if untreated stiffness and weakness persist 
Transverse myelitis 
 Characterised by acute or subacute motor, sensory and autonomic spinal cord dysfunction.  
 Causes  of transverse myelitis

 Causes  of transverse myelitis 
 viral infections: varicella zoster, herpes simplex, cytomegalovirus, Epstein-Barr, influe nza, 
echovirus, human immunodeficiency virus 
 bacterial infections: syphilis, Lyme disease 
 post-infections or vaccination (immune mediated) 
 first symptom of multiple sclerosis (MS) or neuromyelitis optica (NMO) 
 Signs  (develop over hours to days, and are usually bilateral): 
 Sensory level is characteristic.

 Sensory level is characteristic. 
  Midline or dermatomal neuropathic pain can be present.  
 Urinary incontinence or retention, 
  bowel incontinence or constipation, 
  and sexual dysfunction are common but vary in severity. 131

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              127 
  Investigation 
 MRI is indicated to rule out the presence of structural lesions, and determine the presence 
of myelitis, which enhances with gadolinium in the acute phase. 
 There may be more than one area of myelitis, and the lesions usually sp an at least two 
vertebral segments.

vertebral segments. 
  In the acute phase the MRI may be normal.   
 Corticosteroids are first line, and are initially given in high doses intravenously. 
 Plasma exchange can be given to those who fail to respond.  
 Patients with demyelinating disease can be started on long term immunosuppression. 
 prognosis  
 predictors of poor prognosis  
 rapidly progressive course 
  severe weakness 
  hypotonia  
  areflexia

  areflexia 
 improvement can take three months and longer to develop 
 50% -   70% of patients have partial or complete recovery. 
 
Syringomyelia typically causes loss of reflexes, spinothalamic sensory loss (pain and 
temperature), and weakness. It can be asymmetrical initially  
Definition

 Syringomyelia is a degenerative  disease of the spinal cord that is characterized by a fluid-filled 
cavity within the cervical spinal cord. 
 development of cavity (syrinx) within the spinal cord  
 Syrinx (fluid-filled cavitation) in the central spinal cord, usually cervical. This can elongate a nd 
enlarge, causing  compression of the corticospinal and spinothalamic tracts and anterior horn 
cells. 
 if extends into medulla then termed syringobulbia

 Most of the cavities in syringomyelia lie between the second cervical  and the ninth thoracic  
vertebrae. 
 most commonly affecting the cervical region 
 collection of fluids within the central canal of the spinal cord enlargement spinal canal, leading 
to damage of the crossed fibers (anterior white commissure) of the spinothalamic tract   loss of 
pain and temperature sensation in the upper extremities 
 more common in men than women

 more common in men than women 
 usually presents in the 20s and 30s although it can present later in life. 
 
Causes 
 Arnold-Chiari malformation  type I  impaired cerebrospinal fluid circulation   
 The most common cause  
 arachnoiditis, 
 meningeal carcinomatosis, 
 space-occupying lesions  
 Post-traumatic syringomyelia  
 complicate up to 4% of spinal cord injury  
 often presents with pain, which spreads upwards from the initial injury site. 
 idiopathic.

 idiopathic. 
Features 
 maybe asymmetrical initially 
 slowly progressive  sensory and motor symptoms, possibly over years 
132

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              128 
  motor: wasting and weakness of arms 
 sensory: spinothalamic sensory loss (pain and temperature) 
 bilateral loss of pain and temperature sensation in the upper extremities. 
 fine touch sensation, vibration and proprioception are preserved 
 loss of reflexes, bilateral upgoing plantars 
 Horner's syndrome,

 Horner's syndrome, 
 seen in advanced syringomyelia due to disruption of sympathetic trunk  neurons.  
 Bladder, bowel and sexual dysfunction can develop  
MRI is the investigation of choice  
 MRI of the spinal cord  
 the diagnostic modality of choice .  
 MRI enhanced with gadolinium has more sensitivity than regular MRI. 
 Myelography  
 used to confirm the diagnosis but was associated with more deterioration 
Localization of the lesion :

Localization of the lesion :  
 At syrinx (there is anterior horn cell involvement) ĺ lower motor neuron pattern of weakness. 
 At central decussating fibres (spinothalamic tract) ĺ dissociated sensory loss with late 
development of neuropathic arthropathy. 
 At corticospinal tracts below the level of the syrinx results in spastic paraparesis. 
Defferntial diagnosis 
 Amyotrophic lateral sclerosis   NO  sensory deficits. 
 Anterior spinal artery thrombosis

 Anterior spinal artery thrombosis 
 characterised by loss of motor function below the level of injury , loss of pain and 
temperature sensations, and preservation of proprioception, fine touch and vibration. 
 Post-traumatic spinal stenosis 
 result in neurological changes below the level  of stenosis. 
 
 The mainstay of the treatment of is surgery. 
 
May 2010 exam: feature of weakness & wasting of the small muscles of the hand. Which one of the

following features would most support a diagnosis of syringomyelia? Loss of temperature sensation 
in the hands  
 133

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              129 
 
The presence of loss of pain and 
temperature sensation in a 'cape like' 
distribution is highly suggestive of 
syringomyelia. 
 
A fluid filled cavity within the cord 
develops, typically between C2 to T9, 
compressing the cord from inside to out.  
 
Arnold-Chiari malformation 
 Arnold-Chiari malformation describes the downward displacement, or herniation, of the cereb ellar 
tonsils through the foramen magnum.  
 Malformations may be congenital or acquired through trauma. 
 Symptoms of Arnold-Chiari malformation, type I develop as a result of three pathophysiological 
consequences  of the disordered anatomy:  
1. compression of the medulla and upper spinal cord,  
2. compression of the cerebell um,

2. compression of the cerebell um, 
3. disruption of cerebrospinal fluid flow through the foramen magnum. 
 classified by extent with which parts of the brain protrude into the spinal canal.  
 Chiari I malformation ,  
 the only type that can be acquired or can remain asymptomatic until late childhood 
or early adulthood.  
 characterized by: 
 the time of onset (late childhood/early adulthood) and

 the downward herniation of cerebellar tonsils, without the involvement  of 
brainstem tissue. 
 symptoms due to obstruction of cerebrospinal fluid flow.  
 more severe types of Chiari malformations would involve additional herniation 
of brainstem tissue (Types II and III) or incomplete development of the cerebellum as  a 
whole (Type IV). 
Features  
 non-communicating hydrocephalus may develop as a result of obstruction of cerebrospinal  fluid 
(CSF) outflow 
 neck pain  
 headache

 neck pain  
 headache 
  exacerbated by cough, valsalva maneuver and exercise. 
 changes in balance, and poor hand coordination  
 Syringomyelia 134

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              130 
  Downbeat nystagmus is classically associated with lesions at the foramen magnum 
(Arnold-Chiari malformation) 
 
MRI showing herniation of the 
cerebellar tonsils through the 
foramen magnum consistent 
with a Chiaria I malformation  
 
Anterior spinal artery thrombosis 
 
Anterior spinal artery thrombosis  Sudden paralysis and loss of pain and temperature 
sensation  below the level of the lesion.  
 
 it supplies, roughly the anterior 2/3 of the cord.   
Sequelae  
 Occlusion of the anterior spinal artery infarcts the ventral portion of the cord.  
 affects the structures found at the front of the spine 
 corticospinal tracts (motor neurons) 
 spinothalamic tracts (pain/temperature sensation). 
 
Feature

Feature 
 Light-touch sensation and proprioception  are preserved because these are carried in the 
dorsal columns that are supplied by the posterior spinal artery .  
 Power is reduced below the hips 
 Pain and temperature sensation are lost to the waist. 
 Vibration and joint-position sense are normal (found on posterior columns) 
 In the acute stage reflexes are diminished, in keeping with "spinal shock", this may last fo r 
several days  
 Injury level 
135

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              131 
  Anterior spinal cord lesions above  cervical vertebra 6  will result in tetraplegia  with 
involvement of the upper and lower extremities.  
 injuries from T1-T6 have normal upper extremity, although abdominal and chest muscles 
may be affected with diminished respiratory excursion.

 The region of thoracic vertebra 6  is the thoracic watershed (نzone; lesions below 
this level result in loss of bowel, bladder, and sexual functions.   
Anterior spinal arteries supply corticospinal and spinothalamic tracts , and anterior horns of 
the grey matter. 
 
What is the diagnostic possibilities of a lesion involve the anterior two thirds of the  spinal cord which 
spares light touch, vibration and position sense , but causes loss of pain and temperature sensation 
distally?.

distally?.  
The diagnostic possibilities  include : 
1- anterior spinal artery occlusion  sudden onset  
2- and intramedullary spinal cord metastasis  
Types of incomplete spinal cord syndromes 
 All types present with dissociated sensory loss: a pattern of selective sensory loss ( “dissociation 
of modalities ”); suggests a focal lesion of a single tract within the spinal cord 
 Affected spinal 
tracts Etiology Clinical features 
Central cord 
syndrome (most 
common) Bilateral central

common) Bilateral central 
corticospinal 
tracts  and lateral 
spinothalamic 
tracts   Hyperextension injury (e.g., 
car crash) associated with 
chronic cervical spondylosis 
 Spinal cord compression  Bilateral 
paresis: upper  > 
lower extremities 
Anterior cord 
syndrome Corticospinaland sp
inothalamic tracts  Trauma (e.g., penetrating 
injury, burst fracture of 
vertebra) 
 Occlusion of anterior spinal 
artery   Bilateral motor paralysis, 
loss of pain and

loss of pain and 
temperature sensation, 
and autonomic 
dysfunction below the 
level of the lesion 
Posterior cord 
syndrome Bilateral posterior 
columns  Trauma (e.g., penetrating 
injury) 
 Occlusion of the posterior 
spinal artery 
 Multiple sclerosis  Ipsilateral loss 
of proprioception , 
vibration, and touch 
sensationbelow the level 
of the lesion  
Brown-Séquard 
syndrome(hemi
section 
syndrome) Hemisectionof the 
cord  Trauma (e.g., penetrating 
injury)

injury) 
 Spinal cord compression  Ipsilateral  
 Loss 
vibration, and 
tactile discrimination 
below the level of the 
lesion 
 Segmental flaccid 
paresis at the level of 
the lesion, spastic  
paralysis below the 
level of the lesion , 
and 
ipsilateral Babinski 
sign 
 Contralateral : loss 
of pain and temperature 
sensation  one or two 
levels below lesion 136

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              132 
  
Para- spinal abscess 
 often associated with infection in an intravenous (IV) line, which may or may not be appa rent as 
cellulitis. 
 usually due to seeding of Staphylococcus aureus, endocarditis is a possibility. 
Features 
 spinal pain 
 fever

Features 
 fever 
 neurological deficit 
Diagnosis 
 MRI neck  is the investigation of choice 
 MRI of the neck should delineate the anatomy of the abscess, which will not be see n on a 
CT scan of the head. 
 CSF should show an elevated protein with raised white cells, and a low/normal glucose. 
 
 MRI demonstrates an epidural collection with 
peripheral contrast enhancement. The cord is 
displaced posteriorly and to the right.

displaced posteriorly and to the right.  
 Features are consistent with an epidural 
abscess.  
 There are associated changes at the C3/4 level 
consistent with advanced discitis 
osteomyelitis.  
 
Brown-Séquard's syndrome  
 Thoracic spinal cord lesion produced by a hemisection of the spinal cord. 
 Causes include: 
 trauma,  
 tumours, and  
 multiple sclerosis. 
 Presented with 
 ipsilateral weakness

 ipsilateral weakness  
 ipsilateral loss of position and vibration below the lesion (dorsal column dysfunction)  
 Contralateral  loss of pain and temperature. 
Lower back pain 
Lower back pain (LBP) is one of the most common presentations seen in practice. Whilst the majority of 
presentations will be of a non-specific muscular nature it is worth keeping in mind possible cau ses

which may need specific treatment.  
Red flags for lower back pain  
 age < 20 years or > 50 years 
 history of previous malignancy 
 night pain 
 history of trauma 
 systemically unwell e.g. weight loss, fever 
137

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              133 
 The table below indicates some specific causes of LBP: 
Facet joint May be acute or chronic 
Pain worse in the morning and on standing 
On examination there may be pain over the facets. The pain is typically worse on 
extension of the back 
Spinal stenosis  Usually gradual onset

Spinal stenosis  Usually gradual onset 
Unilateral or bilateral leg pain (with or without back pain), numbness, and weakness 
which is worse on walking.  
pain is worse with walking downhill and less with walking uphill. Resolves when sits 
down. Pain may be described as 'aching', 'crawling'. 
Relieved by sitting down, leaning forwards and crouching down 
Clinical examination is often normal 
Requires MRI to confirm diagnosis 
Ankylosing

Ankylosing 
spondylitis  Typically a young man who presents with lower back pain and stiffness 
Stiffness is usually worse in morning and improves with activity 
Peripheral arthritis (25%, more common if female) 
Peripheral 
arterial disease  Pain on walking, relieved by rest 
Absent or weak foot pulses and other signs of limb ischaemia 
Past history may include smoking and other vascular diseases 

Wernicke's encephalopathy 
 
 Wernicke's encephalopathy is a neuropsychiatric disorder caused by thiamine deficiency , 
which is most commonly seen in alcoholics. 
 Rarer causes include :  
 persistent vomiting,  
 stomach cancer,  
 dietary deficiency.  
 A classic triad of: 
 nystagmus, 
 ophthalmoplegia 
  and ataxia  
  In Wernicke's encephalopathy petechial haemorrhages occur in a variety of structures in th e 
brain including the mamillary bodies and ventricle walls

Features  
 nystagmus (the most common ocular sign) 
 ophthalmoplegia 
 ataxia 
 confusion, altered GCS 
 peripheral sensory neuropathy 
 Sometimes bilateral wrist drop but more frequently bilateral foot drop with pain or pressure over 
the long nerves. 
 decreased red cell transketolase 
 MRI 
Treatment is with urgent replacement of thiamine (Pabrinex (Intravenous))  
 
Relationship with Korsakoff syndrome  
 
Inability to acquire new memories and confabulation

suggests the development of Korsakoff's syndrome  
 
 If not treated Korsakoff's syndrome may develop as well. This is termed Wernicke-Korsakoff 
syndrome and is characterised by the addition of antero- and retrograde amnesia and   138

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              134 
 confabulation  in addition to the above symptoms.  
 MRI finding  mammillary body degeneration  
 
Marchiafava Bignami syndrome: Corpus callosum degeneration from chronic alcohol 
excess 

Acute disseminated encephalomyelitis 
 Acute disseminated encephalomyelitis (ADEM) is an autoimmune demylinating disease of th e 
central nervous system. It may also be termed post infectious encephalomyelitis. 
  The aetiology is not fully understood and it can occur following infection with a bacterial or viral 
pathogen. Common infections include measles, mumps, rubella, varicella and small pox, 
however this list is not exhaustive.

however this list is not exhaustive.  
 After a lag time of between a few days to 2 months there is an acute onset of multifocal 
neurological symptoms with rapid deterioration. 
  Non-specific signs such as headache, fever, nausea and vomiting may also accompany  the 
onset of illness.  
 Motor and sensory deficits are frequent and there may also be brainstem involvement including  
occulomotor defects.

occulomotor defects.  
 There are no specific biomarkers for the diagnosis of ADEM. MRI imaging may show areas of 
supra and infra-tentorial demylination. 
  Management involves intravenous glucocorticoids and the consideration of IVIG where t his fails. 
Anti-NMDA receptor encephalitis 
 Anti-NMDA receptor encephalitis is a paraneoplastic syndrome, presenting as prominent

psychiatric features including agitation, hallucinations, delusions and disordered thinking; 
seizures, insomnia, dyskinesias and autonomic instability. 
  Ovarian teratomas are detected in up to half of all female adult patien ts, particularly prevalent in 
Afro-Carribean patients. 
  MRI head can be normal but abnormalities can be visualised on FLAIR sequences in the  deep 
subcortical limbic structures. 
  CSF may demonstrate pleiocytosis but can be normal initially.

 Anti-MuSK is an autoantibody specific to muscle kinase in myasthenia gravis with no evidence of 
a thymoma and without antibodies to acetylcholine receptors.  
 Anti-GM1 is an autoantibody specific to acute inflammatory demyelinating polyneurop athy (AIDP) 
variant of Guillain-Barre syndrome. 
 Treatment of anti-NMDA encephalitis is based of immunosuppresion with intravenous steroi ds, 
immunoglobulins, rituximab, cyclophosphamide or plasma exchange, alone or in comb ination.

Resection of teratoma is also therapeutic.  
Autoimmune encephalitis 
Types  of autoimmune encephalitis include: 
 autoimmune limbic encephalitis (paraneoplastic and non-paraneoplastic) 
 Rasmussen's encephalitis 
 anti-NMDAR (NR1) encephalitis 
 glycine-receptor mediated encephalitis 
 Bickerstaff brainstem encephalitis 
Reye's syndrome

Reye's syndrome  
 Reye's syndrome is a severe, progressive encephalopathy affecting children that is accompanied  
by Microvesicular fatty infiltration  of the liver, kidneys and pancreas.  
 The aetiology  of Reye's syndrome is not fully understood although there is a known association 
with aspirin use and a viral cause has been postulated 
 The peak incidence is 2 years of age,  
 Features  include: 139

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              135 
  may be history of preceding viral illness 
 encephalopathy: confusion, seizures, cerebral oedema, coma 
 fatty infiltration of the liver, kidneys and pancreas  
 hypoglycaemia 
 Management  is supporti ve 
 Prognosis  although has improved over recent years there is still a mortality rate of 15-25%.

CADASIL 
Overview 
 Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy 
(CADASIL) 
 A family history is almost always present, as it is an autosomal dominant condition,  located to 
chromosome 19 . 
Features 
 rare cause of multi-infarct dementia 
 patients often present with migraine 
 Recurrent ischaemic events (transient or permanent) & Severe mood disorders 
Diagnosis

Diagnosis 
 Characteristic MRI changes include T2 weighted hyperintensity of  the periventricular white 
matter. 
 DNA testing  for the notch-3 gene mutation  confirms the diagnosis. 
Treatment 
 the oral contraceptive pill should be stopped , given its association with stroke in migraine. 
Myotonic dystrophy 
 
 Myotonic dystrophy (Steinert's disease)  (also called dystrophia myotonica) is an inherited 
myopathy

myopathy  
 the most common adult  muscular dystrophy. 
 It affects skeletal, cardiac and smooth muscle.  
140

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              136 
  results in a selective atrophy of type I muscle fibers  
 features developing at around 20-30 years old.  
 There are two main types of myotonic dystrophy, DM1 and DM2.  
 Congenital myotonic dystrophy is a more severe form of the disease that occurs in children

born to mothers who have established myotonic dystrophy . Babies are hypotonic and 
frequently require assisted ventilation.  
Genetics  
 autosomal dominant 
 a trinucleotide repeat disorder 
 DM1 is caused by a CTG repeat at the end of the DMPK (Dystrophia Myotonica-Protein Kinase ) 
gene on chromosome 19 
 DM2 is caused by a repeat expansion of the ZNF9 gene on chromosome 3 
The key differences are listed in table below:  
DM1 DM2 
- DMPK gene on chromosome 19

DM1 DM2 
- DMPK gene on chromosome 19 
- Distal weakness more prominent - ZNF9 gene on chromosome 3 
- Proximal weakness more prominent 
- Severe congenital form not seen 
General features 
 myotonic facies (long, 'haggard' appearance) 
 frontal balding 
  some women have hair loss 
 Atrophy of temporalis, masseters and facial muscle 
 bilateral ptosis 
 cataracts 
 myotonia (tonic spasm of muscle)

 myotonia (tonic spasm of muscle) 
 Neck muscles, including sternocleidomastoid, are involved early in the course of disease. 
 weakness of arms and legs (distal initially) 
 Distal weakness is often more marked than proximal weakness 
 mild mental impairment 
 diabetes mellitus (Insulin resistance) 
 testicular atrophy 
 slow-relaxing grip  may be noticed on initial hand-shake with the patient and is typical of 
myotonic dystrophy.

myotonic dystrophy.  
 Dysarthric speech secondary to myotonia of the tongue and pharynx  
 cardiac involvement: heart block, cardiomyopathy 
 dysphagia  
 Cataracts are common 
Diagnosis 
 Diagnosis can be made on electromyogram (EMG) 
 The most appropriate next step to confirm the diagnosis 
 EMG changes are found in almost any muscle  
 Wasxing and waning of potentials , termed the “dive bomber effect ” 
 Genetic testing can confirm the diagnosis 
Evaluation

Evaluation  
 Serology  increased serum CK 
 
Treatment ( mostly symptomatic ) 
 for weakness - which is the main cause of disability-     There is no treatment 
 for myotonia  phenytoin, quinine or procainamide may be useful  
 for cardiac abnormalities   pacemaker 
 for obstructive sleep apnea (common)  CPAP  
 
 141

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              137 
 _____________________________________________________________ 
Dystrophinopathies 
Overview 
 X-linked recessive 
 Affected father (Y, X): 
 All sons will not be affected and not carriers (His sons will get the X chromosome 
from their mother) 
 All his daughters will be carriers 
 Carrier mother (X , X):

 Carrier mother (X , X): 
 50% of sons will be affected  (there is a 1 in 2 chance (50:50) of passing the gene 
on to their sons.) 
 due to mutation in the gene encoding dystrophin, dystrophin gene on Xp21  
 dystrophin is a protein in muscle which connects the muscle membrane to actin, part of th e 
muscle cytoskeleton 
 
Diagnostic investigations 
 1st investigations to order 
 serum CK 
 50 to 100 times normal level consistent with Duchenne muscular dystrophy 
 genetic testing

 genetic testing 
 DNA analysis  Xp21 mutation    may present in both Duchenne and Becker 
muscular dystrophies  
 Investigations to consider 
 EMG 
  EMG can distinguish between neuropathic and myopathic pathology. 
 myopathic reading  with fast firing , short duration  but polyphasic  and 
decreased amplitude  motor units with early recruitment  in the affected muscles 
 muscle biopsy 
 absence of dystrophin    Duchenne  muscular dystrophy

 diminished quantity or quality of dystrophin  Becker  muscular dystrophy 
Duchenne muscular dystrophy (DMD) 
  most common and most rapidly progressive muscular dystrophy 
 there is a  frameshift mutation  resulting in one or both of the binding sites are lost leading to a 
severe form   
 progressive proximal muscle weakness from 5 years  
 Usually, there is severe progression with wheelchair dependence by the age of 12 on 
average

average  
 Death usually occurs as a teenager or in the early 20s from respiratory failure. 
 calf pseudohypertrophy 
 Gower's sign: child uses arms to stand up from a squatted position 
 intellectual impairment ( 30%) 
 urinary and bowel incontinence (common) 
 DMD patients tend to be hyperactive and have difficulty in focusing attention. 
Becker muscular dystrophy 
 there is a non-frameshift insertion  in the dystrophin gene resulting in both binding sites being

preserved leading to a milder form  
 develops after the age of 10 years 
 Similar type of disease to Duchenne's, with a later onset (average age at presentation 12 
years), milder phenotype and longer life expectancy 
 intellectual impairment much less common 
 Occasionally, patients present with CHF and cardiac arrhythmias before complaining of muscle 
weakness and before diagnosis. 
Facio-scapulo-humeral muscular dystrophy

Facio-scapulo-humeral muscular dystrophy 
 Facioscapulohumeral muscular dystrophy (FSHMD) is an autosomal dominant form of muscular 
dystrophy.  
 As the name suggests it stypically affects the face, scapula and upper arms first.  142

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              138 
  Symptoms typically presents by the age of 20 years. 
 may go unrecognised until later life 
 The presence of distal wasting and pes cavus  (indicates a very chronic neuromuscular  
disorder  with axonal loss) 
Foster-Kennedy syndrome

Foster-Kennedy syndrome 
Foster Kennedy's syndrome is a combination of optic atrophy and central scotoma, contralateral 
papilloedema and anosmia. 
 Foster-Kennedy syndrome describes a series of symptoms and signs associated with fron tal lobe 
lesions.  
 It is caused by optic and olfactory nerve compression and raised intracranial pressure. 
  This is often secondary to a mass such as an olfactory groove meningioma . 
Features  
 optic atrophy in the ipsilateral eye

 optic atrophy in the ipsilateral eye 
 central scotoma in the ipsilateral eye 
 papilloedema in the contralateral eye 
 anosmia 
 symptoms of raised intracranial pressure such as nausea and vomiting,  
 frontal symptoms such as emotional lability and memory loss. 
Hypokalaemic periodic paralysis 
 autosomal dominant disorder  
 The underlying defect is a mutation in muscle voltage-gated calcium channels .

Features 
 Episodes of paralysis,  
 Symptoms begin with stiffness and heaviness of the limbs followed by weakness , 
Examination during an attack will demonstrate weakness with hyporeflexia  
 Occasionally the respiratory and bulbar muscles may be involved.  
 Age  Onset usually in adolescence  
 Time Typically occur at night. 
 Duration Attacks can last from several minutes to hours , although they may last 
for up to 3 days  
 Attacks may be precipitated by: 
 Carbohydrate meals.

 Carbohydrate meals. 
 Exercise 
 sodium-rich meals followed by exertion  
 may associate with thyrotoxicosis 
 with thyrotoxicosis called Thyrotoxic hypokalaemic periodic paralysis  
 Without thyrotoxicosis called hypokalaemic periodic paralysis. 
 The prevalence is much higher in patients with thyrotoxicosis of Chinese origin versus 
Caucasians, (13-14% vs. 0.1-0.2%).  
 occurs in 10% of young Latin American or Asian men with thyrotoxicosis (of whatever 
aetiology).

aetiology). 
Diagnosis  
 documentation of hypokalaemia during an attack 
 Potassium infusion  provide immediate relief from symptoms 
 lifelong potassium supplementation 
 continuous cardiac monitoring  
 The periodic paralysis resolves when the thyrotoxicosis is treated. 
 
 143

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              139 
Mental Capacity Act 
 Mental capacity includes the ability to make decisions affecting daily life, healthcare and f inancial 
issues.  
 It applies to adults over the age of 16 and sets out who can take decisions i f a patient becomes

incapacitated (e.g. following a stroke).  
 The Act contains 5 key principles:  
1. A person must be assumed to have capacity unless it is established that he lacks capacity 
2. A person is not to be treated as unable to make a decision unless all practicable steps t o 
help him to do so have been taken without success 
3. A person is not to be treated as unable to make a decision merely because he make s an 
unwise decision

unwise decision 
4. An act done, or decision made, under this Act for or on behalf of a person who lacks 
capacity must be done, or made, in his best interests 
5. Before the act is done, or the decision is made, regard must be had to whether the  
purpose for which it is needed can be as effectively achieved in a way that is less 
restrictive of the person's rights and freedom of action 
Assessment of capacity 
 An adult can only be considered unable to make a particular decision if:

1. has an 'impairment of, or disturbance in, the functioning of the mind or 
brain' whether permanent or temporary AND  
2. unable to undertake any of the following 
 
a) understand the information relevant to the decision 
b) retain that information 
c) use or weigh that information as part of the process of making the decision 
d) communicate the decision made by talking, sign language or other means

 No individual can be labelled 'incapable' simply as a result of a particular medical condition.  
 a lack of capacity cannot be assumed by a person's age, appearance, or any condition o r aspect 
of a person's behaviour 
Best interests  
 
The following should be considered when assessing what is in someone's best interests:  
 1. Whether the person is likely to regain capacity and can the decision wait. 
 2. How to encourage and optimise the participation of the person in the decision.

 3. The past and present wishes, feelings, beliefs, values of the person and any o ther relevant 
factors 
 4. Views of other relevant people 
Lasting Powers of Attorney (LPAs)  
 The Act allows a person to appoint an attorney to act on their behalf if the y should lose capacity 
in the future, replacing the current Enduring Power of Attorney (EPA). 
  In addition to property and financial affairs the Act also allows people to em power an attorney 
make health and welfare decisions.

make health and welfare decisions.  
 The attorney only has the authority to make decisions about life-sustaining treat ment if the LPA 
specifies that.  
 Before it can be used an LPA must be registered with the Office of the Public Guardian 
Advance decisions  
 Advance decisions can be drawn up by anybody with capacity to specify treatments they would 
not want if they lost capacity.  
 They may be made verbally unless they specify refusing life-sustaining treatment (e.g .

Ventilation) in which case they need to be written, signed and witnessed to be va lid.  
 Advance decisions cannot demand treatment 
 
 144

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              140 
Neuromyelitis optica 
Neuromyelitis optica is a demyelinating disease involving the optic nerves and spinal cord b ut sparing 
the brain. The specific test for this is the NMO antibody which is against aquaporin 4.

 Neuromyelitis optica (NMO) is monophasic or relapsing-remitting demyelinating CNS disorder  
 Although previously thought to be a variant of multiple sclerosis, it is now recognised to be a  
distinct disease 
 particularly prevalent in Asian populations 
 typically involves the optic nerves  and cervical spine , with imaging of the brain frequently 
normal .  
 Vomiting is also a common presenting complaint.

 Diagnosis  is requires bilateral optic neuritis, myelitis and 2 of the follow 3 criteria 
1. Spinal cord lesion involving 3 or more spinal levels 
2. Initially normal MRI brain 
3. Aquaporin 4 positive serum antibody 
Oculopharyngeal muscular dystrophy 
Features 
 ptosis 
 weakness of the extraocular muscles 
 dysphagia 
 tongue atrophy 
Superficial siderosis

Superficial siderosis 
Superficial siderosis describes the chronic deposition of iron in neurons of the central nervou s system. 
The most common cause is chronic bleeding secondary to either a subarachnoid haemorr hage or 
subdural haemorrhage. 
 
Features 
 sensorineural hearing loss 
 ataxia 
 dementia 
 anosm ia 
 anisocoria 
 
 145

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              141 
Vertigo 
The table below lists the main characteristics of the most important causes of vertigo 
 
Disorder Notes 
Labyrinthitis  Recent viral infection  or head trauma 
Sudden onset 
Nausea and vomiting 
 typically has associated tinnitus and a history of infection.

Hearing may be affected 
Vestibular neuritis  Recent viral infection 
Recurrent vertigo attacks lasting hours or days 
No hearing loss 
Benign paroxysmal 
positional vertigo  Gradual onset 
Triggered by change in head position 
Each episode lasts 10-20 seconds 
Meniere's disease  Associated with hearing loss, tinnitus and sensation of fullness or pressure in 
one or both ears 
Vertebrobasilar 
ischaemia  Elderly patient 
Dizziness on extension of neck

Dizziness on extension of neck 
Acoustic neuroma  Hearing loss, vertigo, tinnitus 
Absent corneal reflex is important sign 
Associated with neurofibromatosis type 2 
 Cerebellar stroke may present in a similar fashion to vestibular neuritis.  
 Clinically, vertical nystagmus is suggestive of a central cause of vertigo.  
 Additionally, patients usually cannot stand without support, even with the eyes o pen, 
whereas a patient with acute vestibular neuritis is usually able to do so.

Other causes of vertigo include 
 trauma 
 ototoxicity e.g. gentamicin 
 Migraine is a another common cause of vertigo 
Benign paroxysmal positional vertigo  
 Benign paroxysmal positional vertigo (BPPV) is one of the most common causes of vertigo 
encountered.  
 It is characterised by the sudden onset of dizziness and vertigo triggered by changes in h ead 
position.

position.  
 The average age of onset is 55 years and it is less common in younger patients. 
 
Features  
 
Vertigo and nausea, with nystagmus, fit best with benign paroxysmal positional vertigo , 
which occurs due to otolith detachment into the semicircular canals of the inner ear.   
 
 vertigo triggered by change in head position (e.g. rolling over in bed or gazing upwards)  
 may be associated with nausea 
 each episode typically lasts 10-20 seconds 
 positive Dix-Hallpike manoeuvre

 positive Dix-Hallpike manoeuvre 
Treatment:   
 Symptomatic relief may be gained by: 
 Epley manoeuvre (successful in around 80% of cases) 146

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              142 
  teaching the patient exercises they can do themselves at home, for example Brandt-Daroff 
exercises 
 Medication is often prescribed (e.g. Betahistine) but it tends to be of limited value. 
Prognosis:  BPPV has a good prognosis and usually resolves spontaneously after a few wee ks to 
months.

months.  
May 2013 exam: H/O vertigo and dizziness precipitated by a change in head position. What 
is the most appropriate next step to confirm the diagnosis? Dix-Hallpike manoeuvre  
Meniere's disease  
 Meniere's disease is a disorder of the inner ear of unknown cause.  
 It is characterised by excessive pressure and progressive dilation of the endolymphatic system.

 It is more common in middle-aged adults but may be seen at any age.  
 has a similar prevalence in both men and women. 
Features  
 recurrent episodes of vertigo, tinnitus and hearing loss (sensorineural). Vertigo is usually th e 
prominent symptom 
 a sensation of aural fullness or pressure is now recognised as being common 
 other features include nystagmus and a positive Romberg test 
 episodes last minutes to hours

 episodes last minutes to hours 
 typically symptoms are unilateral but bilateral symptoms may develop after a number of  years 
Natural history 
 symptoms resolve in the majority of patients after 5-10 years 
 the majority of patients will be left with a degree of hearing loss 
 psychological distress is common 
 ENT assessment is required to confirm the diagnosis 
 patients should inform the DVLA. The current advice is to cease driving until satisfactory  control

of symptoms is achieved 
 acute attacks: buccal or intramuscular prochlorperazine. Admission is sometimes required 
 prevention: betahistine may be of benefit 
 
May 2013 exam: H/O recurrent attacks of 'dizziness' + 'roaring' sensation in the left ear. 
Weber's test localises to the right ear. What is the most likely diagnosis? Meniere's disease  
Neuropathy  

 Definitions  
 Allodynia : pain caused by a stimulus  that does not normally cause pain (e.g. light touch, 
contact with clothing)  
 Dysesthesia : abnormal spontaneous  sensations (burning, stinging, stabbing) from 
activities that do not normally cause pain )  
 Paresthesia : an abnormal skin sensation in the absence of a stimulus  (described as 
burning, prickling, itching, tingling)  
 Hyperesthesia : increased sensitivity to sensory stimuli

 Hypoesthesia : decreased sensitivity to sensory stimuli  
 
Peripheral neuropathy 
 neuropathy is classified into: 
  mononeuropathy commonly due to entrapment or trauma;  
 mononeuropathy multiplex commonly due to leprosy and vasculitis; and  
 polyneuropathy due to systemic, metabolic or toxic etiology.  
 Peripheral neuropathy may be divided into conditions which predominately cause a mo tor or 
sensory loss 
 
 147

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              143 
  
Predominately motor loss  Predominately sensory loss 
 porphyria 
 lead poisoning 
 hereditary sensorimotor neuropathies 
(HSMN) - Charcot-Marie-Tooth 
 chronic inflammatory demyelinating 
polyneuropathy (CIDP) 
 diphtheria  diabetes 
 uraemia 
 leprosy 
 alcoholism 
 vitamin B12 deficiency

 vitamin B12 deficiency 
 amyloidosis 
 Sjogren's syndrome 
 
Types 
 Large -fibre neuropathy   
 generally causes glove and stocking sensory loss and loss of reflexes . 
 Small-fibre neuropathy  
 typically presents with pain and loss of temperature sensation, with relative preservation 
of other sensory modalities and muscle strength.  
 General neurological examination and reflexes are usually normal

 not detectable on conventional nerve conduction studies, which can only investigate la rge 
fibres.  
 Causes  of small fiber neuropathy  
 Diabetes 
 is a common  cause and should be excluded in any patient with a painful 
peripheral neuropathy. 
 Conditions in which the small fibres are preferentially affected in the early 
stages include diabetes  and amyloidosis . In the later stages however the 
neuropathy in these conditions also affects large fibres. 
 Amyloidosis

 Amyloidosis 
 Fabry's disease 
 X-linked lysosomal storage disorder  
 causes a painful peripheral neuropathy, due to deposition of 
glycosphingolipids within small sensory fibres.  
 Nerve conduction studies are typically normal as large fibres are 
unaffected.  
 Tangier's disease 
 Hereditary sensory and autonomic neuropathy 
 Sjogren's syndrome 
 pure sensory  neuropathy (ganglionopathy). 
 Chronic idiopathic small fiber sensory neuropathy

Small-fibre neuropathy  Large-fibre neuropathy  
Loss of pain and temperature  Loss of touch, vibration and position sense  
Sensory ataxia 
Preservation of reflexes and motor function Reflexes lost early and motor functions impaired 
Electrophysiological test is silent 
Skin biopsy are used  Impaired nerve conduction velocity   
 
 Skin punch biopsy  can be done if a small-fiber neuropathy  is suspected;  
 loss of nerve endings supports that diagnosis.

Nerve biopsy  is occasionally done to help differentiate demyelinating from vasculitic large-fiber 
neuropathies.  
 If vasculitis is a consideration, the biopsy specimen should include skin and muscle  to 
increase the likelihood of a definitive diagnosis.  
 If all limbs are affected, MRI can be done to rule out cervical spinal cord compression . 
 
 148

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              144 
  
 Lead neuropathy  
  purely motor  neuropathy  
 affecting mainly the  upper  limbs . 
 
 Thalamic infarcts 
 commonly cause late-onset of severe neuropathic pain weeks to months after the stroke.   
 The pain is intractable to analgesics. 
 The treatment of choice for neuropathic pain is amitriptyline/gabapentin.

Alcoholic neuropathy  
 Alcohol abuse and diabetes are the commonest causes of peripheral neuropath y in the United 
Kingdom.  
 Typically, all fibre types are affected  and it is seen with a higher alcohol consumption more 
than 30 units.  
 affects mainly the spinothalamic pathway. 
 secondary to both direct toxic effects and reduced absorption of B vitamins ( thiamine 
deficiency ) 
Features

Features  
 slowly progressive 
 sensory symptoms typically present prior to motor symptoms 
 Pain is usually a more dominant feature 
Treatment   
 thiamine  and cessation of alcohol use   
Neuropathy of Vitamin B12 deficiency  
  leads to demyelination   
 usually causes a more rapidly progressive neuropathy with dorsal column involvement (joint

position and vibration involvement with sensory ataxia and pseudoathetosis of upper li mbs).  
 most commonly involves the peripheral nerves, but can also result in subacute degen eration of 
the spinal cord. 
 Peripheral involvement results in loss of vibration sense and proprioception. 
 Cord involvement then affects the posterior columns and corticospinal tracts resulting in 
loss of reflexes, weakness, spasiticity, Babinski's responses and ataxia.

Course of the neuropathy (http://emedicine.medscape.com)  
 Early in the course, poor joint position and vibration sense predominate.  
 dorsal column usually affected first (joint position, vibration ) prior to distal 
paraesthesia 
 Typically, the legs are affected before the arms.   
 On presentation, 50% of patients have absent ankle reflexes with relative hyperreflexia a t the 
knees.  
 Plantars are initially flexor and later extensor.

 As the disease progresses, ascending loss of pinprick, light touch, and temperature sensatio n 
occurs.  
 Later, depending on the predominance of posterior column versus cortical spinal tract 
involvement, ataxia or spastic paraplegia predominates.  
 Then, PNS involvement causes distal limb atrophy. 
 
 149

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              145 
Peripheral neuropathy: axonal vs. demyelinating   
neuropathy  Causes Nerve conduction studies 
(NCS) 
 
Axonal   alcohol  
 isoniazid  
 Simvastatin 
 diabetes mellitus*  
 vasculitis 
 vitamin B12 deficiency*  
 Renal failure

 Renal failure 
(HSMN) type II  
(*may also cause a demyelinating picture)   
 
 normal conduction 
velocity 
 reduced amplitude 
 
Demyelinating  Guillain-Barre syndrome   
 Paraproteinaemia 
 Amiodarone   (Amiodarone can cause 
a mixed demyelinating and axonal 
picture) 
 Refsum's disease 
 hereditary sensorimotor neuropathies

(HSMN)  type I (Charcot-Mar ie-Tooth 
disease) 
 Leukodystrophies.  
 
 reduced conduction 
velocity 
 normal amplitude 
 
 Nerve conduction studies (NCS) are useful in determining between axonal and demyelinating  
pathology   
 Segmental demyelination is a feature seen in axons in the central nervous system with multiple 
sclerosis . 
___________________________________________________________   
Wallerian degeneration

Wallerian degeneration  
  Wallerian degeneration is degeneration of the portion of the nerve distal to the injury. 
 It occurs following axonal injury in both the peripheral and central nervous systems  
 usually begins within 24-36 hours of injury. 
 Chronic inflammatory demyelinating polyneuropathy (CIDP) 
Chronic inflammatory demyelinating polyneuropathy is clinically similar to Guill ain-

Barre  syndrome (hyporeflexia or areflexia, paraesthesia and mild sensory deficits in the u pper 
and lower extremities, weakness) except that it follows a chronic progressive course.  
 
 CIDP is characterised by progressive weakness and impaired sensory function in the upper  and 
lower limbs.  
 subacute  sensory and motor peripheral neuropathy 
 The cause of the demyelination is not understood,  
 More common in young adults and in men.

 More common in young adults and in men.  
 mainly causes motor impairment (distal and proximal). 
 presents with  
 weakness of the limbs 
 areflexia  
 abnormal sensation (which typically begins distally) 
 fatigue. 
  (CIDP) causes a large fibre peripheral neuropathy (Joint position sense and 
vibration are carried through large fibres) 
 Autoantibodies against GM1 gangliosides 
  Differential diagnosis 150

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              146 
 1. CIDP is closely linked to Guillain-Barré syndrome (GBS ), and is thought by some to be 
its chronic counterpart.   
 Both CIDP and GBS can affect motor and sensory nerves 
  (GBS) is an acute  (which reaches its peak in severity within six weeks ), post-
infectious neuropathy

infectious neuropathy 
 Whereas CIDP is subacute (several months history)  
2. Hereditary motor and sensory neuropathy (HMSN)  is normally a very chronic 
neuropathy developing over many years  and usually with a family history of the condition. 
  plasmapheresis  
 intravenous immunoglobulin 
 Physiotherapy  
Electromyogram (EMG)

Electromyogram (EMG)  
 A pattern of rapidly recruited low amplitude short duration motor units on the electromyogram  
(EMG) would be considered to represent myopathic changes rather than de-innervation.  
Multifocal motor neuropathy (MMN) 
 Acquired autoimmune demyelinating motor neuropathy 
 Associated with motor conduction block ( Multifocal motor neuropathy with conduction bl ock 
(MMN -CB) 
Feature:

(MMN -CB) 
Feature:  
 Features of MMN-CB may resemble motor neuron disease but in contrast MMN-CB may 
respond well to intravenous immunoglobulin.  
 Slowly progressive, distal motor neuropathy which progresses over many years 
 asymmetric  muscle weakness, which is slowly progressive , and without sensory signs . 
 Weakness without wasting  is another typical feature. 
 Differential weakness of finger extension is a typical presentation, and reflects a patholog ical

process which selectively affects particular motor fibres within a peripheral nerve (eg: posterior 
interosseous branch of the radial nerve).  
 Nerve conduction studies show areas of conduction block outside usual areas for compression . 
 Anti-GM1 antibodies frequently raised 
 motor neuron disease (MND)  
 bulbar weakness is common in MND but rare in MMN. 
 variable upper motor neuron signs may occur in MND, contrary to MMN which is a purely

lower motor neuron condition occurring in a distribution correlating with named peripheral 
nerves. 
 whereas MND is usually fatal within 5 years, MMN is slowly progressive over decades 
and does not typically cause respiratory failure. 
 Chronic inflammatory demyelinating polyneuropathy(CIDP)  
 (CIDP) typically causes a progressive sensory and motor neuropathy with loss of reflexes.  
 CSF protein is elevation and nerve conduction studies show evidence of demyelination.

 Inclusion body myositis  
 characteristically causes weakness of finger flexion, as well as knee extension and ankle 
dorsiflexion.  
 Affected muscles are wasted, 
 fasciculations do not occur as there is no denervation. 
Treatment:  
 Intravenous immunoglobulin can produce a rapid improvement in weakness. 
Diabetic neuropathy  (see endocrinology system)  
 151

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              147 
  
Neuropathic pain 
 Neuropathic pain may be defined as pain which arises following damage or disruption of the 
nervous system.  
 It is often difficult to treat and responds poorly to standard analgesia. 
 
Examples include:  
 diabetic neuropathy 
 post-herpetic neuralgia 
 trigeminal neuralgia

 trigeminal neuralgia 
 prolapsed intervertebral disc 
 
Management of neuropathic pain (NICE guidance 2013): 
 first-line treatment*: amitriptyline, duloxetine, gabapentin or pregabalin 
 *please note that for some specific conditions the guidance may vary. For example carbamazepin e is 
used first-line for trigeminal neuralgia  
 if the first-line drug treatment does not work try one of the other 3 drugs 
 tramadol may be used as 'rescue therapy' for exacerbations of neuropathic pain

 topical capsaicin may be used for localised neuropathic pain (e.g. post-herpetic neuralgia)  
 pain management clinics may be useful in patients with resistant problems 
 
January 2012 exam: severe 'shooting' pains after blistering rash. What is the most 
appropriate next step in management?  Amitriptyline  
Drugs causing peripheral neuropathy 
Drugs causing a peripheral neuropathy 
 antibiotics: nitrofurantoin, metronidazole

 antibiotics: nitrofurantoin, metronidazole 
 amiodarone 
 isoniazid 
 vincristine 
 tricyclic antidepressants 
Autonomic neuropathy 
Features 
 impotence, inability to sweat, postural hypotension 
 postural hypotension e.g. drop of 30/15 mmHg 
 loss of decrease in heart rate following deep breathing 
 pupils: dilates following adrenaline instillation 
Causes 
 diabetes 
 Guillain-Barre syndrome

Causes 
 diabetes 
 multisystem atrophy (MSA), Shy-Drager syndrome 
 Parkinson's 
 infections: HIV, Chagas' disease, neurosyphilis 
 drugs: antihypertensives, tricyclics 
 craniopharyngioma 
Hereditary sensorimotor neuropathy (HSMN)  
Mixed motor and sensory symptoms, slowly progressing initially in the lower limbs and then to  the upper

limbs, together with a family history suggests a diagnosis of Hereditary sensorimotor neurop athy 
(HSMN)   
 
 Hereditary sensorimotor neuropathy (HSMN) is a relatively new term which encompasses 
Charcot-Marie-Tooth disease  (also known as peroneal muscular atrophy).  
 Over 7 types have been characterised - however only 2 are common to clinical practice 152

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              148 
 1. HSMN type I: primarily due to demyelinating pathology 
2. HSMN type II: primarily due to axonal pathology 
HSMN type I 
 due to defect in PMP-22 gene (which codes for myelin) 
 features often start at puberty 
 motor symptoms predominate 
 distal muscle wasting, pes cavus, clawed toes

 distal muscle wasting, pes cavus, clawed toes 
 foot drop, leg weakness often first features 
Diagnosis 
 Genetic testing usually reveals the diagnosis  
 neurophysiology  : Electro myography (EMG) and nerve conduction studies ( NCS ) may 
distinguish between the demyelinating (type 1) and axonal (type 2) forms. 
 
September 2007 exam: A woman with Charcot-Marie-Tooth disease (type 1), how likely her 
children will get the disease ? 50% (autosomal dominant)

Critical illness polyneuropathy 
 
Prolonged periods in the Intensive Therapy Unit, irrespective of the underlying pathology, are 
associated with a risk of developing critical illness polyneuropathy 
 This is an axonal neuropathy and thus muscle wasting may occur 
 It may be predominantly sensory, predominantly motor or mixed 
 Nerve conduction studies and electromyography may be indicated to confirm the diagn osis and

exclude any other condition that may require specific therapy (eg Guillain-Barre syndrome) 
 A patient with a previous history of chronic alcohol misuse, diabetes or another condition 
predisposing to neuropathy may be more prone to developing significant critical illness 
polyneuropathy 
Mononeuritis multiplex 
 Causes of mononeuritis multiplex include  
 Vasculitis 
  Diabetes 
 Sarcoidosis

  Diabetes 
 Sarcoidosis 
  paraneoplastic syndrome 
  amyloidosis 
 nerve biopsy should be performed to confirm the diagnosis 
 Treatment includes prednisolone and cyclophosphamide  
Vasculitic neuropathy 
 The presence of nail fold infarcts and the multifocal nature of the neuropathy indicate that 
a vasculitic cause is most likely

a vasculitic cause is most likely 
 Hepatitis C infection may be associated with cryoglobulinaemia, which causes a vasculitic 
syndrome including neuropathy 
Other conditions associated with vasculitic neuropathy include 
• Polyarteritis nodosa 
• Churg -Strauss syndrome 
• rheumatoid arthritis  
• systemic lupus erythematosus  
• systemic sclerosis  
• Wegener's granulomatosis  
Treatment include one or several of the following  
 high-dose intravenous steroids 
 plasma exchange

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              149 
Guillain-Barre syndrome 
 
 also known as  Post-infectious polyradiculopathy  
 Guillain-Barre syndrome describes an immune mediated demyelination of the peripheral ne rvous 
system often triggered by an infection :

system often triggered by an infection : 
  classically Campylobacter jejuni  
 cytomegalovirus  
Pathogenesis 
 cross reaction of antibodies with gangliosides in the peripheral nervous system 
 correlation between anti-ganglioside antibody (e.g. anti-GM1) and clinical features ha s been 
demonstrated 
 anti-GM1 antibodies in 25%  of patients 
 
Miller Fisher syndrome 
 
 variant of Guillain-Barre syndrome

 variant of Guillain-Barre syndrome 
 associated with ophthalmoplegia, areflexia and ataxia. The eye muscles are typically 
affected first  
 usually presents as a descending paralysis rather than ascending as seen in other forms of 
 anti-GQ1b antibodies are present in 90% of cases 
Features  
 characteristic features  
 progressive weakness of all four limbs. The weakness is classically ascending i.e. the

lower extremities are affected first, however it tends to affect proximal muscles earlier than 
the distal ones.  
 Sensory symptoms tend to be mild (e.g. distal paraesthesia) with very few sensory  signs.  
However, a sensory level is NOT a feature and would suggest cervical myelopathy  
 symmetrical involvement is typical, asymmetry present in only 9% of patients . 
 Some patients experience back pain in the initial stages of the illness. 
 Other features  
 areflexia

 cranial nerve involvement e.g. diplopia 
 autonomic involvement: e.g. urinary retention 
 Muscle wasting is typical with prolonged illness. 
 Bulbar involvement occurs in 50%,  with a risk of aspiration and respiratory insufficiency  
 urinary incontinence or retention (in 20% of cases). 
 Less common findings 
 papilloedema: thought to be secondary to reduced CSF resorption 

 (CSF) protein elevated, with normal glucose and no pleocytosis . 
 CSF cell counts are usually within normal limits, 
 a rise in CSF protein doesn ’t peak until the second or third week of the illness. 
 MRI may be indicated to rule out spinal cord lesions, peripheral neuropathis and neuromus cular 
junction disorders. 
 IV immunoglobulins (IVIG):   
 First line therapy .  
 as effective as plasma exchange. No benefit in combining both treatments.  
154

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              150 
  IVIG may be easier to administer and tends to have fewer side-effects 
 plasma exchange 
 steroids and immunosuppressants have not been shown to be beneficial 
 FVC regularly to monitor respiratory function .  
 FVC of less than 1 litre would be an indication for immediate ventilation

 Forced vital capacity of 1.4 L   is most likely to predict the need for invasive 
ventilation 
 FVC of less than 15ml/kg (or less than 30% of FVC predicted) or a rising PaCO 2 are 
indications for mechanical ventilation. 
 
Prognosis  
• 20% suffer permanent disability, 5% die 
Poor prognostic features  
 age > 40 years 
 poor upper extremity muscle strength 
 previous history of a diarrhoeal illness (specifically Campylobacter jejuni ) 
 high anti-GM1 antibody titre

 high anti-GM1 antibody titre 
 need for ventilatory support 
There is currently contradictory evidence as to whether a gradual or rapid onset of GBS is associated  
with a poor outcome 
 
Botulism  
 The clinical presentation of descending weakness with autonomic dysfunction (fixed 
dilated pupils) is typical of botulism. 
 It is a neuromuscular junction disorder and therefore nerve conduction studies and EMG are  
normal.

normal. 
 Repetitive nerve stimulation shows incremental responses, which is diagnostic of botulism. 
 Cerebrospinal fluid analysis is usually normal. 
 
May 2012 exam :  a patient developed weakness in his legs extended to his arms after viral 
illness . ĻĻ power, reflexes and sensation in his lower limbs. Developed SOB &ĻĻ (FVC). 
Given the likely diagnosis, what is the treatment of choice? Intravenous immunoglobulin

(Guillain-Barre syndrome (GBS) secondary to a viral illness, possibly the Epstein-Barr virus )  
 
May 2010 exam: H/O double vision & ĻĻ eye movement +  unsteadiness +   ĻĻ reflexes + past-
pointing . What is the most likely diagnosis? Miller Fisher syndrome  
 
January 2008 exam: Regarding nerve conduction studies for suspected Guillain-Barre syndrome. Which 
finding would be most consistent with this diagnosis? Reduced conduction velocity  
 
Bickerstaff's encephalitis

Bickerstaff's encephalitis   
 This is a rare immune disorder affecting the brainstem.  
 usually preceded by an infection, typically Campylobacter jejuni . 
 associated with autoantibodies against gangliosides, typically anti-GQ1b IgG, in the serum.  
 It causes drowsiness, ophthalmoparesis, ataxia and brisk reflexes.  
 The drowsiness and brisk reflexes  can be used to differentiate it from Miller-Fisher.

 It may be seen on MRI as hyperintensities in the brain stem on T2 weighted images. 
 
 155

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              151 
Tinnitus 
Causes of tinnitus include: 
Meniere's 
disease Associated with hearing loss, vertigo, tinnitus and sensation of fullness or pressure in 
Otosclerosis  Onset is usually at 20-40 years 
Conductive deafness 
Tinnitus 
Normal tympanic membrane*

Tinnitus 
Normal tympanic membrane* 
 *10% of patients may have a 'flamingo tinge', caused by hyperaemia 
Positive family history 
Acoustic 
neuroma  Hearing loss, vertigo, tinnitus 
Hearing loss  Causes include excessive loud noise and presbycusis 
Drugs  Aspirin 
Aminoglycosides 
Loop diuretics 
Quinine 
 
The combination of sensorineural deafness, facial nerve palsy and cranial nerve V involvement

suggests a cerebellopontine angle tumour, for example, acoustic neuroma. 
 
Other causes include 
 impacted ear wax 
 chronic suppurative otitis media 
Glomus jugulare tumours 
 Glomus jugulare tumours tend to present with pulsatile tinnitus  and conductive deafness .  
 Cranial nerves  IX, X and XI which run through the jugular foramen are also commonly 
affected to varying degrees.

affected to varying degrees.  
 Cranial nerves VII and XII may be affected if the tumour enlarges sufficiently. 
Meniere's disease 
 Meniere's disease is a disorder of the inner ear  of unknown cause. 
 characterised by excessive pressure and progressive dilation of the endolymphatic system. 
 more common in middle-aged adults but may be seen at any age.  
 similar prevalence in both men and women.

 similar prevalence in both men and women. 
Features  
 Recurrent episodes of vertigo,  
 Vertigo is usually the prominent symptom 
 tinnitus and hearing loss (sensorineural).   
 sensation of aural fullness or pressure  
 nystagmus  
 positive Romberg test 
 symptoms resolve in the majority of patients after 5-10 years

 the majority of patients will be left with a degree of hearing loss 156

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              152 
  psychological distress is common 
 patients should inform the DVLA. The current advice is to cease driving until satisfacto ry control 
 acute attacks: buccal or intramuscular prochlorperazine.

 Restriction of salt and fluid may hasten resolution.  
Hearing loss 
 
 Conductive hearing loss Sensorineural hearing loss 
Age of Onset  commonly in childhood  or young 
adulthood  commonly in middle or late age  
Etiology  Otosclerosis  
 Otitis media  
 Ear barotrauma 
 Cerumen Impaction  
 External auditory canal atresia  Ménière's disease  
 Acoustic neuroma

 Acoustic neuroma  
 Noise-induced hearing loss 
 Internal ear infections 
 Presbycusis  
Pathophysiology  External  or middle  ear pathology 
that disrupts conduction of 
sound  into the inner ear  Inner ear , cochlear , or auditory 
nerve  pathology that impairs 
neuronal transmission  to the brain 
Clinical Features  Hearing improves in noisy 
environments  
 Volume of voice remains normal 
because inner ear and auditory 
nerve are intact 
 Sound normally is not distorted

 Sound normally is not distorted 
 Features of external auditory canal 
pathology 
(e.g., cerumen impaction)  Hearing worsens in noisy 
 Volume of voice may be loud 
because nerve transmissions are 
impaired 
 Tend to lose higher frequencies 
preferentially, such that sounds may 
be distorted 
 Absent features of external auditory 
canal pathology 
Weber 
Test(unilateral 
hearing loss)  Lateralization to impaired 
ear (cannot hear ambient room

ear (cannot hear ambient room 
noise well, so detection of vibration 
is greater)  Lateralization to good ear  (sound 
is not transmitted by damage inner 
ear or auditory nerve) 
Rinne 
hearing loss)  Bone conduction >  air 
conduction (vibrations bypass 
blockage to reach the cochlea)  Air conduction >  bone conduction 
(the inner ear or auditory nerve 
cannot transmit sound information 
well regardless of how vibrations 
reach the cochlea) 
 
Diagnostics

Diagnostics 
 Whispered voice test :  
 screening to determine extent of hearing loss 
 Rinne test and Weber test :  
 to classify hearing loss as conductive  or sensorineural  
 Pneumoscopy   
 (evaluates the mobility of the tympanic membrane):  
 for conductive hearing loss 
 Audiometry   
 for all patients without any obvious cause to hearing loss 
 Laboratory tests   157

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              153 
  (e.g., blood glucose, CBC with differential, TSH, and/or syphilis testing depending on the 
suspected etiology):  
 for patients with unexplained sensorineural hearing loss 
 MRI or CT scan  (of the posterior fossa) 
 indicated in patients with unilateral, gradual sensorineural hearing loss to 
exclude acoustic neuroma

exclude acoustic neuroma  
Rinne's and Weber's test 
 Performing both Rinne's and Weber's test allows differentiation of conductive and se nsorineural 
deafness. 
 Rinne's test  
 tuning fork is placed over the mastoid process until the sound is no longer heard, followe d 
by repositioning just over external acoustic meatus 
 air conduction (AC) is normally better than bone conduction (BC) 
 if BC > AC then conductive deafness

 if BC > AC then conductive deafness 
 Weber's test  
 tuning fork is placed in the middle of the forehead equidistant from the patient's e ars 
 the patient is then asked which side is loudest 
 in unilateral sensorineural deafness, sound is localised to the unaffected side 
 in unilateral conductive deafness, sound is localised to the affected side 
Sensorineural hearing loss

Sensorineural hearing loss  
 Sensorineural hearing loss is caused by lesions in the cochlea or the auditory nerve  or central 
connections .  
 It may be unilateral or bilateral.  
 The overall incidence is about 2 in 1000 children. 
 Language acquisition and secondary educational difficulties follow, with social iso lation, and an 
increased risk of mental health problems. 
The risk factors for sensori-neural deafness include :

 NICU admission - low birth weight, less than 32 weeks gestation, prolonged ventilation, 
prolonged jaundice, ototoxic drugs, hypoxic ischaemic encephalopathy, neonatal mening itis 
 Congenital infection (rubella, CMV) 
 Dysmorphic syndromes (affecting head and neck) 
 Family history of a close relative needing a hearing aid below the age of 5 years  
 Infections - acute bacterial or TB meningitis, mumps 
 Down syndrome - some 10%-15% of children with Down syndrome develop sensorineural

deafness. 
If all risk factors are considered only around 50% of cases could be identified by testing  between 5 and 
10% of all babies. 
Conductive hearing loss  
 Conductive hearing loss is related to middle ear  pathology.  
 This is commoner in: 
 Down syndrome  
 In Down syndrome: 60%-70& of children develop conductive deafness due to glue 
ear.  
 The eustachaian tube is small and glue ear may begin before the age of 1 .

 cleft palate,  
 Turner's syndrome,  
 facial malformation syndromes. 
Motion sickness 
 
 Motion sickness describes the nausea and vomiting which occurs when an apparent discre pancy 
exists between visually perceived movement and the vestibular systems sense of movement 
158

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              154 
  Management  
 the BNF recommends hyoscine (e.g. transdermal patch) as being the most effective 
treatment.  
 Use is limited due to side-effects 
 non-sedating antihistamines such as cyclizine or cinnarizine are recommended in 
preference to sedating preparation such as promethazine

DVLA: neurological disorders 
 
 The guidelines below relate to car/motorcycle use unless specifically stated.  
 For obvious reasons, the rules relating to drivers of heavy goods vehicles tend to be mu ch 
stricter 
Specific rules  
 first seizure : 6 months  off driving*.  
 *previously rule was 12 months. It is now 6 months off driving if the licence holder has

undergone assessment by an appropriate specialist and no relevant abnormality ha s been 
identified on investigation, for example EEG and brain scan where indicated 
 For patients with established epilepsy  they must be fit free for 12 months  before being able to 
drive 
 stroke or TIA : 1 month  off driving 
 multiple TIAs  over short period of times: 3 months off driving 
 craniotomy  e.g. For meningioma: 1 year  off driving

 if the tumour is a benign meningioma  and there is no seizure  history, licence can be 
reconsidered 6 months  after surgery if remains seizure free 
 pituitary tumour:  
 craniotomy: 6 months;  
 trans-sphenoidal surgery 'can drive when there is no debarring residual impairment like ly 
to affect safe driving' 
 narcolepsy/cataplexy:  
 cease driving on diagnosis,  
 can restart once 'satisfactory control of symptoms'

 chronic neurological disorders e.g. multiple sclerosis, motor neuron disease:  
 DVLA should be informed,  
 complete PK1 form (application for driving licence holders state of health) 
 Syncope 
 simple faint: no restriction 
 single episode, explained and treated: 4 weeks off 
 single episode, unexplained: 6 months off 
 two or more episodes: 12 months off 
Susac syndrome 
 Susac syndrome presents with the  triad of:

 Susac syndrome presents with the  triad of: 
 Encephalopathy  
 branch retinal artery occlusion  
 and hearing loss   
due to involvement of the pre-capillary arterioles of the brain, retina and cochlea.  
 Most commonly women in the age range 20- 40 years are afflicted.  
 Encephalopathy is often severe and associated with MRI changes due to corpus callosu m micro 
infarcts.  
159

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              155 
  Branch retinal artery occlusion in Susac is associated with retinal arterial wall plaques (Gass 
plaques) on fundoscopy and distinctive patterns of arterial wall hyper-fluorescence  on fluorescein 
angiography.  
 Hearing loss is of low or middle frequencies and can be profound and require cochlear imp lants.

 The aetiology of the microangiopathy in Susac syndrome remains unproven. Recent lit erature 
highlights the similarity between the microvascular changes observed in Susac syndrom e and 
juvenile dermatomyositis, with preliminary evidence that that Susac syndrome pathog enesis may 
be associated with anti-endothelial cell antibodies.  
 No clinical trials of treatment in Susac syndrome have been conducted. Reported trea tment

strategies involve steroids followed by immunosuppressive therapy including cyclophosphamide, 
mycophenalate mofetil, azathioprine, cyclosporin, immunoglobulins or plasma exchang e.  
Glasgow coma scale (GCS) 
 The Glasgow coma scale (GCS) can be useful as a predictor of outcome and a way to measu re 
and monitor patients with reduced consciousness.

and monitor patients with reduced consciousness. 
 It is made up of three components: eye opening, best verbal response and be st motor response. 
Each of these is scored, as shown below. 
Eye opening: 
Spontaneously 4 
To speech 3 
To painful stimulus 2 
No response 1 
Best verbal response: 
Orientated 5 
Disorientated 4 
Inappropriate words 3 
Incomprehensible sounds 2 
Best motor response: 
Obeys verbal commands 6 
Localises painful stimuli 5 
Withdrawal to pain 4

Withdrawal to pain 4 
Flexion to pain 3 
Extension to pain 2 
 The GCS defines coma as E = 2, V = 2, M = 4 or less. 
 The GCS is meaningless unless it is broken down into its components. 
 It is important to note that the GCS is unreliable and should not be applied to patients who are 
inebriated, intubated or who have a therapeutic or traumatic paralysis. 
 
 160

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              156 
Altitude related disorders 
Types 
 There are three main types of altitude related disorders: 
 All three conditions are due to the chronic hypobaric hypoxia which develops at hi gh altitudes  
1. acute mountain sickness (AMS),

1. acute mountain sickness (AMS),  
 Features  of AMS start to occur above 2,500 - 3,000m,  
 developing gradually over 6-12 hours and potentially last a number of days 
 headache 
 nausea 
 fatigue 
 Prevention and treatment of AMS 
 the risk of AMS may actually be positively correlated to physical fitness 
 gain altitude at no more than 500 m per day 
 acetazolamide (a carbonic anhydrase inhibitor) is widely used to prevent 
AMS and has a supporting evidence base 
 Treatment:

 Treatment:  
 Descent 
 generally a self-limiting condition.  
2. high altitude pulmonary edema (HAPE)  
 A minority of people above 4,000m go onto develop high altitude pulmonary 
oedema (HAPE) 
 potentially fatal conditions 
 HAPE presents with classical pulmonary oedema features 
 Management of HAPE 
 descent 
 nifedipine, dexamethasone, acetazolamide, phosphodiesterase type V 
inhibitors 
 All seem to work by reducing systolic pulmonary artery pressure 
 oxygen if available

 oxygen if available 
3. high altitude cerebral edema (HACE).  
 A minority of people above 4,000m go onto develop high altitude cerebral oedem a 
(HACE),  
 HACE presents with headache, ataxia, papilloedema 
 Management of HACE 
 descent 
 dexamethasone 
Complex regional pain syndrome (CRPS) 
  (CRPS) is the modern, umbrella term for a number of conditions such as reflex sympathetic

dystrophy and causalgia.  
  (CRPS) is a chronic pain condition that can affect any area of the body, but often aff ects an arm 
or a leg, and occurs after an injury or rarely after a sudden illness such as a heart attack or 
stroke.   
 typically occur following surgery or a minor injury.  
 The condition can sometimes appear without obvious injury to the affected limb. 
 3 times more common in women.

 3 times more common in women. 
 CRPS may have three stages (acute, dystrophic, and atrophic), with variable progression from  
one stage to another. 
 
There are two types of CRPS:  
 type I (most common): there is no demonstrable lesion to a major nerve 
 type II: there is a lesion to a major nerve 
 
Character of the pain 
 intense and burning 
 disproportionate to the original injury 
 worse over time 161

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              157 
  Spreads beyond the site of injury and 
 associated with hyperalgesia, hyperpathia or allodynia on examination. These features do not 
occur in DVT, osteomyelitis, or cellulitis. 
Features 
 progressive, disproportionate symptoms to the original injury/surgery 
 allodynia 
 temperature and skin colour changes

 temperature and skin colour changes 
 oedema and sweating 
 motor dysfunction 
 the Budapest Diagnostic Criteria are commonly used in the UK 
Diagnosis 
 clinical diagnosis 
 Plain radiographs  may show soft tissue swelling, peri-articular osteoporosis, and rarely erosions 
 MRI may also show bone marrow oedema apart from these changes 
 In the atrophic phase, imaging may show contractures. 
 99mTc bone scan shows hypervascularity in the acute phase, and hypovasculari ty in the

 early physiotherapy is important 
 neuropathic analgesia in-line with NICE guidelines 
 specialist management (e.g. Pain team) is required 
Cheyne-Stokes breathing 
 Cheyne-Stokes is a type of central sleep apnoea in which there is loss of chest and abdomina l 
movements and crescendo-decrescendo breathing in a repetitive fashion.

 Two-thirds of cases of Cheyne-Stokes breathing appear to have heart failure. ( the most 
common finding in Cheyne-Stokes breathing)  
 Stroke and metabolic dysfunction can also result in Cheyne-Stokes apnoea but are not as 
common as heart failure. 
 Treatments include diuretics and non-invasive ventilation. 
Orbital apex syndrome 
 The combination of optic neuropathy, proptosis, chemosis, Horner syndrome,

ophthalmoplegia and involvement of the first branch of the trigeminal nerve is typical of 
orbital apex syndrome 
 The presence of proptosis, with swelling of eyelids and chemosis (swelling of the ocular s urface 
membrantes),indicates significant mass extension within the orbit 
 The orbital apex syndrome (involvement of cranial nerves II, III, IV and V1) is a superio r orbital 
fissure syndrome with loss of vision 

Causes of absent ankle reflexes and extensor plantars include  
 Subacute combined degeneration of the cord (posterior column signs, positive Romberg's sign, 
anaemia, splenomegaly) 
 Syphilitic taboparesis 
 Friedreich's ataxia 
 Motor neurone disease. 
Prolonged neuromuscular junction (NMJ) blockade 
 may be exacerbated by both corticosteroids and magnesium.

 This condition was originally described with suxamethonium due to hereditary redu ctions in 
plasma cholinesterase activity. 
 However, drugs and electrolyte abnormalities may exacerbate this. 
 Neuromyelitis optica is a demyelinating disease involving the optic nerves and spinal cord b ut 
sparing the brain.  
 The specific test for this is the NMO antibody which is against aquaporin 4. 162

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              158 
Neurodegenerative disease 
 TAR DNA-binding protein 43 (TDP- 43) is associated with neurodegenerative diseases  
including dementia and motor neuron disease. 
Balint's syndrome  
 triad of:

 triad of: 
1. (simultanagnosia)  inability to perceive the visual field as a whole  
2. (oculomotor apraxia)  difficulty in fixating the eyes  (difficultly shifting gaze)   
3. (optic ataxia) inability to move the hand to a specific object by using vision 
 Examining for optic ataxia can be done by Controlling hand-eye 
coordination  asking the patient to reach out and touch an object.  
 Unlike cerebellar problems there is no tremor.

 The patient clearly grabs in the wrong part of space and does not attempt to 
correct unlike cerebellar lesions. 
Dystonia   
Definition: 
 involuntary sustained or spasmodic muscle contractions  
Types 
 Focal dystonias  
 Involves a single body part 
 Cervical dystonia, or torticollis, is the most common focal dystonia. 
 In 20-30% of patients, focal dystonias become segmental or multifocal.

 writer's cramp dystonia  or musician's dystonia  
 A common upper limb dystonia  
 This task-specific dystonia, manifesting as hyperextension or hyperflexion of the 
wrist and fingers,   unable to write  
 may be triggered by repetitive activities such as writing and attempting to play the 
piano or other musical instruments. 
 often relieved by a geste antagoniste, in which palpation of another unaffected  part of the

body leads to relief of symptoms, thought to be a result of alternative sensory input t o 
cortical networks with altered plasticity. 
 segmental  
 Affects 2 or more contiguous regions of the body 
 Multifocal dystonia - Consists of abnormalities in noncontiguous body parts 
 generalised dystonias, which involve a greater number of muscle groups. 
 involves the trunk and limbs. 
Cervical dystonia (torticollis)

Cervical dystonia (torticollis) 
 The term torticollis  is derived from the Latin words tortus  for twisted neck 
 Torticollis is a fixed or dynamic tilt, rotation, or flexion of the head and/or neck.  
 involuntary neck movements 
 commonly affects women  
 Secondary causes need to be excluded such as drugs (eg neuroleptics) and cervical spine 
abnormalities  
 Botulinum toxin injection is the first-line treatment for cervical dystonia (torticollis)

Botulinum toxin  
 Botulinum toxin is produced by Clostridium botulinum, a Gram-positive, spore-forming, 
obligate anaerobe 
 Botulinum toxin type A (or trade name Botox®)  
Action 
 The primary action of the toxin is to block acetylcholine release at the neuromuscular junctio n 
and so to produce muscle weakness. 
 myasthenia gravis would be expected to  worsen  with this treatment 
Indications 163

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              159 
  Botulinum toxin is the treatment of choice for focal dystonia (such as torticollis, and 
hemi-facial spasm) and focal dystonia. 
 Botulinum toxin injections are also used in patients with: 
 hemifacial spasm  
 blepharospasm  
 spasticity 
 spasticity associated with stroke 
  spasticity associated with cerebral palsy

  spasticity associated with cerebral palsy 
 Primary axillary hyperhidrosis 
 Strabismus 
 Cervical dystonia. 
Side effects 
 Occasionally systemic absorption of the toxin can affect distal muscles causing symptoms 
such as diplopia and dysphagia.  
 The main side-effect is excessive weakness in the treated muscle 
 
Contra-indications 
 myasthenia gravis  
 other generalised muscle conditions 

Paraneoplastic cerebellum syndrome 
 The patient with progressive ataxia and dysarthria following malignancy 
 features include ataxia, dysarthria, vertigo, oscillopsia, nystagmus and dysmetria 
 Associated malignancies are lung cancer, breast cancer, ovarian cancer and lymphoma 
 Brain imaging and CSF analysis are either normal or show non-specific changes 
 Serum and CSF may contain anti-Purkinje-cell antibodies

 Occasionally patients respond to steroids, immunoglobulins or plasmapheresis. 
 
Glioblastoma multiforme 
 Glioblastoma multiforme (or anaplastic astrocytoma) is the highest grade (most malignant) form 
of astrocytoma,  
 accounts for about 20% of all cerebral tumours 
 often remain clinically silent until they have reached a large size 
 About half occupy more than one hemisphere at presentation, and som e are multicentric

 Feature  : headache, seizure, hemiparesis 
 CT brain scan shows  multicentric mass lesion  with surrounding vasogenic oedema and some 
hemisphere shift. 
  Biopsy shows high cellularity with mitoses, pleomorphism and vascular hyperplasia 
 Prognosis  is extremely poor with only 20% surviving beyond 1 year and 10% beyond 2 ye ars 
 Treatment may consist of surgical debulking, external-beam radiotherapy and chemotherapy  
 Recent research has focused on the possibility of gene therapy

 A UK trial of intratumoural injections of modified herpes simplex virus, aiming to create local 
tumour necrosis, is underway 
Parinaud's Syndrome 
 also known as dorsal midbrain syndrome  and vertical gaze palsy ,  
 results from dorsal midbrain lesion   
 It is caused by a tumor of the pineal gland  which compresses the vertical gaze center at 
the rostral interstitial nucleus of medial longitudinal fasciculus (riMLF).

 Feature 
 Inability to move the eyes up . Downward gaze is usually preserved 
 convergent nystagmus (Attempts at upward gaze often produce this phenomen on), 
 mydriasis  
 impaired pupillary reflexes 164

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              160 
  Eyelid retraction (Collier's sign): sclera can be seen above the cornea, and further 
upgaze increases the distance between the eyelids and irises   
Peripheral nerves 
Upper limb anatomy

Upper limb anatomy 
The information below contains selected facts which commonly appear in examinations : 
Nerve Motor Sensory Typical mechanism of injury 
& notes 
Musculocutaneous 
nerve (C5-C7) Elbow flexion (supplies 
biceps brachii) and 
supination Lateral part of the 
forearm Isolated injury rare - usually 
injured as part of brachial 
plexus injury 
Axillary nerve 
(C5,C6)  Shoulder abduction 
(deltoid muscle)  Inferior region of the 
deltoid muscle Humeral neck

deltoid muscle Humeral neck 
fracture/dislocation 
Results in flattened deltoid  
Radial nerve  (C5-
C8) Extension (forearm, wrist, 
fingers, thumb) Small area between the 
dorsal aspect of the 1st 
and 2nd metacarpals Humeral midshaft fracture 
 
Palsy results in wrist drop  
Median nerve (C6, 
C8, T1) LOAF* muscles 
Features depend on the 
site of the lesion: 
 wrist: paralysis of 
thenar muscles, 
opponens pollicis 
 elbow: loss of 
pronation of 
forearm and weak

forearm and weak 
wrist flexion Palmar aspect of lateral 
3 and half fingers Wrist lesion ĺ carpal tunnel 
syndrome 
Ulnar nerve (C8, 
T1) Intrinsic hand muscles 
except LOAF* 
Wrist flexion Medial 1and half 
fingers Medial epicondyle fracture 
 
Damage may result in a 'claw 
hand'  
Long thoracic 
nerve (C5-C7)  Serratus anterior   Often during sport e.g. 
following a blow to the ribs. 
Also possible complication of 
mastectomy 
Damage results in a winged

Damage results in a winged 
scapula  
 
*LOAF muscles  
 Lateral two lumbricals 
 Opponens pollis 
 Abductor pollis brevis 
 Flexor pollis brevis 
Erb-Duchenne palsy ('waiter's tip') 
 due to damage of the upper trunk of the brachial plexus (C5,C6) 
 may be secondary to shoulder dystocia during birth 
 the arm hangs by the side and is internally rotated, elbow extended 
Radial nerve 
Overview

Overview 
 arises from the posterior cord of the brachial plexus (C5-8) 165

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              161 
 Motor to 
 extensor muscles  (forearm, wrist, fingers, thumb)  
 The radial nerve supplies: 
 Triceps  
 myotome of triceps and extensor digitorum is C7 
 Both radial nerve palsy and C7 radiculopathy can cause an absent triceps jerk  
 brachioradialis, 
 myotome of brachioradialis is C6

 myotome of brachioradialis is C6 
  extensor carpi radialis longus ( extensor digitorum profundus ) 
  extensor muscles of the forearm (via the posterior interosseous nerve ).  
 The posterior interosseous nerve  
 innervates the extensor carpi ulnaris, extensors of the metacarpo-
phalangeal joints and thumb extensors  
 pure motor nerve  
Sensory to 
 dorsal aspect of lateral 3 1/2 fingers 
 The commonest site of sensory loss is at the anatomical snuffbox

 small area between the dorsal aspect of the 1st and 2nd metacarpals 
Patterns of damage 
 wrist drop  with hand pronation and thumb adduction  
 sensory loss to small area between the dorsal aspect of the 1st and 2nd metacarpals  
Axillary damage 
 as above 
 paralysis of triceps 
 
Site of lesion Sensory symptoms Motor symptoms 
Axilla  All below  All below 
 Paralysis of triceps m 
Mid-arm  All below 
 Numbness, paresthesia, pain along lateral 
posterior arm  All below

posterior arm  All below 
 Wrist drop  
 weakness of 
extensors (hand, 
finger and wrist joint). 
Elbow (radial tunnel)  Pain and tenderness following extension or 
repetitive pronation/supination  Sometimes weakness of 
extension and supination, 
secondary to pain (not t o 
missing innervation) 
Deep Forearm 
(posterior 
interosseous nerve)  None   Paralysis of the finger 
extensors ( no true wrist 
drop ) 
Superficial forearm 
and wrist 
(superficial radial

and wrist 
(superficial radial 
nerve)  Deficits on the radial side of the dorsum of 
the hand (thumb, index finger, and the radial 
half of the middle finger)   None  
 
Median nerve 
Overview 
 arises from lateral and medial cords of the brachial plexus (C6-8, T1) 
 Motor to (LOAF) 166

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              162 
 
When look at hand in this position, can see 
this makes an "L" shape, since L 
Lumbrical. 
 
 Lateral two lumbricals 
 Opponens pollicis   rotates and flexes the thumb 
 Abductor pollicis brevis  Abduction and opposition of the thumb  
 Flexor pollicis brevis  Flexes the thumb at the first metacarpophalangeal joint

 the above three form the thenar eminence muscles  
 also supplies flexor muscles of the forearm 
Sensory to 
 palmar aspect of lateral (radial) 3 1/2 fingers 
Patterns of damage  
 Damage at wrist  
 e.g. carpal tunnel syndrome 
 paralysis and wasting of thenar eminence muscles 
 sensory loss to palmar aspect of lateral (radial) 3 1/2 fingers 
 Damage at elbow, as above plus: 
 unable to pronate forearm 
 weak wrist flexion 
 ulnar deviation of wrist

 ulnar deviation of wrist 
 Anterior interosseous nerve  (branch of median nerve) 
 leaves just below the elbow 
 results in loss of pronation of forearm and weakness of long flexors of thumb and ind ex 
finger 
Carpal tunnel syndrome 
 
Carpal tunnel syndrome is caused by compression of median nerve in the carpal tunnel . 
Causes 
 idiopathic 
 oedema e.g. heart failure  lunate fracture

 oedema e.g. heart failure  lunate fracture 
 rheumatoid arthritis 
 
History  
 pain/pins and needles in thumb, index, middle finger 
 unusually the symptoms may 'ascend' proximally 
 patient shakes his hand to obtain relief, classically at night 
Examination 
 weakness of thumb abduction (abductor pollicis brevis) 
 wasting of thenar eminence (NOT hypo thenar  supplied by ulnar nerve ) 
 Tinel's sign: tapping causes paraesthesia

 Tinel's sign: tapping causes paraesthesia 
 Phalen's sign: flexion of wrist for 60 seconds causes symptoms 
 Which area supplied by the median nerve will be spared if the problem is at the carpal 
tunnel?  
167

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              163 
  the skin over the thenar eminence 
 The palmar cutaneous branch of the median nerve  lies superficial to the flexor 
retinaculum and does not pass through the carpal tunnel. It supplies the skin over 
the thenar eminence, which is therefore spared in carpal tunnel syndrome.  
Electrophysiology

Electrophysiology 
 The most appropriate further investigation  Electromyogram (EMG)/nerve conduction 
studies 
  (EMG)/nerve conduction study is useful for confirming clinical diagnosis prior to actual 
surgery. 
 nerve conduction studies show: 
 decreased conduction velocity  in the median nerve. 
 prolongation of the action potential  
Treatment 
 In patients with mild carpal tunnel syndrome the management should be beha vior modification. 
 corticosteroid injection

 corticosteroid injection 
 wrist splints at night 
 surgical decompression (flexor retinaculum division) 
Pronator teres syndrome    
  entrapment of the median nerve  between the two heads of the pronator teres muscle at the 
elbow  
Features 
 The characteristic physical finding is tenderness over the proximal median nerve, which 
is aggravated by resisted pronation of the forearm . 
Diagnosis

Diagnosis 
 Examination involves excluding carpal tunnel syndrome and pronation of the affected forea rm 
against resistance, which brings on the pain.  
 Unlike carpal tunnel syndrome, the median nerve proximal to the wrist may be tender to 
palpation. 
Treatment 
 Injection of corticosteroids into the pronator teres muscle may produce relief of symptoms, but  a 
strong response to a steroid injection would be more consistent with carpal tunnel syndrome

Anterior interosseous syndrome  
 Anterior interosseous syndrome or Kiloh-Nevin syndrome  is a damage to the anterior 
interosseous nerve (AIN),  
 The anterior interosseous nerve is a motor branch of the median nerve , which arises just 
below the elbow . It passes distally in the anterior interosseous membrane and innervates the 
long flexor muscles of the thumb (Flexor pollicis longus) (FPL), index and middle finger

(flexor digitorum profundus) (FDP).  
Causes 
 neuritis (inflammation of the nerve) in most cases 
 compression of the AIN can happen.  
 Trauma to the median nerve  
Feature 
 pain in the forearm  
 characteristic weakness of the pincer movement of the thumb and index finger. 
 If asked to make the "OK" sign, patients will make a triangle sign instead.  
 This 'Pinch-Test' exposes the weakness of the Flexor pollicis longus muscle and the flex or

digitorum profundus leading to weakness of the flexion of the distal phalanges of th e 
thumb and index finger.  
 difficulty picking up a small item, such as a coin, from a flat surface 
Diagnosis 
 Electromyography (EMG) is generally most useful and will reveal abnormalities in the flexo r 
pollicis longus, flexor digitorum profundus I and II and pronator quadratus muscles. 
 
 168

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              164 
Ulnar nerve 
 
Overview 
 arises from medial cord of brachial plexus (C8, T1)  
Motor to 
 medial two lumbricals 
 adductor pollicis  Adduction of the thumb  
 interossei 
 hypothenar muscles: opponens digiti minimi , abductor digiti minimi, flexor digiti minimi

 flexor carpi ulnaris 
Sensory to 
 medial 1 1/2 fingers (palmar and dorsal aspects) 
 
 'claw hand' - hyperextension of the metacarpophalangeal joints and flexion at the distal 
and proximal interphalangeal joints of the 4th and 5th digits 
 wasting and paralysis of intrinsic hand muscles (except lateral two lumbricals) 
 wasting and paralysis of hypothenar muscles 
 sensory loss to the medial 1 1/2 fingers (palmar and dorsal aspects)

 Damage at elbow  
 the commonest site  for entrapment of ulnar nerve  
 may be due to chronic pressure, leaning on the elbows, and direct trauma.  
 results in numbness in the 5th finger, the medial aspect of the ring finger and the d orsum 
of the hand over the 5th finger.  
 weakness of the small muscles of the hand and, if allowed to progress, a claw hand  
develops where the little and ring fingers curl into the palm. 
 radial deviation of wrist

 radial deviation of wrist 
 ulnar neuropathy is a common complication with ill patients in hospital.  
 Nerve conduction studies will confirm the site of the lesion. 
 
MRCPUK-part-1-sep 2017: H/O dropping things on a frequent basis and muscle wasting at the back of 
the right hand. On examination, you note wasting of the dorsal interossei. What is the nerve supply of 
the dorsal interossei? 
 C8/T1 
 
Neuralgic amyotrophy (Brachial neuritis) 
 Neuralgic amyotrophy is an inflammatory process that affects the brachial plexus  
Precipitating factors:  
 Recent trauma, (minor trauma) 
 infection , usually proceeded by an upper respiratory tract infection  
 surgery, or even vaccination.  
 Rarely it may be hereditary.  
Feature 
169

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              165 
  usually presents with severe pain (pain over the deltoid region) for days to weeks followed by 
weakness  and sensory loss  over the corresponding territory of the brachial plexus  (more 
commonly C5-7).  
 winging of the scapula ( C 5, 6, 7 ) 
 shoulder abduction weakness ( C 5)

 shoulder abduction weakness ( C 5) 
 sensory loss over the lateral aspect of the shoulder ( C 5) 
 absent triceps reflex ( C 7) 
 Weakness of elbow extension ( C7) 
 There may be subsequent rapid wasting of the arm muscles in accordance to which nerve is 
involved.  
 Electrical studies  confirm denervation in affected muscles 
 The CSF is usually normal but may show a slightly elevated protein  level and a small 
lymphocytosis   
Treatment

Treatment  
 It is self-limiting  condition but recovery may be slow ( years ). 
 The prognosis  is usually good except when the phrenic nerve is involved  since this can 
result in significant breathlessness . 
Klumpke's paralysis  (damage to the T1 nerve root)  median & ulnar damage  
 due to damage of the lower trunk of the brachial plexus (C8, T1) 
 This root eventually supplies the median and ulnar nerves.

 The ulnar nerve supplies all of the intrinsic hand muscles except for those of the thenar 
eminence and the first and second lumbricals which are innervated by the median nerve.  
 Causes 
 sudden upward jerk of the hand 
 associated with Horner's syndrome 
 may be secondary to shoulder dystocia during birth.  
 Feature 
 global wasting of the small hand muscles ,  
 sensory loss over the medial border of the forearm around the elbow.

 sensory disturbance affecting the medial half of the ring finger and little finger.  
 
Stretching injury of the arm 
 Sudden upward movement of the abducted arm (fall that has been stopp ed by grasping a fixed 
object with one hand)  causes features of an ulnar nerve palsy which is supplied by the lower 
brachial plexus  roots C8 and T1 (Klumpke's paralysis)  
Common peroneal nerve lesion (L5, S1)

Common peroneal nerve lesion (L5, S1) 
The commonest cause of acute foot drop after prolonged bed rest is entrapment common 
peroneal neuropathy at the neck of fibula .  
Anatomy: 
The sciatic nerve divides into the tibial and common peroneal nerves  in the popliteal fossa.   
 Common peroneal nerve divides into a superficial and a deep branch 
 deep peroneal nerve supplies muscles, which dorsiflex the foot and toes : 
 tibialis anterior 
 extensor hallucis longus

 extensor hallucis longus 
 extensor digitorum longus  
 superficial nerve supplies the muscles, which evert the foot   
 peroneus longus and brevis  
Injury  often occurs at the neck of the fibula.  
Features: 
• The most characteristic feature of a common peroneal nerve lesion is foot drop  
• Other features include:  
 weakness of foot dorsiflexion 
 weakness of foot eversion 170

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              166 
  weakness of extensor hallucis longus 
 Sensory loss over the dorsum of the foot and the lower lateral part of the leg  with 
sparing of the fifth toe.  
 wasting of the anterior tibial and peroneal muscles 
 
 foot-drop is usually due to either a L4-5 radiculopathy or a common peroneal ner ve palsy

(eversion and dorsiflexion are weak with both whilst ankle inversion is spared with the 
latter ) 
Meralgia paraesthetica 
 
Basics 
 caused by compression of lateral cutaneous nerve of thigh 
 typically burning sensation over antero-lateral aspect of thigh 
 pure sensory loss  
 It is usually a consequence of entrapment at the lateral inguinal ligament  or less likely, 
trauma, ischaemia, or a retroperitoneal lesion.

May 2006 exam : A patient presents with a burning sensation over antero-lateral aspect of 
thigh. Which nerve is most likely to be affected ? Lateral cutaneous nerve of thigh  
Sciatic nerve palsy  
 Sciatic nerve palsy is a known complication of a total hip replacement (femoral nerve palsy can 
occur but is much less common). 
 It causes global weakness of the ankle  due to the involvement of both of its branches: tibial

nerve (plantaflexion and inversion) and common peroneal nerve (dorsiflexion and eversio n). 
  ankle jerk is absent due to tibial nerve involvement . 
 Sensory loss is variable but most commonly occurs around the dorsum of the foot a nd lateral 
aspect of the leg 
Other notes 
 Obturator nerve palsy causes  weakness of hip adduction  
Femoral nerve palsy (L234)  
Causes:

Causes:  
 Psoas haematoma  (due to anticoagulant therapy or haemophilia), Psoas abscess  
 Diabetic amyotrophy (proximal neuropathy, seen in patients with diabetes, causes b urning pain 
in the hip and thigh and wasting of thigh muscles) 
 Trauma - hip or pelvic fractures 
 Tumours - eg: Synovial cyst, Sarcoma 
 Iatrogenic: eg: Hip arthroplasty, Pelvic surgery, Coronary angiography. 
Feature

Feature 
 instability of the knee (often described as 'buckling') on climbing stairs. 
 weakness of knee extension  (quadriceps) and hip flexion  (iliopsoas) 
 absent knee jerk 
 The weakness is typically acute or subacute, (in contrast to that caused by myopathy, in wh ich 
the onset is often gradual and usually bilateral). 
 Decreased sensation in anterior thigh (anterior femoral cutaneous nerve) (meralgia 
paraesthetica) and medial distal leg(saphenous nerve) 
 
171

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              167 
 lumbosacral plexopathy 
The patient presents with generalised weakness of the right leg associated with pelvic pain, leg 
oedema and autonomic dysfunction. The most likely diagnosis is a lumbosacral plexopathy.

 Anatomically, the lumbosacral plexus consists of lumbar (L1-L4) and sacral (L5-S 5) portions, 
which are connected by the lumbosacral trunk (L4-L5).   
 Upper lumbar plexus  lesion will cause weakness of hip flexion and adduction of the thigh and 
extension of the leg with anaesthesia over the anterior thigh and leg.  
 Lower plexus lesions  will weaken the posterior thigh and foot muscles. Lesions affecting the

entire plexus will affect all muscle groups causing weakness or paralysis of the leg, areflex ia and 
anaesthesia from the toes, to involve the perianal area. 
Diabetic Lumbosacral Plexopathy (diabetic amyotrophy) 
 Pathology   immune vasculopathy  
 pain in the hip and thigh.   
 asymmetrically weakness and wasting of the thigh muscles,  
 lumbar puncture results may show elevated (CSF) proteins. 
 Good glycemic control 
 Prognosis

 Good functional recovery within 12-24 months is expected in 60%  
Neoplastic lumbosacral Plexopathy 
 incidence is 0.71%. 
 most commonly due to intra-abdominal tumor extension (73% of cases) 
 The most prevalent types of tumors are colorectal tumors (20%) 
 occurs less commonly with growth from metastases, lymph nodes, or bone structures. 
 The most common distant metastatic lesions are caused by breast cancer.

 The lower (sacral) plexus is involved most frequently  
 characterized by significant pain and sensorimotor deficits. 
 diagnosis is confirmed by (MRI) or (CT) scanning of the affected areas.  
 MRI is preferred because it is more sensitive and provides better detail than CT  
 Medical or surgical treatment of the carcinoma when possible is the first treatment of 
choice. 
 The most commonly used treatment with such plexopathy involves radiation trea tment.

 improvement noted in 85% 
 Neuropathic pain may respond to nerve stimulation, antidepressants, and antiepileptics. 
Radiation-Induced Lumbosacral Plexopathy  
 The mechanism may be related to a combination of localized ischemia and subsequent soft-
tissue fibrosis due to microvascular insufficiency.  
 noted in 1.3% of patients after abdominal irradiation and in 0.32% of patients after pelvic 
irradiation.

irradiation. 
 The median symptom-free interval for radiation-induced lumbosacral plexopa thy, from treatment 
to the initial neurologic symptom, is 5 years 
 most commonly present with painless weakness  
 Weakness is asymmetrical 
 commonly are bilateral (80%) and asymmetrical.  
  Treatment 
 tricyclic antidepressants or antiepileptic agents (eg, gabapentin, carbamazepine).  
Saphenous nerve

Saphenous nerve   
 The saphenous nerve supplies the skin over the anteromedial side of the knee, leg and 
medial malleolus.  
 can be injured in such procedures as:  
  femoral artery catheterization for angiography,  
 saphenous vein harvest for coronary artery bypass grafting or  
 long saphenous vein stripping for varicose veins.  172

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              168 
 ___________________________________________________________ 
Tarsal tunnel syndrome  
 also, known as posterior tibial neuralgia  
 Caused by entrapment of the posterior tibial nerve as it travels through the tarsal tunnel, 
this tunnel is found along the inner leg behind the medial malleolus   painful foot

Lower limb anatomy 
The information below contains selected facts which commonly appear in examinations:  
 
Nerve Motor Sensory Typical mechanism of injury & notes 
Femoral 
nerve Knee extension, 
thigh flexion Anterior and 
medial aspect 
of the thigh 
and lower leg Hip and pelvic fractures 
Stab/gunshot wounds 
Obturator 
nerve  Thigh 
adduction  Medial thigh Anterior hip dislocation  
Lateral 
cutaneous 
nerve of the

Lateral 
cutaneous 
nerve of the 
thigh None Lateral and 
posterior 
surfaces of 
the thigh Compression of the nerve near the ASIS ĺ meralgia 
paraesthetica, a condition characterised by pain, tingling and 
numbness in the distribution of the lateral cutaneous nerve 
Tibial nerve Foot 
plantarflexion 
and inversion Sole of foot Not commonly injured as deep and well protected. 
Popliteral lacerations, posterior knee dislocation 
Common 
peroneal 
nerve Foot 
dorsiflexion 
and eversion 
Extensor

nerve Foot 
Extensor 
hallucis longus Dorsum of 
the foot and 
the lower 
lateral part of 
the leg Injury often occurs at the neck of the fibula 
Tightly applied lower limb plaster cast 
 
Injury causes foot drop 
Superior 
gluteal nerve  Hip abduction None Misplaced intramuscular injection 
Hip surgery 
Pelvic fracture 
Posterior hip dislocation 
 
Injury results in a positive Trendelenburg sign  
Inferior 
gluteal nerve Hip extension 
and lateral

and lateral 
rotation None Generally injured in association with the sciatic nerve 
 
Injury results in difficulty rising from seated position. Can't 
jump, can't climb stairs 
Nerve roots 
Deep tendon reflexes: which test for which nerve root? 
C5 – Biceps 
C6 – Biceps, Brachioradialis 
C7 – Triceps 
L4 – Patellar (knee jerk) 
S1 – Achilles (ankle jerk) 
 
173

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              169 
  Brachioradialis is the "supinator" reflex and it is mediated by C5/6. 
 Deltoid is supplied by C5/6. 
 Ankle reflex (tibial nerve mediated)  
 knee reflex (femoral nerve mediated)  
 
 spinal lesion at the level of C8 Weakness of finger flexion

 Loss of sensation over the medial  aspect of the arm; forearm and hand ( Lateral  aspect of 
arm is C5) 
 
Winging of the scapula is caused by paralysis of the long thoracic nerve to serratus anterior (C5, 
6, 7).  
                            
Which nerve (and its nerve root) are you tested in triceps reflex? 
 Radial nerve C7  
Rotator cuff muscles 
 
Muscle Notes 
Supraspinatus aBDucts arm before deltoid 
Most commonly injured

Most commonly injured 
Infraspinatus Rotates arm laterally 
teres minor aDDucts & rotates arm laterally 
Subscapularis aDDuct & rotates arm medially 
 
174

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              170 
Dermatomes 
The table below lists the major dermatome landmarks:  
 
Nerve 
root Landmark Mnemonics 
C2 Posterior half of the skull (cap)  
C3 High turtleneck shirt  
C4 Low-collar shirt  
C5, C6 Thumb + index finger Make a 6 with your left hand by touching

the tip of the thumb & index finger 
together - C6 
C7 Middle finger + palm of hand C7 gives the finger to heaven (as in middle 
finger) 
C8 Ring + little finger  
T4 Nipples T4 at the Teat Pore 
T5 Inframammary fold  
T7 Xiphoid process  
T10 Umbilicus BellybuT-TEN 
L1 Inguinal ligament L for ligament, 1 for 1nguinal 
L4 Knee caps Down on aLL fours - L4 
L5 Big toe, dorsum of foot (except lateral aspect) L5 = Largest of the 5 toes 
L5 root has no lower limb deep tendon

L5 root has no lower limb deep tendon 
reflex representation. Therefore, an acute 
lumber disc prolapse resulting in L5 
radiculopathy is commonly misdiagnosed 
as malingering.  
S1 Lateral foot, small toe S1 = the smallest one 
S2, S3 Genitalia  
 
Symptoms and signs of a C6 root lesion include 
 Paraesthesias in the thumb or lateral distal forearm 
 Weakness of brachioradialis, biceps, or triceps and

 Diminished biceps and brachioradialis reflexes in conjunction with an increased triceps reflex.  
 
 175

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              171 
  
176

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              172 
  
177

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              173 
 Which spinal dermatome is responsible for the initial vague periumbilical  discomfort in 
appendicitis? 
 T10 
 Visceral afferents from the appendix  enter the spinal cord at the level of 
the 10th thoracic vertebra , the same level as the  somatic afferents  from the 
anterior abdominal wall in the region of the umbilicus .

 Hence the initial pain associated with this condition is vague , poorly 
localized, and in the periumbilical region.  
 As the parietal peritoneum adjacent to the appendix becomes inflamed , 
somatic nerves  are activated and localized pain occurs  in the right lower 
quadrant. 
 T12 dermatome is inferior to the umbilicus, and may be responsible for pain 
once appendicular inflammation of the peritoneum has occurred.   
 
Cervical roots

Cervical roots  
Root Dermatome distribution Myotome distribution Tendon reflex 
C4 Upper outer shoulder Shoulder abduction Nil 
C5 Outer arm, forearm Shoulder abduction, elbow flexion Bicep 
C6 Index and thumb Wrist extension Supinator 
C7 Middle finger centre of palm Finger and elbow extension Triceps 
C8 Little finger, ulnar border of hand Wrist/finger flexion Finger jerk 
 
Lumber and sacral roots 
 
178

Neurology 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad              174 
  The L5 reflex is tested by tapping the medial hamstrings, but is typically 
cumbersome to do and not tested. It is the asymmetry which is important as it is 
not necessarily present. 
 S2-4 reflex is part of the anocutaneous reflex or anal wink.

September 2013 exam: H/O neck & arm pain like 'electric shocks ’, worse on turning head + 
decreased sensation on the dorsal aspect of the thumb and index finger. What is the most 
likely underlying diagnosis? C6 radiculopathy  
 
H/O pain affecting  buttock region and the lateral border and sole of his foot, in association with 
paraesthesiae of the sole on walking. What is the correct nomenclature for the nerve root from

which these symptoms have arisen?  S1( The S1 nerve root is mapped to the sole of the foot) 
 
Ref: mrcpuk.org SCE sample question  
 
179

Endocrinology 
 
Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          1 
  
By
 
Endocrinology
 
Updated 
 
2017
 
Contains: 
1/ Passmedicine 2018  
2/ On examination 2018  
3/ Pastest 2018  
 
 180

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          2 
 Pituitary gland conditions 
Antidiuretic hormone (ADH) (Vasopressin) 
 
Overview: 
 Synthesized in the supraoptic nucleus of the hypothalamus. 
 Stored and secreted from the posterior pituitary  gland

 it contains arginine, so called arginine vasopressin  (AVP) or argipressin   
Functions :  
1) Antidiuresis 
 retain water in the body: (It acts on the collecting ducts improving water permeability and 
hence water retention). 
 By acting on V2 receptors   ĹĹ transcription and insertion of water (Aquaporin-
2) channels  into the apical membrane of distal convoluted tubule and collecting duct 
epithelial cells   ĹĹ water permeability  water reabsorption  excretion of more

concentrated urine, i.e., antidiuresis. 
2) Vasoconstriction  
3) Increase platelet aggregation , (prothrombotic at high dose). 
4) Increase factor VIII production , and as such may be of utility in treating some patients with 
haemophilia A. 
181

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          3 
 5) It leads to uterine and GI smooth muscle contraction  and indirectly leads to a reduction in 
coronary artery blood flow. 
 
Vasopressin receptors  
Receptor  Second 
messenger  Location  Action  Agonist  
V 1  Phosphatidyl-
inositol/calcium Vascular 
smooth

smooth 
muscle Vasoconstriction  ♦Terlipressin   Ĺ splanchnic VC  Ļ 
esophageal varices bleeding.  
♦ Felypressin  prolong the action of 
local anesthesia (safer than epinephrine 
in cardiac patients) 
 
V2  
 
Adenylate 
cyclase/cAMP Renal  
 Anti-diuresis  
(Insertion 
of aquaporin-
2 channels)  ♦ Vasopressin (weak , short acting , given 
SC or IM) 
♦ Desmopressin  (more potent, long 
acting, given intra-nasally) 
Extra renal  
(vascular

(vascular 
endothelium) ĹĹ release of von 
Willebrand & 
factor VIII. Desmopressin (used for haemophilia A 
& Von Willebrand disease) 
 The V1 receptor for antidiuretic hormone on vascular smooth muscles is coupled to  
phospholipase C  by a Gq protein . 
 The V2 receptor for antidiuretic hormone  on late distal tubule and collecting du ct is coupled 
to adenylyl cyclase  by a Gs protein . 
 
ADH regulation   
 Feedback mechanism of ADH:

 Feedback mechanism of ADH: 
 Receptors in the hypothalamus measure plasma osmolality (measuring system).  
 If the osmolality exceeds a set point, the neural pituitary gland excretes ADH (controlled 
variable). 
 ADH increases renal reabsorption of water (process unit). 
 Receptors in the hypothalamus detect falling osmolality and reduce ADH secretion, 
which decreases the amount of water reabsorption in the kidneys.

 factors increase secretion  of vasopressin (stimulatory factors): 
182

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          4 
  Increased osmolality of plasma  (The main stimulus ).  
 Reduced extracellular volume (less sensitive stimulus). 
 Angiotensin II 
 Hypoglycemia 
 Increased pain 
 Opiates 
 Nicotine 
 Antineoplastic drugs 
 Carbamazepine  
 Factors decreases secretion  of vasopressin (inhibitory factors):

 Ethanol (alcohol)  ĻĻ calcium -dependent secretion of AVP  
 Atrial natriuretic peptide,  
 by inhibiting Angiotensin II-induced stimulation of AVP secretion 
 Cortisol 
 
Scenario  (MRCPI-part-1- January 2018)  
(hypovolemic hyponatremia) 
H/O RTA + rapid pulse and low BP + low Na. 
 What is the most likely explanation for this patient's hyponatremia? 
 Physiologic ADH (vasopressin) secretion 
 Hyponatremia that develops after massive hemorrhage is likely dilutional.

 When baroreceptors detect decreases in effective arterial volume, such as after 
massive blood loss, they cause antidiuretic hormone (ADH) to be released from 
the pituitary gland to increase renal reabsorption of free water, diluting serum sodium 
levels and causing hyponatremia.  
 What is the appropriate management of this patient? 
 normal saline.  
 Management of hypovolemic hyponatremia  includes volume repletion with normal 
saline.

saline.  
 Correction of hypovolemia removes the stimulus to release ADH, causing free water 
excretion by the kidneys, which leads to rapid correction of serum sodium levels.  
 volume repletion with normal saline must occur at a slow rate, because rapid 
correction of hyponatremia can cause central pontine myelinolysis. 
 
Scenario  (May 2016 exam -part- 1) 
Which adaptive mechanism that prevent dying from dehydration?   
 Increase of aquaporin-2 in the collecting duct.

 ADH (vasopressin)  Ĺ aquaporin-2  expression  Ļ water excretion  protect 
against dehydration   
 183

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          5 
  
Syndrome of inappropriate ADH secretion (SIADH) ( ĹĹ ADH ) 
Causes  
Category Examples 
Malignancy  small cell lung cancer  (The most common cause)  
 also: pancreas, prostate 
Neurological  stroke 
 subarachnoid haemorrhage 
 subdural haemorrhage

 subdural haemorrhage 
 meningitis/encephalitis/abscess 
Infections  tuberculosis 
 pneumonia 
Drugs  Sulfonylureas ,  
 Thiazides 
 SSRIs, tricyclics, mon-amine oxidase uptake inhibitors, phenothiazines 
 vincristine , vinblastine 
 cyclophosphamide, chlorpropamide 
 omeprazole  
Other causes  positive end-expiratory pressure (PEEP) 
 porphyrias ( SIADH is associated with acute intermittent porphyria)  
 
Mechanisms:

Mechanisms:   
 ĹĹ (ADH) ĹĹ water retention   Euvolemic  hyponatraemia  (dilutional effects)  low plasma 
osmolality + high urine osmolality with an elevated urine sodium (above 20 mmol/L)   
 Osmotic fluid shifts ĺ Cerebral edema and Ĺ intracranial pressure  
 
Features 
  Symptoms of hyponatremia  
 usually asymptomatic until the sodium level falls below 120 mmol/l   
 Mild: anorexia, nausea, vomiting, headache, muscle cramps

 The earliest symptoms  of acute hyponatremia are  nausea and 
vomiting.  
 Moderate: muscle weakness, lethargy, confusion 
 Severe: seizures, altered consciousness  
 Normotensive 184

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          6 
  Symptoms of the underlying condition 
 
Diagnostic criteria : SIADH can only be diagnosed when the following criteria are satisfied:  
1. The patient is clinically euvolaemic (no clinical evidence of fluid overload (oedema) or 
dehydration)  
2. Ļ plasma sodium (<134 mmol/l) & osmolality (<280 mosmol/kg)

3. Ĺ urine sodium (>20 mmol/l) and osmolality (>100 mosmol/kg),  
4. Normal adrenal, thyroid and renal function. 
 
which finding would most suggest a diagnosis of (SIADH)?  
 concentrated urine  relative to plasma  
 because normally, low plasma osmolality should suppress (ADH) secretion and lead to 
dilute urine. 
 The low plasma osmolality reflects the hyponatraemia, since sodium is the principal 
determinant of extracellular fluid osmolality. It does not reveal information abo ut the

underlying cause. 
 
SIADH patients are usually euvolemic, normotensive, and have no edema. A hyponatremic 
patient with edema should raise suspicion of other conditions (e.g. congestive heart failure) 
 
Restriction of water intake  is the initial treatment of choice for hyponatraemic patients with 
SIADH who are not at imminent risk of seizures or coma. This precipitates a gradual rise in 
serum sodium, not greater than the recommended maximum of 8 –10 mmol/day.

 sever  acute symptomatic hyponatraemia: 
 hypertonic (3%) saline given via continuous infusion 
 Infusion of hypertonic (3%) saline is reserved for patients with acute severe 
life-threatening hyponatraemia , usually where sodium is less than 120 mmol/ l 
and there are significant neurological features (i.e. seizures or GCS less than 
11). 
 If severe: consider adding a loop diuretic (e.g., furosemide) to hypertonic saline.

Most effective if urine osmolality is > 2x the serum osmolality (typically urine 
osmolality > 500 mOsmol/kg) 
 correction must be done slowly to avoid precipitating central pontine myelinolysis 
 The sodium serum levels may increase by a maximum of 10 mmol/L within 24 
hours or 0.5 mmol/L per hour. 
 acute treatment should be interrupted once any of three end points is reached: 
    (1) the patient's symptoms are abolished

(1) the patient's symptoms are abolished 
    (2) a safe serum [Na+] level (generally ≥120 mmol/L) is achieved; 
    (3) a total magnitude of correction of 18 mmol/L is achieved 185

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          7 
  Mild acute OR chronic hyponatraemia: (Na+ ≥ 120 and NO neurological signs) 
 1st line  fluid restriction  (the initial treatment of choice ) 
 Restriction of fluid to a daily intake of 700–1000 ml  redresses the hyponatraemia. 
 the degree of restriction depends on urine output plus insensible fluid loss

(generally fluids should be limited to 500 mL/day below the average daily urine  
volume ); 
 several days of restriction are usually necessary before a significant increase in 
plasma osmolality occurs 
 2nd  line  demeclocycline  
 it is a semi-synthetic tetracycline antibiotic that can be used off-licence for the 
treatment of hyponatraemia caused by SIADH  
 reduces the responsiveness of the collecting tubule cells to ADH (by 
inducing nephrogenic diabetes insipidus)

inducing nephrogenic diabetes insipidus)  
 treatment must be continued for several days to achieve maximal diuretic effects; 
consequently, one should wait 3 to 4 days before deciding to increase the dose 
 Side effects include: 
 diabetes insipidus  
 photosensitive rash. 
 reversible azotaemia  
 nephrotoxicity, especially in patients with cirrhosis 
 3rd line   ADH (vasopressin) receptor antagonists have been developed (ie. tolvaptan)

Diabetes insipidus  (ĻĻADH ) 
Diabetes insipidus is characterised by a high plasma osmolality and a low urine osmolality 
 The passage of large volumes (>3 L/24 hr) of dilute urine (< 300 mOsm/kg). 
 characterised by either: 
1. deficiency of antidiuretic hormone (ADH)  (cranial DI) ( most common form) 
2. Insensitivity to (ADH)  (nephrogenic DI) ( rare) 
 
Causes of cranial DI  
 post head injury

 post head injury 
 pituitary surgery 
 craniopharyngiomas  histiocytosis X 
 DIDMOAD is the association of cranial Diabetes Insipidus, 
Diabetes Mellitus, Optic Atrophy and Deafness (also known 
as Wolfram's syndrome ) 
Causes of nephrogenic DI 
 genetic: two forms: 
1. vasopressin-2 receptor  (V2 ADH ) mutation  
 the more common form  
 X linked 
 This fits best with only male  members of the family being affected by the 
condition. 186

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          8 
 2. mutations in the aquaporin-2 gene   
 the less common form  
 Autosomal recessive 
 leading to reduced water reabsorption in the distal tubule.  
 electrolytes:  
 hypercalcaemia,  
 hypokalaemia 
 hypokalemia ĺ desensitization of renal tubules to (ADH) ĺ increased water 
excretion

excretion  
 drugs: the commonest precipitants  
 tetracycline  (demeclocycline) 
 lithium ,  
 Lithium inhibits signalling pathways that involve glycogen synthase kinase 
type 3 beta (GSK3beta),   dysfunction of aquaporin-2 water channel  
nephrogenic DI.  
 tubulo-interstitial disease:  
 obstruction,  
 Sickle cell trait 
 pyelonephritis 
Features 
 polyuria 
 Diabetes insipidus (Dl) is suspected when the urine output is > 50 ml/kg per day (3000 
ml for a 60-kg female).

ml for a 60-kg female). 
 Nocturia ĺ Restless sleep, daytime sleepiness  
 In the absence of nocturia, diabetes insipidus is very unlikely  
 Polydipsia 
In suspected DI  the most appropriate next investigation is  Urine and plasma osmolality 
(non-invasive first step)  
 
 high plasma osmolality,  
 plasma osmolality >305 mOsmol/kg 
 serum [Na] >145 mmol/L, and 
 low urine osmolality 
 urine osmolality <200 mOsm/kg 
 urinary [Na] 20-60 mmol/L

 urinary [Na] 20-60 mmol/L 
 urinary specific gravity <1.005. 
 water deprivation test 
 nephrogenic diabetes insipidus  
 the investigation most likely to reveal the underlying diagnosis  
 low urine osmolality and elevated serum osmolality, with no significant 
response to desmopressin.  187

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          9 
  If CDI is diagnosed, a CT scan or MRI of the head should be conducted to rule out brain 
tumors   
 Central (CDI) 
 desmopressin is the drug of choice. 
 synthetic vasopressin without vasoconstrictive effects 
 side effect: hyponatremia 
 increase oral water intake.

 increase oral water intake. 
 In the unconscious patient, nasogastric water and/or intravenous 5% dextrose 
can be administered.  
 Synthetic ADH can be given intra-nasally or intravenously if the urine output continue s 
to be greater than 250 ml/hr. 
 Nephrogenic (NDI)  
 congenital nephrogenic DI 
 congenital nephrogenic DI is generally unresponsive to exogenous ADH. 
 Sildenafil , a phosphodiesterase inhibitor, has been shown to substantially

reduce urine output in patients with congenital x-linked nephrogenic diabetes  
insipidus  
 lithium – induced nephrogenic DI : 
 cessation of lithium. 
 If there is hypovolaemic hypernatraemia ((hypotension, tachycardia, poor 
skin turgor)):  
 The first step is to restore volume with isotonic fluids (0.9% saline).  
 Isotonic fluid is not usually used in hypernatraemia, but it is 
recommended in patients with marked volume depletion and 
haemodynamic instability.

haemodynamic instability.  
 Once euvolaemic, the fluid can be switched to a hypotonic fluid (5% 
dextrose preferred over 0.45% saline) for free water 
supplementation.  
 The serum sodium should be corrected by 0.5 mmol/l/hr without 
exceeding 12 mmol/l in 24 hours. Cerebral oedema can occur if the 
sodium is corrected too quickly. 
 If fail to respond to cessation of lithium.  
 thiazide diuretics 
 Amilioride  (block ENaC  channel in cortical collecting duct

where lithium enter and causes DI)   
 NSADs:   
 indomethacin  
 
Fluid status in DI 
 Total body water: decrease,  
 Extracellular fluid: increase,  188

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          10 
  Intracellular fluid: decrease 
 DI  losing hypotonic fluid in the urine Ĺ osmolarity of the extracellular fluid  water will 
flow out of the intracellular compartment and into the extracellular compartment  
Ĺextracellular fluid volume and Ļintracellular fluid volume.

January 2013 exam: A mutation in the gene that encodes aquaporin 2 is most likely to result 
in…? Diabetes insipidus  
 
Which part of the nephron is most affected in  diabetes insipidus?  
 Cortical and medullary collecting tubules  
 
Water deprivation test  
A dramatic improvement in the ability of the kidneys to concentrate urine following the 
administration of DDAVP  points towards a diagnosis of cranial diabetes insipidus

 The diagnostic test to confirm Dl is a water deprivation test. 
 Normal plasma osmolality is 285-305 mosmol/k g. 
 The normal 24-hour urine osmolality is, on average, 500-800 mOsm /kg of water.  
 
Method 
 prevent patient drinking water 
 patients are deprived of fluids for a period of 8 h or until 5% of body weig ht is lost.  
 ask patient to empty bladder 
 Patients should be weighed hourly.  
 Test urine volume and osmolality every hour

 Test urine volume and osmolality every hour 
 Test sodium and plasma osmolality every two hours 
 Water deprivation continues until one of the following occurs: 
1. Urine osmolality rises and reaches a normal value (> 600 mOsmol/kg) ĺ DI ruled out 
and primary polydipsia  confirmed 
 Where urine osmolality reaches levels above 600 mOsmol/kg without 
desmopressin, then the diagnosis is primary polydipsia.

2. No change in urine osmolality despite a rising plasma osmolality (> 290 mOsmol/kg) 
3. Plasma osmolality> 295 –300 mOsmol/kg or sodium ≥ 145 meq/L  
 In the latter two situations ĺ administer desmopressin  (a synthetic ADH analog) 2 μg 
intramuscular 
 Monitor urine osmolality testing every 30 minutes for 2 hours 
 In CDI: Urine osmolality rises (> 600) after desmopressin administration (renal 
ADH receptors are intact).

ADH receptors are intact). 
 In NDI: Urine osmolality remains low after desmopressin administration 
(defective renal ADH receptors). 189

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          11 
  
 Primary polydipsia  
(psychogenic polydipsia ) CDI NDI 
Lab findings 
on 
presentation  Hyponatremia  (< 137 meq/L) 
 Plasma osmolality: low- normal 
(255–280 mOsmol/kg) 
 Very low urine osmolality (< 250 
mOsmol/kg)  Mild hypernatremia  (> 150 mEq/L) 
 High-normal plasma osmolality(280 –290

 High-normal plasma osmolality(280 –290 
mOsmol/kg) or slightly elevated 
 Low urine osmolality 
 Partial DI: 300–500 mOsmol/kg 
 Complete DI: < 300 mOsmol/kg 
Water 
deprivation 
test results  Plasma osmolality: normal (275 –290 
mOsmol/kg) 
 Urine osmolality: rises, reaches 
normal value (> 600 mOsmol/kg) 
This result shows that 
both ADH release and effect are 
intact.  Plasma osmolality: rises (> 290 
mOsmol/kg)  
 Urine osmolality: no change  
Desmopress
in 
administrati

in 
on results  Water deprivation test results 
confirm diagnosis; no need to 
administer desmopressin   Plasma osmolality: 
normalizes (275 –
290 mOsmol/kg) 
 Urine osmolality  
rises   Plasma  
osmolality 
remains 
elevated 
 Urine osmolality 
remains low 
 
 Differentiate  psychogenic polydipsia from CDI and NDI: 
 Patients with this disorder ingest and excrete up to 6L of fluid/day and are often 
emotionally disturbed.

emotionally disturbed.  
 Unlike patients with CDI and NDI, they do not have nocturia, nor does increased 
thirst wake them at night. 
 Patients with acute psychogenic  polydipsia can concentrate their urine during a water 
deprivation test but chronic water intake diminishes medullary tonicity in the kidney.  
 Patients with long-standing polydipsia  are not able to concentrate their urine to 
maximal levels during water deprivation, a response similar to that of patients with

partial central diabetes insipidus.  
 However, unlike central diabetes insipidus, patients of psychogenic 
polydipsia show no response to exogenous ADH after water deprivation.  
This response resembles nephrogenic diabetes insipidus, but ADH levels are low 
in psychogenic polydipsia and high in nephrogenic polydipsia. 
 
 Wolfram ’s syndrome or the DIDMOAD syndrome is characterised by diabetes insipidus, diabetes 
mellitus, optic atrophy, and deafness

mellitus, optic atrophy, and deafness 
____________________________________________________________  190

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          12 
 Hypopituitarism 
 ĻĻ secretion of one or more of the eight hormones  normally produced by the pituitary gland. 
 Hypopituitarism becomes symptomatic when more than 80% of pituitary cells are damaged . 
 
Etiology 
 Intrasellar/parasellar masses

Etiology 
 Intrasellar/parasellar masses   
 Nonsecretory pituitary macroadenomas (≥ 10 mm  in diameter) are the most 
common cause of hypopituitarism among adults ( ∼ 40% of cases).  
 Less common: internal carotid artery aneurysms, meningiomas, craniopharyngiomas,  
 Pituitary apoplexy  
 results in acute hypocortisolism and hypothyroidism, can present with 
sudden hypotension and hypovolemic shock 
 Sheehan syndrome: postpartum necrosis of the pituitary gland. Usually

occurs following postpartum hemorrhage, but can also occur even without clinical evidence o f 
hemorrhage.  
 Traumatic brain injury (especially around the skull base)  
 Infiltration of the pituitary and/or hypothalamus 
 Hemochromatosis 
 Infections: meningitis, TB 
 Congenital deficiency of hypothalamic hormones 
 GnRH deficiency (Kallman syndrome) 
 
Features - mix (depends on which hormone is deficient).

 The most common  problem is insufficiency of follicle-stimulating hormone ( FSH) 
and/or luteinizing hormone ( LH) leading to sex hormone abnormalities.  
 growth hormone deficiency 
 The first hormone to fall is the growth hormone  
 in children would produce short stature,  
 in adults it causes:  
 lassitude (tiredness)  
 increased fat mass  (weight gain)  
 poor concentration  
 low IGF-1 concentration.  
 low peak growth hormone levels in response to insulin-induced

hypoglycaemia  
 Low ACTH:  
 tiredness,  
 postural hypotension. (Postural hypotension is related to adrenal failure regardless 
of cause)  191

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          13 
  low gonadotrophins: amenorrhoea 
 low TSH: (the last  hormone to fall)  constipated 
 the typical thyroid function tests of a hypopituitarism are with a low thyroid-stimulating 
hormone and therapy would be guided by monitoring the free thyroxine (T4) 
concentration. 

Investigations  
 Dynamic pituitary function tests  
 Used to  assess patients with suspected primary pituitary dysfunction 
 Method: 
 Insulin, TRH and LHRH are given to the patient following which the serum 
glucose, cortisol, growth hormone, TSH, LH and FSH levels are recorded at 
regular intervals. Prolactin levels are also sometimes measured 
 A normal dynamic pituitary function test has the following characteristics: 
 GH level rises > 20mu/l

 GH level rises > 20mu/l 
 cortisol level rises > 550 mmol/l 
 TSH level rises by > 2 mu/l from baseline level 
 LH and FSH should double 
 Insulin stress test 
 Basics 
 used in investigation of hypopituitarism 
 IV insulin given, GH and cortisol levels measured 
 with normal pituitary function GH and cortisol should rise 
 Contraindications 
 epilepsy 
 ischaemic heart disease 
 adrenal insufficiency 
 Hydrocortisone

 Hydrocortisone  
 the most important replacement therapy to be started first  Hydrocortisone  
 to avoid the possibility of precipitating an adrenal crisis.  
 Fludrocortisone is only necessary in patients with adrenal insufficiency who are unable 
to maintain normal blood pressure control. 
 Thyroxine replacement  
 should be begun after commencing hydrocortisone because levothyroxine increases 
the clearance of cortisol and may precipitate an adrenal crisis

 GH therapy:  
  licensed for treatment of symptoms with reduced quality of life on adult 
growth hormone deficiency assessment (AGHDA) questionnaire scor e.  
 Testosterone   
 the most appropriate treatment to prevent the progression of bone loss  Add 
testosterone therapy  
 192

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          14 
 Patients with TSH deficiency should not be treated with levothyroxine until ACTH deficiency 
has been ruled out and/or treated because levothyroxine increases the clearance of cortisol 
and may precipitate an adrenal crisis 
Growth hormone (GH)

Growth hormone (GH) 
 Anabolic hormone secreted by somatotroph cells of the anterior lobe of the pituitary gland.  
 Growth hormone releasing hormone ( GHRH ) release from the hypothalamus stimulates the 
somatotrophs in the anterior pituitary gland to release GH.  
 GHRH  uses (two second messengers ) cAMP and IP3/Ca2+  to stimulate 
growth hormone release. 
 Which signaling pathways does growth hormone (GH) use? 
 A tyrosine kinase receptor that uses the JAK/STAT pathway

 GH, like prolactin, uses tyrosine kinase receptor followed by activation of Janus 
kinase (JAK) followed by signal transduction and activation of transcription 
(STAT).  
 The other tyrosine kinase receptor hormones: 
 PDGF (platelet-derived growth factor),  
 FGF (fibroblast growth factor),  
 IGF-1 (insulin-like growth factor 1)  
Mechanism of action 
 Direct  action on target tissues, such as skeletal muscle, liver, or adipose tissue,

 it uses tyrosine kinase-associated receptors  (transmembrane receptors). 
 Indirect action via insulin-like growth factor 1 (IGF-1), primarily secreted by the liver 
 Many of the effects of growth hormone (GH) are mediated through insulin-like growth 
factor (IGF)-1 the concentrations of which are high in acromegaly.  
 
Functions 
 Direct effects of GH:  
 Ļ Glucose uptake into cells  Ĺ insulin resistance  ĹBlood insulin levels 
 Ĺ Lipolysis  
 Ĺ Protein  synthesis in muscle

 Ĺ Protein  synthesis in muscle 
 Ĺ Production  of IGF 
 
Growth hormone (GH) counteracts in general the effects of insulin on glucose and lipid 
metabolism, but shares protein anabolic properties with insulin. 
 
GH along with cortisol and adrenalin (called counter-regulatory hormones) tell the body to 
increase the availability of glucose – so it counters the effect of insulin. 
 
 193

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          15 
 Regulations 
GH release is increased by: 
(anything Ļ glucose)  GH release is inhibited by: 
(anything Ĺ glucose)  
 Deep sleep 
 Fasting  Hypoglycaemia 
 Alpha adrenergic activity 
 Stress 
 Exercise 
 Ghrelin. the "hunger hormone ” 
 Amino  acids ( Arginine ) 
 Thyroxine

 Thyroxine 
 Sex steroids (estrogen or testosterone)  Somatostatin 
 Cortisol 
 Beta adrenergic activity 
 Hyperglycaemia (DM) 
 Obesity 
 Free fatty  acids 
 Hypothyroidism 
 IGF-1 
 
 Glucocorticoid (acutely – within 3 hours stimulates GH; chronically - by 12 hours suppresses 
GH secretion) 
Conditions associated with GH disorders 
 GH deficiency: resulting in short stature 
 excess GH: acromegaly

 excess GH: acromegaly  
Insulin-like growth factor 1 (IGF- 1) 
 also called somatomedin C  
 Polypeptide hormone produced mainly by the liver  in response to the indirect  action 
of growth hormone  
 GH  activation of liver GH receptor,  promotes IGF-I synthesis which, in turn, is 
released to the circulation 
 Although it is mainly produced by the liver, virtually every tissue is able to secrete IGF- I

for autocrine/paracrine purposes 
 IGF-1 is structurally related to insulin, and is even capable of binding the insulin recep tor 
(tyrosine kinase receptor ), albeit at lower affinity than insulin. 
 80% of circulating IGF-1 is carried by  IGF binding protein-3  (IGFBP-3)  
Regulation:  
 Pituitary (GH) and liver (IGF-I) establish negative feedback mechanisms  
 IGF-I inhibits GH secretion acting on the hypothalamus by two feedback mechanisms:

firstly, inhibiting GH gene expression and secondly by stimulating the secretion of 
somatostatin that inhibits GH production. 
 Causes of increased IGF-1  
 ĹGH 
 Causes of Reduced IGF-1 
 ĻGH 194

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          16 
  Cirrhosis of the liver  reduced synthesis 
Function  
 growth in childhood and continues anabolic effects in adults.  
Action   
 Binding to the IGF1R, a receptor tyrosine kinase,  initiates intracellular signaling;   activate

of the AKT signaling pathway,  Ĺ cell growth and proliferation,+ Ļ  programmed cell death .  
Conditions associated with IGF-I deficiency:  
1. Laron Syndrome, in children;  
2. advanced liver cirrhosis, in adults;  
3. intrauterine growth restriction 
4. Aging including cardiovascular and neurological diseases associated to aging. 
5. higher probability of hepatocarcinoma and poorer prognosis in patients requiring liver surg ery.

As a result IGF-I levels are considered of prognostic value regarding survival in cirrhotic 
patients 
Clinical uses 
 IGF-1 levels can be used as marker of growth hormone levels, but are not diagnostic . 
 IGF-1 levels may remain within normal ranges despite growth hormone deficiency in up 
to 50% of patients, and therefore a normal result does not exclude growth hormone 
deficiency. 
 A synthetic analog of IGF- 1, mecasermin, is used for the treatment of growth failure

Growth hormone deficiency (GHD)  
 
Causes 
 The most common cause is pituitary tumors. 
 Complication of pituitary tumors treatment with surgery, radiation therapy  
 Traumatic brain injury 
 idiopathic, isolated growth hormone deficiency in childhood  
Features  
 Infancy 
 The primary manifestations in infancy are hypoglycemia  and micropenis.  
 Child hood

 Child hood 
 The primary manifestation in early childhood is growth failure. 
 causes premature fusion of the epiphyseal portion of the bone. 
 Adult 
 ĻĻquality of life (QoL) especially reduced energy  levels 
 ĻĻbone mineral density   osteopenia/osteoporosis  
 ĻĻ sweating  Dry skin  
 ĻĻ muscle strength and exercise capacity  195

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          17 
  ĻĻ extracellular fluid volume  
 ĻĻ cardiac function.  
 lipid abnormalities (ĹĹ LDL cholesterol) ( increased fat mass, especially in the trunk )  
 insulin resistance 
 ĹĹ thickness of the intima media of blood vessels  
 ĹĹ levels of fibrinogen and plasminogen activator inhibitor  
 
 decreased serum insulin-like growth factor- 1 (IGF-1) levels. 
 normal IGF-I level does not exclude the diagnosis of GHD  
 insulin-induced hypoglycaemia  
 arginine stimulation test 
Diagnosis (Endocrine Society guideline 2011)  
 there is a significant false-positive error rate in the response to a single GH stimulation test, we 
suggest the use of two tests before making this diagnosis. 
Treatment  
 subcutaneous injections of recombinant human growth hormone.

MRCP-UK. SCE .Sample question 
patients with childhood-onset GHD who are candidates for GH therapy after adult height 
achievement . What is the most appropriate next step in management?  
 should be retested for GHD 
 
Criteria for GH treatment 
 Recombinant human growth hormone (somatropin) treatment is recommended for the 
treatment of adults  with growth hormone (GH) deficiency only if they fulfil all three of the 
following criteria.

following criteria.  
1- Severe GH deficiency, defined as a peak GH response of less than 9 mU/litre (3 ng/m l) 
during an insulin tolerance test. 
2- impairment of Quality of Life (QoL), as demonstrated by a reported score of at least 11  
in the disease-specific 'Quality of life assessment of growth hormone deficiency in 
adults' (QoL-AGHDA) questionnaire. 
3- They are already receiving treatment for any other pituitary hormone deficiencies as 
required.

required. 
 Side effects associated with treatment with recombinant human growth hormone  (hGH) . 
 Headache  
 arthralgia (joint pain), myalgia (muscle 
pain) 
 fluid retention (peripheral oedema),  
 mild hypertension, 
 carpal tunnel syndrome  visual problems 
  nausea and vomiting,  
 paraesthesia,  
 antibody formation,  
 reactions at the injection site.  
 slipped upper femoral epiphysis 196

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          18 
  Idiopathic intracranial hypertension 
(IIH)  
 result from antidiuretic effect of hGH  
 Most common in association  with 
impaired renal homeostasis.  
 In patients with intact homeostatic 
mechanisms, hGH  ↑plasma renin & 
aldosterone which counteracts the 
antidiuretic effect.

antidiuretic effect.  
 If IIH is diagnosed, hGH treatment 
should be interrupted and reinstated 
at a lower dose if  IIH resolves.  (SUFE), 
 malignancies,  
 gynaecomastia  
 impaired glucose metabolism. 
 ↑Lean body mass & ↓ body fat  
 ↓Serum total cholesterol & (LDL) 
& triglycerides but ↑ 
lipoprotein(a)  
 
GH treatment is contraindicated in:   
 evidence of tumour activity  
 In patients with tumours, anti-tumour therapy must be completed before starting GH 
therapy.

therapy. 
 critically ill patients  
 Pregnancy and lactation. 
 
The golden notes 
 Prevalence  of adult-onset GH deficiency is 1 in 10,000 of the adult UK population.   
 Causes  
 Adult onset, GH deficiency commonly due to pituitary tumours or their treatment,  
(e.g cranial irradiation)  
 Sheehan's syndrome is post-delivery infarction of the pituitary and  
growth hormone deficiency is typical .

growth hormone deficiency is typical . 
 Childhood-onset GH deficiency  is often idiopathic   
 only around 8% of referred patients will have GH deficiency. 
 Diagnosis:  
 Insulin tolerance test (ITT)  is the gold standard for the diagnosis of GHD,  
 insulin-induced hypoglycaemia  GH response of less than 9 mU/L (3 
ng/ml)  
 When the ITT is contraindicated (eg: in epilepsy ) other tests – such as 
response to GH-releasing hormone, arginine or glucagon – can be used.

 Management:  replacement therapy with biosynthetic human GH (somatropin).  
 
growth hormone deficiency in the newborn may present with hypoglycemia, micropenis, 
exaggerated jaundice. 
Management of idiopathic, isolated growth hormone deficiency: 
 Most individuals with idiopathic, isolated growth hormone deficiency in childhood have norma l 
growth hormone secretion during late adolescence or young adulthood,  197

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          19 
  presumably because of the stimulatory effects of gonadal steroid hormones on the 
hypothalamic-pituitary axis for growth hormone secretion. 
 At completion of linear growth (growth rate <2cm/year), growth hormone replacement 
therapy can be safely discontinued if biochemical assessment demonstrates normal

growth hormone secretion.   
 Stop rhGH therapy for 2 –3 months and undertake biochemical assessment of 
growth hormone secretion 
 However, if severe growth hormone deficiency persists, continuation of growth hormone 
therapy at adult doses may be considered until adult peak bone mass is achieved, usually 
around 25 years of age.  
 Continuation beyond this point is only recommended if the individual has ongoing sever e

growth hormone deficiency and a perceived impairment of quality of life which im proves with 
rhGH treatment.  
Acromegaly  (excess growth hormone ‘’GH’’)  
 
Approximately 30% of growth hormone (GH) secreting pituitary tumours is associated 
with mutation of the Gs protein alpha subunit  
 Age of onset: 3rd decade of life (mean age at diagnosis usually 40–45 years) 
Causes 
 Pituitary adenoma (95%)

Causes 
 Pituitary adenoma (95%)  
 ectopic GHRH or GH production by tumours e.g. pancreatic 
 mechanism: GH secreting tumours  mutation in the alpha sub-unit of the 
stimulatory guanosine triphosphate (GTP) binding protein   persistent elevation 
of cyclic adenosine monophosphate (cAMP)  production of excess growth 
hormone. 
Features  
 coarse facial appearance, spade-like hands, increase in shoe size 
 large tongue, prognathism, interdental spaces 
 excessive sweating and oily skin

 excessive sweating and oily skin 
 Pseudogout  is a recognised association of acromegaly; gout is not.  
 Hypertension, heart failure and cardiomyopathy may occur. 
 Goitre is seen in 20%, along with other soft tissue swelling. 
 Phosphate levels  are elevated but calcium levels are not significantly increased. 
 features of pituitary tumour: hypopituitarism, headaches, bitemporal hemianopia  
 raised prolactin in 1/3 of cases ĺ galactorrhoea  
 There are 2 Mechanism of  ↑ prolactin:

 There are 2 Mechanism of  ↑ prolactin:  
1. damaged pituitary stalk  ↓dopamine suppression signal   ↑ prolactin  
198

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          20 
 2. pituitary tumour  hypopituitarism  Ļ TSH  ↑ thyrotropin-releasing hormone 
(TRH)  ↑ prolactin  
 6% of patients have MEN-1 
 hypertension 
 Diabetes (>10%)  cardiomyopathy 
 colorectal cancer 
 
 Growth hormone (GH) levels vary during the day and are therefore not diagnostic. 
 Serum insulin-like growth factor 1 (IGF- 1) 
 may also be used as a screening test  and is sometimes used to monitor disease 
 IGF-1 measurement is the most appropriate initial  investigation 
 Normal IGF-1 levels rule out acromegaly 
 Growth hormone stimulates the production of (IGF-1), and IGF-1 has a long half -life, so

it is the ideal measure of growth hormone secretion. 
 If ↑ IGF-1 ĺ conduct OGTT with baseline GH ĺ measure GH after 2 hours  
ĺ if GH suppressed ĺ acromegaly ruled out  
ĺ if GH not suppressed: confirmed acromegaly ĺ conduct pituitary MRI  
 Insulin-like growth factor binding protein 3 (IGFBP- 3) is the main circulating binding 
protein for IGF and might be useful in the future as a screening test for acromegaly. 
 Oral glucose tolerance test (OGTT) with serial GH measurements.

 The definitive test  
 GH secretion is part of the counter-regulatory defence against hypoglycaemia and 
physiological GH secretion is inhibited by hyperglycaemia. 
 In normal patients GH is suppressed to < 2 mu/L with hyperglycaemia.  This  is because  
insulin and GH are antagonistic hormones.  
 in acromegaly there is no suppression of GH 
 may also demonstrate impaired glucose tolerance which is associated with acromegaly 
 Pituitary MRI   
 May demonstrate a pituitary tumour.

 May demonstrate a pituitary tumour. 
 Pituitary tumours in acromegaly are usually macro adenomas. 
 If normal ĺ screen for an extrapituitary cause (e.g., CT scan of the chest and 
abdomen, measure GHRH) 
 
In active acromegaly with associated diabetes mellitus  There is insulin resistance 
 
199

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          21 
  
Acromegaly  Ĺrisk of colon cancer  regular colonoscopy screening, starting at the age of 40 
years.  
 colonoscopic screening with three yearly colonoscopy in the presence of either elevated 
IGF-1 or adenomas at initial screening.

IGF-1 or adenomas at initial screening.  
 High risk features are detection of adenomas or elevated IGF-1 which should prompt three 
yearly follow-up, otherwise colonoscopy can be deferred for five years.           
British Society of Gastroenterology (May 2010)  
 
Trans-sphenoidal surgery is first-line treatment for acromegaly in the majority of patients 
 Surgery: transsphenoidal adenomectomy 
 Medication 
 Somatostatin analogs (e.g., octreotide, lanreotide)

 first line medical therapy.  
 effective in 50-70% of patients  
 may be used as an adjunct to surgery 
 may improve glycaemic control. 
 Dopamine agonists (e.g., bromocriptine , cabergoline)  
 Dopamine agonists are less effective in the treatment of acromegaly 
 Its use now superseded by somatostatin analogues 
 GH receptor antagonists (e.g., pegvisomant)  
 once daily s/c administration 
 very effective - decreases IGF-1 levels in 90% of patients to normal

 doesn't reduce tumour volume therefore surgery still needed if mass effect 
  the major use of pegvisomant is in patients who have an inadequate response to  
surgery or radiotherapy (is a third-line treatment when surgery, radiotherapy and 
somatostatin analogues are not effective.) 
 Growth hormone antagonists used prior to surgery improve metabolic risk factors 
for surgery, such as hypertension and hyperglycaemia 
 Radiotherapy 
 Conventional fractionated radiotherapy

 Conventional fractionated radiotherapy  
 Stereotactic radiosurgery (e.g., Gamma Knife, Cyber Knife, proton beam)  
Danger of hypopituitarism following surgery or radiotherapy 
Long acting somatostatin analogue, Somatuline LA 
 Mode of action  ↓↓meal -time related superior mesenteric artery blood flow  
 One intra-muscular injection should be given every 14 days. 
 Common side effects : pain at injection site, GIT disturbances ,  Cholelithiasis, Sinus

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          22 
 Which test is the best way to monitor for recurrence after trans-sphenoidal surgery for 
resection of a growth hormone-secreting pituitary adenoma? 
 Insulin-like growth factor 1(IGF-1) or growth hormone level 
 The aim of therapy is to keep the growth hormone level below 5 mU/l or the insulin-li ke growth

factor 1 (IGF-1) levels within normal limits.  
 Growth hormone levels above 5 mU/l are associated with a worse prognosis. 
Prognosis 
 Cardiomegaly progressing to CHF is the most common cause of death 
What is the most likely cause of death if treatment is unsuccessful? 
 Left ventricular failure  
 
January 2015 exam: A 45-year-old man presents with bitemporal hemianopia and sp ade-like hands. What

is the definite test to confirm the diagnosis?  Oral glucose tolerance test with growth hormone 
measurements  
Laron's syndrome   
 Definition  
 an autosomal recessive disorder characterized by an insensitivity to  (GH), usually 
caused by a mutant growth hormone receptor.   
 mutations in the gene for the GH receptor.  
 autosomal recessive condition  
 Features  
 short stature

 Features  
 short stature  
 reduced incidence of acne , cancer and diabetes.  
 Seizures are frequently seen secondary to hypoglycemia.   
 low levels of insulin-like growth factor (IGF-1) and its principal carrier protein, insulin-like 
growth factor binding protein 3. 
 injections of recombinant IGF-1.  
 Not respond to growth hormone treatment due to a lack of GH receptors.  
Nelson's syndrome

Nelson's syndrome  
 occurs in approximately 30% of patients adrenalectomised for Cushing's disease.  
 bilateral adrenalectomy as a second line procedure is much rarer than formerly in the 
treatment of Cushing ’s disease  
 It is probably due to the clinical progression of the pre-existing pituitary adenoma after the 
restraint of hypercortisolism on adrenocorticotropic hormone (ACTH) secretion is removed.

 Pigmentation arises from the MSH products of the proteolysis of POMC, which also produces 
ACTH.  
 Plasma ACTH levels are markedly elevated. 
 Pituitary magnetic resonance imaging (MRI) defines the extent of the tumour. 201

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          23 
  Nelson ’s tumours can be aggressive and locally invasive, and prophylactic pituitary 
radiotherapy after adrenalectomy is favoured by many.  
 Monitoring is with ACTH levels and serial pituitary imaging.  
Macroglossia : Causes  
 hypothyroidism

 acromegaly 
 amyloidosis  Duchenne muscular dystrophy 
 mucopolysaccharidosis (e.g. Hurler syndrome) 
 Down's syndrome  apparent macroglossia due to a 
combination of mid-face hypoplasia and hypotonia 
 
Pituitary adenoma 
classifications 
 Type of tumor according to size: 
 Microadenoma: ≤ 10 mm  
 Macroadenoma: > 10 mm 
 Types of tumor according to hormone secretion

 Types of tumor according to hormone secretion 
 Secretory pituitary adenomas (60%): hormone secretion ĺ  hyperpituitarism  
 Most secrete one pituitary hormone. 
 The presence of multiple pituitary hormones should also raise the suspicion of 
atypical pituitary adenomas or pituitary carcinomas. 
 Non-secretory pituitary adenomas 'chromophobe'  
 A chromophobe adenoma refers to no uptake of dye within the tumourous 
specimen. 
 
Type of secretory 
pituitary adenomas  Relative frequency

pituitary adenomas  Relative frequency  
(as a percentage of all 
pituitary adenomas)  Pathophysiology 
Lactotroph adenoma(prolactinoma) ∼ 40% Hyperprolactinemia  
Somatroph adenoma ∼ 15% Ĺ Growth hormone 
ĺ acromegaly/gigantism 
Corticotroph adenoma(Cushing's 
disease) ∼ 5% Ĺ ACTH ĺ secondary 
hypercortisolism 
Thyrotroph adenoma ∼ 1% Ĺ TSH ĺsecondary hyperthyroidism 
 
Prolactinomas are the most common pituitary adenomas 
 
 202

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          24 
  
Features 
The symptoms depends on the tumor size and whether the tumor produce s hormones 
Type of pituitary 
adenoma Secretory adenomas Non-secretory 
adenomas 
Microadenomas  The pituitary hormone which is produced in 
excess is determined by the histopathology of the

pituitary adenoma (see hyperpituitarism).  Asymptomatic  
Macroadenomas  The hormone which is produced in excess is 
determined by the histopathology of the 
pituitary adenoma (see hyperpituitarism);  
 other pituitary hormones may be deficient as a 
result of pituitary destruction. 
 Mass effects  (e.g., headache, bitemporal 
hemianops ia, diplopia)   Hypopituitarism  
 Mass effects(e.g., 
headache, bitemporal 
hemianopsia, diplopia) 
 Mass effects

 Mass effects    
 Superior extension  of the tumour can lead to compression of firstly the optic apparatus 
and later the hypothalamus. 
 Lateral extension  of the tumour with compression or invasion of the cavernous sinus 
can compromise third, fourth, or sixth cranial nerve functions, manifest as diplopia in 5 
to 15% of pituitary tumour patients. 
 
 Cranial contrast MRI (initial test) : reveals an intrasellar mass  
 CT scan may be considered

 CT scan may be considered  
 Hormone assays 
 Basal prolactin levels    
 Insulin-like growth factor-1 (IGF-1)  
 24-hour urine cortisol  
 Thyroid function tests  
 Perimetry: to assess visual field defects 
Treatment 
 Prolactinomas 
 First-line: dopamine agonists (e.g., bromocriptine, cabergoline), which cause the 
pituitary adenoma to shrink. 
 Second-line: transsphenoidal hypophysectomy ± adjuvant radiotherapy 
 Non-secretory pituitary microadenomas  (incidentalomas):

 no treatment (only follow- up with serial MRI)  
 Other pituitary adenomas 
 First-line: transsphenoidal hypophysectomy  
 Second-line: pituitary irradiation 
 203

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          25 
  
Differentiate between non-functioning adenoma and macroadenoma: 
 Although stalk compression with a non-functioning tumour may cause 
hyperprolactinaemia the concentrations of prolactin are usually below 2000 mU/L and 
galactorrhoea would be rare.

galactorrhoea would be rare. 
 
Except Prolactinomas, all other functioning adenomas are treated primarily by surgery ( i.e; 
for secondary hyperthyroidism, acromegaly etc).  
 
Scenario 
 If the CT scan shows a pituitary tumour with suprasellar extension, Which structures 
is likely to be compressed?  
 Optic chiasm  
 The optic chiasm lies 5-10 mm above the diaphragm sellae and anterior to 
the stalk. 
 Adenomas > 1.5 cm frequently have suprasellar extension, and (MRI) will

show compression and upward displacement of the optic chiasm. 
Incidentalomas 
 small pituitary tumors (microadenomas < 1 cm) that are detected on MRI or CT scans do ne for 
other reasons. 
Features 
 asymptomatic 
Approach 
 first rule out Function ( i.e; hormone production). 
 first - do prolactin level, Dexamethasone suppression test, ACTH level, TSH and IGF- 1  

 The most appropriate strategy would be observation and repeat scanning. 
Pituitary apoplexy  
 Caused by acute haemorrhage or infarction of the pituitary gland.  
 A pituitary adenoma usually pre-exists, which may be asymptomatic before presen tation. 
 Predisposing factors  include:  
  bromocriptine,  
 head injury,  
 pregnancy,  
 irradiation and  
 endocrine stimulation tests.  204

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          26 
  The combination of sudden-onset retro-orbital headache, vomiting, visual disturbance 
and hormonal dysfunction should lead you to consider a diagnosis of pituitary apoplexy  
 The visual symptoms include reduced acuity, visual field impairment and ocular motility

dysfunction. This is due to involvement of the optic nerve, chiasm and cavernous sinu s. 
 Ocular paresis occurs in up to 80% of patients, with third nerve palsy the commonest f inding.  
 The expanding mass can compress the cavernous sinus with the Ocular nerves and the 
trigeminal nerve can also be affected.  
 The mild hyponatraemia may be a consequence of the either syndrome of inap propriate 
antidiuretic hormone (SIADH) or secondary hypoadrenalism.

 The main initial problem is ĻĻ (ACTH),   ĻĻ cortisol  features of an 'Addisonian crisis', i.e. 
hypotension, hyponatraemia, hyperkalaemia and hyp oglycaemia. Subacutely, there can be Ļ 
(TSH) and gonadotropins (LH and FSH).  
 Diagnosis  Magnetic resonance imaging  
 Urgent steroid replacement  
 Consideration of neurosurgical decompression.  
 Over the long-term  corticosteroid, testosterone and thyroid hormone 
replacement.

replacement.  
____________________________________________________________   
Sheehan syndrome  
 Incidence: 1 in 10,000 deliveries. 
 Occur in women who have had a postpartum haemorrhage and hypovolaemic shock,  
 Risk factors  increase with  
 type 1 diabetes who have microvascular disease  
 sickle cell anaemia 
 immediate steroid therapy  
 full endocrine assessment  
 replacement of pituitary-dependent hormones (eg thyroxine) as required.

 Subsequent conception can be difficult and require pulsed gonadotropin th erapy to restart 
ovulation. 
_____________________________ _______________________________   
Hyperprolactinaemia  
Prolactin and galactorrhoea 
 
Prolactin inhibits GNRH. If there is no GNRH, the body cannot release LH and FSH. 
 
The first test to do when seeing anyone with hyperprolactinaemia is to exclude pregnancy, as 
it is the most common cause.  
 
Prolactin  
 secreted by the anterior pituitary gland  205

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          27 
  Regulation 
 thyrotropin-releasing hormone (TRH) stimulates prolactin release  
 Hypothalamic dopamine inhibits prolactin  
 dopamine agonists such as bromocriptine may be used to control galactorrhoea. 
 Function s  
 Prolactin is important for development of the fetal lung

 lactation and breast development during pregnancy.  
 Sex: ♀ > ♂ 
 Hyperprolactinemia is the most common form of hyperpituitarism.  
 Ĺ Prolactin ĺ galactorrhea and suppression of GnRH ĺ Ļ LH, Ļ FSH ĺ Ļ estrogen, Ļ 
testosterone (hypogonatrophic hypogonadism) 
Causes 
 
1. Hypothalamic stimulation:  
 primary hypothyroidism (due to thyrotrophin releasing hormone (TRH) stimulating prolactin 
release)  
 Adrenal insufficiency.

release)  
 Adrenal insufficiency. 
 Certain types of focal epilepsy: directly after temporal lobe seizures, due to close  proximity to 
the hypothalamus. 
2. Medications (inhibit dopamine release, leading to reduced inhibition and therefore higher 
prolactin release):  
 Levels less than 1000 are most likely to be drug related 
 metoclopramide (most common) , domperidone 
 Neuroleptics - phenothiazines, haloperidol 
 Antihypertensives - calcium-channel blockers, methyldopa

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          28 
  Anti-ulcer agents - Hs antagonists 
 Opiates and opiate antagonists. 
3. Neurogenic (via autonomic nervous system):  
 Chest wall injury 
 Breast stimulation 
 Breast feeding. 
4. Physiological causes (via oestrogen stimulation):  
 Coitus 
 Exercise   Sleep 
 Stress.

 Coitus 
 Stress. 
 
5. Increased prolactin production:  
 Ovarian: polycystic ovarian syndrome 
 Pituitary tumours  
 Prolactin-secreting pituitary adenomas ( Prolactinomas ),  
 Pituitary adenomas are the most common cause ( ∼ 50%) of pathological 
hyperprolactinemia  
 hypothalamic stalk interruption,  
 hypophysitis ,  
 acromegaly (1/3 of patients)  
 The grossly elevated prolactin concentration is most suggestive of a 
microprolactinoma.

microprolactinoma. 
 The presence of hyperprolactinaemia with hypogonadotrophic 
hypogonadism (↓↓ sex hormones) suggests a diagnosis of a 
microprolactinoma 
 In case of combination between microprolactinoma and recurrent 
dyspepsia (  gastro-entero-pancreatic tract tumours (gastrinomas, 
insulinomas, carcinoid) ), a diagnosis of multiple endocrine neoplasia (MEN) 
type 1 should be considered.  
 Microprolactinoma is associated with levels of prolactin of 1,000-3,000 mU/L.

 In macroprolactinomas, the prolactin concentration is greater than 3000 mU/L. 
 Combined oral contraceptives can lead to mild rises in serum prolactin, and 
therefore should only be used with caution in patients with prolactinomas. 
 In males, the decreased libido and erectile dysfunction are the result of 
decreased FSH, LH, and testosterone due to the upstream inhibition of GnRH , 
which would normally result in the release of these hormones from the anterio r 
pituitary.

pituitary.  
 inhibitory effect of prolactin on GnRH  Ļ FSH, LH, and testosterone  
decreased libido and erectile dysfunction 207

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          29 
 6. Reduced prolactin elimination:  
 Hepatic insufficiency 
7.  idiopathic hyperprolactinaemia 
 over time prolactin levels stay the same around 50% of the time. 
 A reduction in prolactin levels occurs in around a third of people presenting with idiopathic 
hyperprolactinaemia.

hyperprolactinaemia. 
 A further increase in prolactin is seen in the remainder 
 
Features of excess prolactin  
 men: impotence, loss of libido, galactorrhoea 
 women: amenorrhoea, galactorrhoea 
 
Hormonal 
changes Clinical features 
Female Male 
Ĺ Prolactin  Galactorrhea    Galactorrhea is rare.  
Ļ LH + Ļ FSH  Primary  and/or secondary amenorrhea,  
or irregular menses  
 Infertility   Clinical features 
of Ļ testosterone (see below)

of Ļ testosterone (see below) 
Ļ Testosterone  Loss of libido  Loss of libido, erectile dysfunction 
 Gynecomastia  
Ļ Estrogen  Atrophic endometrium and vaginal 
atrophy (menopausal symptoms) 
 Osteoporosis  (after several years)  Little to no noticeable effects 
 
The presence of amenorrhea, galactorrhea, and vaginal atrophy in a woman with new-onset 
headaches and blurry vision should raise suspicion of which diagnosis? 
 prolactinoma. 
 The most likely hormonal result will be?

 The most likely hormonal result will be? 
 ↑Prolactin ↓FSH ↓LH 
 elevated FSH leads to a normal/high estrogen and would not be consistent 
with vaginal atrophy, which is a sign of decreased estrogen. 
 serum prolactin 
Levels of prolactin   
 < 1000  drug-induced prolactinaemia   
 1000 -- 3000 mU/l  microprolactinoma . 
 > 3000  macroprolactinoma.  
 HOOK EFFECT: 208

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          30 
  Very high prolactin concentrations can interfere with immunoassay systems 
resulting in falsely low prolactin determination. this is due to "hook effect" which 
describes the inhibition of immune complex formation by excess antigen 
concentrations.

concentrations.  
 this is an important consideration in patients with large pituitary adenomas when 
the clinical suspicion of prolactinoma is strong, as in patients with amenorrhoea-
galactorrhoea or longstanding hypogonadism.  
 appropriate dilution of the serum in such cases helps in accurate estimation of 
serum prolactin concentration. 
 Dopamine antagonist tests using metoclopramide may also be used in the investigation of 

hyperprolactinaemia.  
 A normal response is at least a twofold rise in prolactin.  
 A blunted prolactin response suggests a prolactinoma 
 MRI 
 The most accurate diagnostic test is an MRI of the brain. 
  Be aware MRIs do not rule out small microadenomas  
 
Hyperprolactinaemia  ↓ GRH  ↓ LH & FSH  
 
Treatment of prolactinomas 
Prola ctinoma manag ement - me dical therapy is alm ost always first-line  
 
 dopamine agonist therapy  (cabergoline and Bromocriptine)

 effective in most patients 
 they are able to normalize the prolactin levels, restore gonadal function and reduce 
tumor size 
 If patient is asymptomatic, there is no absolute requirement for treatment. 
 Indications for treatment are adverse effect of tumour size or effects of 
prolactinaemia. 
 Contraindications to treatment are cardiac valve fibrosis and pulmonary fibrosis. 
 A meta-analysis suggested that cabergoline is more efficacious than

bromocriptine in normalising prolactin and has a better side effect profile, and 
is therefore  the treatment of choice.  
 Both pergolide and  cabergoline  may be associated with pericarditis , cardiac 
valve regurgitation, pericardial effusion and pulmonary hypertension.  
 ropinirole may be an appropriate alternative in this case, otherwise surgery 
would be the next most appropriate step. 
 If possible, dopamine agonists can be held during pregnancy but if treatment

is required bromocriptine has the most safety data. 
  Bromocriptine is the first drug of choice in symptomatic pregnant.  
 Cabergoline may be considered if the adenoma does not respond to bromo criptine 
 
 Women should stop her bromocriptine once she knows she is pregnant  .  209

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          31 
  It is advisable to stop the use of Dopamine agonists (DAs) immediately once 
pregnancy is confirmed, except in the case of women with invasive 
macroprolactinomas or pressure symptoms.  
 There is no evidence that bromocriptine is teratogenic, but  Once pregnancy is

established, bromocriptine is not necessarily required, and so most physicians 
recommend stopping it for the duration.  
 
 If Prolactin Producing Macroadenomas are associated with mass effect  Still bromocriptine 
must be tried first. Only if no response, Surgery ( trans sphenoidal resection) is done.  
 Remember that prolactinomas even when large and causing symptoms , they can  
shrink with dopamine agonists.

shrink with dopamine agonists. 
 Pituitary surgery  is rarely required in prolactinomas and is generally reserved for patients 
intolerant of or resistant to dopamine agonist therapy. Radiotherapy can be used to re duce the 
chance of tumour recurrence, but is rarely required. 
Cabergoline  Bromocriptine  
higher affinity and selectivity for D2 dopamine 
receptors. D2 receptor agonist with agonist and antagonistic 
properties on D1 receptors.  
has long duration of action allowing

has long duration of action allowing 
administration once or twice weekly with better 
tolerability and patient compliance required multiple dosing throughout the day 
because of its short half life 
 
Which hormones are expected to be low in hyperprolactinaemia? 
 Hyperprolactinaemia suppresses the release of gonadotropin-releasing hormone 
(GRH), which leads to reduced production of luteinising hormone (LH) and follicle-
stimulating hormone (FSH).

stimulating hormone (FSH).   
 There can also be a direct effect of prolactin itself on the ovary to disrupt LH and 
FSH signalling. 
 
Prolactinomas in pregnancy  
 During pregnancy, the pituitary gland undergoes global hyperplasia due to a progressive 
increase in serum estrogens level that may lead to increase of the tumor volume with potential 
mass effect and visual loss 
 The risk of tumor enlargement during pregnancy is found to depend on tum or size:  
 3% for microprolactinomas,

 3% for microprolactinomas,  
 32% for macroprolactinomas that were not previously operated on 
 In case the patient becomes symptomatic with visual disturbance or progressive headaches, 
an MRI without gadolinium (not a CT) should be performed to assess changes in tu mor size. 
 pregnancy is not recommended in women with drug resistant  large  macro prolactinomas and 
they should not conceive even if the tumor is intrasellar, until the size is reduced by 
transsphenoidal surgery.

transsphenoidal surgery. 
 
Cranial irradiation  may  initially  cause hyperprolactinaemia  but a low PRL  is typical after a year . 
 
A patient presented with elevated oestradiol  and prolactin with suppressed (LH/FSH) and recent 210

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          32 
 amenorrhoea.  what is  the most likely diagnosis ?  
 Pregnancy  
Bromocriptine   
 Action 
 Bromocriptine is an ergotamine dopamine agonist that leads to activation of D2 
receptors 
 Agonist at central and peripheral D2 receptors 
 Indications

 Indications 
 used to inhibit prolactin release from the anterior pituitary 
 preferred in women who are looking to get pregnant or are having unprotected 
sex. 
 Bromocriptine has less teratogenicity than cabergoline.  
 Side effects 
 Common  
 nausea  
 nasal congestion 
 constipation 
 Uncommon  
 Dizziness (orthostatic hypotension.) 
 dyskinesia 
 Rare  
 Tinnitus 
 Excessive sleepiness   (it is seen more commonly with modern agents such as 
ropinirole).

ropinirole). 
 Pulmonary fibrosis 
 diarrhoea  
 vasospasm in the peripheral circulation  
 Higher doses may cause cold-induced peripheral digital vasospasm 
(Raynaud's phenomenon ). 
 hallucinations and psychosis   
 exacerbation or unmasking of depression and psychosis. 
 only at very high drug doses 
TSH-producing pituitary tumour (secondary hyperthyroidism)

If free T4 and T3 are high, but TSH is normal or high, a pituitary MRI should be done to look 
for a pituitary mass (TSH-secreting adenoma). 
 
The diagnosis should be suspected when TSH concentrations are not suppressed in the 
presence of hyperthyroidism. 
 
Definition 211

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          33 
  secondary hyperthyroidism due to a pituitary tumour (thyrotrophinoma ) that is producing 
thyroid-stimulating hormone (TSH). with elevated tri-iodothyronine (T3) and thyroxine (T4) 
and inappropriately normal  or high (TSH).  
Epidemiology   
 rare approximately less than 1% of all pituitary adenomas ,  
Features

Features 
 features of thyrotoxicosis: sweating , weight loss, lethargy, tachycardia 
 Clinical examination: There is a diffuse, smoothly enlarged thyroid due to TSH stimulatio n. 
 free T4 and T3 are high  
 TSH is normal or high 
 Alpha subunit is also secreted in large amounts   
 measurement of this should yield an elevated alphaSU: TSH ratio  (usually 1:1). 
 Pituitary MRI  
 the next investigation of choice

 the next investigation of choice   
 to look for a pituitary mass (TSH-secreting adenoma).  
 If there is no pituitary mass, but there is end-organ evidence of hyperthyroidism, a care ful 
family pedigree should be obtained as well as genetic testing for the possibility of thyroid 
hormone resistance.   
Treatment 
 Trans-sphenoidal resection of the tumour is the therapy of choice.

________________________________________________________________________________________  
Thyroid and parathyroid conditions 
Physiological effects of thyroid hormones 
 Thyroid hormones production 
 The thyroid utilises tyrosine and iodine to manufacture thyroxine and T3. 
 Iodide is taken into the thyroid follicular cells by active transporters and then oxidised to 
iodine by thyroid peroxidase.

iodine by thyroid peroxidase.  
 Organification occurs when iodine is attached to tyrosine molecules which themselves 
are attached to thyroglobulin, forming monoiodotyrosine (MIT) and diiodotyrosine  (DIT). 
The coupling of 2 molecules of DIT forms thyroxine. 
 T4 vs T3 
 More T4 is produced than T3 but T4 is less potent.  
 A deiodinase  in the blood converts T4 to the biologically active T3.T4 is therefore a 
hormonal precursor (prohormone).

hormonal precursor (prohormone). 
 Peripheral metabolism of thyroxine is the only source of T3. 
 The half-life of T3 is about one day ( ∼ 20 hours), whereas the half-life of T4 is about one 
week ( ∼ 190 hours). This longer half-life  makes T4 suitable for use as a depot form that 
can be used replacement therapy. 
 Thyroid hormone receptor  
 The thyroid hormone receptor is a nuclear receptor. 212

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          34 
  Functions of thyroid hormones  
 Enhancement of : 
 insulin-dependent entry of glucose into cells (Enhance insulin sensitivity  ) 
 myocardial oxygen consumption 
 nerve conduction 
 gluconeogenesis, and 
 oxidation of fatty acids. 


  
What is the defect Which responsible for thyroid hormone dyshormonogenesis? 
 Defect in iodine organification  
 
Calcitonin   
 polypeptide hormone 
 produced by the parafollicular cells (also known as C-cells) of the thyroid,  
 acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH). 
 Calcitonin-gene related peptide causes vasodilatation. 
 Secretion of calcitonin is stimulated by: 
 an increase in serum [Ca2+]

 an increase in serum [Ca2+] 
 gastrin and pentagastrin. 
 calcitonin lowers blood Ca2+ levels in two ways: 
1. Major effect: Inhibits osteoclast activity in bones 
2. Minor effect: Inhibits renal tubular cell reabsorption of Ca2+ and phosphate, allowing 
them to be excreted in the urine 
 calcitonin receptor,  
 found on  osteoclasts , and in the kidney and regions of the brain,  
 is a G protein-coupled receptor, which is coupled by G s to adenylate cyclase and

thereby to the generation of cAMP in target cells.  
 It may also affect the ovaries in women and the testes in men. 
 Despite high serum calcitonin levels, which mechanism best explains the normal 
calcium levels in a patient with thyroid nodule ? 
 High levels of calcitonin down regulates its receptor 
 Calcitonin's primary function is to act on osteoclasts and decrease serum calcium 
levels. 
 Huge amounts of calcitonin are secreted in medullary carcinoma of the thyroid, or

when calcitonin is used therapeutically to treat certain medical conditions, such as 
Paget's disease, osteoporosis, and hypercalcemia. Its effects on osteoclasts 
disappear after one week of therapy. This is called the 'calcitonin escape 
phenomenon' . 
 The biochemical basis for the 'calcitonin escape phenomenon' is the down 
regulation of its receptor.  
 Whenever the levels of calcitonin become high, they down regulate the receptor by

rapid and prolonged down regulation of calcitonin receptor messenger RNA. 
 
 213

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          35 
 Thyroid disorders and respiratory physiology  
 
Thyroid function tests : The interpretation of thyroid function tests is usually straightforward:  
Diagnosis TSH  Free 
T4 Notes 
Thyrotoxicosis (e.g. Graves' disease) Low  High In T3 thyrotoxicosis the free T4 will be normal 
Primary hypothyroidism (primary

Primary hypothyroidism (primary 
atrophic hypothyroidism) High  Low  
Secondary hypothyroidism Low  Low Replacement steroid therapy is required prior to 
thyroxine 
Sick euthyroid syndrome* Low**  Low Common in hospital inpatients 
T3 is particularly low in these patients 
Subclinical hypothyroidism High  Normal  
Poor compliance with thyroxine High  Normal  
Steroid therapy Low  Normal  
*now referred to as non-thyroidal illness 
**TSH may be normal in some cases

**TSH may be normal in some cases 
Thyrotropin is a  glycoprotein hormone ( glycosylated ) 
 
Thyroid disorders: a very basic introduction 
 Disorders of thyroid function are very commonly encountered in clinical practice. Around 2% of 
the UK population has hypothyroidism (an under active thyroid gland) whilst around 1% ha ve 
thyrotoxicosis (an over active gland).  
 Both hypothyroidism and hyperthyrodism (also known as thyrotoxicosis) are around 10 times 
more common in women than men.

more common in women than men.  
Structure and function  
 The thyroid gland is one of the largest endocrine organs in the body. It is a bi- lobed structure 
which is found in the anterior neck. As with many endocrine organs it is part of a 
hypothalamus-pituitary-end organ system with negative feedback cycles to main.  
 On a simple level the hypothalamus secretes thyrotropin-releasing hormone (TRH) which

stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH). This then acts 
on the thyroid gland increasing the production of thyroxine (T4) and triiodothyronine (T3), the 
two main thyroid hormones. These then act on a wide variety of tissues, helping to reg ulate the 
use of energy sources, protein synthesis, and controls the body's sensitivity to other hormone s. 
How are thyroid problems classified?  
 Hypothyroidism may be classified as follows  
214

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          36 
  primary hypothyroidism: there is a problem with the thyroid gland itself, for example an 
autoimmune disorder affecting thyroid tissue (see below) 
 secondary hypothyroidism: usually due to a disorder with the pituitary gland (e.g.pituitary  
apoplexy) or a lesion compressing the pituitary gland

 congenital hypothyroidism: due to a problem with thyroid dysgenesis or thyroid 
dyshormonogenesis 
What causes thyroid problems?  
 The majority of thyroid problems seen in the developed world are a consequence of  
autoimmunity. 
 
The table below shows the different autoimmune problems which cause thyroid dysfunction: 
 
Hypothyroidism Thyrotoxicosis 
Most 
common 
cause  Hashimoto's thyroiditis  
 most common cause 
 autoimmune disease, 
associated with type 1

associated with type 1 
diabetes mellitus, Addison's 
or pernicious anaemia 
 may cause transient 
thyrotoxicosis in the acute 
phase 
 5-10 times more common in 
women Graves' disease 
 most common cause of 
thyrotoxicosis 
 as well as typically features of 
thyrotoxicosis other features 
may be seen including thyroid 
eye disease 
Other 
causes  Subacute thyroiditis (de Quervain's) 
 
 associated with a painful 
goitre and raised ESR 
Riedel thyroiditis

Riedel thyroiditis 
 fibrous tissue replacing the 
normal thyroid parenchyma 
 causes a painless goitre 
Postpartum thyroiditis 
Drugs 
 lithium 
Iodine deficiency  
 the most common cause of 
hypothyroidism in the 
developing world Toxic multinodular goitre 
 
 autonomously functioning 
thyroid nodules that secrete 
excess thyroid hormones 
Drugs 
 amiodarone 215

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          37 
  
It should be remembered that a lot of the conditions mentioned above don't alwa ys cause either 
hypothyroidism or hyperthyroidism, there is sometimes some overlap, as shown below: 
 
Venn diagram showing how different causes of thyroid dysfunction ma y manifest. Note how many causes of hypothyroidism may hav e

an initial thyrotoxic phase. 
 
216

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          38 
  
Symptoms and signs  
Thyroid disorders can present in a large variety of ways. Often (but not always) the symp toms present 
are the opposite depending on whether the thyroid gland is under or over active, for e xample 
hypothyroidism may result in weight gain whilst thyrotoxicosis normally leads to weight loss

Feature Hypothyroidism Thyrotoxicosis 
General  Weight gain  
 Weight loss  
 
Lethargy  
 'Manic', restlessness 
 
Cold intolerance Heat intolerance 
Cardiac  Bradycardia Palpitations , may even provoke 
arrhythmias e.g. atrial fibrillation 
Skin  Dry (anhydrosis), cold, yellowish 
skin 
 Increased sweating 
 
Non-pitting oedema (e.g. hands, 
face) 
 Pretibial myxoedema: erythematous, 
oedematous lesions above the lateral 
malleoli 
- Thyroid acropachy: clubbing

malleoli 
- Thyroid acropachy: clubbing 
Hair Dry, coarse (خشنscalp hair, loss of 
lateral aspect of eyebrows Fine (ناعم )
Gastrointestinal  Constipation Diarrhoea 
Gynaecological  Menorrhagia Oligomenorrhea 
Neurological  Decreased deep tendon reflexes 
 
Carpal tunnel syndrome Anxiety  
 
Tremor  
 
Investigations and diagnosis  
 
The principle investigation is 'thyroid function tests', or TFTs for short:  
 these primarily look at serum TSH and T4 levels 217

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          39 
  T3 can be measured but is only useful clinically in a small number of cases 
 Note that T3 concentrations are of no value when evaluating hypothyroidism 
because the T3 values are often normal due to increased T4 to T3 conversio n.

 remember that TSH and T4 levels will often be 'opposite' in cases of primary hypo- o r 
hyperthyroidism. For example in hypothyroidism the T4 level is low (i.e. not enough thyroxine ) 
but the TSH level is high, because the hypothalamus/pituitary has detected low lev els of T4 
and is trying to get the thyroid gland to produce more 
 TSH levels are more sensitive than T4 levels for monitoring patients with existing thyroid 
problems and are often used to guide treatment

problems and are often used to guide treatment 
 
The table below shows how thyroid function tests are interpreted: 
 
Diagnosis TSH Free 
T4 Notes 
Thyrotoxicosis (e.g. 
Graves' disease) Low High  
Primary 
hypothyroidism (e.g. 
Hashimoto's 
thyroiditis) High Low  
Secondary 
hypothyroidism Low Low  
Sick euthyroid 
syndrome Low Low Common in hospital inpatients. Changes are reversible 
upon recovery from the systemic illness and no treatment is 
usually needed 
Subclinical

Subclinical 
hypothyroidism High Normal This is a common finding and represents patients who are 
'on the way' to developing hypothyroidism but still have 
normal thyroxine levels. Note how the TSH levels, as 
mentioned above, are a more sensitive and early marker of 
thyroid problems 
Poor compliance with 
thyroxine High Normal Patients who are poorly compliant may only take their 
thyroxine in the days before a routine blood test. The

thyroxine levels are hence normal but the TSH 'lags' and 
reflects longer term low thyroxine levels 
 
 218

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          40 
  
Different patterns on thyroid function test: 
Situation TSH fT4 fT3 
Over-replacement with thyroxine Low High Normal/High 
Sick euthyroid syndrome Normal/ High Low Normal/Low 
Subclinical hypothyroidism High Normal Normal 
TSH-secreting tumour High High High

TSH-secreting tumour High High High 
Untreated hypopituitarism Low/Low normal Low/Low normal Low/Low normal 
  
A number of thyroid autoantibodies can be tested for (remember the majority of thyroid disorders are  
autoimmune). The 3 main types are: 
 
 Anti-thyroid peroxidase (anti-TPO) antibodies 
 present at high titre, in Hashimoto's thyroiditis  
 low titre in Graves' disease, De Quervain's thyroiditis, 
  8% of males, and 10% of females without thyroid disease.

 TSH receptor antibodies 
 Thyroglobulin antibodies 
 
There is significant overlap between the type of antibodies present and pa rticular diseases, but 
generally speaking TSH receptor antibodies are present in around 90-100% of patients w ith Graves' 
disease and anti-TPO antibodies are seen in around 90% of patients with Hashimoto's thyroid itis 
 
Other tests include:  
 nuclear scintigraphy; toxic multinodular goitre reveals patchy uptake

Anti-TPO antibodies are present in 10% females without thyroid pathology 
 
Treatment  
 This clearly depends on the cause.  
 For patients with hypothyrodism:  thyroxine is given in the form of levothyroxine to 
replace the underlying deficiency.  
 Patients with thyrotoxicosis may be treated with:  
 propranolol: this is often used at the time of diagnosis to control thyrotoxic 
symptoms such as tremor 219

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          41 
  carbimazole: blocks thyroid peroxidase from coupling and iodinating the tyrosine 
residues on thyroglobulin ĺ reducing thyroid hormone production. 
Agranulocytosis is an important adverse effect to be aware of 
 radioiodine treatment

 radioiodine treatment 
 A history of an acutely painful, left-sided goitre in euthyroid and apyrexial patient with norm al labs 
and no prior history of thyroid disease ? 
 Haemorrhage into a cyst  
 
Hypothyroidism: causes  
Hypothyroidism affects around 1-2% of women in the UK and is around 5-10 times more co mmon in 
females than males.  
 Primary atrophic hypothyroidism 
 most common cause

 most common cause 
 autoimmune disease, associated with IDDM, Addison's or pernicious anaemia 
 5 times more common in women 
 
 Hashimoto's thyroiditis  
 autoimmune disease with goitre (positive microsomal antibodies) 
 may cause transient thyrotoxicosis in the acute phase 
 10 times more common in women 
 After thyroidectomy or radioiodine treatment  
 Drug therapy  (e.g. lithium, amiodarone or anti-thyroid drugs such as carbimazole)

 "The common clinical side effects of the lithium are goitre in up to 40% and 
hypothyroidism in about 20%. Lithium increases thyroid autoimmunity if present 
before therapy. Treatment with levothyroxine is effective and lithium therapy should 
not be stopped."  
 Dietary iodine deficiency  
 Iodine deficiency  is extremely unlikely in the United Kingdom  
 common in parts of central Africa,  where the diet is poor in iodine and access to 
sea fish is relatively difficult.

sea fish is relatively difficult.  
 It may present as goitre without hypothyroidism, or in severe cases can progress to 
frank hypothyroidism. 
 Secondary hypothyroidism (rare) :From pituitary failure 
 Other associated conditions  
 Down's syndrome 
 Turner's syndrome 
 coeliac disease 
 Hyperprolactin (hyperPRL) hypogonadism:  
 Hypothyroidism  ↑↑TRH (thyrotropin-releasing factor)  act as prolactin-
releasing factor  release of prolactin and hyperprolactinaemia.

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          42 
  In hypothyroidism, the activity of bilirubin UDP-glucuronyl transferase is 
decreased, resulting in a reduction in bilirubin excretion.   
 Dyslipidaemia :  may well resolve following the appropriate replacement with 
thyroxine. 
 Hypercarotenaemia (high blood levels of beta-carotene)

 Carotonemia is yellowing of the skin (xanthoderma) associated with beta-
carotene excess and can be seen in hypothyroidism .  
 It occurs because of a decrease in conversion from carotene to vitamin A.  
 decreased consumption of vitamin A in hypothyroidism.  
 thyroxine , normally speeds the conversion of beta-carotene to retinol. 
 Ļ thyroxine  ĹBeta-carotene   
 Beta-carotene is more prominent in areas where the stratum corneum is 
thickened (palms and soles).

thickened (palms and soles). 
 Carotenemia is most commonly seen in young children who are fed excessive 
amounts of beta-carotene rich foods  (squash, sweet potatoes, carrots).  
 It may also be seen in some instances of diabetes 
mellitus, hyperlipidemia, anorexia nervosa or hepatic and renal disease. 
 
 Low thyroid hormone means reduced use of glucose and FFAs as fuel. This is why 
glucose intolerance and hyperlipidemia occur in hypothyroidism.

 Low thyroid = Decreased metabolic rate = Weight gain 
 
Feature 
 Constipation,  
 dry skin,  
 Menorrhagia  
 Weight gain  
 Clinically silent pericardial effusion is common in untreated hypothyroidism  
 The predominant lipid picture in hypothyroidism is mixed dyslipidaemia  ( ĹLDL ,  ↑ triglycerides ) 
 
Thyroxine in patient receiving oestrogen/progesterone (HRT): 
 Thyroxine is mostly bound to thyroxine binding globulin in the circulation.

 Oestrogen therapy is associated with elevation of thyroxine binding globulin in the serum. 
 Thus the total serum thyroxine  may be misleading in this case, and serum free thyroxine 
will confirm whether this patient is hypothyroid or euthyroid.   
 
confusion and coldness with erythema ab igne suggest a diagnosis of hypothyroidism . 
 
Which laboratory tests is most likely to confirm the diagnosis of hypothyroidism? 
 Serum thyroid-stimulating hormone (TSH) measurement

 TSH levels usually rise above normal before serum thyroxine(T4) and serum triiodothyronine 221

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          43 
 (T3) levels do, even in mild cases of hypothyroidism.  
 anti-thyroid antibodies is characteristic of chronic thyroiditis, which is the most common cause 
of hypothyroidism. However, detection of these antibodies would not indicate that 
hypothyroidism was present. 
 
Myxoedema coma

Myxoedema coma  
 usually occurs in the elderly who are typically non-compliant.  
 can be the initial presentation of hypothyroidism, but more usually occurs against a 
background of long-standing disease where patients are unable to comply with their th yroxine 
 carries a high mortality 
 The clues toward this diagnosis are: 
 'yellowish hue' (referring to carotinaemia) 
 obesity 
 bradycardia 
 hypothermia, and 
 coma.

 coma. 
 Facial features include general coarsening with periorbital oedema and hair thinning. 
 should be treated initially with IV thyroid hormone - either T4 or T3 - and IV 
hydrocortisone even before results are obtained. 
 Treatment with hydrocortisone is recommended until Addison ’s disease can be 
excluded, as just giving thyroid hormone alone may precipitate an adrenal crisis.  
 Other treatment includes rewarming.

 Other treatment includes rewarming. 
 should be rewarmed slowly  in order to improve the chance of neurological recovery. 
 IV fluids should be used cautiously, as these patients are typically fluid overloaded. 
 
High dose aspirin may affect interpretation of free T4 values, but low dose aspirin and 
clopidogrel are not known to interfere with thyroid function testing. 
 
A number of agents are known to interfere with thyroxine absorption.  These include binding

agents such as cholestyramine and sevelamer, iron sulphate, and proton pump inhibitors. 
 
 222

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          44 
 Primary vs secondary hypothyroidism  
 
primary vs secondary hypothyroidism  
 primary hypothyroidism  
 menorrhagia,  
 skin will be coarse,  
 macroglossia will be severe,  
 diastolic BP elevated, 
 delayed relaxation of deep tendon reflexes. 
 High TSH, low T4, low T3 
 secondary hypothyroidism

 secondary hypothyroidism 
 skin and hair which are dry but not very coarse,  
 skin depigmentation,  
 only minimal macroglossia,  
 atrophic breasts ,   
 low blood pressure ,  
 normal or low TSH, low T4, low T3  
 Amenorrhea, menorrhagia and other menstrual irregularities are all associated with 
both primary and secondary hypothyroidism. 
 
223

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          45 
 Hypothyroidism: management 
 
Key points 
 initial starting dose of levothyroxine should be lower in elderly patients and those with 
ischaemic heart disease. The BNF recommends that for patients with cardiac disease, severe 
hypothyroidism or patients over 50 years the initial starting dose should be 25mcg od with

dose slowly titrated. Other patients should be started on a dose of 50-100mcg o d 
 following a change in thyroxine dose thyroid function tests should be checked after 8-12  weeks 
 the therapeutic goal is 'normalisation' of the thyroid stimulating hormone (TSH) level. As t he 
majority of unaffected people have a  TSH value 0.5-2.5 mU/l it is now thought preferable to 
aim for a TSH in this range  
 women with established hypothyroidism who become pregnant should have their do se

increased 'by at least 25-50 micrograms levothyroxine due to the increased deman ds of 
pregnancy. The TSH should be monitored carefully, aiming for a low-normal value 
 there is no evidence to support combination therapy with levothyroxine and liothyronine 
 Over-replacement can lead to accelerated bone loss and osteoporosis, particularly in women 
so regular monitoring of TSH is recommended.  
 
Monitoring of thyroid status

Monitoring of thyroid status 
Thyroid-stimulating hormone (TSH) is the most sensitive indicator of thyroid st atus. 
 Normal TSH  result suggests  adequate thyroxin replacement & euthyroidism  
 ↑↑ (TSH) with normal (T4)  suggest   poor compliance   
 ↓↓ (TSH) with  normal - high (T4)  suggests   over-replacement  
 
Side-effects of thyroxine therapy 
 hyperthyroidism: due to over treatment 
 reduced bone mineral density 
 worsening of angina 
 atrial fibrillation

 atrial fibrillation 
Interactions: Drugs interfere with absorption of thyroxine  leading to a hypothyroid crisis.  
 rifampicin 
 calcium supplements 
 Amiodarone 
 and ferrous sulphate (give at least 2 hours apart)  
 
Overdoses of thyroxine  
• are relatively rare, 
• In reality, patients may be partially protected from thyroid hormone excess by production of 
reverse T3.  
 
224

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          46 
 • The vast majority can be managed with regular propranolol to alleviate symptoms of 
tachycardia and anxiety. 
• In severe cases , 
 plasmapheresis to remove protein bound thyroxine,  
 and cholestyramine to reduce enterohepatic circulation of thyroxine  
 
Hashimoto's thyroiditis

Hashimoto's thyroiditis 
 
 Hashimoto's thyroiditis is an autoimmune disorder of the thyroid gland.  
 It is typically associated with hypothyroidism although there may be a transient thyrotoxicosis 
in the acute phase. 
 Early in the course of disease, T4 and TSH levels are normal and there are high levels of 
thyroid peroxidase antibodies  and, less commonly, anti-thyroglobulin antibodies.  Thyroid

radioiodine uptake may be increased because of defective iodide organification, together 
with a gland that continues to trap iodine. 
 Later in the course of the disease , patients develop hypothyroidism with decreased T4, 
decreased radioiodine uptake, and increased TSH. 
 It is the most common hypothyroidism in UK , Irrespective of gender. 
 It is 10 times more common in women 
 Commonly associated with Turner's syndrome.  
Features

Features  
 features of hypothyroidism (eg hair loss, hoarse voice and periorbital oedema ) 
 goitre: firm, non-tender 
 antibodies  
 anti-thyroid peroxidase (anti TPO) also known as ( Anti-microsomal antibodies)  
 anti-thyroglobulin antibodies (anti-Tg ) 
 
Hashimoto's encephalopathy  
 Hashimoto's encephalopathy is extremely rare. 
 result in altered mental state, myoclonus and ataxia. 
225

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          47 
  Should be suspected in TSH derangement however there may be no clinical eviden ce of 
thyroid dysfunction. 
  the next laboratory tests should be  Anti-thyroid peroxidase antibodies  
 It is a steroid responsive encephalopathy

 It is a steroid responsive encephalopathy  
 
January 2009 exam: Feature of feeling tired and cold + firm, non-tender goiter. TSH = 24.2 mU/l, Free 
T4 = 5.4 pmol/l. What is the most likely diagnosis? Hashimoto's thyroiditis  
 
 September 2009 exam: A patient diagnosed with autoimmune thyroiditis. Which type of thyroid 
cancer is she predisposed to developing?  Lymphoma  
 
September 2009 exam: Which one of the following is most likely to be found in a patient with

Hashimoto's thyroiditis? Anti-thyroid peroxidase antibodies.  
 
Profound hypothyroidism  
 greatly reduced free T4 concentration, 
  hypothermic 
  unconscious  
  evidence of  associated heart failure. 
Management   
 T3 is usually given via a nasogastric tube or by intravenous injection at the rate of 2.5- 5 pg 
every 8 hours, with  conversion to T4 after the patient regains consciousness.

 There is a risk of precipitating heart failure if larger doses  are given in the initial period. 
Prognosis 
 Mortality associated with this condition used to be as high as 50%, but survival has improved  
with modern intensive-care management.  
_____________________________ _______________________________
Pendred's syndrome  Autosomal recessive disorder of defective iodine uptake  
signs of deafness and hypothyroidism  Pendred's syndrome 
Features 
 sensorineural deafness

Features 
 sensorineural deafness 
 The patients tend to present with : 
 progressive hearing loss  
 delay in academic progression.  
 Often head trauma tends to make the sensorineural deafness worse, leading to  
patients having to avoid contact sports. 
 goitre 
 euthyroid or mild hypothyroidism 
 Thyroid function tests are also often normal, requiring the perchlorate discharge test to aid  
diagnosis. 
 diagnosed via : 226

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          48 
  genetic testing  (Pendred syndrome (PDS) gene , chromosome 7 ),  
 audiometry and MRI imaging to look for characteristic one and a half turns in the 
cochlea , compared to the normal two and a half turns.  
 Treatment  with: 
  thyroid hormone replacement   
 cochlear implants.

 cochlear implants. 
Sick euthyroid syndrome 
 In sick euthyroid syndrome (now referred to as non-thyroidal illness) it is often said that 
everything (TSH, thyroxine and T3) is low. 
 In the majority of cases however the TSH level is within the normal range (inappropriately 
normal given the low thyroxine and T3). 
Pathology   
 down regulation of type 1 deiodinase, reducing the peripheral conversion of T4 to T 3 and thus

reducing the basal metabolic rate during periods of stress.  
 Upregulation of type 3 deiodinase to inactive (reverse) T3 also aids to reducing basal 
metabolic rate. 
 
Causes   
 myocardial infarctions,  
 starvation,  
 burns, trauma, surgery,  
 malignancy,  
 diabetic ketoacidosis,  
 any organ failure (particularly common in patients with chronic renal failure)   
 inflammatory conditions. 
 
Features: Typically:

Features: Typically:  
 Thyroid-stimulating hormone (TSH) decreases during the acute phase of the illne ss and 
increases during recovery. 
 Free tri-iodothyronine (fT3) is low due to reduced peripheral conversion of thyroxine (T4) to T3 
by deiodinase enzymes. Similar issues can occur in chronic nutritional deficiency, poorly 
controlled diabetes mellitus and drug treatment with hydrocortisone or beta blockers. 
 Reverse T3 (rT3) is made instead of normal T3.

 Reverse T3 (rT3) is made instead of normal T3. 
 T4 is often normal or slightly low. 
 Thyroid binding proteins. 
 Changes are reversible upon recovery from the systemic illness. 
 the most appropriate next step in management   repeat thyroid function tests in 3 
months 
 September 2012 exam: A patient admitted to ITU with a severe pneumonia. Thyroid function tests 
are most likely to show:? TSH normal / low; thyroxine low; T3 low  227

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          49 
 ____________________________________________________________  
Skin disorders associated with thyroid disease 
Skin manifestations of hypothyroidism 
 dry (anhydrosis), cold, yellowish skin 
 non-pitting oedema (e.g. hands, face) 
 dry, coarse scalp hair, loss of lateral aspect of eyebrows 
 eczema 
 xanthomata

 eczema 
 xanthomata 
Skin manifestations of hyperthyroidism 
 pretibial myxoedema:  
 erythematous, oedematous lesions above the lateral malleoli 
 It can occur anywhere, but typically it occurs on the shins and dorsum of feet. 
 treatment: 
 No treatment is usually required,  Reassurance   
 when there is more severe localised pain, then patients may be considered for local 
use of a potent corticosteroid such as fluocinolone.

 Topical fluocinolone  is the first line treatment for pretibial myxoedema, 
but usually only when there is significant pain and discomfort . 
 Systemic steroids are only rarely used for very severe disease, usually in 
conjunction with compression bandaging.  
 thyroid acropachy: clubbing 
 scalp hair thinning 
 increased sweating 
Pruritus can occur in both hyper- and hypothyroidism 
Subclinical hypothyroidism 
Basics

Basics 
 TSH raised but T3, T4 normal 
 no obvious symptoms 
Significance 
 risk of progressing to overt hypothyroidism is 2-5% per year (higher in men) 
 risk increased by presence of thyroid autoantibodies 
Treat if 
 TSH > 10 
 thyroid autoantibodies positive 
 other autoimmune disorder 
 previous treatment of Graves' disease 
 For patients with atherosclerotic cardiovascular disease 
 Pregnancy or pregnancy planned in the near future 
 
 228

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          50 
  
Frequency of TFT testing : 
 if anti-TPO antibodies are negative and asymptomatic   Review every 3 years with 
thyroid function tests 
 Where antibodies are positive, a 1-year testing interval is recommended for patients with out 
symptoms of hypothyroidism.

symptoms of hypothyroidism. 
Pregnancy: thyroid problems  
Physiological changes 
 thyroid gland hypertrophy  
 The thyroid gland needs to produce 50% more thyroid hormone during pregna ncy to 
maintain a euthyroid state.  
 increase in thyroid-binding globulin and albumin due to increased hepatic synthesis.  
 pregnancy  ĹĹ thyroxine-binding globulin (TBG)  ĹĹ total thyroxine but 
does not affect the free thyroxine level

does not affect the free thyroxine level 
 Thyroid-binding globulin has a twofold increase in concentration during pregnancy 
as a result of reduced hepatic clearance and increased synthesis under oestrogen 
stimulus  
 Increase in  total T3 and T4 
 in normal pregnancy  (T 3) and T 4 levels show a slight increase with 
suppressed (TSH)  in the first trimester due to the partial thyroid-stimulating 
action of human chorionic gonadotrophin (beta- HCG ).

 Free T3 and T4 remains within normal ranges 
 HCG  activation of the TSH receptor  transient gestational hyperthyroidism.  
 TSH may be mildly suppressed in up to 13.5% of pregnancies during the first 
trimester, and 4.5% of women in the second trimester , and this is considered a 
normal variant. 
 HCG levels will fall in second and third trimester  
Daily requirement of iodine 
 Maternal thyroid hormone is needed for neuronal development until 12-13 we eks, and recent

research has shown children of mothers with hypothyroidism may have a lower IQ than those 
born to women with normal thyroid function. 
 American Thyroid Association's 2017 Guidelines recommends: 
 all pregnant women should ingest approximately 250 micrograms of iodine daily.  
 In most countries, women who are planning pregnancy or currently pregnant, should 
supplement their diet with a daily oral supplement that contains 150 micrograms  of

iodine in the form of potassium iodide . This is optimally started 3 months before 
conception.  
 
Thyrotoxicosis  
 Untreated thyrotoxicosis increases the risk of fetal loss, maternal heart failure and premature 
labour 229

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          51 
  When there are TSH receptor antibodies present at high concentration they may cross the  
placenta. 
 Fetal hyperthyroidism occurs in children born to mothers with Graves' disease due to 
circulating  thyroid stimulating antibodies   which can cross the placenta.

 A pregnant woman with positive thyroid antibodies but who is euthyroid has a higher 
risk of spontaneous abortion. A meta-analysis confirms the association between anti-TPO 
antibodies and premature foetal loss.  
 Graves' disease is the most common cause of thyrotoxicosis in pregnancy.  
 Investigations 
 Serum TSH can exclude primary thyrotoxicosis.  
 Confirm diagnosis with free T4 levels.  
 If TSH is suppressed but free T4 levels are normal then, if not previously supplied, free

T3 level is necessary (T3 toxicosis occurs in 5% of patients). 
 It is important to remember that the ranges of TSH, T3 and T4 are different in 
pregnancy:  
 TSH - levels are trimester-dependent:  
 0.2-2.5 mlU/L in the first trimester. 
 0.3-3.0 mlU/L in the second trimester. 
 Up to 3.5 mlU/L in the third trimester. 
 TRAb  can cross the placenta, stimulating the fetal thyroid, so it is important to measure 
during pregnancy. 

Due to the small risk of fetal abnormalities with carbimazole it is recommended to use PTU in 
the first trimester during organogenesis and then carbimazole in trimester 2 + 3.  
 
 Early pregnancy (1st trimester) 
 Due to the small risk of fetal abnormalities with carbimazole it is 
recommended to use PTU in the first trimester during organogenesis 
and then carbimazole in trimester 2 + 3.

and then carbimazole in trimester 2 + 3. 
 Propylthiouracil is more highly protein bound and is ionized at pH 7.4, thus 
making it  less likely to cross the placenta or breast milk.   
 PTU may be more protein bound and so less is transmitted to the fetus, but 
compliance with carbimazole is generally better. 
 Carbimazole has rarely been associated with aplasia cutis of the neonate 
 Late pregnancy (2nd  + 3rd trimester):

 Late pregnancy (2nd  + 3rd trimester):  
 Carbimazole is the recommended option in late pregnancy because of 
reports of hepatotoxicity associated with Propylthiouracil. 
 Despite this some endocrinologists use carbimazole and the BNF states both 
drugs may be used in pregnancy.  
 Postpartum Patients:  
 Postpartum Patients may continue to breast-feed 230

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          52 
  the risk of propylthiouracil and carbimazole being secreted into breast milk is 
negligible.  
 PTU has the advantage of being excreted to a lesser extent than carbimazole in 
breast milk.  
  PTU is the most appropriate treatment for pregnant who plan to breast-

feed her baby after deliver y. (medical-masterclass.com 2017 part 2)  
 However, neonatal thyroid function should be checked regularly. 
 Investigations and targets 
 maternal free thyroxine levels should be kept in the upper third of the normal 
reference range to avoid fetal hypothyroidism 
 thyrotrophin receptor stimulating antibodies should be checked at 30-36 weeks 
gestation - helps to determine risk of neonatal thyroid problems 
 Contraindications:

 Contraindications:  
 block- and-replace regimes should not be used in pregnancy 
 radioiodine therapy is contraindicated 
 
Hypothyroidism  
 Overview  
 Hypothyroidism is the commonest pre-existing endocrine disorders in pregnancy 
 occurs in 2.5% of pregnant women.  
 most commonly caused by Hashimoto's thyroiditis. 
 Monitoring 
 thyroid function tests should be assessed at 6- 8 weeks gestation, 16-20 and at 28-
32 weeks (each trimester and 6-8 weeks post-partum)

 Thyroid function tests should be measured every 8-12 weeks if stable, and 4- 6 
weeks if medication is changed. 
 Thyroxine  
 safety  
 thyroxine is safe during pregnancy and breast feeding 
 dose adjustment 
 Patients with established hypothyroidism 
 at the first prenatal visit the dose is usually increased by 30- 50%  
 During pregnancy, the average thyroxine requirements typically 
increase by 25-50 mcg.

increase by 25-50 mcg.  
 The patient normally returns to their original dose of levothyroxine straight 
after delivery. 
 Patients newly diagnosed with hypothyroidism whilst pregnant 
 treatment commenced immediately with a starting dose of 100 microgram 
daily. 
 thyroxine dose should be adjusted to reach and maintain serum TSH 
concentrations in the low normal range (0.4 - 2.0mU/L) in the first trimester 
(or trimester specific normal TSH values) 
 Complications

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          53 
  congestive cardiac failure, 
 megacolon, 
 adrenal crisis,  
 psychosis, 
 myxoedema coma  
 hyponatraemia. 
 pre-eclampsia,  
 placental abruption  
 consequences for the foetus: 
 miscarriage  
 low birth weight,  
 increase in stillbirth rate  
 Prognosis for mother and foetus

 Prognosis for mother and foetus  
 excellent with appropriate treatment. 
 
September 2007 exam: Pregnant lady investigated for excessive sweating and tremor. Blood tests reveal 
the following:  TSH < 0.05 mu/l.  T4 =188 nmol/l.What is the most appropriate management? 
Propylthiouracil  
Post-partum thyroiditis 
 thyroid dysfunction occurring within the first 6 months after delivery.  
Course of disease

Course of disease 
 Hyperthyroid status followed by a hypothyroid phase at three to six months, followed by  
spontaneous recovery in one third of cases. In the remaining two-thirds, a  single-phase pattern 
or the reverse occurs. 
Pathophysiology  
 The exact aetiology is unknown but lymphocytic infiltration  of the thyroid is typical , 
suggesting auto-immunity. 
Prevalence 
 occurs in approximately 5- 7% of females   
Risk factors

 Common in whom thyroid peroxidase (TPO) antibodies were positive prior to delivery 
 twice common in patients with type 1 diabetes mellitus. 
Three stages 
 1. Thyrotoxicosis 
 2. Hypothyroidism 
 3. Normal thyroid function (but high recurrence rate in future pregnancies) 
 
 Thyroid peroxidase (TPO) antibodies  are found in 90% of patients  
Management 232

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          54 
  the thyrotoxic phase is not usually treated with anti-thyroid drugs as the thyroid is not 
overactive.  
 Symptomatic treatment using  beta-blockers  for relief of tremor or anxiety. 
 Propranolol is typically used for symptom control  
 the hypothyroid phase is usually treated with  thyroxine

 withdrawal period after 6 months to measure recovery of thyroid function. 
Prognosis 
 Recurrence of thyroiditis is common in subsequent pregnancies  
 in up to 40% permanent hypothyroidism develops. 
Subacute (De Quervain's) thyroiditis 
 
 Subacute thyroiditis also known as De Quervain's thyroiditis and subacute granulomatous  
thyroiditis  
 Occur after viral infection

 Occur after viral infection  
 The thyroid gland will be firm, enlarged bilaterally or unilaterally due to extravasation of 
colloid from the follicles causing a granulomatous reaction.   
 typically presents with hyperthyroidism 
 It is associated with HLA-B35  
 
233

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          55 
  
Features  
Tender goitre, hyperthyroidism and raised ESR + globally reduced uptake on 
technetium thyroid scan is typical (De Quervian) 
 Hyperthyroidism  
 As the condition resolves patients become hypothyroid and then euthyroid.  
 painful goitre , raised temperature

 painful goitre , raised temperature 
 The thyroid enlargement is typically rapid, occurring over a period of days. 
 raised ESR (>50 and usually 100)  
 globally reduced uptake on iodine-131 scan 
 the most helpful investigation in establishing the diagnosis  Radioactive 
iodine uptake scan 
 Radioiodine uptake is typically less than 1% at 24 hours (Tc 99m uptake is similarly 
low). 
 usually self-limiting - most patients do not require treatment

 The most appropriate treatment of de Quervain's thyroiditis is symptomatic control.  
 thyroid pain may respond to aspirin or other NSAIDs 
 in more severe cases  steroids ( Prednisolone  ) are used, particularly if hypothyroidism 
develops 
Prognosis 
 The hypothyroidism is usually mild but persists for two to four months.  
 A few patients (~5%) remain hypothyroid and need longterm thyroid hormone replacem ent.  
 Recurrences are uncommon.

 Recurrences are uncommon. 
 
 May 2012 exam: H/O palpitations and heat intolerance. O/E pulse is 90/min & a small, diffuse goitre 
is noted which is tender to touch. TFT:  Free T4=24 pmol/l. TSH< 0.05 mu/l. What is the most likely 
diagnosis?  De Quervain's thyroiditis  
 
Subclinical hyperthyroidism 
It is defined as: 
 normal serum free thyroxine and triiodothyronine levels

 with a thyroid stimulating hormone (TSH) below normal range (usually < 0.1 mu/l) 
Causes 
 multinodular goitre, particularly in elderly females 
 excessive thyroxine may give a similar biochemical picture 
 
The importance in recognising subclinical hyperthyroidism  lies in the potential effect on the 
cardiovascular system (atrial fibrillation) and bone metabolism (osteoporosis).  It may also impact 234

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          56 
 on quality of life and increase the likelihood of dementia 
 TSH levels often revert to normal - therefore levels must be persistently low to warrant 
 a reasonable treatment option is a therapeutic trial of low-dose antithyroid agents f or

approximately 6 months in an effort to induce a remission 
Thyrotoxicosis   
 
Causes  
 Graves' disease (50-60% of cases of thyrotoxicosis) 
 toxic nodular goitre 
 subacute (de Quervain's) thyroiditis 
 post-partum thyroiditis 
 acute phase of Hashimoto's thyroiditis (later results in hypothyroidism) 
 toxic adenoma (Plummer's disease) 
 amiodarone therapy 
 factitious hyperthyroidism

 factitious hyperthyroidism  
 diagnosis of factitious hyperthyroidism  undetectable thyroglobulin. 
 thyroglobulin is the precursor of thyroid hormones, therefore if undetectable, 
indicates an external source of thyroid hormone has been administered. 
 Which of the investigation is likely most to differentiate between self-
administration of thyroid hormone and endogenous causes of 
thyrotoxicosis? 
 Radioactive uptake thyroid scan

Radioactive uptake thyroid scan  
 endogenous causes of thyrotoxicosis   increased radioactive uptake 
 In thyrotoxicosis factitia, uptake is globally reduced. 
 Excess iodine ingestion  
 Kelp is a very rich source of iodine.  
 In patients with pre-existing thyroid hyperplasia or adenoma, the ingestion of 
largeamounts of iodine can precipitate thyrotoxicosis.  
 Treatment is withdrawal of the kelp with monitoring of thyroid  function.  
 struma ovarii

 struma ovarii 
 a rare cause of hyperthyroidism which is due to thyroglobulin production by ectopic 
thyroid tissue in an ovarian teratoma (also known as dermoid cysts).  
 Teratomas include tissues from all three germ layers and commonly have hair, 
teeth, and sebum.  
 negative neck ultrasound and neck exam in the setting of hyperthyroidism  and 
low radioiodine uptake. 
 can be visualized with a  pelvic ultrasound  or abdominal CT. 
235

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          57 
 Feature 
 Lid retraction and lag are signs of sympathetic overactivity, and occur in any thyrotoxic 
state (thyroxine potentiates the action of catecholamines). 
 Decreased libido  
 High bone turnover and osteoporosis  may be associated with thyrotoxicosis. Bone turnover

involves increased osteoclastic and osteoblastic activity, leading to  elevated alkaline 
phosphatase levels derived from bone. 
 AF occurs in 10% to 25% of patients with hyperthyroidism, more commonly in men and th e 
elderly than in women or patients less than 75-years-old.  
 AF generally caused by increased beta-adrenergic tone. Propranolol is effective in 
controlling all symptoms prior to initiation of specific therapy (e.g. carbimazole,

which will have a more delayed effect on symptoms).  
Metabolic changes 
 Serum glucose levels typically  increase in patients with hyperthyroidism. 
 Hypocholesterolemia  due to increased LDL receptor expression. 
 TSH down, T4 and T3 up 
 The most sensitive test to diagnosis hyperthyroidism is TSH level. 
 In primary hyperthyroidism the TSH should always be suppressed by negative 
feedback 
 Non-suppressed (TSH)  suggests  excessive TSH production by the pituitary

gland, the possibility of a thyrotroph adenoma  do MRI scan pituitary gland  
 thyroid autoantibodies 
 other investigations are not routinely done but includes isotope scanning 
Toxic multinodular goitre  (TNG) (Plummer's disease)  
 Toxic multinodular goitre describes a thyroid gland that contains a number of autonom ously 
functioning thyroid nodules that secrete excess thyroid hormones.

 TNG is the second most common cause of hyperthyroidism in the Western world, after G raves 
disease. In elderly individuals and in areas of endemic iodine deficiency, TNG is the most 
common cause of hyperthyroidism. 
 Mechanism: related to iodine deficiency.  
 Iodine deficiency  Ļ T4  thyroid cell hyperplasia to compensate for the low levels 
of T4  Ĺthyroid cell replication  somatic mutations of the TSH receptor  further 
growth  clonal proliferation  multiple nodules.

 Soma tic mutations of the TSH receptors and G α protein  activation of cyclic 
adenosine monophosphate (cAMP) cascade of the inositol phosphate pathways 
functional autonomy of the thyroid  
 Endothelin-1 (ET-1) production may be involved in thyroid gland growth and 
vascularity. 
 usually occurs in women aged over 55 years  
 Evidence of hyperthyroidism  (ĻTSH + Ĺ or normal free T4)  236

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          58 
  Nuclear scintigraphy reveals  patchy uptake  
 Toxic nodular goiter (TNG)  patchy uptake 
 Graves disease  homogeneous diffuse uptake. 
 Thyroiditis  low uptake. 
 CT of the chest  is the investigation of choice to determine the degree of retrosternal 
involvement

involvement  
 Ultrasonography is a highly sensitive to detect nodules that are not palpable during th yroid 
examination. 
 helpful when correlated with nuclear scans to determine the functionality of nodules. 
 Dominant cold nodules should be considered for fine-needle aspiration biopsy  prior 
to definitive treatment of a TNG. 
 Fine-needle aspiration is not usually indicated in an autonomously functioning (ie, 
hot) thyroid nodule. The risk of malignancy is quite low.

 Perform a fine-needle aspiration biopsy if a dominant cold nodule is present  in a 
multinodular goiter. 
Treatment 
 The treatment of choice is radioiodine therapy 
 In patients with uptake of less than 20%, pretreatment with lithium, PTU, or 
recombinant TSH can increase the effectiveness of iodine uptake and treatment.  
 Surgical therapy is usually reserved for young individuals, patients with 1 or more large

nodules or with obstructive symptoms, patients with dominant nonfunctioning or suspicio us 
nodules, patients who are pregnant, patients in whom radioiodine therapy has failed , or 
patients who require a rapid resolution of the thyrotoxic state.  
Radioiodine treatment 
 Anti-thyroid drugs can be recommenced after radioiodine administration, but treatment should 
be withdrawn gradually and guided by 6-8-weekly thyroid function testing.

  Early post-radioiodine hypothyroidism might be transient. 
 Mild thyrotoxic symptoms after radioiodine occur in about one-third of patients, an d about 4% 
of patients develop a clinically significant radiation-induced thyroiditis. These patients shou ld 
be treated symptomatically with beta blockers. 
  (TSH) level should be monitored every 6 months after radioiodine therapy to d etect late 
hypothyroidism.

hypothyroidism. 
 Patients should not have close contact with children under the age of 11 years for about 
2 weeks after treatment  
 September 2010 exam:  H/O thyrotoxicosis. O/E goitre containing multiple irregular nodule s. Nuclear 
scintigraphy with technetium 99m reveals patchy uptake. What is the  treatment of choice? Radioiodine  (∆Toxic 
multinodular goitre )  
 
 237

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          59 
  
Graves' disease 
  
Basics 
 Graves' disease is the most common cause of thyrotoxicosis.  
 typically seen in women aged 30-50 years.  
 genetic susceptibility to Graves' disease is associated with the presence of  HLA-DR3 and 
HLA- B8 
Mechanism

HLA- B8 
Mechanism 
 Graves' disease, an autoimmune disorder in which there are antibodies to the TSH receptor 
mimicking the action of endogenous TSH. Binding to the TSH receptor then activ ates adenyl 
cyclase and results in increased secretion of thyroid hormones. 
 Antibodies overstimulating adenyl cyclase 
Features 
 typical features of thyrotoxicosis 
 specific signs limited to Grave's  
Features seen in Graves' but not in other causes of thyrotoxicosis

 eye signs (30% of patients): exophthalmos, ophthalmoplegia 
 pretibial myxedema ( commonly described as orange peel skin present on both shins )  
pathognomonic  
  Infiltrative dermopathy  
 raised, indurated pinkish patches.  
 characterized by non-pitting infiltration by proteinaceous ground substance, usually 
in the pretibial area.  
 It can occur anywhere, but typically it occurs on the shins and dorsum of feet.

 It is often found with acropachy and ophthalmopathy and a high titre of th yroid-
stimulating hormone (TSH) receptor antibodies would be expected.  
 It rarely occurs in the absence of ophthalmopathy.  
 The lesion is often pruritic and erythematous in the early stages, and subsequently 
becomes brawny.  
 may appear years before, or after, hyperthyroidism.

 Thyroid acropachy  (a dermopathy characterized by soft-tissue swelling of the hands 
and clubbing of the fingers.  
 Radiographic imaging of affected extremities typically demonstrates periostitis, most 
commonly the metacarpal bones) 
 thyroid bruit 
 tachycardia 
 Globally increased uptake on thyroid scan. 
 
238

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          60 
 The most likely associate of Graves' disease is vitiligo  occurring in approximately 7% of 
cases. 
 
Laboratory tests in hyperthyroidism 
 Both thyroxine (T4) and triiodothyronine (T3) levels are raised. However,  T3 is more sensitive 
because occasional cases of isolated T3 toxicosis can occur

 thyroid-stimulating hormone (TSH) level is suppressed, but there are rare instances of TSH 
hypersecretion 
 increased  levels of sex hormone-binding globulin (SHBG)  
 
Which blood tests is most sensitive in establishing whether there is excess thyroid activity? 
 Free T3 level 
Autoantibodies 
 anti-TSH receptor stimulating antibodies  (90%)  ( specific for Graves' disease)  
 anti-thyroid peroxidase antibodies (50%) 

TSH is used to assess t he response of patient t o carbimazole for treating Grave ’s 
 Despite many trials there is no clear guidance on the optimal management of Graves' d isease. 
 Treatment options include titration of anti-thyroid drugs (ATDs, for example carbimazole), 
block- and-replace regimes, radioiodine treatment and surgery. 
  Propranolol is often given initially to block adrenergic effects

 Propranolol, a nonselective beta blocker, may help to lower the heart rate, control 
tremor, reduce excessive sweating, and alleviate anxiety. Propranolol is also known 
to reduce the conversion of T4 to T3. 
 In patients with underlying asthma, beta-1 selective antagonists, such as atenolol or 
metoprolol, would be safer options. 
 In patients with contraindications to beta blockers (eg, moderate to severe asthma),

calcium channel antagonists (eg, diltiazem) may be used to help control the heart  
rate. 
ATD titration  
 carbimazole is started at 40mg and reduced gradually to maintain euthyroidism 
 typically continued for 12-18 months 
 patients following an ATD titration regime have been shown to suffer fewer side-eff ects than 
those on a block-and-replace regime 
 Long -term remission following antithyroid drugs is of the order of 15% , with the vast

majority relapsing. Thus, frequently, radio- iodine is advocated as a primary treatment - 
particularly for multi-nodular or toxic solitary nodules. 
Block-and-replace 
 carbimazole is started at 40mg 
 thyroxine is added when the patient is euthyroid 
 treatment typically lasts for 6-9 months 239

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          61 
 Radioiodine iodine (RAI) treatment 
 contraindications include pregnancy (should be avoided for 4-6 months following treatment) 
and age < 16 years.  
 Thyroid eye disease is a relative contraindication, as it may worsen the condition

  Hypothyroidism is the most common adverse effect.  the proportion of patients who 
become hypothyroid depends on the dose given, but as a rule the majority of pa tient will 
require thyroxine supplementation after 5 years 
 approximately 80% will have long-term hypothyroidism following radio-iodine. 
 There is no evidence of increased risk of thyroid neoplasia or gastric neoplasia following 
radioactive iodine (RAI). 
 Goitre shrinkage may occur in up to 30% following RAI.

Carbimazole 
 Carbimazole is used in the management of thyrotoxicosis.  
 It is typically given in high doses for 6 weeks until the patient becomes euthyroid before bein g 
reduced. 
Mechanism of action  
 The active metabolite of carbimazole, methimazole, reduces the synthesis of n ew thyroid 
hormones by inhibiting the iodination of tyrosine

 blocks thyroid peroxidase from coupling and iodinating the tyrosine residues on thyroglobulin 
(Inhibition of the iodination of tyrosine ) ĺ reducing thyroid hormone production  
 It also has an immunosuppressive action leading to a reduction in serum thyroid-stimulating 
hormone (TSH) receptor antibody (TRAb) concentrations 
 There is a subjective improvement within 10-14 days of starting carbimazole but euth yroid

levels are reached only after 3-4 weeks, since the synthesis rather than the release of 
hormones is affected 
 in contrast propylthiouracil as well as this central mechanism of action also has a peripheral 
action by inhibiting 5'-deiodinase which reduces peripheral conversion of T4 to T3 
 
 Carbimazole-induced agranulocytosis (The major complication) 
  defined as neutrophil count less than 0.5 ×109/L

 the incidence of leukopenia/neutropenia with carbimazole is less than 1%.  
 should be stopped if neutrophil count below 1.5 ×109/L (1.5-7). 
 In fact a mild decrease in WBC can also occur with hyperthyroidism. 
 If neutrophil count are just below normal  The most appropriate treatment 
would be to continue the carbimazole. 
 Treatment  
 Thionamides should be withdrawn,  
 infection treated with appropriate antibiotics (broad spectrum cephalosporin)

 and occasionally, granulocyte colony-stimulating factor (G-CSF) is required when 
white count fails to respond. 240

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          62 
  crosses the placenta, but may be used in low doses during pregnancy 
 (also Propylthiouracil does cross the placenta , although thyroxine does not) 
 Neonatal hypothyroidism will occur in approximately 10% of babies, because carbima zole

crosses the placenta and switches off the fetal thyroid axis. The goitre that occurs is transient 
and will disappear following delivery 
Interaction 
 carbimazole effect is potentiated by the liver enzyme-inhibitor (eg: erythromycin) 
 
January 2013 exam:  H/O a smooth, non- tender goiter , thyrotoxicosis and exophthalmos + ĹĹAnti -thyroid 
peroxidase antibodies. What is the most appropriate management?  Carbimazole (Radioiodine treatment should

be avoided given the presence of thyroid eye disease)  
 
January 2012 exam:  H/O weight loss & palpitations in a 35-year-old female.TSH < 0.05 mu/l, T4=178 mmol/l. 
Which feature would most suggest a diagnosis of Grave's disease? Pretibial myxedema (Pretibial myxoedema is 
not seen in other causes of thyrotoxicosis and points towards a d iagnosis of Graves')  
 
January 2006 exam: A 30-year-old female is started on carbimazole 20mg bd following a diagnosis of

Grave's disease. What is the best biochemical marker to assess her response to treatment? TSH  
 
September 2011 exam : H/O eye pain & ĻĻ visual acuity following the initiation of treatment for recently 
diagnosed Grave's disease. Which treatments is likely to have been started?  Radioiodine treatment 
(Radioiodine treatment  ĹĹ thyroid eye disease in 15% of patients with Grave's disease)  
 
 May 2015 exam: What is the mechanism of action of carbimazole? Blocks thyroid peroxidase from

coupling and iodinating the tyrosine residues on thyroglobulin  
 
___________________________________________________________ _ 
Propylthiouracil (PTU) 
Propylthiouracil (PTU) vs carbimazole  
 Propylthiouracil (PTU) and carbimazole are derivatives of thiourea 
 Both inhibit the organification of iodine at the thyroid gland as their major mechanism  of action 
 PTU, but not carbimazole, is an inhibitor of thyroxine to tri-iodothyronine, giving it a m odest

therapeutic advantage over the latter agent because it reduces the proportion of active  thyroid 
hormone as well as reducing the total amount of T4 
 Carbimazole is approximately 15 times as potent as PTU 
Cautions 
 Both PTU and carbimazole are excreted in very small quantities in breast milk, so breast 
feeding is not advised with either 
Side-effects 
 Thiourea derivatives have several side-effects including a maculopapular rash, hepatocellular 
damage and vasculitis 241

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          63 
  The most serious side-effect of both agents is agranulocytosis, although it is more commo n to 
see a fall in, rather than total absence of, white cells 
Advantages  
 its risk of fetal abnormalities when used in pregnant women is lower than that of met himazole.

 the medication of choice in the first trimester of pregnancy 
 contraindicated in patients with liver dysfunction  
 PTU has a documented risk of hepatotoxicity.  
 
___________________________________________________________  
Thyrotoxic periodic paralysis (TPP) 
Features 
 abrupt onset of paralysis of the lower extremities,  
 often associated with hypokalaemia, with thyrotoxicosis.  
 increase Na+/K+-ATPase activity   shift of potassium into tissues

 It is most commonly seen in Asian  men in their third to fifth decades,  
 The neuromuscular presentation of both TPP and autosomal dominant  familial periodic 
paralysis (FPP ) is identical, thus confirmation of family history  and features of 
hyperthyroidism should be sought.  
 FPP : 
 more common in Caucasian  populations  
 may be triggered by: 
 strenuous exercise followed by abrupt rest,  
 high-carbohydrate or high-salt meals,

 high-carbohydrate or high-salt meals,  
 temperature change and  
 emotional stress. 
Treatment 
 It is curable once euthyroidism is achieved.  
 non-selective beta-blocker such as propranolol blunts the hyperadrenergic stimulation of 
Na+/K+-ATPase and thus prevents intracellular shift of potassium and phosphate.  
 Potassium replacement should be given in low dose to reduce the chance of rebound 
hyperkalaemia.

hyperkalaemia.  
 Definitive therapy is with anti-thyroid medication, radioiodine or surgery to achieve 
euthyroidism. 
Thyroidectomy  
Post-thyroidectomy hypocalcaemia 
 Up to 10% of patients who undergo subtotal thyroidectomy suffer transient 
hypocalcaemia due to local trauma at the time of surgery . Thankfully, it becomes 
permanent hypoparathyroidism in fewer than 1% of patients. 
 Features: 242

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          64 
  usually presents 24-48 hours postoperatively  
 perioral tingling, twitching or tetany. This may progress to seizures. 
 ventricular arrhythmias .ECG may show a prolonged QT interval (QTc is prolonged 
if >440 ms in men or >460 ms in women.)  is associated with increased risk of 
torsades de pointes

torsades de pointes  
 Treatment for serum calcium levels <2 mmol/L is urgent intravenous calcium (10 ml of 10% 
calcium gluconate) followed by an infusion if necessary. 
Thyroidectomy complications  
 transient hypoparathyroidism  occur in 8% of cases  (the most likely post-operative 
complication)  
 permanent hypoparathyroidism seen in 1-2%  
 Infection is seen in 1-2%  
 Bleeding is less common, seen in around 0.5% or less

 Permanent recurrent laryngeal nerve palsy occurs in 1% of patients; 
superior laryngeal nerve palsy affects more patients (3-4% in case series).  
What is the most common postoperative complication following subtotal thyroidectomy? 
 Hypothyroidism  occurs in about 10% of patients within 1 year of 
surgery.  
Which structures is most closely related to the recurrent laryngeal nerve? 
 Inferior thyroid artery

 Inferior thyroid artery 
- The nerve is found deep to the inferior thyroid artery in 40%, superficially in 20%, 
and between branches of the artery in 35%.  
- The position between nerve and artery on one side of the neck is similar to that 
found on the other side in only 17% of the population.  
 The superior thyroid artery runs closest to the  superior  laryngeal nerve.  
Thyroid eye disease   
 
Feature  Assessment  Frequency  
Lid lag / lid retracted Measure lid fissure width 50-60%

Grittyness, discomfort, periorbital oedema, pain, 
excessive tears. Self-assessment score by patient 40% 
Proptosis (aka exophthalmos) this is where the eye 
bulges out of its socket.  Exopthalmometry or evaluation on 
MR/CT scan.  20% 
Extraocular muscle dysfunction –typically causes 
diplopia (double vision) when looking up and out. Hess chart + CT/MR to detect muscle 
size 10% 
Corneal involvement, causing exposure keratitis Flourescin staining <5%

Loss of sight due to optic nerve compression Visual acuity tests, visual field tests. 
CT/MR scan <1% 
 
  also called Graves ’ Ophthalmopathy or Graves ’ eye disease 
 Thyroid eye disease affects between 25-50% of patients with Graves' disease. 
 In about 10% of patients, the signs will only be unilateral .  243

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          65 
  can occur with normal thyroid function.  
 The diagnosis can be made by thyroid stimulating receptor antibody in the serum. 
 Ophthalmopathy may occur before the onset of hyperthyroidism , or as late as 20 years 
afterward.

afterward.  
 definition of lid retraction: When looking at the patient from the side, you see tha t the eyes are 
proptosed. 
 definition of lid lag: When the patient follows your finger, moving downwards from abo ve, the 
sclera can temporarily be seen above the iris.                                                                                         
Graves' eye disease can occur in euthyroid, hypothyroid or hyperthyroid setting.

The slide shows characteristic features of severe Graves' eye disease - termed ' malignant 
exophthalmos' in this case - proptosis, chemosis, palpebral oedema and periorbital swelling. It may 
require orbital decompression. 
 
 it is thought to be caused by an autoimmune response against an autoantigen, po ssibly the 
TSH receptor ĺ retro -orbital inflammation 
 the inflammation results in glycosaminoglycan and collagen deposition in the muscles

 The levator palpebrae superioris is the muscle that lifts the eyelid, innervated  by the third 
cranial nerve. Hyperthyroidism stimulates the beta receptors of the third cranial nerve. High 
thyroid levels pull up the eyelid by stimulating the levator muscle. 
 The ophthalmoplegia is thought to be the result of an increased proliferation o f retro-orbital 
connective tissues and local edema due to the increased secretion of glycosaminogly cans like 
hyaluronic acid.

hyaluronic acid.  
 It most commonly affects the inferior rectus , but usually results in a complex pattern of 
gaze restriction bilaterally.   
 The pathogenesis of infiltrative ophthalmopathy, which is responsible for exophthalmo s may 
result from immunoglobulins directed against specific receptors in the orbital fibroblasts and  
244

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          66 
 fat. This results in release of proinflammatory cytokines, inflammation, and accumulation of 
glycosaminoglycans. 
 the most likely underlying pathogenesis  Excessive fibroblast proliferation 
 
Which eye signs are  specific to Graves ’ disease ?

Eye signs found in most thyrotoxic states eye signs specific to Graves ’ disease: 
Both lid lag and lid retraction reflect enhanced 
sensitivity to circulating catecholamines, and may 
therefore be found in most thyrotoxic states.   proptosis 
 chemosis 
 periorbital oedema  
 
Prevention 
smoking is the most important modifiable risk factor for the development of thyroid eye 
disease 
 Radioiodine treatment  ĹĹ thyroid eye disease   malignant exophthalmos

  Prednisolone may help reduce the risk 
 patients with thyroid eye disease are generally treated with steroids for one to two 
weeks prior to starting radioiodine therapy. 
 In patients with thyroid eye disease undergoing radioiodine treatment, post-
radioiodine hypothyroidism should be avoided, because of the risk of 
worsening Grave ’s eye disease . For this reason patients are stabilised on a block 
replace regimen before moving to radioiodine therapy. 
 
Features

Features 
 the patient may be eu-, hypo- or 
hyperthyroid at the time of presentation 
 exophthalmos 
 conjunctival oedema 
 optic disc swelling  ophthalmoplegia 
 inability to close the eye lids may lead to 
sore, dry eyes. If severe and untreated 
patients can be at risk of exposure 
keratopathy 
 topical lubricants to prevent corneal inflammation caused by exposure 
 steroids (the mainstay of initial therapy ).

 steroids (the mainstay of initial therapy ). 
 Block replace with high dose carbimazole and full dose thyroxine replacement is the 
optimal step . (may be continued for up to 18 months until thyroid eye disease is stable).  
 Stability of thyroid function  ↓↓progression of thyroid eye disease.  
 Periods of hypothyroidism  worsen peri-orbital oedema  symptoms related to 
optic nerve compression.  
 Radiotherapy

 Radioiodine is a definitive treatment option for relapsed Graves ’ thyrotoxicosis.  
 There is concern that radioiodine could exacerbate Graves ’ ophthalmopathy.  245

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          67 
  Patients with active Graves ’ ophthalmopathy receiving radioiodine treatment should 
be offered steroid cover.  
 Radioiodine treatment can safely be given to patients with inactive Graves ’ 
ophthalmopathy provided hypothyroidism is avoided.

 For sight-threatening  (malignant exophthalmos, diplopia and loss of colour vision) 
 the initial treatment is IV glucocorticoids  (methylprednisolone 500 mg once 
weekly and subsequently tapering down). 
 surgical orbital decompression may be necessary. 
 performed 1-2 weeks after IV glucocorticoids if the response is poor. 
 
The following symptoms/signs should indicate the need for  urgent review by an 
ophthalmologist : 
 unexplained deterioration in vision

 unexplained deterioration in vision 
 awareness of change in intensity or quality of colour vision in one or both eyes  
 (Impaired perception of colour implies  acute progressive neuropathy ) 
 history of eye suddenly 'popping out' (globe subluxation) 
 obvious corneal opacity 
 cornea still visible when the eyelids are closed 
 disc swelling 
 __________________________________________________ __________
Thyroid storm (crisis)

Thyroid storm (crisis)  
 Thyroid storm is a rare but life-threatening complication of thyrotoxicosis.  
 Associated with a significant mortality rate (30-50%)  
 It is typically seen in patients with established thyrotoxicosis and is rarely seen as the 
presenting feature.  
  Iatrogenic thyroxine excess does not usually result in thyroid storm.   
 
Precipitating factors  
 Any acute stressful condition such as 
surgery  
 acute infections  postpartum

surgery  
 acute infections  postpartum  
 when antithyroid drugs are being 
withdrawn. 
 
Clinical features include:  
 fever > 38.5C 
 confusion and agitation 
 nausea and vomiting  hypertension 
 heart failure 
 abnormal liver function test 
 
Diagnosis 
 The points system of Burch and Wartofsky  is sometimes used for clinical diagnosis of thyroid 
storm. In presence of a previous hyperthyroid state, the following point system is used to ar rive

at a clinical score. Here the score is 60. 
 A score of >45 is highly suggestive of thyroid storm.  246

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          68 
  25-44 is suggestive of “impending ” storm  
 score below 25 is unlikely to represent thyroid storm. 
 
Criteria Observation Point 
Atrial fibrillation Absent 0 
Atrial fibrillation Present 10 
Precipitating event Absent 0 
Precipitating event Present 10 
Pulse rate 90–109 5 
Pulse rate 110–119 10

Pulse rate 110–119 10 
Pulse rate 120–129 15 
Pulse rate 130–139 20 
Pulse rate ≥140  25 
GI symptoms Absent 0 
GI symptoms Moderate 10 
GI symptoms Severe jaundice 20 
CNS effects Absent 0 
CNS effects Mild 10 
CNS effects Moderate (incl. delirium) 20 
CNS effects Severe (seizure/coma) 30 
Temperature 99–99.9 5 
Temperature 100–100.9 10 
Temperature 101–101.9 15 
Temperature 102–102.9 20 
Temperature 103–103.9 25 
Temperature ≥104  30 247

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          69 
 CCF Absent 0 
CCF Mild 5 
CCF Moderate 10 
CCF Severe 15 
 
 Transfer the patient to the Intensive Therapy Unit   
 symptomatic treatment e.g. Paracetamol 
 Chlorpromazine can be used to treat agitation and, because of its effect in inhibiting central

thermoregulation, it can be  useful in treating the hyperpyrexia.  
 treatment of underlying precipitating event 
 propranolol 
 anti-thyroid drugs: e.g. methimazole or propylthiouracil 
 Lugol's iodine used in conjunction with Carbimazole   more rapid resolution . 
 Iodine: Blocks uptake of iodine into the thyroid gland and blocks the release of 
hormone.  
 dexamethasone - e.g. 4mg IV qds - blocks the conversion of T4 to T3

 Plasmapheresis and peritoneal dialysis can be effective in cases resistant to 
pharmacological measures. 
Thyroid cancer  
there are five main types of thyroid  carcinoma and their properties are given below:  
Cell type  Frequency  Behaviour  Spread  Prognosis  
Papillary  70% Often young females 
present as "cold nodules" on isotope 
scanning Local – 
sometimes bone 
/ lung 
secondaries excellent prognosis

/ lung 
secondaries excellent prognosis  
Follicular  20% More common in females Lung / Bone Good if resectable 
Medullary 
cell 5% Often familial.   
Cancer of parafollicular cells (c cell), 
secrete calcitonin , part of MEN-2 Local and mets Poor , but often very 
slow course 
Anaplastic  <5% Aggressive, Not responsive to treatment, can 
cause pressure symptoms  Locally invasive Very Poor  
lymphoma  2% *almost always non-Hodgkin lymphomas 
* Associated with Hashimoto's

* Associated with Hashimoto's  
*often elderly women.  Locally invasive Poor  – but sometimes 
responds to radiotherapy 
 
 248

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          70 
  
Types 
 Papillary thyroid carcinoma  
 the commonest type of thyroid cancer,  
 histopathology  
 The presence of Orphan-Annie nuclei is pathognomonic of papillary thyroid 
neoplasms. 
 large thyrocytes and psammoma bodies are features typically seen on histology.

 Abnormalities are often multi-focal, with local spread via lymphatics being seen. 
 Follicular thyroid carcinoma (FTC) 
 (FTC)  is a well-differentiated tumour. In fact, FTC resembles the normal microscopic 
pattern of the thyroid.  
 originates in follicular cells  
 the second most common cancer of the thyroid after papillary carcinoma. 
 Medullary thyroid carcinoma  
 occurs in conjunction with MEN2  
 Medullary thyroid carcinoma is the most important diagnosis to confirm, with the

pentagastrin stimulation test  the best way to do this.  
 It measures calcitonin levels at 2 and 5 minutes, however, and a rise in calcitonin is 
suggestive of medullary thyroid carcinoma. 
 Anaplastic thyroid carcinoma  
 rapidly growing  
 occurs most commonly in the elderly. 
Risk factors of developing thyroid cancer  
 Females are three times more likely to develop thyroid cancer than males.  
 Endemic goitre, Hashimoto ’s thyroiditis and thyroid adenoma

 Family history of familial adenomatous polyposis (FAP) 
 FAP is caused by an APC gene mutation on chromosome 5 
Features 
 The most common presentation of thyroid cancer is an asymptomatic thyroid mass, or a 
nodule, that can be felt in the neck. 
 Features of hyperthyroidism or hypothyroidism are not commonly seen in patients with thyroid 
malignancies as they rarely secrete thyroid hormones 
 
 Ultrasound scanning thyroid

 Ultrasound scanning thyroid  
 The initial investigation of choice in small non-symptomatic thyroid mass 
 can show cystic lesions 2 mm wide and solid lesions 3 mm wide.  
 It is far more sensitive than palpation alone, and only 4-7% of nodules detecte d by 
US are clinically palpable. 
 Fine needle aspiration cytology  (FNA) 
 The appropriate investigation after ultrasound  
 FNA is the most important investigation once a lesion is recognised as solitary. 249

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          71 
   diagnostic in over 85% of cases.  
 Excision biopsy is required for equivocal lesions on fine needle aspiration.  
 Radioisotope scanning confirms uptake by one or more nodules in the thyroid; nodules wh ich 
take up the isotope are less likely to be malignant.

 Exclusion of phaeochromocytoma is crucial before considering thyroidectomy  
Abdominal MRI.  
 Medullary thyroid carcinoma (MTC) and pheochromocytoma are associated in MEN 
type 2A and MEN type 2B. 
 Pheochromocytoma has to be ruled out before thyroidectomy, because any major 
surgery can precipitate hypertensive crisis due to release of massive amounts 
of catecholamines.  
 
The association of Horner's syndrome and a thyroid nodule suggest invasion of the

sympathetic chain and suggest that this thyroid nodule is malignant. 
 
Which familial condition that carries an increased risk of papillary carcinoma of the thyroid 
? 
 Gardner's syndrome (intestinal tumours & lipomas. Also Osteomas & fibromas ). 
 carries an increased risk of papillary carcinoma  
 
Papillary carcinoma  
 Histologically, papillary thyroid carcinoma appears as “ground glass ” or “Orphan Annie ” 
nuclei with psammoma bodies (calcified spherical bodies).

 Thyroid cancer associated with Graves' disease is not uncommon  and usually due to 
papillary carcinoma and must be considered in suspicious/expanding nodules rather than 
attributing purely to Graves' disease. 
 hyperthyroidism with prominent nodule which is 'cold' on uptake scanning is 
highly suggestive of thyroid carcinoma and the mostly likely diagnosis is 
Graves' disease (periorbital puffiness and thyroid bruit) associated with 
papillary thyroid carcinoma.

papillary thyroid carcinoma. 
 
Which proto-oncogenes is most associated with papillary carcinoma of the thyroid? 
 Trk is a proto-oncogene, mutation of which leads to activation of tyrosine kinase 
receptors. 
 Trk activation is thought to play a role in the pathogenesis of papillary thyroid 
carcinoma  
 
 250

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          72 
 Management of papillary and follicular cancer 
 total thyroidectomy with thyroxine replacement 
 followed by radioiodine (I-131) to kill residual cells 
 yearly thyroglobulin levels to detect early recurrent 
disease 
Prognosis 
 Papillary  5-year survival rate is only 5%

 Papillary  5-year survival rate is only 5%  
 Follicular  5-year survival rate is 80% 
Factors that suggest a poor prognosis in thyroid cancer  
 increasing age 
 male sex 
 poorly differentiated histological features, and 
 distant spread. 
 
Which test is most useful in the assessment of airflow obstruction due to the retrosternal 
goitre? 
 Flow volume curve  
 airflow obstruction may be present in up to 40% of patients with retrosternal goitre

 symptoms arises after at least 50% obstruction of the airway   
 
Staging 
 The staging of well-differentiated thyroid cancers is related to age for the first an d second 
stages but not related for the third and fourth stages. 
 Younger than 45 years: 
 Stage I - Any T, any N, M0 (Cancer is in the thyroid only). 
 Stage II - Any T, any N, M1 (Cancer has spread to distant organs). 
 Older than 45 years:

 Older than 45 years: 
 Stage I - T1, N0, M0 (Cancer is in the thyroid only and may be found in one or bo th 
lobes). 
 Stage II - T2, N0, M0 and T3, N0, M0 (Cancer is in the thyroid only and is larger than 
1.5 cm). 
 Stage III - T4, N0, M0 and any T, N1, M0 (Cancer has spread outside the thyroid b ut not 
outside of the neck). 
 Stage IV - Any T, any N, M1 (Cancer has spread to other parts of the body). 
 
 Surgery is the definitive management of thyroid cancer.

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          73 
  Lobectomy with isthmectomy  is the minimal operation for a potentially malignant 
thyroid nodule.  
 Patients less than 40 years who have FTC nodules less than 1 cm, well defined, 
minimally invasive, and isolated may be treated with hemithyroidectomy and 
isthmectomy.

isthmectomy. 
 If feasible, subtotal thyroidectomy (small part of contralateral lobe retained) is prefera ble 
since it carries a lower incidence of complications (for example, hypoparathyroidism, 
superior and/or recurrent laryngeal nerve injury). 
 Total thyroidectomy  
 Approximately 10% of patients who have had total thyroidectomy (removal of a ll 
thyroid tissue preserving the contralateral parathyroid glands) demonstrate 
cancer in the contralateral lobe.

cancer in the contralateral lobe.  
 Total thyroidectomy should be performed in patients who are more than 40 years 
with FTC and in any patient with bilateral disease. Total thyroidectomy is 
recommended for any patient with a thyroid nodule and a history of irradiation. 
Some studies show lower recurrence rates and increased survival rates in 
patients who have undergone total thyroidectomy. This surgical procedure also

facilitates earlier detection and treatment of recurrent or metastatic carcinoma. 
 Patients receive radioiodine four to six weeks after thyroidectomy to detect and destroy an y 
metastases and any residual tissue in the thyroid. 
 Following thyroidectomy, patients will need to take thyroid replacement therapy. 
 External beam radiation is used in the management of FTC if the cancer cannot be resecte d,

or if there is extension into adjacent structures. Radiotherapy may also be administered 
postoperatively to reduce the risk of local-regional recurrence. It may also be used pa lliatively 
to treat pain from bone metastases. 
marker of thyroid cancer recurrence after thyroidectomy 
 Thyroglobulin 
 thyroid is the only source of thyroglobulin.  
 Normal or elevated serum thyroglobulin values indicate the presence of residual normal 
or cancerous thyroid tissue

or cancerous thyroid tissue  
The most appropriate investigation at annual follow-up for papillary thyroid cancer. 
 Ultrasound scan is the most sensitive investigation for the detection of locally 
recurrent papillary carcinoma.  
 Other investigations should be considered if ultrasound scan is negative or distant 
metastases are suspected. 
____________________________________________________________  252

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          74 
 Riedel's thyroiditis  
 Riedel's thyroiditis is often confused with thyroid carcinoma. 
 It is characterised by marked fibrous infiltration of the thyroid gland.  
 Hypothyroidism &Thyroid autoantibodies are negative.  
 The cause of this remains unidentified. 
  Treatment is with thyroxine replacement.

  Treatment is with thyroxine replacement. 
T3 thyrotoxicosis and factitious thyrotoxicosis  
 The patient has symptoms and signs of thyrotoxicosis and a suppressed thyroid-stimulating 
hormone (TSH), but with low thyroid-stimulating hormone (T4) and fT4. 
 The main differentials are between triiodothyronine (T3) thyrotoxicosis and factitious

thyrotoxicosis (purposeful or inadvertent ingestion of large quantities of thyroid hormone). 
  (T3) thyrotoxicosis associated with around 5% of cases of thyrotoxicosis.  
 The diagnosis of T3 toxicosis  should be suspected in patients presenting with: 
 symptoms of thyrotoxicosis (including a goitre)  
 serum T4 and fT4 are normal or low  
 RAIU is increased. 
 In factitious thyrotoxicosis , the proportions of T3 and T4 depend on the preparation of the

thyroid hormone replacement tablets.  
 Both T3 and T4 concentrations will be increased if the preparation contains both 
hormones;  
 serum T3 is elevated and T4 depressed in those taking T3;  
 T4 elevated and T3 suppressed in those taking T4.  
 However, radioactive iodine uptake (RAIU) and plasma thyroid-binding globulin 
(TBG) will be depressed and a goitre will not be palpable.  
 
Thyrotoxicosis factitia ( thyroxin abuse ) The combination of low thyroglobulin,  decreased uptake

on scintigraphy and raised T4 can only really be thyrotoxicosis fatitia. 
 
Calcium metabolism 
The two hormones which primarily control calcium metabolism are: 
 parathyroid hormone (PTH) 
 1,25-dihydroxycholecalciferol (calcitriol, the active form of vitamin D) 
Other hormones include 
 calcitonin: secreted from the parafollicular cells (C-cells) of the thyroid gland 
 thyroxine 
 growth hormone 253

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          75 
 Actions of parathyroid hormone 
 increases plasma calcium, decreases plasma phosphate 
 increases renal tubular reabsorption of calcium 
 increases osteoclastic activity 
 increases renal conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol 
 decreases renal phosphate reabsorption

 decreases renal phosphate reabsorption 
Actions of 1,25-dihydroxycholecalciferol 
 increases plasma calcium and plasma phosphate 
 increases renal tubular reabsorption and gut absorption of calcium 
 increases renal phosphate reabsorption 
Actions of the Hormones Involved in Calcium Homeostasis 
HORMONE  EFFECT ON BONES  EFFECT ON GUT  EFFECT ON KIDNEYS  
Parathyroid 
hormoneĹCa++, 
ĻPO 4 levels in blood Supports osteoclast 
resorption Indirect effects

resorption Indirect effects 
viaĹcalcitriol from 1 -
hydroxylation Supports 
Ca++resorption and 
PO 4excretion, activates 
1-hydroxylation 
Calcitriol (vitamin 
D)ĹCa++,ĹPO 4 levels in 
blood No direct effects ĹCa++ and 
PO 4absorption No direct effects 
Calcitonin causes 
ĻCa++, ĻPO 4 levels in 
blood when 
hypercalcemia is 
present Inhibits osteoclast 
resorption No direct effects Promotes Ca++ and 
PO 4 excretion 
 
254

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          76 
 Absorption 
 The intestinal absorption of calcium is facilitated by 1,25 dihydroxy-vitamin D , which 
stimulates the microvillous membrane of the enterocyte to synthesise the calcium -binding 
carrier protein necessary for active calcium ion absorption. 
 In serum, most of the calcium ion is bound to albumin

 Low albumin levels can affect the total serum calcium level.  
 Less than 50% of calcium is in the ionised form in serum, the rest being bound to protein a nd 
other anions such as phosphate and citrate 
 The ionised form is most important in regulation of body functions 
 99% of filtered calcium is reabsorbed in the kidneys, around 55% in the proximal c onvoluted 
tubule 
Excretion  
 Calcitonin is the most important factor regulating calcium excretion.

 Calcitonin is secreted by the parafollicular cells of the thyroid gland and responds to raised 
calcium levels by inhibiting bone resorption and increasing renal excretion 
_____________________________________________________________________________  
Hypercalcaemia: causes 
 
The most common causes of hypercalcemia are primary hyper-parathyroidism and 
malignancy (90 %).  
 
In the presence of hypercalcaemia and hypophosphataemia, is highly suggestive of 
hyperparathyroidism.

hyperparathyroidism. 
The most common causes of hypercalcaemia are: 
1. primary hyperparathyroidism ( Thyrotoxicosis ) due to increased bone turnover. 
 The most useful investigation is   Sesta MIBI  scan of the neck 
2. malignancy (bone metastases, myeloma, PTHrP from squamous cell lung cancer) 
 In malignancy, roughly 80% of cases are due to parathyroid-hormone-related 
peptide release.  The vast majority of remaining cases are due to osteolysis, and some

due to calcitriol-mediated hypercalcaemia and ectopic PTH secretion. 
 Raised alkaline phosphatase associated with hypercalcaemia is more likely to be due to 
bony metastases; 
 Normal alkaline phosphatase raises the possibility of underlying myeloma. 
 The LFTs show increased globulin fraction (TP-ALB) indicating the possibility of 
myeloma. 
 In myeloma, hypercalcaemia is primarily due to increased osteolysis and high-

dose steroids - e.g. prednisolone 40 mg od can rapidly reduce the calcium level. 
 malignancy should  be considered in hypercalcaemia without 
hypophosphataemia. 
 the best initial investigation to contribute to the underlying diagnosis  Skeletal 
survey 
Other causes include  
255

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          77 
  Tertiary hyperparathyroidism  
  in a patient with chronic renal failure with prolonged hypocalcaemia the parathyroids 
become autonomous, even if renal function is improved with transplantation. This can 
lead to hypercalcaemia.  
 Tertiary hyperparathyroidism occurs when PTH production becomes autonomous and

levels do not fall once serum calcium is corrected with supplementation of calcium and 
vitamin D. 
 Note that secondary hyperparathyroidism is a response to hypocalcaemia, not a 
cause of hypercalcaemia. 
 Sarcoidosis ( Granulomatous disease  - sarcoidosis, leprosy, TB and histoplasmosis) 
 Increased intestinal absorption is the main cause for raised calcium levels in sarcoidosis 
due to increased production of 1,25-OH vitamin D from activated pulmonary 
macrophages

macrophages 
 Sarcoidosis  activated pulmonary macrophages  Ĺvitamin D Ĺintestinal 
absorption of Ca  ĹCa 
 vitamin D intoxication 
 Increased sun exposure  results in increased vitamin D production.  
 Patients often drink more cola drinks whilst on holiday, leading to increased phosphat e 
intake.  
 The combination of increased vitamin D and phosphate availability in the presence  of 
sarcoidosis is thought to lead to hypercalcaemia. 
 Milk-alkali syndrome

 Milk-alkali syndrome 
 Milk-alkali syndrome  - the triad of hypercalcaemia, metabolic alkalosis and renal 
impairment secondary to the ingestion of large amounts of calcium and absorba ble 
alkali (such as sodium bicarbonate for the treatment of peptic ulcer disease).  
 The age of the patient, the dyspeptic symptoms and the raised bicarbonate level 
suggest the most likely diagnosis is the milk-alkali syndrome, caused by the 
ingestion of antacids.

ingestion of antacids. 
 The condition can lead to mild renal impairment, but this may well return to normal on ce 
calcium intake is reduced. 
 drugs:  
 thiazides,  reduce excretion  hypercalcaemia. 
(Furosemide  hypocalcaemia but thiazides  hypercalcaemia). 
 calcium containing antacids 
 lithium ,  
 vitamin D overdose,  
 vitamin A toxicity  (including analogs used to treat acne) 
 dehydration 
 Addison's disease 
 Paget's disease of the bone**

 Paget's disease of the bone** 
 **usually normal in this condition but hypercalcaemia may occur with prolonged 
immobilisation 
 Infections : HIV, histoplasmosis 256

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          78 
  Williams' syndrome  - a rare genetic disease affecting chromosome 7 and characterised by 
hypercalcaemia in infancy, anxiety and learning disability. 
 Familial hypercalcaemic hypocalciuria  - autosomal dominant mutations in the calcium

sensing receptor gene, leading to calcium hyposensitivity, compensatory hypercalcaemia and 
hypocalciuria.  
 
Secretion of which substances by the tumour is most likely to cause hypercalcaemia? 
 In patients with solid tumours, non-metastatic hypercalcaemia is most frequently 
the result of secretion of parathyroid hormone-related peptide (PTHrP) by the 
tumour  and is reported in association with gastric cancer. Non-parathyroid secretion of 
PTH itself is very rare.

PTH itself is very rare. 
 
mild hypercalcaemia + Normal parathyroid hormone (PTH)  primary hyperparathyroidism.  
  (PTH)  is inappropriately normal as it should, by homeostatic mechanisms, be 
suppressed if the hypercalcaemia were a consequence of another disorder.  
 Also low phosphate concentration is typical of PHPTH. 
 
Differentiate between hypercalcaemia in primary hyperparathyroidism  and malignancy: 
 in primary hyperparathyroidism  
 Parathyroid hormone is elevated or normal

 Parathyroid hormone is elevated or normal  
 calcium level is often < 3 mmol/l 
 Hypercalcaemia is often asymptomatic and might have been present for months 
or years.  
 in malignancy   
 patients are usually acutely ill 
 often with neurological symptoms 
 calcium level is usually > 3 mmol/l 
 Parathyroid hormone is suppressed  
 Cancer (eg lung, breast or myeloma) is often clinically apparent. 
Features 
Features include the classic mnemonic, " bones, stones, groans, and moans ":

 Bones  - bone pain, especially if the PTH is elevated 
 Stones  - renal calculi 
 Groans  - constipation and likely subsequent abdominal pain 
 Pyschic moans  - depression and confusion 
 
 Musculoskeletal manifestations  (Bones ) 
 Bone pain  
 Malaise ,  fatigue, muscle weakness 
 Osteoporosis of cortical bone, such as the wrist, is mainly associated with primary 
hyperparathyroidism.  257

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          79 
  Excess PTH also can result in subperiosteal resorption, leading to osteitis fibrosa 
cystica with bone cysts and brown tumors of the long bones.  
 Renal manifestations  (Stones ) 
 polydipsia and polyuria  
 due to a type of nephrogenic diabetes insipidus - modification of the renal

response to antidiuretic hormone causing dehydration. 
 Dehydration  thirst  
 nephrolithiasis resulting from hypercalciuria.  
 nephrocalcinosis.  
 Gastrointestinal manifestations  (Groans ) 
 abdominal pain,  
 Nausea, anorexia, dyspepsia,  
 constipation  
 peptic ulcer disease  
 Calcium stimulates gastrin release and promotes increased secretion of gastric 
acid. 
 pancreatitis  
 Neurological manifestations  (Pyschic moans ) 
 impaired concentration, confusion,

 impaired concentration, confusion,  
 Hyporeflexia  
 corneal calcification,  
 depression 
 Cardiovascular manifestations  
 hypertension,  
 vascular calcification   
 Cardiac arrhythmias are rare.  
 ECG changes include:  
 Short QT interval   significantly increases the risk of cardiac arrhythmias.  
 PR prolongation (but is much less common than QT shortening).  
 Bradycardia 
 Ventricular fibrillation has been reported in extreme cases.  
 widened T waves

 widened T waves  
 In severe hypercalcaemia J (osborn) waves can be seen.  
 Others 
 Itching 
 Keratitis, conjunctivitis  
 Hypokalaemia  
 hypercalcaemia  ↓ reabsorption of potassium, promoting its loss in the urine. 
 
MECHANISM OF VOLUME DEPLETION IN HYPERCALCEMIA 
 High calcium levels inhibit the effect of ADH on the collecting duct, inducing nephrogenic diabetes 
insipidus.  
 High calcium filtration also promotes osmotic diuresis. 
 258

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          80 
  
Interpreting Laboratory Values in Hypercalcaemia  
Condition  Serum 
Phosphate  Serum Alkaline 
Phosphatase  Urine 
Calcium  Urine 
Phosphate  PTH 
Hyperparathyroidis
m Low Normal-high High (in 
67% of 
patients) High High 
Vitamin D excess Normal-high Low High High Low 
Malignancy Often low High (except in

Malignancy Often low High (except in 
haematological 
malignancy, 
when normal) Variable High Variable 
259

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          81 
 Interpreting Laboratory Values in Hypercalcaemia  
Granulomatous 
disease Normal-high Normal-high High Normal Low 
Calcium alkali 
syndrome Normal-high Normal Normal Normal Low 
Familial 
hypocalciuric 
hypercalcemia Normal or 
low Normal Low 
(<200 
mg/day) Normal High 
 
Hypercalcaemia: management

Hypercalcaemia: management 
 The initial management of hypercalcaemia is rehydration with normal saline, typically 3-
4 litres/day.  
 The most appropriate management is with 0.9% sodium chloride .  
 If the sodium level were 150 or above an initial treatment would be with 0.45% 
sodium chloride reverting to 0.9% sodium chloride when the sodium 
concentration fell below 150. 
 gentle hydration with intravenous saline may be enough but if congestive heart f ailure

ensues or if more rapid lowering of serum calcium is desired, a loop diuretic will 
enhance calcium excretion 
 ECF volume depletion must be avoided because this will worsen hypercalcaemia 
 in a setting of renal insufficiency, higher doses of loop diuretics are needed 
 intravenous saline plus a loop diuretic should decrease the serum calcium 
rapidly, usually by 0·25-0·75 mmol/L in 1 or 2 days. if this reduction is insufficient 
bisphosphonate may be required.

bisphosphonate may be required. 
 
 Following rehydration bisphosphonates may be used. They typically take 2-3 days to wo rk with 
maximal effect being seen at 7 days 
 If calcium is still elevated despite adequate hydration with saline. The most 
appropriate next step is to give pamidronate , a bisphosphonate, to inhibit bone 
resorption and formation, thus reducing bone turnover. 
In the context of hypercalcaemia secondary to malignancy the below advice is suggested by 
NICE:

NICE:  
 Advice about maintaining good hydration (drinking 3 - 4 L of fluid per day),  provided 
there are no contraindications (such as severe renal impairment or heart failure). 
 Reassure that a low calcium diet is not necessary, as intestinal absorption of calcium is usually 
reduced. 
 Advise the person to avoid any drugs or vitamin supplements that could exacerbate th e 
hypercalcaemia. 
 Encourage mobilization where possible to avoid exacerbating the hypercalcaemia. 260

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          82 
  Advise the person to report any symptoms of hypercalcaemia. 
Other options include:  
 calcitonin - quicker effect than bisphosphonates 
 If hydration and furosemide do not control the calcium and you need something fa ster 
than a bisphosphonate, then calcitonin is the answer.

 Calcitonin use is limited by its association with anaphylaxis. 
 Non-steroidal anti-inflammatory drugs (NSAIDs) should not be prescribed in patients with 
hypercalcaemia as they reduce renal blood flow thus inhibiting urinary calcium excretion.  
 steroids in sarcoidosis 
 There is a limited role for the use of furosemide in hypercalcaemia. It may be useful in patien ts 
who cannot tolerate aggressive fluid rehydration

who cannot tolerate aggressive fluid rehydration 
 loop diuretics such as furosemide increase urine calcium excretion but may also induce ECF 
volume depletion, increasing renal calcium resorption and worsening the hypercalcaemia 
 
Parathyroidectomy: 
NICE guidelines clearly stipulate the circumstances under which parathyroidectomy should be 
considered in primary hyperparathyroidism. These are listed below:  
 Age under 50 years.

 Age under 50 years. 
 Adjusted serum calcium concentration that is 0.25 mmol/L or more above the upper end  of the 
reference range. 
 Estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 although this 
threshold depends on other factors, such as age. 
 creatinine clearance reduced by 30% or more  
  Renal stones or presence of nephrocalcinosis on ultrasound or CT. 
 24 hour total urinary calcium excretion greater than 10 mmol

  Presence of osteoporosis or osteoporotic fracture. 
 bone mineral density T- score less than −2.5 at any site  
 Symptomatic disease  
 unwillingness of patient to follow advice of medical surveillance. 
Pseudohypercalcaemia  
 heat cramps  
 (painful muscular cramping during or after exertion in hot environments).  
 The patient developed haemoconcentration and elevated protein (and album in), leading

to a phenomenon of pseudohypercalcaemia.  
 In this condition, the total serum calcium is high but the ionised calcium should be 
normal. 
 As a rule of thumb, the first step in the diagnostic evaluation of hypercalcaemia (and 
more often hypocalcaemia) should be to make sure that the "abnormality" in th e total 
serum calcium levels is not due to abnormal albumin concentrations. In cases of 
abnormal albumin level, adjusted calcium might better reflect the correct calcium lev el. 261

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          83 
  Only ionised (or free) calcium is physiologically active and should be checked if in 
doubt, such as in patients with very abnormal albumin level. Extensive investigation, 
such as protein electrophoresis, should be omitted if pseudohypercalcaemia is 
confirmed.

confirmed. 
 Pseudohypercalcaemia is asymptomatic and should not affect the ECG. 
 the most appropriate immediate management  Intravenous saline infusion and 
check ionised calcium . 
Familial benign hypocalciuric hypercalcaemia (FHH)  
 FHH is a rare, benign,  autosomal dominant  disorder  
 due to a defect in the calcium sensing receptor 
 pattern of inheritance with complete penetrance.

 The mutation causes a reduced ability of the calcium sensor to detect hypercalcaem ia, so the 
body tolerates levels of serum calcium that would usually be said to be outside the norm al 
range. 
  It leads to reduced calcium excretion and consequent mild to moderate hypercalcaem ia. 
Feature 
 asymptomatic hypercalcaemia  (often diagnosed incidentally) 
 Affected heterozygous patients typically present in childhood with the incidental discovery o f: 
 mild hypercalcemia 
 hypocalciuria

 hypocalciuria 
 a normal PTH level, and 
 high-normal to frankly elevated serum magnesium levels. can present with renal stones .  
 Rarely, can be associated with episodes of acute pancreatitis.  
 Management 
 Mild  adequate hydration to reduce the risk of stone formation. 
 Total parathyroidectomy effective for recurrent severe pancreatitis.  
 
Diagnosis 
 We recommend a two-step diagnostic procedure (The diagnostic sensitivity of this setup  is 
98%)

98%) 
 First, the calcium/creatinine clearance ratio is measured from a 24-h urine.  
 Second, all patients with calcium/creatinine clearance ratio of 0.020 or less are tested 
for mutations in the CASR gene . 
Treatment 
 In general, FHH does not require treatment.  
 individuals with FHH are typically advised to avoid parathyroidectomy 
 
 262

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          84 
Hypocalcaemia 
Parathyroid hormone is the single most useful test in determining the cause of 
hypocalcaemia  
Causes 
 ĻĻ calcium and phosphate + ĹĹalkaline phosphatase  Osteomalacia

 normal  calcium and phosphate + ĹĹalkaline phosphatase  Paget's disease  
 Serum biochemistry is normal in osteoporosis , although alkaline phosphatase 
can be elevated following a fracture.  
 vitamin D deficiency (osteomalacia)  (Osteomalacia causes hypocalcaemia associated with 
a low serum phosphate, rather than a raised phosphate level)  
 chronic renal failure 
 hypoparathyroidism (e.g. post thyroid/parathyroid surgery)

 pseudohypoparathyroidism (target cells insensitive to PTH) (short fourth finger, round face,  
and mental retardation) 
 rhabdomyolysis (initial stages) 
 magnesium deficiency (due to end organ PTH resistance) 
 Magnesium is needed to release PTH from the gland.  
 Patients with ileostomies can lose large amounts of magnesium through their stomas; 
hypomagnesaemia  ĻĻPTH  hypocalcaemia that is resistant to an increased 
provision of calcium

provision of calcium  
 Acute hyperphosphatemia: Phosphate binds with the calcium and lowers it.  
 Fat malabsorption: This binds calcium in the gut.  
 massive blood transfusion 
  anticoagulant citrate  in the bags  citrate accumulation  in blood  chelates (binds 
to) circulating ionized calcium ( iCa)  Ļplasma iCa. 
 Acute pancreatitis may also cause hypocalcaemia.  
 Contamination of blood samples with EDTA may also give falsely low calcium levels 
 
Features

Features  
 
As extracellular calcium concentrations are important for muscle and nerve function many of t he 
features seen in hypocalcaemia seen a result of neuromuscular excitability 
Features  
 tetany: muscle twitching, cramping and spasm 
 perioral paraesthesia 
 Carpopedal spasm (wrist flexion and fingers drawn together) 
 Muscle cramps. 
263

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          85 
  Hyperreflexia 
 Bronchospasm 
 Laryngospasm  
 Seizures 
 if chronic: depression, cataracts   
 Trousseau's sign  
 carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and 
maintaining pressure above systolic 
 wrist flexion and fingers drawn together

 wrist flexion and fingers drawn together 
 seen in around 95% of patients with hypocalcaemia and around 1% of normo- calcaemic 
people 
 Chvostek's sign  
 tapping over parotid causes facial muscles to twitch 
 seen in around 70% of patients with hypocalcaemia and around 10% of normo-
calcaemic people 
 ECG changes are associated with hypocalcaemia: 
 Common: Corrected QT interval prolongation 
 Rare: Atrial fibrillation or torsade de pointes 
 
 acute management of severe hypocalcaemia is with intravenous replacement. The preferred 
method is with intravenous calcium gluconate, 10ml of 10% solution over 10 minutes 
 intravenous calcium chloride is more likely to cause local irritation 
 ECG monitoring is recommended 
 further management depends on the underlying cause 
Vitamin D

Vitamin D 
Vitamin D is a fat soluble vitamin that plays a key role in calcium and phosphate metabolism . 
Sources  
 vitamin D2 (ergocalciferol): plants 
 vitamin D3 (cholecalciferol): dairy products, can be synthesised by the skin from sunlight 
Functions 
 increases plasma calcium and plasma phosphate   
 stimulates intestinal absorption of magnesium and phosphate  
 increases renal tubular reabsorption of calcium and phosphate

 Calbindin is an intestinal transporter of calcium , and by upregulating calbindin  
expression , vitamin D leads to increased calcium absorption from the small intestine. 
 Suppression of synthesis of type 1 collagen.  This is balanced by upregulation of 
osteocalcin, the balance of these changes is an increase in bone mineralisatio n. 
 Vitamin D is recognised to modulate cytokine production and may have a role in the treatment

of inflammatory disorders in the future. One example is decreased production of IL6  in 
response to vitamin D supplementation. 264

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          86 
  stimulate calcium deposition in the extracellular matrix of bone.  
Consequences of vitamin D deficiency: 
 rickets: seen in children 
 Radiographs of the limbs will demonstrate epiphyseal widening with metaphyseal 
fraying.  
 Osteomalacia: seen in adults

fraying.  
 Osteomalacia: seen in adults  
 It classically presents in the female Asian population whose clothing offers little 
exposure to sunlight.   
 Proximal myopathy is often a presenting feature of osteomalacia  
 The phosphate and calcium are usually low normal, and the alkaline phosphata se is 
high 
Diagnosis 
Measurement of serum 25-OH vitamin D is the best way of estimating vitamin D status. 
Optimal: > 75nmol/l 
Adequate: 50 --75nmol/l 
Insufficiency: 30-49nmol/l

Insufficiency: 30-49nmol/l 
Deficiency: < 30nmol/l 
 
Treatment ( Load with vitamin D and then continue on maintenance ). 
 Serum 25OHD < 30 nmol/l: treatment recommended 
 Serum 25OHD 30-50 nmol/l: treatment is advised in patients with: fragility fracture, 
osteoporosis, symptoms suggestive of vitamin D deficiency, reduced exposure to sunlight, 
raised PTH, conditions associated with malabsorption 
 Serum 25OHD > 50 nmol/l: provide reassurance and give advice on maintaining adequate

vitamin D levels through safe sunlight exposure and diet 
 In patients with good calcium intake and normal serum calcium, giving oral calcium may 
actually be detrimental. This is due to evidence suggesting adverse cardiovascular outcomes, 
which is thought to be related to accelerated tissue and vascular calcification.  
 
Vitamin D supplementation 
The following groups should be advised to take vitamin D supplementation:

 all pregnant and breastfeeding women should take a daily supplement containin g 10µg of 
vitamin D 
 all children aged 6 months - 5 years. Babies fed with formula milk do not need to  take a 
supplement if they are taking more than 500ml of milk a day, as formula milk is fortified wit h 
vitamin D 
 adults > 65 years 
 'people who are not exposed to much sun should also take a daily supplement' 
Testing for vitamin D deficiency

Testing for vitamin D deficiency  
The NOS guidelines specify that testing may be appropriate in the following situtatio ns: 265

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          87 
  patients with bone diseases that may be improved with vitamin D treatment e.g. known 
osteomalacia or Paget's disease 
 patients with bone diseases, prior to specific treatment where correcting vitamin deficiency is 
appropriate e,g, prior to intravenous zolendronate or denosumab

 patients with musculoskeletal symptoms that could be attributed to vitamin D deficie ncy e.g. 
bone pain ?osteomalacia 
Testing for vitamin D deficiency is not necessary in:  
• Patients with osteoporosis  should always be given calcium/vitamin D supplements  
• People at higher risk of vitamin D deficiency  should be treated anyway  
 
January 2015 exam: elderly woman with osteoporosis. Prescribed vitamin D

supplementation. Which benefits will vitamin D result in?  Increased calcium absorption in 
the gut  
Hyperparathyroidism 
• PTH indirectly stimulates osteoclasts by binding to its receptor on osteoblasts, inducing RANK-
L and M-CSF synthesis 
• occurs in 0.1% of the population 
• 90% result from a single adenoma 
• remaining 10% from parathyroid hyperplasia

• remaining 10% from parathyroid hyperplasia 
• parathyroid carcinoma accounts for less than 1% of all cases 
 
Classification  
  Serum Ca  Serum Phos  Serum PTH  
Primary Ĺ Ļ Ĺ 
Secondary  normal or Ļ Ĺ Ĺ 
Tertiary  Ĺ Ĺ Ĺ 
 
• Primary  
 typically the result of hypersecretion of PTH by a parathyroid adenoma/hyperplasia 
 may result in osteitis fibrosa cystica 
 breakdown of bone 
 common involves the jaw 
• Secondary

• Secondary 
 secondary parathyroid hyperplasia as compensation from hypocalcemia or 
hyperphosphatemia 
 Ļ gut Ca2+ absorption 
 Ĺ phosphorous  
 Pathophysiology 
 CRF  Ļ phosphate excretion  hyperphosphatemia.  266

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          88 
  CRF  Impaired renal conversion of 25-hydroxycholecalciferal to 1,25-
dihydroxycholecalciferol (vitamin D, calcitriol)  Ļ intestinal absorption of 
calcium.  
 Ĺserum phosphate + Ļ vitamin D production  hypocalcemia  ĹPTH levels.  
 As a consequence of prolonged hypocalcemia, parathyroid chief cell hyperplasia

occurs and PTH secretion increases. 
 secondary and tertiary HPT primarily result from four gland hyperplasia 
 Causes 
 most commonly “secondary ” to chronic renal failure (CRF) 
 90% of patients with CRF develop this disease by the time hemodialysis is 
initiated 
 CRF  Ļ vit D  Ļ Ca2+ absorption  
 Other causes of secondary HPT include osteomalacia, rickets, and 
malabsorption.  
 Features 
 hypocalcemia or normocalcemia 
 decreased vitamin D. 
 hyperphosphatemia.

 hyperphosphatemia. 
 extremely elevated PTH  
 complications 
 progressive bone disease,  
 osteitis fibrosa cystica, 
 soft-tissue calcifications.  
 Management  
 predominantly medical,  
 Supplementation of calcium using oral calcitriol and vitamin D is usually 
sufficient  
 alternative therapies If become refractory to replacement of calcium and 
vitamin D,  
 These agents are designed to bridge patients to r enal transplant, the

optimal treatment for secondary HPT.  
 calcimimetics, such as cinacalcet , 
 It works as an agonist at the site of the calcium sensor on the 
parathyroid gland. This leads to a suppression of PTH levels.  
 Cinacalcet may currently be used in patients on renal replacement 
therapy as an adjunct to vitamin D or phosphate binders. 
 used to treat secondary hyperparathyroidism. 
 It mimics the effect of calcium on the parathyroid glands (and

elsewhere) with the intention of limiting parathyroid hormone (PTH) 
production and deleterious effects on bone architecture. 
 new phosphate binders, and  
 vitamin D analogues that are less likely to result in hypercalcemia. 
 About 1 –2% of patients with secondary HPT require parathyroidectomy each 
year 
 indication for parathyroidectomy  
 The most life threatening indication is calciphylaxis 267

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          89 
  occurs in only 4% of patients undergoing surgery. 
 Calciphylaxis results in expanding, painful, cutaneous, purpuritic 
lesions that cause tissue calcification and ischemic necrosis which 
lead to dry gangrene if untreated 
 surgery has been shown to help avoid amputation, decrease pain,

and reduce the use of narcotics 
• Tertiary . 
 parathyroid glands become dysregulated after secondary hyperparathyroidism 
 secrete PTH regardless of Ca2+ level 
 classically caused by hyperplasia of all four glands 
 Causes 
 most commonly in the setting of renal transplant where patients with secondary 
HPT continue to have elevated PTH levels after receiving a renal allograft  
 After correction of the primary disorder (CRF) by renal transplant, the

hypertrophied parathyroid tissue fails to resolute and continues to over-
secrete PTH.  
 occurs in up to 30% of kidney transplant recipients 
 other causes: after any long-standing period of hypocalcemia such as those se en 
with chronic dialysis or gastrointestinal malabsorption. 
 Features 
 normal or elevated serum calcium  
 decreased vitamin D 
 decreased serum phosphate 
 moderately elevated PTH  
 elevated alkaline phosphatase 
  bone pain or fractures,

  bone pain or fractures,  
 pruritus ,  
 nephrolithiasis,  
 pancreatitis,  
 soft tissue or vascular calcifications, 
 mental status changes. 
 treatment of patients with tertiary HPT is surgical. 
 medical treatment is not curative and, generally, not indicated. 
 tertiary HPT requiring surgical intervention occurs in 1 –5% of patients with HPT 
after undergoing kidney transplant. 
 Serology  
 primary 
 hypercalcemia 
 Ĺ PTH

 primary 
 Ĺ PTH  
 secondary 
 hypocalcemia/normocalcemia  268

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          90 
  Ĺ PTH  
 malignancy 
 Ļ PTH  
 Ĺ alkaline phosphatase  
 normal anion gap metabolic acidosis 
 Ļ renal reclamation of bicarbonate  
 Urinalysis 
 primary 
 hypercalciuria (renal stones) 
 Ĺ cAMP  
 Radiograph 
 cystic bone spaces ("salt and pepper") 
 often in the skull 
 loss of phalange bone mass

 loss of phalange bone mass 
 Ĺ concavity  
 subperiosteal thinning (cortical resorption)  
 EKG  
 shortened QT 
Thiazide diuretics might unmask underlying primary hyperparathyroidism (PHPT), as they 
cause mild hypercalcemia by reducing urinary calcium excretion.  
Primary hyperparathyroidism  
 
MECHANISM OF PARATHYROID HORMONE (PTH) EFFECT 
 Reabsorbs  calcium at distal tubule

 Reabsorbs  calcium at distal tubule   
 Excretes phosphate at proximal tubule  
 A mnemonic to remember this is PTH = “Phosphate Trashing Hormone. ” 
 Activates vitamin D from 25 to the 1,25 dihydroxy form  
 increased activity of renal 1-α-hydroxylase  (which converts inactive 25-
hydroxycholecalciferol into active 1, 25-dihydroxycholecalciferol),  
 Reabsorbs both calcium and phosphate from bone 
 
In exams primary hyperparathyroidism is stereotypically seen in elderly females with an

unquenchable thirst and an inappropriately normal or raised parathyroid hormone  level. 
 
 the most common cause of hypercalcemia  
 most commonly found in women between 50 and 60 years of age 
 Two to three times more common in women than men. 
  most commonly due to a solitary adenoma  
 Parathyroid carcinoma is more likely when PTH is grossly elevated  
Causes of primary hyperparathyroidism   
 80%: solitary adenoma 
 15%: hyperplasia  4%: multiple adenoma 
 1%: carcinoma 269

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          91 
 Parathyroid hormone has a number of direct effects: 
 it enhances the release of calcium from bones by binding to osteoblasts which stimula tes the 
formation of osteoclasts, and 
 it enhances reabsorption of calcium in the distal tubules. 
Features  - 'bones, stones, abdominal groans and psychic moans'

The PTH level in primary hyperparathyroidism may be normal  
 polydipsia, polyuria  (Chronic hypercalcaemia can compromise the renal concentrating ability 
leading to polydipsia and polyuria from nephrogenic diabetes insipidus ). 
 peptic ulceration/constipation/pancreatitis 
 bone pain/fracture  ( kyphosis due to osteoporosis) 
 renal stones  calculi-induced hydronephrosis  Renal impairment 
 depression , Confusion  
 hypertension, Short QT syndrome on the ECG  
Associations

 multiple endocrine neoplasia: MEN I and II 
 The association of primary hyperparathyroidism and a gastrinoma would 
suggest a diagnosis of multiple endocrine neoplasia type 1.  
 
MECHANISM OF NEURAL INHIBITION IN HYPERCALCEMIA  
 Ĺ calcium levels Ļ depolarization of excitable tissue such as nerves .  
 Ĺ calcium moves the threshold for depolarization away from the resting membrane pote ntial.  
 Bowels are a long muscular tube.

 Bowels are a long muscular tube.  
 Ĺ calcium   Ļ smooth muscle contraction  constipation  
 Low calcium = Hyperexcitable  
 raised calcium, low phosphate 
 Hypophosphataemia is due to  reduced renal reabsorption of phosphate.  
 PO 43- is usually elevated or normal in Bone metastases (this clue could 
differentiate primary hyperparathyroidism from cancer metastases ) 
 PTH may be raised or normal (A high or even normal PTH concentration in the presence

of hypercalcaemia would support the diagnosis of hyperparathyroidism)  
 technetium-MIBI subtraction scan 
 Technetium (99mTc) sestamibi scanning has a high specificity and sensitivity for 
parathyroid adenoma.  
 Sestamibi (Technetium-99m sestamibi) scanning is most likely to inform on 
location of any adenoma prior to a surgical approach. 
 The most sensitive and specific technique for tumor localization 
 has a sensitivity of 90.7% and specificity of 98.8%.

 Sestamibi is a derivative of technetium that avidly incorporates into mitochondria.  
 The large amounts of mitochondria  in hyperactive parathyroid glands allow for 
more intense labeling of parathyroid tumors relative to the surrounding tissue. 270

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          92 
  24 hour urinary calcium may be useful if used in comparison to the serum calcium in ord er to 
distinguish familial hypocalciuric hypercalcaemia from primary hyperparathyroidism. 
 Urinary cAMP increases, because PTH works on the G protein pathway, Gs, which uses cAMP  
as a secondary messenger.

as a secondary messenger. 
The effect of PTH on calcium and phosphate  
Mechanism  calcium Phosphate 
Excretion by kidneys Ļ Ĺ 
Absorption from gut Ĺ Ĺ 
Absorption from bone Ĺ Ĺ 
Net Serum concentration Ĺ Ļ 
 
Hyperparathyroidism: Types  
Type  PTH  Calcium  Causes  
Primary  Normal High Tumour of the parathyroid gland (parathyroid adenoma)  
Secondary  High Low A low level of Ca2+ induces the parathyroid gland to produce large 
amounts of PTH.

amounts of PTH.  
Low levels of Ca2+ are commonly due to renal failure.  
Can also be caused by: 
 insufficient vit D,  
 insufficient Ca2+ in the diet,  
 excessive Mg2+ in the diet  
Tertiary  High High occurs after years of secondary hyperparathyroidism, but then the 
secondary cause is resolved. The parathyroid gland secretes high 
levels of PTH even though levels of Ca2+ are now responsive to 
PTH. There is hyperplasia of the glands, and loss of response to

ca2+. PTH is raised, calcium is raised and so is phosphate, whilst 
eGFR is significantly deceased . 
Cinacalcet  should be only offered in patients who are unfit for 
surgery. 
 
 Patients with renal disease however are not treated for hyperparathyroidism until the PTH le vel 
breaches twice the upper limit of the normal range. This is because of the risk of p recipitating 
adynamic bone disease. 
 Usual first line therapy is weekly 1-alphacalcidol. 
 
Treatment 
 total parathyroidectomy

Treatment 
 total parathyroidectomy 
Indications for parathyroidectomy: 
 markedly elevated corrected serum calcium (above 3 mmol/l),  
 Serum albumin-adjusted calcium greater than 0.25 mmol/L above the normal range 
 24 hour total urinary calcium excretion greater than 10 mmol (400 mg) 
 impaired renal function, Creatinine clearance reduced by 30% or more 
 Bone mineral density T- score less than −2.5 at any site  (at any site)  271

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          93 
  Age less than 50 
 Unwillingness of patient to follow advice of medical surveillance. (Patient request; adequa te 
follow-up unlikely). 
 indications for surgery in hyperparathyroidism,  
  previous marked hypercalcaemic episode, 
  renal stones, 
  reduced bone mineral density.

  reduced bone mineral density.  
Patients with hyperparathyroidism kept under observation require; 
 annual plasma calcium, renal function and blood pressure checks, repeat bone mine ral 
density check every 2 –3 years and renal ultrasound scan. 
Familial isolated hyperparathyroidism (FIHP)  
 It is closely related to MEN1 but the development of other tumours is not seen ove r the course 
of many years  
 Parathyroidectomy is the treatment of choice.

 Parathyroidectomy is the treatment of choice.  
Hyperparathyroidism jaw tumour syndrome  
 is a syndrome of hyperparathyroidism and fibro-osseous tumours of the jaw.  
 It is described as having increased incidence in Romany families.  
 
Secondary hyperparathyroidism  
 Raised PTH, low calcium, high phosphate , high alkaline phosphatase 
 Due to chronic renal failure.  
Feature 
 Raised parathyroid hormone (PTH) (low calcium increases PTH release from the parathyroid 
glands)

glands) 
 Low serum calcium (kidneys are involved in the activation of vitamin D) 
 Raised serum phosphate (kidneys normally excrete phosphate so levels of the latt er increase 
in renal failure) 
 High alkaline phosphatase (renal osteodystrophy). 
 
Mechanism 
 occurs because of loss of tubules and decreased calcium absorption. Calcium wasting cause s 
a reactive elevation in parathyroid hormone. 
 kidneys are involved in the activation of vitamin D  

 vitamin D replacement  (Alphacalcidol) normally given dose twice per week.  
 Surgery may be considered if parathyroidism does not respond to medical manageme nt.  
 NICE guidelines suggest only using cinacalcet in patients with end stage renal failure on renal 
replacement or in those who are unable to undergo surgery. 
 
 272

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          94 
 Osteitis fibrosa cystica  
 The cystic bone spaces seen on radiography are most likely osteitis fibrosa cystica, a 
condition in which brown, fibrous tissue fills bone cysts.  
 most commonly associated with parathyroid adenoma, the most common cause of 

hyperparathyroidism.  
Hungry bone syndrome 
 Hungry bone syndrome is an uncommon entity but can occur after parathyroidectomy if the 
hyperparathyroidism has been long standing. 
  The mechanism is thought to be thus: high pre-operative levels of parathyroid hormone 
provide a constant stimulus for osteoclast activity creating the hypercalcaemic state by de-
mineralizing the bones.

mineralizing the bones.  
 This process can result in x-ray changes very similar to metastatic lytic lesions if left untreated. 
Upon removal of the parathyroid adenoma the hormone levels fall rapidly (they hav e a very 
short half life) and the osteoclast activity is subsequently diminished and the bo nes rapidly 
begin re-mineralisation - 'hungry bone syndrome'. 
  This process can be uncomfortable and also result in systemic hypocalcaemia.

Bilateral hand radiographs in a middle-aged woman demonstrating generalised  osteopenia, erosion of 
the terminal phalyngeal tufts (acro-osteolysis) and sub-periosteal resorption  of bone particularly the radial 
aspects of the 2nd and 3rd middle phalanges. These changes are consistent with a diagnosi s of 
 
 273

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          95 
Hypoparathyroidism 
Primary hypoparathyroidism 
 decrease PTH secretion 
 e.g. secondary to thyroid surgery 
 Frequency increased in alcoholics , particularly in association with 
hypomagnesaemia .

hypomagnesaemia . 
 Alcohol  Hypercalciuria & hypermagnesuria  hypocalcemia and 
hypomagnesemia  hypoparathyroidism (ĻPTH & ĻCa)    
 low calcium, high phosphate 
 treated with alfacalcidol 
The main symptoms of hypoparathyroidism are secondary to hypocalcaemia : 
 Trousseau's sign: carpal spasm if the brachial artery occluded by inflating the blood pressure 
cuff and maintaining pressure above systolic

cuff and maintaining pressure above systolic 
 Chvostek's sign: tapping over parotid causes facial muscles to twitch 
 if chronic: depression, cataracts 
 ECG: prolonged QT interval 
 
Pseudohypoparathyroidism  
 Pseudohypoparathyroidism is caused by target cell insensitivity to parathyroid hormone (PTH) 
due to a mutation in alpha subunit of  the G-protein. 
 It is an autosomal dominant condition and is due to defects in the gene (GNAS1) encod ing the

alpha subunit of the stimulatory G protein (Gsa) 
 The G-protein-coupled receptor for parathyroid hormone (PTH) becomes unresponsive 
to the hormone, hence patients become hypocalcaemic in the face of normal or elevated 
PTH levels. 
 occurs twice as frequently in females as in males. 
Types 
 type I :  there is a complete receptor  defect  
 type II : the cell receptor is intact. 
Bloods  
 PTH: high 
 calcium: low   phosphate: high 
 alkaline phosphatase: high 
Features

Features 
 short fourth and fifth 
metacarpals 
 short stature  obesity 
 round face 
 subcutaneous calcification 274

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          96 
  cognitive impairment, low IQ  dental hypoplasia 
 Slipped femoral epiphysis  
 Diagnosis is made by measuring urinary cAMP  and phosphate levels following an  infusion 
of PTH. 
 In hypoparathyroidism  this will cause an increase in both cAMP and phosphate 
levels.

levels. 
 In pseudohypoparathyroidism type I  neither cAMP nor phosphate levels are 
increased 
 whilst in pseudohypoparathyroidism type II  only cAMP rises. 
 
Radiographic features 
 Musculoskeletal manifestations 
 soft tissue calcification 
 exostoses: short metaphyseal or more central and perpendicular to long axis of bon e 
 broad bones with coned epiphyses 
 CNS / head and neck manifestations 
 basal ganglia calcification 
 sclerochoroidal calcification

 sclerochoroidal calcification 
 deep white matter calcification 
 Calcium and vitamin D supplementation 
 
Pseudopseudohypoparathyroidism  
 similar phenotype to pseudohypoparathyroidism but normal biochemistry 
 
Pseudohypoparathyroidism  is when the defect is inherited from the mother  
while pseudopseudohypoparathyroidism  is inherited from the father .  
 
Adrenal gland conditions 
Adrenal cortex

Adrenal cortex 
  
 Adrenal cortex (mnemonic GFR  - ACD ) 
 zona Glomerulosa (on outside): mineralocorticoids, mainly Aldosterone 
 zona Fasciculata (middle): glucocorticoids, mainly Cortisol 
 zona Reticularis (on inside): androgens, mainly Dehydroepiandrosterone (DHEA) 
Adrenal medulla 
The adrenal medulla secretes  
275

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          97 
  all the adrenaline in the body   
 Small amounts of noradrenaline. 
 It essentially represents an enlarged and specialised sympathetic ganglion 
noradrenaline metabolism 
The action of noradrenaline released at sympathetic nerve endings is terminated by which 
mechanism?

mechanism? 
 The majority are  Re-uptaked by the axonal terminals   into the neurosecretory granules  
 small amount is metabolised by monoamine oxidase (MAO). 
  smaller quantities that escape into the circulation are metabolised by catechol-O-methyl 
transferase (COMT). 
 
De-hydro-epi-androsterone (DHEA)  
 Dehydroepiandrosterone is the most abundant circulating adrenal steroid.  
 Adrenal glands are the main source of dehydroepiandrosterone in females - loss of function ing

adrenal tissue as in Addison's disease may result in symptoms secondary to androgen 
deficiency, such as loss of libido.  
 Research is ongoing as to whether routine replacement of DHEA is beneficial 
May 2008 exam: Addison's disease C/O a decrease in her libido. On examination there is a slight loss 
of pubic hair. What is the most likely cause?  Dehydroepiandrosterone (DHEA) deficiency  
Cortisol

Cortisol  
Cortisol levels are increased in: 
 conditions of physical and emotional stress  
 oestrogens 
 oral contraceptives  amphetamin es 
 cortisone 
 spironolactone. 
 
Primary hyperaldosteronism 
 
276

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          98 
  
 with the wide diffusion of the aldosterone to renin ratio (ARR) as a screening test, the 
estimated prevalence of primary aldosteronism (PA) has risen from 1 to  10–30% of all forms 
of hypertension  
Causes 
1. The most common  Bilateral idiopathic adrenal hyperplasia (70% of cases) .

2. Common  adrenal adenoma, termed Conn's syndrome .  
3. rare   Adrenal carcinoma  
4. Glucocorticoid deficiency - also called glucocorticoid-remediable aldosteronism  high ACTH 
levels   increased aldosterone production.  
Features  
 Hypertension 
 The most common cause of hypertension,( (up to 12%) of hypertension , and as 
such should always be considered.  
 May present with untreated or resistant hypertension  
 Hypokalaemia , may leads to:

 Hypokalaemia , may leads to: 
 fatigue, muscle weakness, cramping, headaches, and palpitations.  
 polydipsia and polyuria from hypokalemia-induced nephrogenic diabetes insipidus.  
 Abdominal distention (ileus from hypokalemia) 
 elevated aldosterone and low renin.  
 (aldosterone- to-renin ratios are typically ≥  20).  
 Low magnesium and normal/high sodium. 
 Metabolic alkalosis 
 resulting from the action of aldosterone on the renal distal convoluted tubule

(DCT ) (ie, enhancing sodium reabsorption and potassium and hydrogen ion 
excretion). 
 Patient with adrenal adenoma  do not have features of hyperandrogenaemia like hirsutism as 
benign adrenal tumours produce cortisol but not the androgens. Absence of hirsutism and 
277

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          99 
 virilisation in a patient with other features of Cushing's syndrome favours adrenal 
adenoma  but needs further investigations. 
Screening for hyperaldosteronism  (using aldosterone / renin ratio) should be considered for : 
 Hypertensive patients with hypokalaemia (not due to treatment),

 those with marked diuretic-induced hypokalaemia (<3.0)  
 and those with refractory hypertension (failure to respond to three or more agents).  
 high serum aldosterone 
 low serum renin 
 high-resolution CT abdomen with contrast  
 (the initial radiologic investigation) and better than MRI . 
 sensitivity greater than 90% 
 If CT or MRI is normal in a patient with primary aldosteronism, a 6- to 12-month

treatment trial with aldosterone antagonists is recommended, after which the 
imaging studies should be repeated.  
 adrenal vein sampling 
 its greatest utility when adrenal imaging is normal despite biochemical evidence for 
primary aldosteronism  
 If aldosterone/renin ratios is ĹĹ  definitive confirmation or exclusion of diagnosis  
suppression testing with measurement of aldosterone response to fludrocortisone or to salt 
loading.

loading. 
 genetic testing for the hybrid gene causing familial hyperaldosteronism type I (glucocorticoid-
remediable aldosteronism). 
 A negative genetic test should be followed by adrenal CT and adrenal venou s 
sampling to differentiate unilateral from bilateral forms. 
Aldosterone: renin ratio  
 causes of false-positive  results:  
 ingesting large amounts of sodium,  
 renal impairment,  
 beta-blockers  
 
 causes of  false-negative  results  
 Salt-restriction,

 Salt-restriction, 
 ACE inhibitors and angiotensin-receptor blockers,  
 spironolactone and other diuretics 
 
 The aldosterone concentration is usually higher when the patient is erect than when 
supine (in bilateral hyperplasia) 
 (ACEi), ARB, diuretics, calcium- channel blockers and ȕ -blockers all ideally require a 
washout period of 2 weeks to make the aldosterone: renin ratio assay meaningful.  While

it may seem dangerous to wash out, a definitive diagnosis is impossible if you do no t. 
 Spironolactone requires a washout period of 6 weeks. 
  A high aldosterone: renin ratio is suggestive of primary hyperaldosteronism.  278

Notes & Notes for MRCP                                                                                                  By Dr. Yousif Abdallah Hamad          
100 
  The blood sample should be taken in the morning, standing, and with a norma lised potassium 
concentration (using supplementation) if possible. 
 Alpha-blockers (for example, doxazosin) and calcium channel blockers (for example,

amlodipine) are the hypertensives of choice in patients undergoing renin/aldosterone ratio 
measurements.  
 Alpha blockers such as doxazosin have the lowest  effect on the renin-angiotensin 
system; thus can be continued during the renin/aldosterone ratio test .  
 
The effect of drugs on renin and angiotensin is seen below: 
Drug Renin Aldosterone Effect 
Non-dihydropyridine CCB Minimal Minimal No effect 
Dihydropyridine CCB Minimal Decreased/minimal No effect

Alpha-blockers Nil Nil No effect 
Hydralazine Minimal Minimal No effect 
  
ACE inhibitors & ARBs Increased Decreased False negative 
Diuretics Increased 
markedly Increased False negative 
Minoxidil Increased Minimal False negative 
  
Beta-blockers Decreased Minimal False positive 
Methyldopa Decreased Minimal False positive 
 
 Hypertension is also a feature of Liddle syndrome and steroid 11β -hydroxylase 
deficiency , but aldosterone concentrations are low .

 In secondary aldosteronism, aldosterone secretion is increased secondary to an 
increase in renin secretion, and plasma renin activity is normal or increased.  
 Adrenal hyperplasia can be differentiated from adrenal adenoma by 
measuring aldosterone levels on awakening, and 2-4 hours later while 
standing: 
 In adenoma, aldosterone levels decline on standing 2-4 hours later. 279

101 
  in hyperplasia, levels increase. 
 adrenal adenoma: surgery 
 Surgery is the treatment of choice for Conn's adenoma and leads to resolution of  
hypertension in around 70% of patients. 
 For hypertension 
 Aldosterone inhibition with spironolactone will bring the greatest additional

reduction in blood pressure . 
 bilateral adrenocortical hyperplasia: aldosterone antagonist e.g. spironolactone  
Prognosis 
 After removal of the adenoma the blood pressure is normal in 70% of patients a t 1 year; 
 50% of patients are still normotensive after 5 years. 
 
January 2016 exam: A 24-year-old woman with BP: 170/100 mmHg during a routine medical check. Blood 
tests show:  Na+ =140 mmol/l. K+ = 2.6 mmol/l. Bicarbonate = 31 mmol/l. Urea = 3.4 m mol/l. Creatinine =77

µmol/l. Which one of the following investigations is most likely to be diag nostic? Renin:aldosterone ratio  (∆ 
Conn's syndrome)  
 
Bilateral hyperplasia vs adrenal adenoma: 
bilateral hyperplasia adrenal adenoma 
idiopathic adrenal hyperplasia (IAH)  Aldosterone-producing adenomas (APAs) 
 
Commonest  common 
 higher prevalence in African Americans, persons 
of African origin, and, potentially, other blacks.  have more severe hypertension, hypokalemia,

and higher urinary aldosterone than IAH. 
  4 times more prevalent in men than in women more common in women than in men, with a 
female- to-male ratio of 2:1.  
peaking in the sixth decade of life The typical patient with an APA is a woman aged 
30-50 years. 
renin-angiotensin system (RAS) –mediated 
increase  in aldosterone level occurs  with 
upright posture.  decrease  in the aldosterone level with upright 
posture  
 Loss of normal circadian rhythm of aldosterone

Loss of normal circadian rhythm of aldosterone 
secretion (normally: lowest around midnight, and 
highest in early morning) preserved of normal circadian rhythm of 
aldosterone secretion  
 
aldosterone-producing adrenal adenomas are commoner in young women, whereas bilateral 
adrenal hyperplasia tends to occur later and is commoner in men. 
 
____________________________________________________________  280

102 
 Congenital adrenal hyperplasia (CAH) 
Overview 
 group of autosomal recessive disorders  
 Congenital adrenal hyperplastia is caused by an inherited defect in the cortisol and/or 
aldosterone biosynthetic pathways. Non-classical forms result from milder enzyme dysfunction

and therefore manifest later in life (adolescence or adulthood).  
 associated with HLA B47  
 affect adrenal steroid biosynthesis 
 affects males and females in equal numbers.  
 Results from a defect in the biosynthetic pathway of cortisol and/or aldosterone.  
 in response to resultant low cortisol levels the anterior pituitary secretes high levels of ACTH 
 ACTH stimulates the production of adrenal androgens that may virilize a female infan t 
Cause

Cause 
 21-hydroxylase deficiency (90%)  most common cause  
 due to mutation of the CYP21A2 gene  on chromosome 6  
 Ļ aldosterone  
 Ĺ testosterone  
 All forms of CAH cause  Ļ cortisol + Ĺ ACTH  
 11-beta hydroxylase deficiency (5%) 
 patients with 11β -hydroxylase will present with increased blood pressure, hypokalemia 
and increased androgen levels, differentiating it from 17α -hydroxylase deficiency. 
 Ĺ testosterone

 Ĺ 11-deoxycorticosterone  ,  Ĺ 11-Deoxycortisol  
 11 Beta-hydroxylase is responsible for conversion of 11-deoxycorticosterone and 
11-deoxycortisol to corticosterone and cortisol. As this enzyme is not active in 
patients with 11-beta hydroxylase deficiency, levels of these steroids accumulate in 
patients suffering from the disorder. 
 Whilst levels of 17-OH steroids are elevated in those with 11-beta hydroxylase

deficiency, the elevation seen is not as great as that seen with 21-hydroxylase 
deficiency, occasionally an incorrect diagnosis of 21-hydroxylase deficiency may 
however be made. 
 17-hydroxylase deficiency (very rare) :  
 Ĺ mineralocorticoids (aldosterone)  hypertension and hypokalemia  
 Ļ testosterone  
 amenorrhea, no secondary sexual characteristics,  
 This enzyme converts progesterone to 17- α-hydroxyprogesterone, which

subsequently is converted to androstenedione, testosterone, and finally 
estradiol.  281

103 
  Ļestradiol results in a failure of development of the estrogen-dependent 
menstrual cycle and the appearance of normal secondary sexual 
characteristics. 
 Progesterone accumulates and is pushed off into the aldosterone 
pathway. This increased synthesis of mineralocorticoids then results in

hypertension and hypokalemia as a result of Na+ retention, K+ expulsion, 
and fluid retention. 
 
Feature 
 Premature epiphyseal closure 
 Under- and over-treatment of CAH  risk of short stature:   
 over-treatment  glucocorticoid-induced inhibition of the growth axis. 
 ACTH excess  hyperpigmentation 
 Cortisol deficiency  
 aldosterone deficiency   salt-losing crises  
 androgen excess   
 in boys  ambiguous genitalia, precocious puberty

 in girls  virilism, hirsutism, clitoromegaly and primary amenorrhoea. 
 Hyperreninaemia due to sodium loss and hypovolaemia.  
Diagnosis  cortisol + Ĺ ACTH + Ambiguous genitalia Ļ  
CAH 
ĻAldosterone +   
testosterone Ĺ  
21-α hydroxylase 
deficiency Ĺ Aldosterone +  
Ļ testosterone  
17-α hydroxylase 
deficiency   Ļ Aldosterone +  
 + Ĺ testosterone  
↑ 11-deoxycorticosterone   
11-β 
hydroxysterone 
deficiency 282

104 
  17-OH progesterone is elevated because of the enzyme deficiency.  
 Measurement of 17-OHP levels, can help to distinguish between PCOS and 
non-classical CAH.  
 The clinical presentation may be indistinguisable from polycystic ovarian 
syndrome, with hirtusism being a dominant feature.The synacthen stimulation

test can evaluate adrenal gland function, and when 17-OHP levels are measured 
concurrently, can help to distinguish between PCOS and non-classical CAH. 
 Diagnosis is by finding raised serum 17-hydroxyprogesterone levels that show a 
hyper-responsiveness to adrenocorticotropic hormone (ACTH).  
 The ACTH stimulation test ( synacthen stimulation test ) is the best screening 
evaluation, and can diagnose 21-OH deficiency when the plasma 17-OH progesterone  
are more than 30 nmol/L.

are more than 30 nmol/L.   
Treatment  
 glucocorticoid replacement  
 the drug of choice? 
 hydrocortisone  
 it minimises growth suppression in children. 
 The dose? 
 The lowest dose of glucocorticoid that suppresses (not totally) adrenal 
androgens, whilst maintaining normal growth and weight gain. 
 Hydrocortisone has a relatively short half-life and must therefore be administered 
twice daily. 
Monitoring of treatment

Monitoring of treatment 
 Efficacy of treatment is best monitored by 17-OH progesterone and androstenedione 
levels  
 Renin activity levels can be used to monitor the adequacy of mineralocorticoid and sodium 
replacement. 
 Over treatment with mineralocorticoids leads to hypertension, suppressed plasma rennin 
activity and possibly growth retardation. 
 
 283

105 
  
Non-classic congenital adrenal hyperplasia (NCAH) 
classical CAH (C-CAH) Nonclassical CAH (NC-CAH) 
 The SEVERE form 
 begins in early fetal life, usually detected in 
the newborn period or in early childhood. 
 Have  a partial enzyme deficiency 
 Less common 
 Lack of both cortisol and aldosterone

 Lack of both cortisol and aldosterone 
predispose 3/4 of severely affected 
individuals with CAH to “adrenal crises ”  
 characterized by ambiguous genitalia in 
girls.  
 Severely affected girls may be mistaken 
for boys at birth.  
 Affected boys have no genital 
malformations at birth, but continued 
androgen excess causes unusually fast 
body growth.  The milder form 
 usually asymptomatic at birth and typically

 usually asymptomatic at birth and typically 
present in late childhood, adolescence, or 
adulthood 
 may cause symptoms at any time from 
infancy through adulthood.  
 NC-CAH 21-OH deficiency is much  more 
common than C-CAH  
 In adolescent and adult females, the 
symptoms of hyperandrogenism include 
hirsutism, acne, menstrual irregularity, 
androgenic alopecia, and impaired fertility 
 not characterized by ambiguous genitalia 
in girls. 
 
 Genetics  
 autosomal recessive disorder

 Genetics  
 autosomal recessive disorder  
 due to P450c21 (21-hydroxylase)  deficiency   
 due to mutations in the CYP21A2  gene.  
 Non-classical forms are characterised by milder enzyme dysfunction, and therefore 
usually only manifest in adolescence or adulthood.  
 Incidence:  
 Non-classic congenital adrenal hyperplasia is a cause of hyperandrogenism in up to 1 in 
1000 females, particularly those of Hispanic, Yugoslavian or Eastern European Jewish 
descent .  
 Feature

descent .  
 Feature   
 Patients might complain of no other symptoms apart from primary amenorrhoea . 
 The clinical presentation may be indistinguisable from polycystic ovarian syndrome, with 
hirtusism being a dominant feature.  
 Normal ultrasound scan will rules out other causes of primary amenorrhoea 
(Turner syndrome and testicular feminization). 
  Diagnosis  
 17-OHP concentration above 33 nmol/L would be diagnostic. 

 glucocorticoid supplementation in juveniles , 
 Flutamide (used as an anti-androgen) in adults  with mild symptoms. 
 If the main concern is infertility, ovulation induction is the treatment of choice.  
 If hirsutism is the presenting problem then anti-androgens (such as flutamide) 
should be used. 284

106 
Glucocorticoid remediable aldosteronism (GRA)  
 mutation leads to ACTH responsive aldosterone production from the zona fasciculata ra ther 
than the zona glomerulosa.

than the zona glomerulosa.  
 ectopic expression of aldosterone synthase and novel steroids in the adrenal zona 
fasciculata under the regulation of  ACTH. 
 It occurs because the regulatory portion of the 11b-OH gene binds to the aldosterone  synthase 
gene.  
Features  
 strong family history   
 family history of early hypertension and haemorrhagic strokes is characteristic. 
 resistant hypertension ,  
 hypokalaemia ,

 hypokalaemia , 
 potassium is normal in more than one-half of cases  of GRA in contrast to the 
hypokalaemia frequently seen in primary aldosteronism  
 responsive to corticosteroid therapy , 
Treatment  
 physiologic doses of a glucocorticoid will correct the overproduction of aldosterone by 
suppressing ACTH. 
Pseudohyperaldosteronism  

 Pseudohyperaldosteronism is characterized by a clinical picture of hyperaldosteronism with 
suppression of plasma renin activity and aldosterone.   
 Feature: 
 hypertension, 
 salt retention 
 hypokalaemia  
 low renin and aldosterone concentrations.  
Causes 
 Direct mineralocorticoid effect, as with desoxycorticosterone, fluorohydrocortisone, 
fluoroprednisolone, estrogens, and the ingestion of high amounts of glycyrrhe tinic acid.

 inhibition of 11 beta hydroxysteroid dehydrogenase (11 bHSD)  
 11bHSD is responsible for the conversion of cortisol to the inactive cortisone, preventing 
activation of the mineralocorticoid receptor by cortisol but permitting activation by 
aldosterone.  
 Both liquorice  and carbenoxolone inhibit 11bHSD and produce 
pseudohyperaldosteronism  
 Licorice has aldosterone-like properties and prevents inactivation of cortisol, resulting in

107 
  
 Liddle syndrome, which is due to a mutation of the gene encoding for beta and g amma 
subunits of the sodium channels.  
Apparent mineralocorticoid excess (AME) 
 (AME) is a rare form of pseudohyperaldosteronism characterized by very early-onset and

severe hypertension, associated with low renin levels and hypoaldosteronism. 
Causes 
 Autosomal recessive mutation in the HSD11B2  gene (16 q 22) which encodes 
the kidney isozyme of 11β-Hydroxy- Steroid Dehydrogenase type  2 (11-beta-HSD2)  
  acquired reduction of the activity of the (11 bHSD)  enzyme caused by: 
 glycyrrhetinic acid,  
 carbenoxolone,  
 grapefruit juice.  
 (rarely) Ĺ liquorice  consumption  inhibition of 11-hydroxysteroid dehydrogenase type

2  Ĺ cortisol  AME. (Liquorice : black substance produced from the root of a plant 
used in midicine and sweets)  
 Normally 11-hydroxysteroid dehydrogenase type 2  converts cortisol into inactive 
cortisone at the renal parenchyma (In order to prevent cortisol activation of the 
mineralocorticoid nuclear receptor and subsequent hyperaldosteronism)  
 Ļ11β-hydroxysteroid dehydrogenase type 2  Ĺ cortisol in the kidney  activate

the mineralocorticoid receptor  aldosterone-like effects in the kidney  
hypokalemia, hypertension, and hypernatremia  
Feature:   
 usually diagnosed within the first years of life 
 polyuria and polydipsia, 
 failure to thrive,  
 hypokalemia, hypertension, and hypernatremia  
 low renin and aldosterone levels  
 metabolic alkalosis 
 nephrocalcinosis.  
 Stroke has been observed before the age of 10 years in untreated children.  
Diagnosis :

Diagnosis :  
 Ĺ ratio of free urinary cortisol to free urinary cortisone. (AME patients create less cortisone)   
 differentiate between AME and Liddle's Syndrome by administering a potassium-spari ng 
diuretic:  
 Liddle's syndrome: only respond to a diuretic that binds the ENaC channel,  
 AME: respond to a diuretic that binds to ENaC or mineralcorticoid receptor.  
Treatment:  Two main strategies:

Treatment:  Two main strategies: 
1. blockade of the mineralocorticoid receptor by spironolactone (2-10 mg/kg/day), combined with 
thiazides to help to normalize blood pressure and reduce hypercalciuria and nephroc alcinosis.  286

108 
 2. administration of exogenous corticoids to block ACTH and suppress the endogenous 
secretion of cortisol.  
 
Phaeochromocytoma 
 
Pheochromocytoma = Episodic hypertension 
 
Pheochromocytoma is part of MEN II.

Pheochromocytoma is part of MEN II. 
 
 Phaeochromocytoma is a rare catecholamine secreting tumour.  
 The tumors arise from the chromaffin cells of the adrenal medulla 
 Chromaffin cells are modified post-ganglionic sympathetic cells  that release 
catecholamines after stimulation by pre-ganglionic sympathetics. 
 The peak incidence is between ages 20 to 40. 
 About 10% are familial  
 may be associated with : 
  MEN type II.  
 Neurofibromatosis.  
 von Hippel-Lindau syndrome.

 von Hippel-Lindau syndrome. 
Basics  
 bilateral in 10% 
 malignant in 10% 
287

109 
  extra-adrenal in 10% (most common site = organ of Zuckerkandl, adjacent to the bifurcat ion of 
the aorta) 
Features are typically episodic 
 hypertension (around 90% of cases, may be sustained) 
 it can also present with severe hypotension from catecholamine-induced 
cardiomyopathy

cardiomyopathy 
 headaches (80%) the most common presenting feature  
 Palpitations  (70%)  
 sweating  Hyperhidrosis (60%)  
 anxiety  
 (sense of impending doom) 
 symptoms occur primarily at night 
 Hyperglycemia or glycosuria may be present. 
 Paroxysmal attacks may be provoked by:  
 palpation of the tumor,  
 abdominal compression or massage,  
 postural changes,  
 induction of anesthesia,  
 emotional trauma,  
 micturition if the tumor is in the bladder.

 micturition if the tumor is in the bladder.  
 Drugs that exacerbate or unmask the symptoms  (drugs that inhibit catecholamine 
reuptake) 
 unopposed beta blocker  
 tricyclic antidepressants  
 cocaine 
Tests 
 24 hr urinary collection of metanephrines (sensitivity 97%) 
 this has replaced a 24 hr urinary collection of catecholamines (sensitivity 86%) 
 False positive urinary metanephrines can occur as a result of:

 hypoglycaemia, stress , exercise, drugs such as methyldopa, dopamine agonists or 
ganglion-blocking antihypertensives, and also various foodstuffs including coffee, 
chocolate, bananas and citrus fruits.  
 the definitive methods for localisation  
 Magnetic resonance imaging and me ta-iodo-benzyl guanidine (MIBG) scanning 
 Scanning with (MIBG) demonstrates specific uptake in sites of sympathetic activity,  
particularly useful with extra-adrenal tumours .

 A scan with 131iodine-labelled metaiodobenzylguanidine (MIBG) is used in cases where 
a tumour is confirmed biochemically but cannot be identified on computerized 
tomography (CT) or magnetic resonance imaging (MRI) scanning. 
 The presence of noradrenaline alone usually indicates an extra-adrenal tumour . 288

110 
   
The image reveals a large left 
suprarenal mass. The appearances 
are typical of a which, unlike most 
other adrenal tumours, demonstrates 
a distinctive ‘bright white ’ signal on 
T2-weighted MRI.  
 
definitive management   Surgery.

definitive management   Surgery. 
Initial management The patient must first however be stabilized with medical management:  
 alpha-blocker (e.g. phenoxybenzamine), given first, before a beta-blocker.  
 β-blockade without first adequate α -blockade will result in significantly increased blood 
pressure 
 to avoid a hypertensive crisis  upon tumor manipulation at the time of surgery . 
 beta-blocker (e.g. propranolol)

 beta-blocker (e.g. propranolol) 
 It is also important to fill patients well with intravenous fluids prior to surgery in order to preven t 
a sudden loss of vascular tone in the postoperative period  as a result of a  sudden fall in 
catecholamines leading to profound hypotension . These are important anesthetic 
considerations.  
 Management of phaeochromocytoma in pregnancy   ( initiate alpha-blockade and 
arrange delivery by C- section)

arrange delivery by C- section)  
  Alpha blockade (phenoxybenzamine) should be started as soon as the diagnosis is 
made, and should be given for 10-14 days.  
o Doxazosin is also safe in pregnancy but can be displaced by high levels of 
endogenous catecholamines. 
o  Unopposed beta blockade should not be used in the management of 
phaeochromocytoma because of the risk of paradoxical increases in blood 
pressure

pressure  
 Laparoscopic adrenalectomy is indicated if the tumour mass is less than 7 cm  
289

111 
  However, after 24 weeks of gestation surgical removal is recommended after an 
elective caesarean section.  
 Vaginal delivery carries a higher mortality rate of 31%, compared to 19% with C-section.  
 The anaesthetic approach is extremely important, as anaesthetia can precipitate a

hypertensive crisis. General anaesthesia is recommended.  
 
Preoperative and intraoperative precautions to be undertaken in patients with 
pheochromocytoma: 
 
 Anesthesia should be induced with a non-arrhythmogenic drug like thiopentone 
 Anesthesia should be continued with enflurane 
 If muscle relaxants are needed, drugs that do not release histamine are preferred 
 Atropine should not be used preoperatively 
 
Prognosis :  
 benign phaeochromocytoma The 5-year survival rate is 95%

 malignant phaeochromocytoma   The 5-year survival rate is 40% 
 Phaeochromocytomas are three times more likely to be malignant in women. 
 
May 2013 exam : A 43-year-old man is found to have a phaeochromocytoma. Which anti-
hypertensive medication should be started first? Phenoxybenzamine  
 
January 2015 exam: A 41-year-old patient C/O recurrent headaches, sweating and 
palpitations. BP: 210/110 mmHg. Given the likely diagnosis, what is the most appropriate

next test? 24 hour urinary collection of metanephrines (∆ Phaeochromo cytoma)  
 290

112 
  The image reveals a large left 
suprarenal mass. The 
appearances are typical of a 
phaeochromocytoma which, 
unlike most other adrenal 
tumours, demonstrates a 
distinctive ‘bright white ’ signal 
on T2-weighted MRI.  
 
291

113 
  
292

114 
 ____________________________________________________________   
Hypoadrenalism  
Primary hypoadrenalism ( Addison's disease ) 
 
 A disorder caused by the destruction of the adrenal cortices 
 involves all three layers of the cortex

 involves all three layers of the cortex 
 results in Ļ production of glucocorticoid (cortisol), mineralcorticoids (aldosterone), and 
steroids 
 clinical findings are noted after 90% of the adrenal cortex has been destroyed. 
 Addison's disease (primary hypoadrenalism) is associated with: 
 Low aldosterone secretion (leading to salt wasting) 
 High plasma renin 
 High adrenocorticotrophic hormone (ACTH) 
 High lipotropin 
 Elevated plasma vasopressin, and Angiotensin II. 
Prevalence

Prevalence  
 Prevalence is around 5 per 100,000. 
 There is a female: male preponderance of 2:1 
 (aldosterone insufficiency )leads to loss of salts an water(kidneys)  blood volume decreases 
so does the cardiac work   hypotension. also K+ and H+ renal secretion is impaired  
hyperkalemia and metabolic acidosis.  
  insufficiency of glucocorticoids leads to hypoglycemia and inability of kidney to excrete a w ater 
load (hyponatremia) 
Causes  
 Autoimmune

Causes  
 Autoimmune   
 Autoimmune destruction of the adrenal glands is the commonest cause of 
hypoadrenalism in the UK , accounting for 80% of cases  
 70% of patients have circulating anti-adrenal antibodies. 
 infectious (eg, mycobacterial, fungal), 
 Tuberculosis  
 accounts for a further 15% of cases.  
 the predominant cause of Addison disease in developing countries. 
 In case with high ESR, TB adrenalitis should be considered

 the best investigation to establish the diagnosis in this patient  CT 
abdomen  
 absence/shrinkage or enlargement of the adrenals may be seen. 
293

115 
  Although a CXR would be an appropriate initial investigation this may be 
normal despite the possibility of TB. 
 The differential diagnosis for a pyrexia of unknown origin and bilateral adrenal swelling 
would be lymphoma, tuberculosis, or histoplasmosis.

 Acute meningococcal sepsis due to Neisseria meningitidis  can lead to sepsis, 
disseminated intravascular coagulation (DIC), endotoxic shock, and acute primary 
adrenal insufficiency, also known as Waterhouse-Friderichsen syndrome . 
 Neisseria meningitidis  is a gram-negative diplococcus that grows on 
chocolate agar. 
 The adrenal insufficiency is secondary to acute adrenal hemorrhage which ma y 
be attributable to DIC or an endotoxin-mediated process.

 purpuric rash  classically appears on the trunk and extremities secondary to the 
DIC 
 HIV 
 neoplastic (eg, primary, metastatic), 
 (e.g. bronchial carcinoma) 
 vascular (eg, hemorrhage, emboli, thrombus),  
 anti-phospholipid syndrome (Hughes' syndrome)   
 precipitate adrenal infarction and haemorrhage through adrenal vein thrombosis. 
 Anticoagulant overdose 
 bilateral hemorrhage in the adrenal glands resulting in severe acute adrenal 
insufficiency.

insufficiency.  
 Flank pain, hypotension refractory to resuscitative efforts , and hypoglycemia 
indicate acute adrenal insufficiency due to heparin overdose. 
 traumatic, iatrogenic (eg, surgery, medication),  
 metabolic (eg, amyloidosis) 
Features  
 lethargy, weakness, anorexia,  
 Nausea, vomiting, and diffuse abdominal pain are present in approximately 90% of patie nts 
and usually represent an impending addisonian crisis. 
 weight loss,  
 'salt-craving'

 'salt-craving' 
 hyperpigmentation (present in 95% of patients)  (especially palmar creases ), Buccal 
pigmentation  
 Ĺ ACTH  melanocyte stimulating hormone (MSH)  hyperpigmentation  
 Oral mucous membrane hyperpigmentation is pathognomonic for the disease. 
 Increased tanning during winter is particularly suggestive and due to the action 
of excess ACTH on melanocytes. 
 vitiligo,  
 loss of pubic hair and axillary in women,

 loss of pubic hair and axillary in women, 
  Women may have loss of androgen-stimulated hair, such as pubic and axil lary hair, 
because androgens are produced in the adrenal cortex.  294

116 
  Men do not have hair loss because androgens in males are produced primarily in the 
testes. 
 Hypotension 
 marked postural drop in blood pressure, 
 crisis: collapse, shock, pyrexia 
 
Associations with Addison's  Other autoimmune conditions such as  
 pernicious anaemia  
 thyroid disease

 thyroid disease  
 Type 1 diabetes  
 Vitiligo  
 Chronic active hepatitis . 
 
 ACTH stimulation test ( short Synacthen test ): is the definitive diagnostic test   
 Plasma cortisol is measured before and 30 minutes after giving Synacthen 250ug IM. 
  Cosyntropin (synthetic ACTH) stimulation test: You measure the level of cortisol before 
and after the administration of cosyntropin. If there is adrenal insufficiency, there will be

no rise in cortisol level. 
 Adrenal autoantibodies such as anti- 21-hydroxylase may also be demonstrated.   
 21 hydroxylase is the enzyme involved in the cholesterol steroid pathway 
 present in approximately 80% of cases. 
 serum cortisol: If a ACTH stimulation test is not readily available (e.g. in primary care) then 
sending a 9 am serum cortisol can be useful: 
 500 nmol/l makes Addison's very unlikely 
 < 100 nmol/l is definitely abnormal

 < 100 nmol/l is definitely abnormal 
 100-500 nmol/l should prompt a ACTH stimulation test to be performed 
 Serum electrolyte: Associated electrolyte abnormalities are seen in around one-third of 
undiagnosed patients: 
 Hypo natraemia (90%)  
 due to both loss of sodium in the urine (due to aldosterone deficiency) and to 
movement into the intracellular compartmen t. 
 Hyper kalaemia (65%)  
 Caused by a combination of aldosterone deficiency, impaired glomerular filtration

(due to hypotension) and acidosis.  
 Hyperkalemia with a mild metabolic acidosis from the inability to excrete either 
H+ or K+ because of the loss of aldosterone. 
 Hypo glycaemia  
 (due to loss of the glucogenic effect of glucocorticoids)  
 (Ļ cortisol -stimulated gluconeogenesis) 
295

117 
  Mild to moderate hyper calcaemia  occurs in 10-20% patients, the cause of which is 
uncertain. 
 Modest  hyper prolactinaemia  is reported in Addison's disease and is glucocorticoid-
responsive. 
 High plasma renin and angiotensin II. 
 High adrenocorticotrophic hormone (ACTH) 
 High lipotropin

 High lipotropin 
 Elevated plasma vasopressin 
 metabolic acidosis 
 due to Ļ bicarbonate  
 normocytic normochromic anaemia is often present,  
 eosinophilia, lymphocytosis, and neutropenia 
 due to Ļ cortisol  
 normally suppresses levels of eosinophils and lymphocytes 
 normally de-marginates a portion of the neutrophil population which results in Ĺ 
measurable neutrophil count 
 
This patient has buccal pigmentation which raises 
the possibility of adrenal insufficiency,

the possibility of adrenal insufficiency,  
 
Addisonian crisis 
Causes 
 sepsis or surgery causing an acute exacerbation of chronic insufficiency (Addison's, 
Hypopituitarism) 
 adrenal haemorrhage eg Waterhouse-Friderichsen syndrome (fulminant meningoco ccemia) 
 steroid withdrawal 
 Sick euthyroidism is a recognised feature of Addison's disease and  treatment with thyroxine 
may exacerbate the condition and precipitate acute hypoadrenalism.  
Signs/symptoms of Addisonian crisis:

Signs/symptoms of Addisonian crisis:  
Neurological Haemodynamic Biochemical 
 syncope 
 lethargy 
 convulsions   hypotension 
 hypothermia 
  hyponatraemia 
 hyperkalaemia 
 hypoglycaemia 
 
Management of Addisonian crisis (medical emergency):  
296

118 
  intravenous fluids 
 1 litre normal saline infused over 30-60 mins or with dextrose if hypoglycaemic 
 corticosteroids (e.g iv dexamethasone) 
 hydrocortisone 100 mg im or iv 
 Note: iv dexamethasone is often preferred as this will not interfere with cortisol assays

needed for a short synacthen test, unlike hydrocortisone. 
 continue hydrocortisone 6 hourly until the patient is stable. No fludrocortisone is 
required because high cortisol exerts weak mineralocorticoid action 
 oral replacement may begin after 24 hours and be reduced to maintenance over 3- 4 
days 
 
Wolman ’s syndrome is characterised by primary adrenal failure, hepatosplenomegaly, and  
steatorrhoea.

steatorrhoea.  
 
Waterhouse-Friderichsen syndrome  is bilateral adrenal haemorrhage occurring due to massive 
septicaemia, often associated with severe, life-threatening meningococcal disease. It can prese nt, 
with tiredness, lethargy and postural hypotension a short period after discharge fro m hospital 
following the precipitating illness. 
 
Conditions associated with hyponatraemia and hyperkalaemia:

 Carbenoxolone therapy due to pseudohypoaldosteronism through inhibition of th e enzyme 11 
beta hydroxysteroid dehydrogenase. 
 Type IV renal tubular acidosis is associated with hyporeninaemic hypoaldosteronism and both 
hyponatraemia and hyperkalaemia can occur. 
 Hypoadrenalism  
 Co-amilofruse, the combination of amiloride and furosemide 
 cardiac failure, hepatic and renal failure. 
Secondary hypoadrenalism

Secondary hypoadrenalism   
 adrenal hypofunction due to a lack of adrenocorticotropic hormone (ACTH) 
 Causes 
 panhypopituitarism,  
 pituitary tumors 
 craniopharyngioma (in youngers) 
 irradiation 
 Exogenous glucocorticoid therapy (by any route, including high doses of inhaled, intra-
articular, or topical), or after corticosteroids are stopped.  297

119 
  Patients receiving corticosteroids for > 4 wk may have insufficient ACTH 
secretion during metabolic stress to stimulate the adrenals to produce adequate 
quantities of corticosteroids, or they may have atrophic adrenals that are 
unresponsive to ACTH. These problems may persist for up to 1 yr after

corticosteroid treatment is stopped.  
 Inadequate ACTH can also result from failure of the hypothalamus to stimula te pituitary 
ACTH production, which is sometimes called tertiary adrenal insufficiency. 
 Feature  
 Symptoms and signs are similar to those of Addison disease 
 Differentiating features  include: 
 absence of hyperpigmentation 
 relatively normal electrolyte and BUN levels; hyponatremia, if it occurs, is usually 
dilutional.

dilutional. 
 Patients with panhypopituitarism have depressed thyroid and gonadal function 
and hypoglycemia.  
 Adrenal crisis is likely if a patient is treated with thyroxine, without 
hydrocortisone replacement. 
Confirmatory Serum Testing for Secondary Adrenal Insufficiency 
Test Result 
ACTH Low (< 5 pg/mL) 
Cortisol Low (< 5 μg/dL [138 nmol /L]) 
ACTH stimulation test Normal or subnormal 
Prolonged (24-h) ACTH stimulation test Cortisol should continue to rise for 24 h

 ACTH stimulation testing 
 done by injecting cosyntropin (synthetic ACTH) 250 mcg IV or IM followed by 
measurement of serum cortisol levels.  
 Some authorities believe that in patients with suspected secondary adrenal 
insufficiency, a low-dose ACTH stimulation test using 1 mcg IV instead of the 
standard 250 mcg-dose should be done because such patients may react 
normally to the higher dose.  
 Patients taking glucocorticoid supplements or spironolactone should not take

them on the day of the test. 
 A normal response to cosyntropin may occur in secondary adrenal insufficiency. 
However, because pituitary failure may cause adrenal atrophy (and hence failure 
to respond to ACTH), the patient may need to be primed with long-acting ACTH 1 
mg IM once/day for 3 days before the ACTH stimulation test if pituitary disease is 
suspected. 
 prolonged ACTH stimulation test  (sampling for 24 h)

 may be used to diagnose secondary (or tertiary, ie, hypothalamic) adrenal 
 Cosyntropin 1 mg IM is given, and cortisol is measured at intervals for 24 
h, typically at 1, 6, 12, and 24 h.  298

120 
  Results for the first hour are similar for both the short (sampling stopped 
after 1 h) and prolonged tests, 
 in Addison disease there is no further rise beyond 60 min.  
 In secondary and tertiary adrenal insufficiency, cortisol levels 
continue to rise for ≥ 24 h.

continue to rise for ≥ 24 h.  
 Only in cases of prolonged adrenal atrophy is adrenal priming (with long-
acting ACTH) necessary.  
 The simple short test is usually done initially , because a normal 
response obviates the need for further investigation. 
 If adrenal crisis is suspected, confirmation of Addison disease by ACTH 
stimulation testing is deferred until the patient has recovered. If ACTH 
stimulation testing is done, elevated ACTH levels together with low cortisol

levels confirm the diagnosis. 
 CT or MRI of the brain to rule out a pituitary tumor or pituitary atrophy. 
Corticosteroids 
  
 Corticosteroids are hydrophobic small molecules and thus freely pass through cell 
membranes. They bind to inactive cytosolic glucocorticoid receptors, which then translocate to 
the nucleus to act as nuclear transcription regulators.

The relative glucocorticoid and mineralocorticoid activity of commonly used  steroids is shown 
below: 
 
Minimal 
glucocorticoid 
activity, very high 
mineralocorticoid 
activity, Glucocorticoid 
activity, high 
activity, Predominant glucocorticoid 
activity, low 
mineralocorticoid activity Very high glucocorticoid 
activity, minimal 
mineralocorticoid activity 
Fludrocortisone Hydrocortisone Prednisolone Dexamethasone 
Betmethasone 
Side-effects

Side-effects  
 The side-effects of corticosteroids are numerous and represent the single greatest limitation  on 
their usage.  
 Side-effects are more common with systemic and prolonged therapy. 
 Glucocorticoid side-effects  
 endocrine: 
299

121 
  impaired glucose regulation,  
 increased appetite/weight gain,  
 hirsutism,  
 hyperlipidaemia 
 Cushing's syndrome: moon face, buffalo hump, striae 
 musculoskeletal:  
 osteoporosis,  
 proximal myopathy,  
 avascular necrosis of the femoral head 
 immunosuppression:

 increased susceptibility to severe infection,  
 reactivation of tuberculosis 
 psychiatric:  
 insomnia,  
 mania,  
 depression,  
 psychosis 
 gastrointestinal:  
 peptic ulceration,  
 acute pancreatitis 
 ophthalmic:  
 glaucoma,  
 cataracts 
 suppression of growth in children 
 intracranial hypertension 
 Mineralocorticoid side-effects 
 fluid retention 
 
The pathogenesis of corticosteroid induced osteoporosis is multifactorial:

1. Corticosteroids reduce osteoblastic activity , and the resulting osteoblast/osteoclast 
imbalance causes loss of bone. 
2. Corticosteroids reduce intestinal calcium absorption  and lower circulating sex steroid 
levels.  
Selected points on the use of corticosteroids: 
 patients on long-term steroids should have their doses doubled during intercurrent illne ss 
 For milder concurrent illnesses oral prednisolone is usually doubled for a few days.

 For sever illness convert prednisolone temporarily to IV glucocorticoids , 
conventionally 50-100 mg of hydrocortisone six hourly.  
 Mineralocorticoid dose is always left unchanged.  300

122 
  the BNF suggests gradual withdrawal of systemic corticosteroids if patients have: received 
more than 40mg prednisolone daily for more than one week, received more than 3 w eeks 
treatment or recently received repeated courses 
 Low dose i.v hydrocortisone  improve outcome in sepsis

 More recent randomised controlled trials have suggested that there is a benefit in sepsis 
when lower physiological doses of steroids are given. 
 Lactose-containing methylprednisolone preparations should not be used in patients 
with cows' milk allergy 
 Corticosteroids are recognised to inhibit osteoblast activity and increase osteoblast 
apoptosis . This is thought to be a more important component in bone loss with respect to

steroid induced osteoporosis versus any effect on osteoclasts. 
 Whilst corticosteroids do increase osteoclast activity, it is thought to be their effect on 
osteoblast activity which has a greater impact on bone mineral density. 
 Steroid induced hypogonadism  
• Body builders may be involved in the illicit use of anabolic and androgenic steroids . These 
results are consistent with ongoing use of androgens.

• The hypogonadism, if persistent, may be treated with human chorionic gona dotropin.  
Relative potencies of the glucocorticoids  
• It is important to know the relative potencies of the glucocorticoids. 
• 1 mg prednisolone is equivalent  to 4 mg of hydrocortisone  
• Dexamethasone for instance is roughly 30 times more potent than hydrocortisone. 
 
Steroid doses  equivalence  
 1mg prednisolone = 4mg hydrocortisone 
 1mg dexamethasone = 7mg prednisolone

 1mg dexamethasone = 7mg prednisolone 
 Dexamethasone is roughly 30 times more potent than hydrocortisone. 
 
May 2012 exam: Which effect is linked to long-term steroid use?  Avascular necrosis (Long-term 
corticosteroid use is linked to osteopaenia and osteoporosis, rather than osteomalacia)  
Anabolic steroids 
 Anabolic steroids can be taken orally (eg stanozolol) or may have to be injected because of 
their high first-pass metabolism (eg testosterone enantate)

 Among their many unwanted effects, they increase the risk of cardiovascular disease: 
 blood pressure is elevated 
 blood lipid profiles change, with increased LDL-cholesterol and decreased HDL-
cholesterol 
 haematocrit is increased, leading to a prothrombotic tendency, although there is a  
protective decrease in plasma fibrinogen concentrations with prolonged use  
Abuse of androgenic steroids  
 The abuse of androgenic steroids amongst people who practise certain sports is quite

123 
  side effects  
 Paranoid delusions 
 aggressive behaviour. 
 Other side effects of these illicit drugs include: 
 Acne 
 Gynaecomastia (also increase in breast cancer risk) 
 Hypertension 
 Hypercholesterolaemia, and 
 Hepatic tumours. 

Cushing's syndrome (Hypercortisolism) 
 
Pathological definition  
 Cushing's syndrome  hypercortisolism from any cause. 
 Cushing's disease  hypercortisolism caused by ACTH-secreting pituitary adenoma the 
most common cause of Cushing's syndrome (80% of cases). 
Causes 
 ACTH dependent causes (also called Secondary hypercortisolism)  
 pituitary ACTH : Cushing's disease (80%): pituitary tumour secreting ACTH producing 
adrenal hyperplasia

adrenal hyperplasia 
 ectopic ACTH  production (5-10%): e.g. small cell lung cancer 
 weight loss suggests there is an underlying malignancy  ectopic (ACTH) 
 Ectopic ACTH secretion (e.g. secondary to small cell lung cancer) is 
characteristically associated with very low potassium levels.  
 ACTH independent causes (also called Primary hypercortisolism)  
 adrenal adenoma (5-10%)  Undetectable serum adrenocorticotropic hormone 
(ACTH) level  
 adrenal carcinoma (rare)

 adrenal carcinoma (rare)  
 Serum potassium  is most likely to be low in cases of ectopic ACTH or adrenal 
carcinoma. 
 features of virilisation  (development of male physical characteristics (such as 
muscle bulk, body hair, and deep voice) in a female or precociously in a boy, 
typically as a result of excess androgen production) 
 abnormal liver function tests (LFTs)  suggest metastases  
302

124 
  Abdominal ultrasound/CT is a most appropriate next investigation. 
 iatrogenic: steroids 
 Most common cause of hypercortisolism 
 exogenous corticosteroids that causes Cushing syndrome results in decreased 
ACTH, which in turn causes bilateral adrenal atrophy .

 Carney complex: syndrome including cardiac myxoma 
 micronodular adrenal dysplasia (very rare) 
 Pseudo-Cushing's 
 often due to alcohol excess or severe depression  (Obese patients who consume 
alcohol to excess over a prolonged period can acquire a cushingoid appearance ) 
(alcohol-induced Cushing's syndrome ) 
 mechanism may be due to increased CRH secretion or impaired hepatic 
metabolism of cortisol.  
 raised MCV is helpful in this context .

 raised MCV is helpful in this context .  
 usually mild and disappears rapidly during abstinence from alcohol. . 
 causes false positive dexamethasone suppression test or 24 hr urinary free cortisol 
 insulin stress test  is used to differentiate between true Cushing's and pseudo-
Cushing's 
 in pseudo-Cushing's the insulin tolerance test will demonstrate hypoglycaemia 
with a rise in ACTH and cortisol.  
 In Cushing's syndrome, this hypoglycaemia induced response is lost.

 insulin tolerance test is contraindicated in epilepsy, ischaemic heart disease, or 
hypoadrenalism.  
 Management  lifestyle measures to promote weight loss, and strict control of alcohol 
intake.  
Endogenous Cushing's syndrome 
Types Primary hypercortisolism (ACTH-
independent Cushing's syndrome) Secondary hypercortisolism 
Pituitary ACTH productio
n (Cushing's disease) Ectopic ACTH 
production 
frequency  5–10%  ∼ 75%  ∼ 15% 
Sex  ♂ < ♀ (1:4)  ♂ < ♀ (1:4)  ♂ = ♀

Sex  ♂ < ♀ (1:4)  ♂ < ♀ (1:4)  ♂ = ♀ 
Causes  Autonomous overproduction 
of cortisol by the adrenal gland 
ĺACTH  suppression 
 Adrenal adenomas  
 Adrenal carcinoma  
 Macronodular adrenal hyperplasia  Pituitary 
adenomas  ĺ ACTH 
secretion   Paraneoplastic 
syndrome ĺ A
CTH secretion 
 Small cell 
lung cancer  
 Renal cell 
carcinoma 
 303

125 
  
Features 
 Fat redistribution: Truncal obesity, “moon face, ” buffalo hump, thin arms and legs   
 Proximal myopathy , easy bruising  and thin skin are clinical features that are most 
suggestive of Cushing's syndrome.   
 Cortisol breaks down proteins so the free amino acids can be used to make

sugar . Specifically, bone and skin proteins are broken down and made into sugar. This 
leads to bruising, striae, muscle wasting, and osteoporosis. 
 Necrosis of the femoral head due to osteoporosis. 
 Osteoporosis may lead to  Vertebral collapse  
 elevated corticosteroid levels can lead to early development of cataracts . 
 Most commonly  Posterior subcapsular  cataract  
 The predominant feature of a posterior subcapsular cataract is glare when looking into

bright lights, either from the sun or car headlights. 
 Hyperglycemia (Diabetes mellitus may occur in 30%). 
 Cortisol  ↑gluconeogenesis (from protein break down  free amino acids )  
Ĺglucose levels 
 hyperlipidemia 
 Hypertension: From fluid and sodium retention  
 Hirsutism: From increased adrenal androgen levels 
 hypokalaemic metabolic alkalosis  
 caused by increased urinary loss of H+ (acid) 
 Leukocytosis 
 low oestradiol

 low oestradiol  
 in deferential diagnosis: The low oestradiol excludes pregnancy and PCOS   
 in pregnancy oestradiol will be elevated 
 typically in PCOS oestradiol is normal or elevated. 
Disorder  Investigation of choice  
Cushing Overnight Dexamethasone Test 
Cushing- vs. Pseudo-cushing Insulin Stress Test 
Addison Short Synacthen Test 
Pheochromocytoma 24H Urinary metanephrines 
Acromegaly Oral Glucose Tolerance Test 304

126 
  
 Investigations are divided into confirming Cushing's syndrome and then localising the lesion .  
 Tests to confirm Cushing's syndrome (hypercortisolism) : The two most commonly used 
tests are: 
1. overnight dexamethasone suppression test (ODST)  (most sensitive )

 The ODST has a sensitivity and specificity of 98%   
 Failure to suppress cortisol below 50 nmol/L on this test is highly suggestive of 
Cushing's   
 sensitivity and specificity 75-80% in obese  subjects therefor (UFC)  will be 
best than (ODST) in obese 
 If cortisol is not suppressed by the low or high dose dexamethasone suppression 
test then either  
 primary adrenal Cushing's syndrome  (low/undetectable ACTH)  
 or ectopic ACTH  is the cause (high ACTH).

 or ectopic ACTH  is the cause (high ACTH). 
 If cortisol is not suppressed by low dose dexamethasone but is by high dose then 
Cushing's disease  is the likely cause. 
 Interactions with the test: 
 cytochrome p450 inducers false-positive ODST  (meaning that a 
diagnosis of Cushing is suggested incorrectly).  
 Dexamethasone is metabolised by the cytochrome p450 system, 
specifically by the CYP3A4 isoenzyme. 
 Patients need to be off all oestrogen-containing medication for six weeks

prior to any measurements of serum cortisol 
  If (ODST) is not offered in a question then 24 hour urinary free cortisol is the 
next best answer 
2. 24 hr urinary free cortisol (UFC)  
 An ideal initial test  because it can be done as an outpatient and is non-invasive. 
 this test is more likely to give a false negative than an overnight dexamethasone 
suppression test.  
 Because the false-negative rate approaches 10%, it is never used alone as a

screening  test for Cushing syndrome and should be followed by an overnight 
dexamethasone suppression test . 
 If both of these tests  are normal, then Cushing syndrome could be ruled out. 
It is a difficult choice between an overnight dexamethasone suppression test and th e urine free 
cortisol estimation and there are no clear national guidelines regarding which is best. 
However, a recent BMJ article states that  if the clinical suspicion of endogenous Cushing's

syndrome is high then either a 24 hour urinary free cortisol (if the patient has normal rena l function) 
or a late night salivary cortisol are the most likely to make a diagnosis. 
Localisation tests  305

127 
 source of the hypercortisolism: 
 The first step is to measure  ACTH level:  
 ACTH level low : This means the origin is in the adrenal gland   Scan the gland with 
a CT or MRI. 
 ACTH level high : This means the origin is either in the pituitary  gland or from the 
ectopic  production of ACTH.

ectopic  production of ACTH.  
 The next step is a high-dose dexamethasone suppression test. 
 If high-dose dexamethasone suppresses the ACTH , the origin is the  pituitary . Scan 
the pituitary.  
 If high-dose dexamethasone does not suppress the ACTH , the origin is an ectopic 
production of ACTH or a cancer that is making ACTH. Scan the chest for lung cancer or 
carcinoid.  
 
If a 24-hour urine free cortisol is elevated, and there is an inadequate suppression on 1 mg

overnight dexamethasone test in a patient suspected of Cushing syndrome, the next step  would be 
to measure ACTH.  
After the 1 mg overnight test and the 24-hour urine test confirm the prese nce of hypercortisolism, 
then we must determine the location or origin to treat it. 
The first-line localisation is 9 am and midnight plasma ACTH  (and cortisol) levels. If ACTH is 
suppressed then a non-ACTH dependent cause is likely such as an adrenal adenoma

 High-dose dexamethasone suppression test  
 mechanism 
 High doses of dexamethasone send a negative feedback response to the  brain to 
decrease ACTH production. Since the pituitary is receptive to negative feedb ack 
loops but ectopic foci are resistant to negative feedback, cortisol levels will 
decrease to < 50% of baseline  following high doses of dexamethasone if the 
patient has Cushing's disease, but will be relatively unchanged in ectopic ACTH 
production.

production. 
 In the high dose dexamthasone suppression test, classically, the cortisol should 
suppress to 50% of the level found after low dose dexamethasone in cases of 
pituitary dependent CS.  
 However 50% suppression is found on less than 80% of occasions and so 
is far from diagnostic. 
 Explanati on 
 if cortisol suppressed  pituitary source 
 if no change in cortisol  ectopic/adrenal  
 CRH stimulation  
 if cortisol rises  pituitary source

 if cortisol rises  pituitary source  
 if no change in cortisol  ectopic/adrenal  
 Inferior Petrosal sinus sampling (IPSS)  306

128 
  (IPSS ) is the only test with sufficient diagnostic accuracy to differentiate 
Cushing's disease from ectopic ACTH production  
 high gradient of ACTH from sinus compared with a peripheral sample is diagnostic of 
pituitary dependent disease.

pituitary dependent disease. 
 Patients with an IPSS central/peripheral gradient >2:1 or 3:1 after corticotrophin-
releasing hormone (CRH) stimulation  Cushing's disease  
 Patients without an IPSS central/peripheral gradient >2:1 or 3:1  ectopic ACTH  do 
CT of the chest, abdomen, and pelvis to look for a tumour secreting ACTH.  
 CT scan and octreotide scintigraphy should be employed when results of IPSS 
suggest an ectopic source.

suggest an ectopic source. 
 The most common tumours that secrete ACTH are bronchial or thymic 
carcinoids. 
 Up to 40% of patients with Cushing's disease will not have visible lesions on 
pituitary/sellar MRI.  
 Patients without definitive lesions on MRI should undergo inferior petrosal sinus 
sampling 
 
Serum cortisol levels would remain unchanged with both low-level and high-level 
dexamethasone testing  due to the lack of glucocorticoid receptors  to facilitate negative

feedback on the ectopic cells producing the ACTH.  Anterior pituitary corticotrophs do have these 
receptors and, therefore, will be suppressed by any dose of dexamethasone. 
 
Diagnostic steps 
 After exclusion of exogenous corticosteroid use, patients with suspected Cushing's 
syndrome should be tested for hypercortisolism with 1 of 4 high-sensitivity tests 
1) late-night salivary cortisol;  
2) 1 mg overnight low-dose dexamethasone suppression testing,

3) 24-hour urinary free cortisol; or  
4) 48-hour 2 mg dexamethasone suppression testing. 
 At least 1 additional test should be used to confirm hypercortisolism in patients with a 
positive initial screening test. 
 Once endogenous hypercortisolism is confirmed, plasma (ACTH)  should be measured.  
 If ACTH is suppressed, diagnostic testing should focus on the adrenal glands.  
 If ACTH is not suppressed, pituitary or ectopic disease should be sought. 
 
 307

129 
  
The differentiation between Cushing's disease and ectopic ACTH secretion  is made by carrying 
out low- and high-dose dexamethasone suppression tests. With Cushing's disease, th e pituitary 
usually remains susceptible to feedback by glucocorticoids but is less sensitive, low-dose

dexamethasone does not suppress cortisol secretion but high-dose dexamet hasone does. In cases of 
ectopic ACTH secretion (and also adrenal tumors), there is usually no response to dexameth asone 
because pituitary ACTH secretion is already maximally suppressed by the high plasma co rtisol levels.  
 
Classically pituitary dependent Cushing ’s disease is differentiated from ectopic ACTH production and 
non-ACTH dependent Cushing ’s by: 
 measurement of plasma ACTH levels and

 measurement of plasma ACTH levels and  
 suppression of plasma cortisol by 50% from baseline after 48 hours of high dose 
dexamethasone. 
  In a normal individual, plasma cortisol suppresses to < 50 nmol/l after 48 hours of 
dexamethasone 0.5 mg 6 hourly.  
 When differentiating pseudo-Cushing ’s from Cushing ’s syndrome a cut off of 38 nmol/l 
at this time point gave 100% specificity for diagnosing Cushing ’s syndrome

 Approximately 10% of subjects with pituitary dependent Cushing ’s may fail to suppress 
however, and a few people with ectopic ACTH production also will.  
 
Which techniques is the best in differentiating between ectopic Cushing's syndrome and 
pituitary dependent Cushing's disease? 
 Inferior petrosal sinus sampling  
 It samples venous blood draining from the pituitary gland, using a femoral approach .  
 A raised ACTH from here compared to the periphery suggests a pituitary cause.

 complication rate is low and is most commonly only groin haematoma. 
 The high-dose dexamethasone suppression test can differentiate between  the two 
forms of Cushing's syndrome, but is not as accurate as inferior petrosal sinus 
sampling. 
 
The following table summarizes the characteristics of the 3 sources of Cushing disease. 
 Pituitary Tumor Ectopic ACTH Production Adrenal Adenoma 
ACTH High High Low 
High-dose 
dexamethasone Suppression No suppression No suppression

Specific test MRI Petrossal vein 
sampling Scan chest and abdomen Scan adrenals  
Treatment                              Removal     
 
 308

130 
  
Which feature would favour benign adrenal adenoma as the cause of Cushing's syndrome 
over the other causes? 
 Absence of hirsutism and virilisation  (adrenal adenoma produces cortisol but not the 
androgens) 
Treatment 
 the initial treatment of choice Trans-sphenoidal hypophysectomy/adenomectomy

 Laparoscopic adrenalectomy would be advised where pituitary surgery has failed. 
 Ketoconazole may be an effective treatment for patients unfit for surgery. 
 The recurrence rate for Cushing's disease after surgery is of the order of 20-30% in most 
series and depends on the size of the tumour with macroadenomas having a h igher rate of 
relapse. 
 
Which drug is most appropriate to improve metabolic parameters prior to surgery 
in pituitary-dependent Cushing's? 
 Metyrapone

 Metyrapone 
 Metyrapone  inhibits 11-beta hydroxylase    inhibits cortisol production. 
 It has rapid onset of action and as such may be of value pre-operatively in improv ing 
BP and glycaemic control without associated weight gain of other options such as 
insulin.  
 Metyrapone can be used as short-term treatment for Cushing ’s syndrome 
before definitive treatment.  
 Metyrapone blocks cortisol synthesis by inhibiting 11 β -hydroxylase.

 This blockade can be measured by the urinary increase of the 
metabolites of cortisol precursors in the urine (17-hydroxycorticosteroids 
[17-OHCS] and 17-ketogenic steroids [17-KGS]).  
 
What is the optimum time for the administration of hydrocortisone to a patient undergoing 
bilateral adrenalectomy for Cushing's disease? 
 Immediately following the removal of both adrenal glands.  
 
May 2008 exam: A 62-year-old man is investigated for hypertension and proximal myopathy.

On examination he is noted to have abdominal striae. Which one of the following is most 
associated with ectopic ACTH secretion? Small cell lung cancer  
 
309

131 
Glucocorticoid resistance syndrome 
 rare  
 due to a mutation of the glucocorticoid receptor.  
 Subjects have high ACTH levels and high cortisol  levels because of lack of negative 
feedback via the glucocorticoid receptors.

feedback via the glucocorticoid receptors.  
 Women may demonstrate the virilising effects of excess androgen secretion under the 
influence of increased ACTH ,  
  may have hypertension  due to the action of salt retaining steroids,  
 but fail to demonstrate the other features of Cushing ’s syndrome such as thinning of the skin 
and myopathy  
Diabetology 
Basics

Basics  
Pancreatic Hormones  
 Islet A cells produce glucagon  
 Islet beta cells produce: 
1. insulin  
2. C peptide 
3. pro-insulin  
4. amylin  
5. GABA 
 Islet D cells produce somatostatin  
 F cells produce pancreatic polypeptide  
Glucose transporters 
Sodium/glucose cotransporter (SGLT) 
 Glucose uptake into the enterocyte from the lumen of the GI tract occurs primarily via the

sodium-dependent  SGLT-1  secondary active transport mechanism.  
  SGLT-1 is a transporter found predominantly in the gut, and is responsible for glucose  
absorption. 
 The Na+-glucose cotransporter also transports galactose. Thus, when the cotransporter 
is congenitally defective, the resulting glucose and galactose malabsorption causes 
severe diarrhea that can be fatal if glucose and galactose are not removed from t he diet.  
 Function

 Function 
 transport glucose actively across lumen against concentration gradient 
 energy provided by transport of sodium down its concentration gradient 
 location 
 small intestine (SGLT1)   2:1 Na+:Glu 310

132 
  proximal tubule of nephron (SGLT2)   1:1 Na+:Glu 
 Glucose exit from the enterocyte into the extracellular fluid occurs by facilitated diffusion and  is 
mediated by the membrane transporter, Glut-2 . 
GLUT-1 
 function 
 basal glucose uptake (GLUT1 and GLUT3 continually transport glucose into cells at an

essentially constant rate.) 
 high affinity 
 transporters saturated at normal blood glucose levels 
 ensures glucose entry to cells 
 location 
 wide distribution in tissues in the body (brain, erythrocytes, endothelial cells, cornea 
etc.) 
 especially  expressed in cells with barrier functions, such as Blood- Brain barrier, blood-
retinal barrier, blood placental barrier, blood testes barrier 
 most importantly it is expressed in erythrocytes. 
GLUT-2

GLUT-2 
 GLuT 2 is a glucose transporter expressed in pancreatic beta cells .  
 It is a fundamental part of the glucose sensing apparatus in the pancreatic beta cells a nd helps 
trigger insulin release in response to increasing glucose concentrations in the extracellular 
fluid. 
 GluT 2 is also expressed in hepatocytes and may act as a glucose sensor in the portal v ein 
system.  
 It may have a role in regulating glucagon secretion and feeding behaviour. 
 function

 function 
 low affinity glucose uptake ( high-capacity but a low affinity transporter)  
 in the fasting state glucose does not enter cells 
 mediates glucose surplus storage in liver when blood glucose levels rise 
 facilitates insulin release in β-cells 
 location 
 hepatocytes 
 pancreatic β -cells 
 kidney 
 small intestines 
In healthy individuals, which glucose transporter is required for triggering insulin secretion i n response 
to elevated blood glucose concentration?

to elevated blood glucose concentration? 
 GluT 2 
 
GLUT-3 
 function 
 high affinity glucose uptake 
 glucose preferentially accessed by neurons in low-glucose states 311

133 
  location 
 brain 
 neurons 
GLUT-4 
  GLUT-4 is the only glucose transporter that is responsive to circulating insulin levels.  
 Ĺplasma glucose concentration  Ĺcirculating insulin   Ĺexpression of GLUT-4  
Ĺglucose transport into the cell.

Ĺglucose transport into the cell. 
  The other types of glucose receptors (GLUT-1,2,3,&5) are not responsive to circulating 
insulin levels 
 exogenous insulin in the treatment of diabetes mellitus results in increased glucose 
uptake via the GLUT-4 transporter.  
 This high-affinity glucose transporter plays a crucial role in avoiding postprandial 
hyperglycemia, since insulin secreted by the pancreatic beta cells promotes glucose 
uptake into myocytes. 
 function

 function 
 insulin-controlled uptake of glucose  
 basal level of glucose intake without insulin 
 presence of insulin Ĺ translocation of transporters to the cell membrane  
 ĹĹĹ glucose uptake  
 also stimulated by exercise 
 location 
 adipocytes 
 myocytes 
 cardiomyocytes 
 
312

134 
  
Which glucose transporter is responsible for assisting glucose across the plasma 
membrane in myocytes? 
 GLUT 4  
 
Glut-5   
 located on the apical portion of the enterocyte  
 function:  entry of fructose  into the cell.

 Glut-1 and Glut-3  have a very low Km (less than 1 mM). It means that they have high affinity 
for glucose ,so even in situation of relative hypoglycemia they can continue transporting 
glucose to the brain.   
 Glut 2 , in liver, has a Km of about 15 mM, so it works properly when glucose concentration 
in blood is high  (like in postpandrial situations; recall that after meals blood arrives first to 
liver through the portal system). 
 GLUT-1 = BBB (Blood- Brain barrier)

 GLUT-1 = BBB (Blood- Brain barrier) 
 GLUT-3 = "Brain" 
 
Glycaemic index 
 The glycaemic index (GI) describes the capacity of a food to raise blood glucose compared 
with glucose in normal glucose-tolerant individuals.  
 Foods with a high GI may be associated with an increased risk of obesity and the post-pr andial 
hyperglycaemia associated with such foods may also increase the risk of type 2 diabete s 
mellitus.

mellitus.   
 
Classification Examples 
High GI White rice (87), baked potato (85), white bread (70) 
Medium GI Couscous (65), boiled new potato (62), digestive biscuit (59), brown rice (58) 
Low GI Fruit and vegetables, peanuts 
 
The glycaemic index is shown in brackets. Glucose, by definition, would have a glycaemic inde x of 
100 
 
____________________________________________________________  313

135 
 Metabolic syndrome 
 
The cardinal features of the metabolic syndrome include: 
 the hypertension 
 central adiposity 
 hyperlipidaemia 
 fatty liver  
 pre-diabetes.  
 It is thought that the key pathophysiological factor is insulin resistance. 
Diagnostic criteria

 SIGN  recommend using criteria similar to those from the American Heart Association . The 
similarity of the International Diabetes Federation criteria should be noted.  
 For a diagnosis of metabolic syndrome at least 3 of the following should be identified: 
1. elevated waist circumference: men > 102 cm, women > 88 cm 
2. elevated triglycerides: > 1.7 mmol/L 
3. reduced HDL: < 1.03 mmol/L in males and < 1.29 mmol/L in females

4. raised blood pressure: > 130/85 mmHg, or active treatment of hypertension 
5. raised fasting plasma glucose > 5.6 mmol/L, or previously diagnosed type 2 diabetes 
 The International Diabetes Federation  produced a consensus set of diagnostic criteria in 
2005, which are now widely in use .  
 These require the presence of central obesity (defined as waist circumference > 94cm 
for Europid men and > 80cm for Europid women, with ethnicity specific values for other

groups) plus any two of the following four factors: 
1. raised triglycerides level: > 1.7 mmol/L, or specific treatment for this lipid 
abnormality 
2. reduced HDL cholesterol: < 1.03 mmol/L in males and < 1.29 mmol/L in females, 
or specific treatment for this lipid abnormality 
3. raised blood pressure: > 130/85 mm Hg, or active treatment of hypertension 
4. raised fasting plasma glucose > 5.6 mmol/L , or previously diagnosed type 2 
diabetes

diabetes 
 In 1999 the World Health Organization  produced diagnostic criteria which required  
 the presence of diabetes mellitus, impaired glucose tolerance, impaired fasting g lucose 
or insulin resistance, AND two of the following: 
1. blood pressure: > 140/90 mmHg 
2. dyslipidaemia: triglycerides: > 1.695 mmol/L and/or high-density lipoprotein 
cholesterol (HDL-C) < 0.9 mmol/L (male), < 1.0 mmol/L (female)

3. central obesity: waist:hip ratio > 0.90 (male), > 0.85 (female), and/or body mass 
index > 30 kg/m2 
4. microalbuminuria: urinary albumin excretion ratio > 20 mg/min or 
albumin:creatinine ratio > 30 mg/g 314

136 
  The ATP III criteria (2001):  three of these five criteria must be present to diagnose metabolic 
syndrome. 
 
NECP ATP IIIM Male Female 
Waist circumference ≥ 102 cm  ≥ 88 cm  
Blood pressure ≥ 130/85 mmHg  ≥ 130/85 mmHg  
HDL ≤1.03 mmol/L  ≤1.29 mmol/L  
≤40 mg/dL  ≤ 50 mg/dL

≤40 mg/dL  ≤ 50 mg/dL  
Triglyceride ≥ 1.7 mmol/L  ≥ 1.7 mmol/L  
≥ 150 mg/dL  ≥ 150 mg/dL  
Fasting glucose ≥ 6.1 mmol/L  ≥ 6.1 mmol/L  
≥ 110 mg/dL  ≥ 110 mg/dL  
 Other associated features include: 
 raised uric acid levels 
 non-alcoholic fatty liver disease 
 polycystic ovarian syndrome 
 the most appropriate strategy to reduce the future risk of developing diabetes mellitus  
is  Treatment with orlistat and diet

is  Treatment with orlistat and diet   
 The XENDOS study revealed that orlistat, in combination with diet, will reduce the risk 
of diabetes in these obese patients by 38% more than just diet alone plus placebo . 
 
 315

137 
  
Pre-diabetes and impaired glucose regulation (IGR) 
 
 normal Prediabetes Diabetes mellitus 
Fasting glucose   ≤ 6 mmol/l  ≥ 6.1 –  6.9 mmol/l 
impaired fasting glucose (IFG) ≥ 7 mmol/l  
2h glucose 
during an OGTT < 7.8 mmol/l 7.8 -n 11 mmol/l

during an OGTT < 7.8 mmol/l 7.8 -n 11 mmol/l 
Impaired glucose tolerance (IGT) ≥ 11.1 mmol/l 
HA1c < 42 mmol/mol 
< 6% 42 – 47 mmol/mol 
(6.0 – 6.4%) ≥ 6.5%  
NICE however classifies those at "High Risk" of Type 2 Diabetes as: 
 fasting plasma glucose of 5.5-6.9 mmol/l or  
 HbA1c of 42-47 mmol/mol [6.0-6.4%] 
 
Prediabetes 
 Definition :  
 impaired glucose levels which are above the normal range but not high enough for a 
diagnosis of diabetes mellitus.

diagnosis of diabetes mellitus.  
 Includes impaired fasting glucose (IFG) and impaired glucose tolerance (IGT).  
 Terminology  
 Diabetes UK currently recommend using the term prediabetes when talking to patients 
and impaired glucose regulation (IGR) when talking to other healthcare professionals 
 Types:  
 Impaired fasting glucose (IFG)  
 Definition  fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l  
 Mechanism  due to hepatic insulin resistance

 Mechanism  due to hepatic insulin resistance  
 people with IFG should then be offered an oral glucose tolerance test (OGTT) to 
rule out a diagnosis of diabetes.  
 Impaired glucose tolerance (IGT)  
 Definition  fasting plasma glucose less than 7.0 mmol/l and OGTT 2-hour value 
greater than or equal to 7.8 mmol/l but less than 11.1 mmol/l 
 Mechanism  due to muscle  insulin resistance 
 patients with IGT are more likely to develop T2DM and cardiovascular disease

than patients with IFG 
 The risk of progression from (IGT) to frank diabetes is 20- 30% within 5 
years. 
 Incidence:   316

138 
  Diabetes UK estimate that around 1 in 7  adults in the UK have prediabetes.  
 Many individuals with prediabetes will progress on to developing type 2 diabetes 
mellitus (T2DM) and they are therefore at greater risk of microvascular and 
macrovascular complications.

macrovascular complications. 
 What would be the risk of developing type 2 diabetes in patient with (IGT)?  
 60% over 6 years  
 This increased to 64.5% if individuals had both (IGT) and (IFG).  
 
 Identification of patients with prediabetes 
 Who should be assessed for the risk of type 2 diabetes? 
 all adults aged 40 and over,  
 people of South Asian and Chinese descent aged 25-39,  
 adults with conditions that increase the risk of type 2 diabetes:

 cardiovascular disease, stroke, hypertension,  
 obesity,  
 polycystic ovary syndrome,  
 history of gestational diabetes 
 mental health problems. 
The best way to reduce the incidence of type 2 diabetes in individuals with IGT is  
Intensive lifestyle change  
 
 lifestyle modification: weight loss, increased exercise, change in diet 
 intensive diet and lifestyle change ( that results in loss of approximately 5% of

initial body weight ) can reduce progression from impaired fasting glucose (or 
impaired glucose tolerance) to frank type 2 diabetes by approximately 50%.  
 at least yearly follow-up with blood tests is recommended 
 NICE recommend metformin for adults at high risk 'whose blood glucose measure 
(fasting plasma glucose or HbA1c) shows they are still progressing towards type 2 
diabetes, despite their participation in an intensive lifestyle-change programme'

 As well as demonstrating a reduction in risk of new onset type 2 diabetes of 25%,  
acarbose  was associated in the STOP-NIDDM study with a 49% reduction in 
cardiovascular events.  
 Metformin and pioglitazone have not been shown to reduce cardiovascular disease  in 
impaired glucose tolerance.  
 
Which drug classes is most well known as a cause of impaired glucose tolerance? 
 Atypical antipsychotics  
 
 317

139 
  
Both typical antipsychotics and antihypertensives (thiazides and beta blockers), have been 
shown in meta-analyses to be associated with impaired glucose tolerance and increased 
risk of type 2 diabetes. 
The risk is relatively larger for risperidone than thiazides & β.blocker

September 2009 exam: The fasting glucose of asymptomatic patient comes back as 6.5 
mmol/l. The test is repeated and reported as 6.7 mmol/l. How should these results be 
interpreted? Impaired fasting glycaemia  
Diabetes mellitus 
Types of diabetes mellitus   
Type Notes 
Type 1 diabetes 
mellitus (T1DM)   5–10% of cases  
 Caused by autoimmune B-cell destruction.  
Type 2 diabetes 
mellitus (T2DM)   90% of cases

mellitus (T2DM)   90% of cases  
 caused by a relative deficiency of insulin  
 defective insulin secretion, usually with defective insulin action.  
Prediabetes   patients who don't yet meet the criteria for a formal diagnosis of 
T2DM to be made but are likely to develop the condition over the next 
few years.  
Gestational diabetes   raised glucose levels during pregnancy.  
Maturity onset 
diabetes of the young 
(MODY)  Genetic defects of B-cell function

(MODY)  Genetic defects of B-cell function  
 Results in younger patients developing symptoms similar to those with 
T2DM, i.e. asymptomatic hyperglycaemia with progression to more 
severe complications such as diabetic ketoacidosis 
Latent autoimmune 
diabetes of adults 
(LADA)   patients who develop autoimmune DM later in life.  
 often misdiagnosed as having T2DM 
 
 318

140 
 Type Notes 
Ketosis-prone 
diabetes (KPD)  presents with DKA or ketosis, but insulin requirements decline over 
weeks l months, and insulin can often be stopped.  
 Most commonly seen in patients of African origin who are antibody 
 –ve.  
 Patients should be advised that they may develop ketosis again during

illness and be given ketone-monitoring equipment. 
Secondary diabetes   Diseases of the exocrine pancreas  
 Pancreatitis, trauma, pancreatectomy, neoplasia,  
 pancreatic destruction (including cystic fibrosis and 
haemochromatosis)  
 Drug-induced: 
 Thiazide diuretics 
 Beta-blockers 
 Antipsychotics 
 Statins  
 thyroid hormone,  
 diazoxide, may act directly to increase glucose production 
and inhibit glucose uptake. 
 G-interferon  chronic type 1 diabetes

 G-interferon  chronic type 1 diabetes   
 antiretroviral treatment (HIV).  
 Polycystic ovary syndrome (PCOS) 
 Cushing's syndrome 
 Infections: Congenital rubella, cytomegalovirus (CMV), others.  
 
Genetic syndromes 
associated with 
diabetes 
  Down ’s syndrome, Klinefelter ’s syndrome, Turner ’s syndrome,  
 Wolfram syndrome (or DIDMOAD —diabetes insipidus, DM, optic 
atrophy, and sensorineural deafness),  
 Friedreich ’s ataxia, Huntington ’s chorea, Lawrence –Moon –Biedl

syndrome, myotonic dystrophy, Prader –Willi syndrome, others. 
 
Type 1 DM Type 2 DM 
 Weight loss  
 Polyuria   Often picked up incidentally on routine 
blood tests 
 Polydipsia 319

141 
 Type 1 DM Type 2 DM 
 May present with diabetic ketoacidosis 
 abdominal pain 
 vomiting 
 reduced consciousness level  Polyuria 
 Remember that the polyuria and polydipsia is due to water being 'dragged' out of the body due to the

osmotic effects of excess blood glucose being excreted in the urine (glycosuria). 
Aetiological diagnosis in diabetes diagnosed 
 
320

142 
Type 1 DM 
 Type 1 diabetes accounts for about 5% to 10% of all patients with diabetes.  
 more common in Europeans and less common in Asians. 
 Mechanism 
 autoimmune disease 
 antibodies against beta cells of pancreas

 antibodies against beta cells of pancreas 
 primarily T cell mediated disorder.  
 Type 1 diabetes becomes clinically evident upon destruction of approximately 70-
80 % of beta cell mass. 
 HLA DR4 > HLA DR3 
 Enteroviruses may play a role in both protection from and susceptibility to type 1 
diabetes.  
 antibodies  detected in patients who later go on to develop type 1 DM:  
 glutamic acid decarboxylase (GAD) antibody 
 found in 70-90% of type1 diabetics.

 found in 70-90% of type1 diabetics. 
 The presence of GAD autoantibodies  signifies a 10 fold increased risk of 
developing IDDM. 
 10% of adults who have been classified as having type 2 diabetes may 
have circulating islet cell antibodies or antibodies to glutamic acid 
decarboxylase (GAD), indicating autoimmune destruction of beta cells. 
 islet cell antibodies (ICA)  
 antibodies to insulin (IAA)  
 ZnT8 is found within the beta cell; whilst ZnT8 autoantibodies are often positive

in patients with type 1 diabetes, it is not invariable. 
 Risk of development of diabetes over a five year period.  
 The presence of autoantibodies such as IA2 and ZnT8 is associated with around a 50 % 
risk of development of diabetes over a five year period. This is less than the risk of 
development of diabetes with loss of first phase insulin response, which is nearer to 
100% over two years. 
 Conventionally, anti-GAD and anti-IA2 antibodies are measured to support the 
diagnosis.

 Which feature  is most closely associated with the imminent development of type 
1 diabetes? 
 Loss of first phase insulin response  
 100% of subjects with loss of first phase insulin response and anti-IA2 
antibodies progressing to type 1 diabetes within 2 years.  
 When weighing up which of the possible answers has the greatest 
contribution to the risk of diabetes development, it's important to 
remember that individuals may remain antibody positive for many

years before developing T1DM,  but the loss of first phase insulin 321

143 
 response is an indicator of significant impending beta cell 
destruction.  
 Loss of second phase insulin response is associated with a risk of 
diabetes intermediate between autoantibodies alone, and loss of first 
phase insulin response. 
 Genetics  
 Only 10% of patients have a positive family history

 Genetic risks for developing diabetes  
 if your mother has type 1 diabetes  2-3% 
 if your father has type 1 diabetes  3–6% 
  the risk of Type 1 diabetes in offspring in families where both parents have the 
disease   around 40%. 
 Offspring of parents who both have Type 1 diabetes have a tendency to  develop 
the disease at a younger age than their parents. 
 if a sibling (brother or sister) has type 1 diabetes  5–6%

 if one identical twin has type 1 diabetes,  the risk in the unaffected twin  30-50%.  
 
 Features 
 ketosis 
 rapid weight loss 
 age of onset below 50 years 
 BMI below 25 kg/m2 
 Personal and/or family history of autoimmune disease.  
 
 Consider C-peptide and/or diabetes-specific autoantibody titres if: 
 atypical features (for example, age 50 years or above, BMI of 25 kg/m2 or above, 
slow evolution of hyperglycaemia or long prodrome) or

 suspicion of monogenic form of diabetes (MODY) (test may guide the use of 
genetic testing)  
 Ļ C-peptide levels indicate an absolute insulin deficiency ĺ type 
1 diabetes 
 Ĺ C-peptide levels may indicate insulin 
resistance and hyperinsulinemia ĺ type 2diabetes 
 
 HbA1c  
 should be monitored every 3-6 months 
 adults should have a target of HbA1c level of 48 mmol/mol (6.5%) or lower.  
 NICE do however recommend taking into account factors such as the

person's daily activities, aspirations, likelihood of complications, 
comorbidities, occupation and history of hypoglycaemia 322

144 
  
 A diagnosis of type 1 diabetes can still reduce the life expectancy of patients b y 13 
years and the micro and macrovascular complications are well documented. 
Diabetes mellitus: management of type 1 (NICE guidelines 2015)

In newly diagnosed adults with type 1 diabetes, the first-line insulin regime should be a basal –
bolus using twice-daily insulin detemir  
 Diet 
 Do not advise adults with type 1 diabetes to follow a low glycaemic index diet for bloo d 
glucose control.  
 
 Frequency of self-monitoring of blood glucose 
 recommend testing at least 4 times a day, including before each meal and before bed. 
 more frequent monitoring is recommended if frequency of hypoglycaemic episodes

increases; during periods of illness; before, during and after sport; when planning 
pregnancy, during pregnancy and while breastfeeding.  
 Referral indication for islet or pancreas transplantation 
 type 1 diabetes with recurrent severe hypoglycaemia that has not responded to o ther 
treatments  
 type 1 diabetes with suboptimal diabetes control who have had a renal transplant an d 
are currently on immunosuppressive therapy. 
 Awareness of hypoglycaemia

 Awareness of hypoglycaemia 
 Assess awareness of hypoglycaemia at each annual review. Use the Gold score or 
Clarke score to quantify awareness of hypoglycaemia 
 Thyroid disease monitoring 
 Measure (TSH) levels in adults with type 1 diabetes at annual review. 
 Targets 
Test  Targets 
HbA1c ≤ 48 mmol/mol (6.5%) 
fasting plasma glucose 5–7 mmol/litre on waking   
4–7 mmol/litre before meals  
plasma glucose at least 90 minutes after eating 5–9 mmol/litre

during surgery or acute illness 5–8 mmol/litre 
blood pressure 135/85 mmHg 
 
 Type of insulin 
 offer multiple daily injection basal –bolus insulin regimens , rather than twice-daily 
mixed insulin regimens, as the insulin injection regimen of choice for all adults  323

145 
  twice-daily insulin detemir is the regime of choice.  Once-daily insulin glargine or 
insulin detemir is an alternative 
 offer rapid-acting insulin analogues  injected before meals, rather than rapid-acting 
soluble human or animal insulins, for mealtime insulin replacement for adults with type 1 
diabetes

diabetes 
 insulin dose 
 normal insulin requirements are around 0.5 –0.6 units/kg/day, split equally between 
background (basal) and mealtime (bolus) requirements 
 dose adjustments 
 Reduce evening basal insulin after alcohol or exercise by 25 –50%. 
 Metformin 
 NICE recommend considering adding metformin if the BMI ≥ 25 kg/m² 
Type 2 DM 
 greater incidence among those of black and South Asian origin.

 Most are over 40yrs, but teenagers are now getting type 2 DM 
 Caused by a relative deficiency of insulin and the phenomenon of insulin resistance.  
 The presence of amyloid polypeptide on pancreatic histology is highly suggestive 
of type 2 diabetes.  
 amyloid deposition is associated with reduced islet cell number and 
function.  
 ↑Plasminogen activator inhibitor 1 ( ↑in obesity &  ↓ in weight loss  insulin 
resistance  type 2 diabetes mellitus.

resistance  type 2 diabetes mellitus. 
 Haemochromatosis is an example of secondary diabetes  
 Adiponectin secretion by adipocytes tends to be reduced and peripheral resistance 
to its actions increases among obese individuals.  
 Adiponectin is secreted by adipocytes and is involved in lipid catabolism, 
improved insulin response, decreased risk of atherosclerosis, and reduced 
inflammatory markers in diabetic patients.

inflammatory markers in diabetic patients.  
 It is inversely correlated with the risk for diabetes and lower levels are present 
with worsening levels of insulin resistance in diabetic patients.  
 Risk factors 
 Age, obesity and ethnicity are important risk factors.  
 Genetics 
 Genetic risks for developing diabetes 
 Concordance between identical twins is higher in type 2 diabetes mellitus 
than type 1 
 if one identical twin has type 2 diabetes, the risk in the unaffected twin 

146 
  TCF7L2 ( Transcription factor 7-like 2 protein) in chromosome 10q has the largest effect 
on type 2 diabetes risk 
 
Beta cell mass  
 Compared with subjects with normoglycaemia,  
 beta cell mass is reduced by 50% in subjects with Impaired Fasting Glucose,  
 by 65% in subjects with Type 2 diabetes , and

 by 65% in subjects with Type 2 diabetes , and  
 over 90% in subjects with type 1 diabetes.  
 
Immunosuppression in poorly controlled diabetes  
 Immunosuppression with susceptibility to infection is an inevitable consequence of poorly 
controlled diabetes mellitus.  
 Impaired neutrophil chemotaxis and phagocytosis is the most important mechanism of 
immunosuppression in diabetes  and would certainly cause an increased propensity for 
bacterial infections, such as the recurrent UTIs

bacterial infections, such as the recurrent UTIs 
Polyuria: 
 Polyuria is urine excretion of more than 40 mL/kg  body weight per day. 
 Polydipsia is defined as water intake of more than 100 mL/kg/day.  
Causes 
Common (>1 in 10) Infrequent (1 in 100) 
 Rare (1 in 1000) 
 Very rare (<1 in 10 000) 
 
 diuretics, caffeine & 
alcohol 
 lithium 
 heart failure  hypercalcaemia 
 hyperthyroidism

 hyperthyroidism 
  chronic renal 
failure 
 primary 
polydipsia 
 hypokalaemia  diabetes insipidus 
 
There are four mechanisms , which can cause polyuria .  
1. Increased intake of fluids as in psychogenic causes, stress and anxiety 
2. Increased GFR as in hyperthyroidism, fever, hypermetabolic states 
3. Increased output of solutes as occurs in DM, hyperthyroidism, hyperparathyroidism, use of 
diuretics (which present more solute at the DCT)

diuretics (which present more solute at the DCT) 
4. Inability of the kidney to reabsorb water in DCT as in CDI, NDI, drugs and chronic renal failure 
(CRF). 
 thiazide diuretic abuse    polyuria and polydipsia of recent onset + high calcium, glucose 
and hypokalaemia, with an elevated bicarbonate.  ĹSerum Osmolality > 300  
 
 325

147 
  
Diabetes mellitus (type 2): diagnosis 
 
 The diagnosis of type 2 diabetes mellitus can be made by either a plasma glucose or a Hb A1c 
sample.  
 Diagnostic criteria vary according to whether the patient is symptomatic (polyuria, polydipsia

etc) or not. 
 If the patient is symptomatic:  
 fasting glucose greater than or equal to 7.0 mmol/l 
 random glucose greater than or equal to 11.1 mmol/l (or after 75g oral glucose 
tolerance test) 
 If the patient is asymptomatic,   
 the above criteria apply but must be demonstrated on two separate occasion s. 
 If the fasting or random values are not diagnostic, the two hour value should be 
used.  
 Diabetes UK suggests :'People with IFG should then be offered an oral glucose

tolerance test to rule out a diagnosis of diabetes. A result below 11.1 mmol/l but 
above 7.8 mmol/l indicates that the person doesn't have diabetes but does have  
IGT.' 
 WHO guidance on the use of HbA1c on the diagnosis of diabetes: 
 a HbA1c of greater than or equal to 6.5% (48 mmol/mol) is diagnostic of diabetes 
mellitus 
 a HbAlc value of less than 6.5% does not exclude diabetes (i.e. it is not as sensitive as 
fasting samples for detecting diabetes)

fasting samples for detecting diabetes) 
 in patients without symptoms, the test must be repeated to confirm the diagn osis 
 it should be remembered that misleading HbA1c results can be caused by increased 
red cell turnover (see below) 
 Conditions where HbA1c may not be used for diagnosis: 
 haemoglobinopathies 
 haemolytic anaemia 
 untreated iron deficiency anaem ia 
 suspected gestational diabetes 
 children 
 HIV 
 chronic kidney disease 
 patients who are acutely ill,  
326

148 
  patients taking steroids or antipsychotics (which can cause a rapid glucose rise), 
 patients with acute pancreatic damage  
 Impaired fasting glucose and impaired glucose tolerance.  
 A fasting glucose greater than or equal to 6.1 but less than 7.0 mmol/l implies imp aired 
fasting glucose (IFG)

fasting glucose (IFG) 
 Impaired glucose tolerance (IGT) is defined as fasting plasma glucose less than 7.0 
mmol/l and OGTT 2-hour value greater than or equal to 7.8 mmol/l but less than 11.1 
mmol/l 
 
 The relationship between type 2 diabetes and colonic cancer?  
 Type 2 diabetes is associated with a 40-60% increase in the risk of cancer of the large 
bowel. This increase is linked to changes in HbA1 c.

 No association has been found between colonic malignancy and type 1 diabe tes, nor 
gestational diabetes.  
 Increased concentrations of C peptide are a marker of increased colorectal 
cancer risk 
 
Which lipid abnormalities are most likely to be detected in a patient with type 2 diabetes? 
Small dense LDL molecules  
 small dense LDL  is more atherogenic, able to be oxidised more readily and penetrate 
endothelium and macrophages.  
 LDL is not typically elevated in type 2 diabetes

 HDL is typically low in the patient with type 2 diabetes. 
 Triglycerides are often elevated with poor glycaemic control.  
 
The OGTT  
 Used to diagnose diabetes.  
 Particularly useful in cases of borderline diabetes or gestational diabetes. 
 The test requires: 
 Overnight fast prior to the test 
 Normal eating the previous day 
 Baseline sample for glucose using a fluoride tube

 75 g oral anhydrous glucose usually washed down in 250-300 ml water (if hydrous 
glucose is used, the same weight represents a lower proportion of glucose in molar 
measurement) 
 Further glucose sample taken at 120 minutes 
 Plasma tubes, such as fluoride oxalate, must be used as the test results have n ot been 
validated using serum samples 
 Serum samples without additives allow further metabolism of the glucose by the red 327

149 
 cells and may give a falsely low value. Fluoride oxalate prevents further metabolism of 
glucose. 
 
Glycosylated haemoglobin 
 
 Glycosylated haemoglobin (HbA1c) is the most widely used measure of long-term glycaem ic 
control in diabetes mellitus.

control in diabetes mellitus.  
 HbA1c is produced by the glycosylation of haemoglobin at a rate proportional to the gluco se 
concentration.  
 HbA1c is generally thought to reflect the blood glucose over the previous '2-3 months' alth ough 
there is some evidence it is weighed more strongly to glucose levels of the past 2-4 weeks  
 The level of HbA1c therefore is dependant on 
 red blood cell lifespan 
 average blood glucose concentration 
 HbA1c is affected by many factors:

 HbA1c is affected by many factors: 
 Elevated HbA1c can occur in iron deficiency, vitamin B 12 deficiency, alcohol 
dependence, chronic renal failure, hyperbilirubinaemia and splenectomy 
 Reduced HbA1c can occur in chronic liver disease, hypertriglyceridaemia, some 
haemoglobinopathies, splenomegaly, rheumatoid arthritis and certain medications, 
including iron or vitamins B 12, C or E, antiretrovirals and dapsone.

A number of conditions can interfere with accurate HbA1c interpretation:  
Lower-than-expected levels of 
HbA1c(due to reduced red blood cell 
lifespan) Higher-than-expected levels of HbA1c(due to increased red 
blood cell lifespan) 
Sickle-cell anaemia 
GP6D deficiency  
Hereditary spherocytosis Vitamin B12/folic acid deficiency 
Iron-deficiency anaemia 
Splenectomy 
 
A new internationally standardised method for reporting HbA1c has been developed by the

International Federation of Clinical Chemistry (IFCC). This will report HbA1c in mmol per mol of 
haemoglobin without glucose attached. 
 
328

150 
  
HBA1c 
(%) Average plasma glucose 
(mmol/l) IFCC-HbA1c (mmol/mol) 
5 5.5  
6 7.5 42 
7 9.5 53 
8 11.5 64 
9 13.5 75 
10 15.5  
11 17.5  
12 19.5  
 
From the above we can see that  
average plasma glucose = (2 * HbA1c) - 4.5 
 
When is the first time that HbA 1c is likely to be accurate post blood 
transfusion?

transfusion? 
 3 months  
 
September 2011 exam: What is the minimum time period after which the HbA1c should be repeated? 
3 months (A more accurate answer would probably be 2 months but this is not given as an option )   
 
 September 2013 exam: A Fasting glucose of one patient is = 7.7 mmol/l, but his HA1c is  = 31 mmol/mol 
(5.0%).Which would explain the discrepancy between the HbA1c and fasting glucose levels? Sickle-cell 
anaemia  
 
 329

151 
 ___________________________________________________________  
Diabetes mellitus: management of type 2 (NICE 2015 ) 
 
Why is the management of diabetes mellitus so important? 
 The main focus of diabetes management now is reducing the incidence of macrov acular

(ischaemic heart disease, stroke) and microvascular (eye, nerve and kidney damage) 
complications.  
 
The new changes of NICE guidance on the management of type 2 diabetes mellitus (T2DM) in 
2015 include: 
 HbA1c targets have changed. They are now dependent on what antidiabetic drugs a p atient is 
receiving and other factors such as frailty 
 there is more flexibility in the second stage of treating patients (i.e. after metformin has bee n

started) - you now have a choice of 4 oral antidiabetic agents 
 Dietary advi ce 
 encourage high fibre, low glycaemic index sources of carbohydrates 
 include low-fat dairy products and oily fish 
 control the intake of foods containing saturated fats and trans fatty acids 
 limited substitution of sucrose-containing foods for other carbohydrates is allowable,  but care 
should be taken to avoid excess energy intake 
 discourage use of foods marketed specifically at people with diabetes

 initial target weight loss in an overweight person is 5-10% 
 
HbA1c targets 
 individual targets should be agreed with patients to encourage motivation 
 HbA1c should be checked every 3-6 months until stable, then 6 monthly 
 NICE encourage us to consider relaxing targets on 'a case- by-case basis, with particular 
consideration for people who are older or frail, for adults with type 2 diabetes'  
 in 2015 the guidelines changed so HbA1c targets are now dependent on treatment :

152 
 Lifestyle or single drug treatment  
Management of T2DM HbA1c target 
Lifestyle 48 mmol/mol (6.5%) 
Lifestyle + metformin 48 mmol/mol (6.5%) 
Includes any drug which may cause hypoglycaemia (e.g. lifestyle + 
sulfonylurea) 53 mmol/mol (7.0%)

sulfonylurea) 53 mmol/mol (7.0%) 
Already on one drug, but HbA1c has risen to 58 mmol/mol (7.5%) 53 mmol/mol (7.0%) 
 
Practical examples  
 a patient is newly diagnosed with HbA1c and wants to try lifestyle treatment first. You  agree a 
target of 48 mmol/mol (6.5%) 
 many local protocols now recommend starting metformin upon diagnosis 
 you review a patient 6 months after starting metformin. His HbA1c is 51 mmol/mol (6.8%). You

increase his metformin from 500mg bd to 500mg tds and reinforce lifestyle factors 
 you review an established type 2 diabetic on maximum dose metformin. Her HbA1c is 5 5 
mmol/mol (7.2%). You do not add another drug as she has not reached the threshold of 58  
mmol/mol (7.5%) 
 a type 2 diabetic is found to have a HbA1c of 62 mmol/mol (7.8%) at annual review. The y are 
currently on maximum dose metformin. You elect to add a sulfonylurea 
Drug treatment  
 First line

 First line 
 titrate up metformin  and encourage lifestyle changes to aim for a HbA1c of 48 
mmol/mol (6.5%),  
  If gastrointestinal side effects are not tolerated, then a trial of modified release 
metformin would be appropriate.  
 If metformin is not tolerated at all then a dipeptidyl peptidase-4 inhibitor, sulfony lurea or 
pioglitazone would be indicated.  
 Second line 
 should only add a second drug if the HbA1c rises to 58 mmol/mol (7.5%)

 there is more flexibility in the second stage of treating patients (i.e. after metformin has 
been started) - you now have a choice of 4 oral antidiabetic agents 
 There are essentially two pathways, one for patients who can tolerate metformin , and one for 
those who can't: 331

153 
  Tolerates metformin:  
 metformin is still first-line and should be offered if the HbA1c rises to 48 mm ol/mol (6.5%)* on 
lifestyle interventions 
 if the HbA1c has risen to 58 mmol/mol (7.5%) then a second drug  should be added from the 
following list: 
1. ĺ sulfonylurea  
2. ĺ gliptin  
3. ĺ pioglitazone

154 
  if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then triple therapy  
with one of the following combinations should be offered: 
 ĺ metformin + gliptin + sulfonylurea  
 ĺ metformin + pioglitazone + sulfonylurea  
 ĺ metformin + sulfonylurea + SGLT-2 inhibitor

 ĺ metformin + sulfonylurea + SGLT-2 inhibitor 
 ĺ metformin + pioglitazone + SGLT -2 inhibitor 
 ĺ OR insulin therapy should be considered  
Criteria for glucagon-like peptide1 (GLP1) mimetic (e.g. exenatide)  
 if triple therapy is not effective, not tolerated or contraindicated then NICE advise that we 
consider combination therapy with metformin, a sulfonylurea and a glucagonlike peptide1 
(GLP1) mimetic if:

(GLP1) mimetic if: 
 ĺ BMI ≥ 35 kg/m² and specific psychological or other medical problems associated with 
obesity or 
 ĺ BMI < 35 kg/m² and for whom insulin therapy would have significant occupational 
implications or Weight loss would benefit other significant obesity related comorbidities 
 only continue if there is a reduction of at least 11 mmol/mol [1.0%] in HbA1c and a weight loss 
of at least 3% of initial body weight in 6 months

 Exenatide should be used only when insulin would otherwise be started, obesity is a pro blem 
(BMI > 35 kg/m^2) and the need for high dose insulin is likely.  
 
Cannot tolerate metformin or contraindicated  
 if the HbA1c rises to 48 mmol/mol (6.5%) on lifestyle interventions, consider one of  the 
following: 
 ĺ sulfonylurea  
 ĺ gliptin  
 ĺ pioglitazone  
 if the HbA1c has risen to 58 mmol/mol (7.5%) then a one of the following combination s should 
be used:

be used: 
 ĺ gliptin + pioglitazone 
 ĺ gliptin + sulfonylurea  
 ĺ pioglitazone + sulfonylurea  
 if despite this the HbA1c rises to, or remains above 58 mmol/mol (7.5%) then consider insulin  
therapy 
Starting insulin  
 if HbA1c > 58 mmol/mol (DCCT = 7.5%) then consider human insulin 
 Metformin should be continued. In terms of other drugs NICE advice: 'Review the continued 
need for other blood glucose lowering therapies'

 NICE recommend starting with human NPH insulin (isophane, intermediate acting) taken at 
bed-time or twice daily according to need 
 if the patient is at risk from hypoglycaemia (or the consequences of) then a DPP -4 inhibitor or 
thiazolidinedione should be considered rather than a sulfonylurea 
 meglitinides (insulin secretagogues) should be considered for patients with an erratic life style 
 However, you can consider using sitagliptin or a thiazolidinedione instead of insulin if

there would be employment (eg: truck driver), social, recreational or personal issues.  333

155 
   In patients with diabetes starting thyroxine, doses of antidiabetic drugs including insulin may 
need to be increased. 
Risk factor modification  
 Blood pressure  
 target is < 140/80 mmHg (or < 130/80 mmHg if end-organ damage is present) 
 ACE inhibitors are first-line 
 Antiplatelets

 Antiplatelets  
 should not be offered unless a patient has existing cardiovascular disease 
 Lipids  
 following the 2014 NICE lipid modification guidelines only patients with a 10-yea r 
cardiovascular risk > 10% (using QRISK2) should be offered a statin. The first-line statin 
of choice is atorvastatin 20mg on 
Which laboratory test results would be most significantly associated with an increased 
incidence of cardiovascular disease in type 2 diabetics?  Raised proinsulin levels

January 2013 exam:  A taxi driver with type 2 DM , on metformin and the dose was titrated up. His HbA1c 
one year ago was 75 mmol/mol (9%) and is now 69 mmol/mol (8.5%). His BMI 33 kg/m². What is the most 
appropriate next step in management?  Add sitagliptin  ( because DPP-4 inhibitors are weight neutral & no risk 
of hypoglycaemia)  
 
September 2010 exam:  H/O (T2DM) & bladder cancer on gliclazide and atorvastatin. A recent trial of

metformin was unsuccessful due to gastrointestinal side-effects. He works as an accountant, is a non-smoker  his 
BMI is 31 kg/m². HisHbA1c = 62 mmol/mol (7.8%) What is the most appropriate next step in management? 
Add sitagliptin  (Pioglitazone is contraindicated in bladder cancer and may contribute to his obesity. he does not meet the NICE 
body mass index criteria of 35 kg/m².)  
Metformin

Metformin 
 
 Metformin is a biguanide used mainly in the treatment of type 2 diabetes mell itus.  
 metformin is now sometimes used in pregnancy, for example in women with polycystic ovari an 
syndrome 
 It has a number of actions which improves glucose tolerance (see below). 
 Metformin is the only oral hypoglycaemic shown to reduce macro vascular complications and 
death 
 The UKPDS (United Kingdom Prospective Diabetes Study) showed that metformin was

superior to sulphonylureas or insulin in terms of macrovascular risk, showing a statistically 
significant risk reduction for myocardial infarction 
 Unlike sulphonylureas it does not cause hypoglycaemia and weight gain and is therefore first-
line, particularly if the patient is overweight.  
 Metformin is also used in polycystic ovarian syndrome and non-alcoholic fatty liver dise ase 
334

156 
  Mutations in organic cation transporters are known to be associated with differences in 
metformin response  
 
 increases insulin sensitivity 
 decreases hepatic gluconeogenesis 
 may also reduce gastrointestinal absorption of carbohydrates 
Adverse effects

Adverse effects  
High dose (> 2 gm daily) interferes with enterohepatic circulation of the bile salts  (Bile salt 
malabsorption)  diarrhoea 
 gastrointestinal upsets are common (nausea, anorexia, diarrhoea), intolerable in 20% 
 GIT side-effects are more likely to occur if metformin is not slowly titrated up.  
 The BNF advises leaving at least 1 week before increasing the dose. 
 modified release preparations reduce the risk further.

 High dose metformin is thought to interfere with the enterohepatic circulation of bile 
salts, leading to reduced reabsorption of bile salts from the ilieum chronic 
diarrhoea .  
 vitamin B 12 deficiency   
 rarely a clinical problem 
 Long -term treatment with metformin increases the risk of vitamin B 12 deficiency .  
 The possibility of metformin-associated B 12deficiency should be considered in patients 
on metformin who suffer cognitive impairment, peripheral neuropathy, subacute

combined degeneration of the cord or anaemia.  
  Regular measurement of vitamin B 12 concentrations during long term metformin 
treatment should be strongly considered.  
 lactic acidosis  with severe liver disease or renal failure 
 it is now increasingly recognised that lactic acidosis secondary to metformin is rare, 
although it remains important in the context of exams   
 factors increases the risk of metformin lactic acidosis : 
 Raised serum creatinine

 Raised serum creatinine  
 Drugs causes kidney injury:  
 contrast media,  
 Metformin should therefore be stopped before, and for 48 h 
after, contrast radiography.  
 cyclosporin  
 aminoglycosides.  
 Excess alcohol  intake 
 Cimetidine 
 Metformin is excreted by the renal tubules and this process can be 
inhibited by cimetidine, but not the other H2 receptor antagonists. 
 The mainstay of treatment is rehydration.  
 Despite aggressive treatment,  mortality still 50%.  335

157 
  
 chronic kidney disease:  
 NICE recommend that the dose should be reviewed if the creatinine is > 130 mmol/l (or 
eGFR < 45  ml/min)  (reduce the those and monitor renal function every three months)  
and stopped if the creatinine is > 150 mmol/l (or eGFR < 30 ml/min)

 In regards to metformin and renal impairment, guidance has recently been revised to 
support metformin initiation at glomerular filtration rate as low as 45ml/min.  
 The drug should be stopped once eGFR falls to less than 30 mL/min/1.73 m2 (creatinine 
more than 150 µmol/L). 
  metformin may cause lactic acidosis if taken during a period where there is tissue hypo xia. 
Examples include a recent myocardial infarction, sepsis, acute kidney injury and severe 
dehydration

dehydration 
 Metformin should be stopped in patients who have an unstable circulation post-MI  
 The British National Formulary (BNF) states that there should be a six week "coolin g 
off" period post-MI before the commencement or recommencement of metformin.  
 In controlled heart failure, metformin may be used with caution.  
 iodine-containing x-ray contrast media:  examples include peripheral arterial angiography,

coronary angiography, intravenous pyelography (IVP); there is an increasing risk of provoking 
renal impairment due to contrast nephropathy; metformin should be discontinued on the 
day of the procedure and for 48 hours thereafter  
 sepsis 
 alcohol abuse is a relative contraindication 
 alcohol intake  increases the risk of lactic acidosis in diabetic patients on 
metformin  
Action of metformin in polycystic ovary syndrome increasing peripheral glucose uptake

 Lowering serum insulin concentrations with metformin ameliorates hyperandrogenism by 
reduction of ovarian enzyme activity that results in ovarian androgen production. 
 Clinical studies have shown that metformin reduces insulin resistance and have demonstrat ed 
a fall in serum androgens, luteinising hormone and weight. 
 The reduced insulin resistance is associated with reduced insulin drive to the insulin sensitiv e

ovary in polycystic ovarian syndrome and hence reduces androgen production. 
 
Metformin overdose  (medical-masterclass.com 2017 part 2)  
 Metformin classically causes a type-B lactic acidosis in overdose,  especially in patients who 
have co-ingested alcohol  or who have underlying renal or hepatic dysfunction.  
 Feature 
 gastrointestinal upset   
 severe lactic acidosis.  
 Hypoglycaemia is not often seen in metformin overdose.  336

158 
  Prognosis 
 If lactic acidosis occurs following overdose, mortality is usually greater than 50%.   
 gastric decontamination and use of activated charcoal  
 correction of acidosis with 8.4% sodium bicarbonate .

 Patients with resistant acidosis  should be considered for haemodialysis, which also 
clears metformin.  
Sulphonylureas  
Action  
 blocks potassium channels.  
 acts by blocking ATP-dependent potassium channels in the beta cells of the pa ncreas. 
Membrane depolarization results in influx of calcium and release of insulin.  
 Act by enhancing pancreatic islet cell function  promotes insulin release

 Also, act on the liver, stimulating the glycolytic pathway and inhibiting the production  of 
glucose.  
 On a molecular level they bind to an ATP-dependent K+(KATP) channel on the cell membrane of 
pancreatic beta cells. 
Side effects  
 Common adverse effects  
 Hypoglycaemia (more common with long acting preparations such as chlorpropamide) 
 weight gain 
 Rarer adverse effects  
 syndrome of inappropriate ADH secretion (SIADH) 
 bone marrow suppression

 bone marrow suppression 
 liver damage (cholestatic) 
 photosensitivity 
 peripheral neuropathy 
 Of the sulphonylureas, chlorpropamide is the main drug associated with facial 
flushing following alcohol intake , although a lesser reaction may be seen with other 
sulphonylureas. This disulfiram-like reaction is also seen with metronidazole. 
Contraindications :  
 Pregnancy and breast feeding  
Interaction

 As a result of drug interaction  hypoglycaemia  may be potentiated when a sulfonylurea is used 
concurrently with agents such as: 
 Long -acting sulfonamides 
 Tuberculostatics 
 Phenylbutazone 
 Clofibrate 
 Monoamine oxidase (MAO) inhibitors 337

159 
  Coumarin derivatives 
 Salicylates 
 Probenecid 
 Propranolol 
 Cimetidine 
 Disopyramide, and 
 Angiotensin converting enzyme inhibitors. 
 Fluconazole  has a low level of plasma protein binding and it is excreted by the kidney.

However, it is also a potent inhibitor of CYP2C8 and CYP2C9 and can thus interact with 
gliclazide and other sulphonylureas (for example, glimepiride, glibenclamide, 
tolbutamide and glipizide). 
 Further notes:  
 Although sulphonylurea therapy was proved by the UK Prospective Diabetes Study to prov ide 
micro vascular benefits, NO benefit was demonstrated for macro vascular outcomes  
(cardiovascular disease), in contrast to metformin.  
 Glibenclamide  
 long-acting sulfonylurea,

 long-acting sulfonylurea,  
 associated with a greater risk of hypoglycaemia  
 therefore should be avoided in the elderly, and shorter-acting alternatives, such 
as gliclazide or tolbutamide, should be used instead 
 metabolism 
 cleared by hepatic metabolism but has two active metabolites, 4-trans-
hydroxyglibenclamide and 3-cis-hydroxyglibenclamide, which are both renally 
excreted.  
 Renal impairment therefore increases the risk of hypoglycaemia in patients

taking glibenclamide.  
 with moderate CKD (eGFR 60-90 mL/min)  (reduced dose, frequent 
monitoring due to increased risk of hypoglycemia).  
 contraindicated in stage ≥ 3 CKD (eGFR < 60 mL/min)  
 Gliclazide  
 intermediate half-life of around 11 hours.  
  causes less hypoglycemia than other sulfonylureas.  
 Metabolism 
 extensively metabolised within the liver by CYP2C9 . Within the circulation, 
gliclazide is highly bound to plasma proteins, about 94%.

 Renal clearance accounts for only 4% of total drug clearance. 
 In CKD stage 1, 2, 3 (eGFR > 30 mL/min) gliclazide can be used safely.  
 in patients with severe CKD  reduced dose can be used  338

160 
  Therefore gliclazide action can be potentiated predominantly by two mechanisms:  
 Displacement of the drug from plasma proteins to give more free (unbound) drug 
- some agents such as aspirin  can do this, and 
 Interference with the hepatic metabolism of the drug.(e.g fluconazole ) 
 Glipizide

 Glipizide  
 Glipizide is the best choice of sulfonylureas in a patient with renal impairment.  
 does not need dose adjustment in severe and moderate renal disease 
 It is metabolized by the liver into inactive metabolites and therefore, renal insufficien cy 
does not affect the drug's clearance.  
 Chlorpropamide   
 is a first generation sulfonylurea.  
 may produce a syndrome of inappropriate anti-diuretic hormone (ADH) secretion.  
 It has a higher side effect profile

 It has a higher side effect profile 
Meglitinides (glinides ) (e.g. repaglinide, nateglinide) 
 
Meglitinides (nateglinide and repaglinide)  increase postprandial insulin release specifically  
 
Action 
 insulin secretagogues 
 like sulfonylureas they bind to an ATP-dependent K+(KATP) channel on the cell membrane of 
pancreatic beta cells   but have a weaker binding affinity and faster dissociation from the SUR1

binding site  (acts by closure of the ȕ -cell K+-ATP channel ) 
 It is short-acting  
Indications 
 often used for patients with an erratic lifestyle 
 particularly useful for post-prandial hyperglycaemia or an erratic eating schedule, as p atients 
take them shortly before meals  
 taken to coincide with meals.  
Advantages 
 The shorter action of duration appears to result in less weight gain compared to traditional 
sulphonylureas.

sulphonylureas. 
 Nateglinide is more expensive than sulphonylureas but offers advantages for shift workers 
and patients who tend to fast for a period of time because doses can be skipped when 
meals are missed.In these patient groups there may be a lower incidence of hyperglycae mia.  
 Repaglinide can be used even in CKD stages 4 and 5 without dose reduction. 
  weight gain and hypoglycaemia (less so than sulfonylureas)

161 
 Thiazolidinediones (pioglitazone ) 
Peroxisome Proliferator Activated Receptor (PPAR)  gamma  agonists  have been shown to reduce 
bone mineral density. 
 
 The PPAR-gamma receptor is:  
 an intracellular nuclear receptor.   
 Its natural ligands are free fatty acids

 Its natural ligands are free fatty acids 
 it is thought to control adipocyte differentiation and function. 
 activated by:  
 free fatty acids  and 
  thiazolinediones such as pioglitazone. 
 Pioglitazone, a PPAR gamma agonist , is an insulin sensitiser.  
 It upregulates genes for enzymes which deal with the metabolism of free fatty acids. 
 lead to increased peripheral insulin sensitivity, and improve glucose uptake.

 The main cytochrome P450 enzyme pathway responsible for pioglitazone metabolism is 
CYP2C8  
 Advantages 
 reduces HbA1c by between 1 and 1.3%.  
 raises HDL cholesterol by around 10%,  
 MOA 
 They are agonists to the PPAR-gamma receptor  Ĺfatty acid metabolism  Ļ visceral 
obesity  reduce peripheral insulin resistance. 
 Metformin also boosts insulin sensitivity, but  pioglitazone has more effect on 
peripheral insulin resistance.

peripheral insulin resistance.  
 They act at the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) 
receptor site, promoting binding as a heterodimer with the retinoid X-receptor to 
DNA  
 This then leads to  ĹĹ lipid metabolism  ĻĻ free fatty acids  reduction in hepatic 
insulin resistance, a rise in adiponectin and improved peripheral insulin sensitivity.  
 activate adiponectin 
 
 Adverse effects

 Adverse effects 
 Weight gain  (caused by a combination of fat accumulation and fluid retention). 
 liver impairment: monitor LFTs 
 Fluid retention :  therefore contraindicated in heart failure.  
340

162 
  in 10% of patients,  
 mechanism: by means of an action on the collecting ducts of the kidney so 
promoting sodium and water retention.  
 Rosiglitazone was withdrawn in 2010 following concerns about the c  The risk of 
fluid retention is increased if the patient also takes  insulin  , or other drugs

that cause fluid retention (for example,  NSAIDs , calcium antagonists )  
 ardiovascular side-effect profile. 
 increased risk of osteoporotic fractures  
 due to reduced bone mineral density. 
 The underlying mechanism is thought to be due to bone cell precursors 
differentiating into adipocytes rather than osteoblasts. 
 bladder cancer : recent studies have showed an increased risk of bladder cancer in 
patients taking pioglitazone (hazard ratio 2.64)

patients taking pioglitazone (hazard ratio 2.64) 
 NICE guidance on thiazolidinediones  
 only continue if there is a reduction of > 0.5 percentage points in HbA1c in 6 months 
 
 MRCPUK- part-1-January 2007 : Which one of the following problems is most likely to be 
caused by pioglitazone?  Peripheral oedema  
 
MRCPUK- part-1-January 2013 : What is the mechanism of action of thiazolidinediones?  
PPAR-gamma receptor agonist   
 
Insulin therapy

Insulin therapy 
 
 Insulin is released by beta cells as a result of increased intracellular calcium.  
 Insulin is released in pulses about every 9-13 minutes.This pulsing release mechanism is 
important because it is thought that this keeps cells sensitive to insulin. this is one of th e first 
things that disappears when insulin sensitivity disappears.  
 Action  
 Insulin inhibits gluconeogenesis by inhibiting pyruvate carboxylase . It increases

glycolysis by inducing the synthesis of glucose-6-phosphate dehydrogenase. Bo th 
pyruvate dehydrogenase and glycogen synthetase are activated by insulin. 
 Insulin induces the synthesis of phosphofructokinase, which increases glycolysis, and 
stimulates acetyl-CoA carboxylase to increase the synthesis of fatty acids.  
 It acts via a similar mechanism to cell surface receptors. 
 Insulin binding to its receptor results in receptor autophosphorylation on tyrosine

residues and the tyrosine phosphorylation of insulin receptor substrates (IRS-1, IRS- 2 
and IRS-3) by the insulin receptor tyrosine kinase. 
 It is synthesised in the beta cells of the islets of Lagerhans. 
 It causes an increased glucose-protein transport on the endoplasmic reticulum  
 C-peptide  
  is a protein that is cleaved from proinsulin when it is activated.  341

163 
  This has a much longer half-life than insulin itself, and thus is a useful measure o f 
insulin secretion (it is more accurate than measuring insulin itself).  
 The level of this can be measured in the urine.  
 GLUT-4 is the main insulin responsive glucose transporter.  
 Enzymes and insulin

 Enzymes and insulin 
 Insulin inhibits Pyruvate carboxylase, an enzyme involved in gluconeogenesis 
 Insulin stimulate glycogen synthetase  increases glycogenesis in the liver and 
muscle  
 Insulin activates the hexose monophosphate (HMP) shunt by inducing the synthesis 
of glucose 6-phosphate dehydrogenase 
 Both acetyl-CoA carboxylase and ATP citrate lyase are stimulated to increase the 
synthesis of fatty acids.

synthesis of fatty acids.  
 
the most appropriate initial insulin regime for young patient after being diagnosed with new 
onset Type1 DM  Meal time Actrapid and insulatard at night. 
 
Classification of insulin  
 By manufacturing process  
 porcine: extracted and purified from pig pancreas 
 human sequence insulin: either produced by enzyme modification of porcine insulin 
(emp) or biosynthetically by recombinant DNA using bacteria (crb, prb) or yeast (pyr) 
 analogues

 analogues 
 By duration of action 
 
 Onset Peak Duration 
Rapid-acting insulin analogues  5 mins 1 hour 3-5 hours 
Short-acting insulin  30 mins 3 hours 6-8 hours 
Intermediate-acting insulin  2 hours 5-8 hours 12-18 hours 
Long-acting insulin analogues  1-2 hours Flat profile Up to 24 hours 
Premixed preparations  - - - 
 
 Rapid-acting insulin analogues 
 the rapid-acting human insulin analogues act faster and have a shorter duration 
of action than soluble insulin (see below)

of action than soluble insulin (see below) 
 may be used as the bolus dose in 'basal-bolus' regimes (rapid/short-acting 'bolus' 
insulin before meals with intermediate/l ong-acting 'basal' insulin once or twice 
daily) 
 insulin aspart: NovoRapid 
 insulin lispro: Humalog 342

164 
  If there is a pre-lunch ↑↑ glucose, that means there is a significant post-breakfast 
peak in glucose levels. As such,  the best way to manage this is with a  
breakfast time injection of rapid acting insulin.  
 Short-acting insulins 
 soluble insulin examples: Actrapid (human, pyr), Humulin S (human, prb)

 may be used as the bolus dose in 'basal-bolus' regimes 
 Intermediate-acting insulins 
 isophane insulin 
 NICE guidelines advise that, in general, a humane isophane insulin 
(also referred to as a Neutral Protamine Hagedorn [NPH] insulin) is 
the first-line recommended insulin to use in a type 2 diabetic. These 
are intermediate acting insulins usually used once daily at night or twice a 
day. 
 many patients use isophane insulin in a premixed formulation with 
 Long -acting insulins

 Long -acting insulins 
 insulin determir (Levemir): given once or twice daily 
 insulin glargine (Lantus): given once daily 
 A long-acting insulin analogue might be useful in someone who struggles to 
inject a twice a day NPH insulin to reduce the frequency of injections to once a 
day (e.g. someone who requires assistance to inject from a carer or district 
nurse). 
 Premixed preparations 
 combine intermediate acting insulin with either a rapid-acting insulin analogue or

soluble insulin 
 Novomix 30: 30% insulin aspart (rapid-acting), 70% insulin aspart protamine 
(intermediate-acting) 
 Humalog Mix25: 25% insulin lispro (rapid-acting), 75% insulin lispro protamine 
(intermediate-acting); Humalog Mix50: 50% insulin lispro, 50% insulin lispro 
protamine 
 Humulin M3: biphasic isophane insulin (human, prb) - 30% soluble (short-acting), 
70% isophane (intermediate-acting) 
 Insuman Comb 15: biphasic isophane insulin 9human, prb) - 30% soluble (short-

acting), 70% isophane (intermediate-acting) 
 A biphasic 'mixed' preparation is recommended if an individual's diabetic control 
is especially poor (HbA 1c > 75 mmol/mol). 
 
Advantages of Short-acting insulin analogue VS short-acting soluble insulins. 
 Short-acting insulin analogue, like lispro-insulin, aspart insulin and glulisine insulin ha ve a 
rapid onset of action  and a shorter duration of action  than conventional short-acting 
soluble insulins.

soluble insulins. 
 Consequently studies reveal reduced post-prandial glucose excursions  versus soluble 
insulin and potentially a reduced incidence of hypoglycaemia although the eviden ce for this is 
debated. 
 343

165 
  
Insulin analogues 
 
Insulin lispro : 
 short-acting insulin   
 The first insulin analogue to be developed, by reversing the position of two am ino acids ( lysine 
and proline) in the B chain of human insulin.  
 This allows larger amounts of prandial insulin to be available soon after injection and reduces

the chance of betwe en-meal hypoglycaemia.  
 Short-acting analogues are useful for reducing postprandial hypoglycaemia  because their 
profile is more in keeping with physiological insulin release.  
 
Insulin glargine   
 long-acting insulin analogue  (up to 24-hour duration of action)  
 produced by recombinant DNA  technology utilizing a non-pathogenic laboratory strain 
of Escherichia coli (K12)  as the production organism.

 Insulin glargine differs from human insulin in that the amino acid asparagin e at position 
A21 is replaced by glycine  and two argin ines are added to the C-terminus of the B-chain. 
344

166 
  the main advantage   Reduced nocturnal hypoglycaemia  
 in which situations does insulin glargine have the clearest advantage 
over isophane? 
 In patients with type-1 diabetes who have significant nocturnal hypoglycaemia 
on isophane

on isophane 
 suitable for providing a basal level of insulin which attempts to mimic the normal physiolog ical 
state. 
 and when given at night, provides good control of the fasting blood glucose. 
 Unlike crystalline suspensions, insulin glargine does not need to be mixed thoroughly prior to  
injection, thus making it easier to use. 
 NICE have reviewed use of long acting insulin analogues and they are only appropriate in  
cases of significant hypoglycaemia.

cases of significant hypoglycaemia. 
 NICE only recommends use of insulin glargine in patients - with type-2 diabetes -   who 
have significant hypoglycaemia on isophane insulin 
 Glargine and detemir are insulin analogues, as such they are considered by NICE to be  only 
suitable in cases:  
 nocturnal hypoglycaemia is a problem on isophane (NPH) insulin 
 morning hyperglycaemia on isophane (NPH) insulin results in difficult day-time blood 
glucose control

glucose control 
 rapid-acting insulin analogues are used for meal-time blood glucose control.   
 
Administration of insulin 
 The vast majority of patients administer insulin subcutaneously.  
 It is important to rotate injection sites to prevent lipodystrophy.  
 Insulin pumps are available ('continuous subcutaneous insulin infusions') wh ich delivers a 
continuous basal infusion and a patient-activated bolus dose at meal times.

 Intravenous insulin is used for patients who are acutely unwell, for example with d iabetic 
ketoacidosis.  
 Intravenous insulin  is the optimal management of high blood sugar in acute 
myocardial infarction.   
 
Insulin prescription  
 Starting dose  
 The guidelines recommend starting with either morning or evening long-acting insulin, 
or with bedtime intermediate acting insulin.  
 0.2 U/kg or a flat dose of 10 U is the recommended starting dose for intermediate 
acting insulin.

acting insulin. 
 Targets 
 The ADA/EASD consensus 2006 recommends a target of between 3.9 and 7.2 mmol/L 
for fasting and pre-prandial glucose levels. 
 Generally, if patients are not using insulin, sulphonylureas or glinides 
(repaglinide or netaglinide), then the ADA/EASD consensus does not recommend 
self-monitoring of blood glucose levels.  345

167 
  Once daily long-acting insulin taken at night is monitored using pre-breakfast fa sting 
glucose measurements. A fasting glucose level of 4-7 mmol/L is the ideal aim. 
 If fasting levels are in range yet the HbA 1c is elevated, post-prandial monitoring is

recommended, aiming for glucose levels of less than 10 mmol/L. 
 Dose adjustment 
 At least three consecutive, self-monitored fasting glucose readings should be used to 
adjust doses (i.e. three days minimum between dose adjustments).  
 Up-titration  
 If the fasting plasma glucose is more than 10 mmol/L, then a more aggressive 
uptitration schedule of 4 U every three days can be considered. 
 increase  2 U of insulin every three days until fasting glucose is in the target

range of 3.9-7.2 mmol/L. 
 Use the '10% rule' for up-titration of insulin. 
 Down-titration  
 If fasting glucose is less than 4, then the insulin dose should be reduced.  A 
good general rule of thumb is that when reducing the insulin doses you 
should do so in steps of 20%.  
 Reduce insulin dose in steps of 20% if hypoglycaemia occurs. 
 Insulin in renal failure 
 The kidneys carry out one third of exogenous insulin degradation.

 The dose of exogenous insulin is reduced 25% when eGFR is 10-50 mL/min and 50% 
when eGFR is < 10 mL/min 
  
Insulin therapy: side-effects  
Hypoglycaemia 
 patients should be taught the signs of hypoglycaemia: sweating, anxiety, blurred v ision, 
confusion, aggression 
 conscious patients should take 10-20g of a short-acting carbohydrate (e.g. a glass of 
Lucozade or non-diet drink, three or more glucose tablets, glucose gel)

 every person treated with insulin should have a glucagon kit for emergencies where the  patient 
is not able to orally ingest a short-acting carbohydrate 
 patients who have frequent hypoglycaemic episodes may develop reduced awarene ss. If this 
develops then allowing glycaemic control to slip for a period of time may restore their 
awareness 
 beta-blockers reduce hypoglycaemic awareness 
Lipodystrophy 
 typically presents as atrophy of the subcutaneous fat

 can be prevented by rotating the injection site 
 insulin-related worsening of heart failure and fluid overload  
 occurs because insulin itself promotes salt and water retention and increased 
sympathetic drive .  
 furosemide to promote salt and water excretion,  346

168 
  Once fluid status is stable, if he still has symptoms of heart failure, addition of a 
cardioselective beta blocker such as bisoprolol may be of value.  
 Insulin detemir  has been associated with less weight-gain or even slight weight-loss 
compared with other insulins.  
Types of

Types of 
insulin Effect Application Special features 
Rapid-acting insulin 
Insulin 
lispro  Onset: 5 –30 min 
 Peak: 30 min –3 h 
 Duration: 3 –5 h  Intensified 
conventional insulin 
therapy  Injected before a meal time  
 Used in combination with longer-
acting insulin  Insulin 
aspart 
Insulin 
glulisine 
Short-acting insulin 
Regular 
insulin  Onset: ∼30 min 
 Peak: 2.5 –5 h 
 Duration: 4 –24 h  “Standard insulin ” for 
lowering blood

lowering blood 
glucose levels in an 
acute setting  
 Conventional insulin 
therapy  
 Intensified 
therapy  Mandatory interval between 
injections and meal times: ∼30 
min 
acting insulin 
 Intravenous therapy available  
(only for this type of insulin) 
Intermediate-acting insulin 
NPH 
insulin  Onset: 1 –2 h 
 Peak: 4 –12 h 
 Duration: 14–24 h  Conventional insulin 
therapy 
 Component of basal 
supported oral 
therapy (BOT)

therapy (BOT) 
for treatment-
resistant type 2 
diabetes mellitus  Crystalline suspension 
 Mandatory interval between 
injections and meal times: 30–60 
min 
 Used in combination with rapid 
or short- acting insulin 
 Usually administered twice daily 
Long -acting insulin 
Insulin 
glargine  Onset: 1.5 –4 h 
 Peak: flat; not 
defined 
 Duration: ∼ 24 h   Intensified 
therapy 
therapy (BOT)  Insulin analogs

therapy (BOT)  Insulin analogs 
 More consistent efficacy profile 
and longer duration of effect 
compared to NPH insulin 
or short-actinginsulin Insulin 
detemir 
Insulin 347

169 
 Types of 
degludec for treatment-
diabetes mellitus  Administered once or twice daily 
Ultralente 
insulin 
Mixed insulin 
Mixed 
insulin  Biphasic effect 
 Short-term effect 
like that of regular 
insulin/lispro/aspart 
 Long -term effect

 Long -term effect 
like that of NPH 
insulin  Conventional insulin 
therapy  Contains regular insulin and NPH 
insulin mixed according to a 
defined ratio  
 Example: Actraphane® 30/70, 
contains 30% regular insulin and 
70% NPH insulin 
 Administered two or three times a 
day 
 
Mixtard- associated nocturnal hypoglycemia 
 Diabetics often have hypoglycaemic attacks at night. This is a common scenario in som eone 
on a twice-daily mixed regime.

on a twice-daily mixed regime.  
 The patient has a hypoglycaemic attack at about 0200 h in the morning. Th is is because the 
insulatard component of the Mixtard peaks about 6 h after it has been given. This, along  with 
some residual actrapid activity, gives an excess of insulin in the middle of the night, leadin g 
hypoglycaemia.  
 If the evening dose of Mixatard is split up in to its component insulins, taking the a ctrapid pre-

evening meal and the insulatard taken before bed, hypoglycaemia is normally  avoided. 
 Split evening insulin so take actrapid before evening meal and insulatard before 
bedtime  
 
September 2011 exam:  A diabetic patient on simvastatin, gliclazide and metformin, admitted 
with acute MI. How should his diabetes be managed whilst in CCU?  Stop metformin & 
gliclazide + intravenous insulin  
 
Hypoglycaemic episodes which occur during the day in a patient takes a basal bolus insulin

regime of  long-acting insulin (Insulatard®) and short- acting insulin (Actrapid®) with each 
meal: 
 the most appropriate next step  Refer for Dose Adjustment for Normal Eating education 
(DAFNE  ) 
 the next step after DAFNE, should hypos persist, would be continuous glucose monitoring , 
to learn more about fluctuations in serum blood glucose over the course of the day. 
 those patients who have problems with nocturnal hypoglycaemia   changing Insulatard to 
insulin glargine 
 
 348

170 
  
Counselling a diabetic started on insulin about what to do if the y are unwell (eg: 
they have a pneumonia)  
 For type 1 diabetics, if they are unwell: 
 test their blood glucose and ketones at least every 4 hours. 
For this question we have used the TREND UK and Leicestershire NHS insulin 
guidelines.

guidelines. 
 The TREND UK guidance (Training, research and education for nurses in diabetes UK)  
advises that if blood glucose is less than 13 mmol/L and no ketones are present then  
insulin should be taken as normal;  
 if blood glucose is more than 13 mmol/L and ketones are present then insulin 
adjustment is needed. 
 add 10% of the daily insulin dose as rapid acting insulin every four hours, 
and then four hourly glucose and ketone monitoring  to guide ongoing 
dosage/management.

dosage/management. 
 The Leicestershire NHS guidance is identical aside from it using a cut-off of 11 mmol/L 
rather than 13 mmol/L. 
 For type 2 diabetics, if they are unwell: 
 they should test their blood glucose at least every 4 hours. 
 if blood glucose is more than 13 mmol/L then insulin adjustment is needed. 
 add two units of insulin to each dose and continue to monitor the glucose levels

every four hours. 
 
Diabetes mellitus: GLP-1 and the new drugs 
 
Incretins increase insulin release and decrease glucagon secretion from the pancreas. 
DPP-IV metabolizes GLP. Inhibiting DPP-IV maintains high levels of GLP. 
 glucagon-like peptide-1 (GLP-1), a hormone released by the small intestine in respon se to an 
oral glucose load   
 In normal physiology an oral glucose load results in a greater release of insulin than if the

same load is given intravenously - this known as the incretin effect . This effect is largely 
mediated by GLP-1 and is known to be decreased in T2DM.  
 The two hormones responsible  for the incretin effect, glucose-dependent insulinotropic 
hormone (GIP) and glucagon-like peptide-1 (GLP-1), are secreted after oral glucose loa ds and 
augment insulin secretion in response to hyperglycaemia. 
 TCF7L2 mutations may be associated with a reduced incretin response  349

171 
  Increasing GLP-1 levels, either by the administration of an analogue (glucagon-like peptide -1, 
GLP-1 mimetics, e.g. exenatide) or inhibiting its breakdown (dipeptidyl peptidase-4 ,DPP- 4 
inhibitors - the gliptins), is therefore the target of two recent classes of drug.

GLP is a confusing misnomer: Glucagon raises glucose and FFA levels. GLP decreases 
glucagon.  
 
Incretin response in type 1 DM 
In new onset type 1 diabetes, a paradoxical incretin  response to mixed meal testing is seen, 
where a rise in glucagon occurs . Elevated glucagon  and consequent gluconeogenesis and 
glycogenolysis is thought to drive further negative impact on remaining beta cells, accelera ting their 
demise 
 
Glucagon-like peptide-1 (GLP-1) mimetics (e.g. exenatide)

GLP analogs such as exenatide, liraglutide, slow gastric emptying, promote weight 
loss and lower glucose 
 
 Example  
 Exenatide, Liraglutide   
 Metabolic effects 
 increase insulin secretion  
 inhibit glucagon secretion.  
 inhibits glucose production in the liver, 
 slows gastric emptying  
 Suppresses appetite  
 
 Indications  
 NICE state that:  Consider adding exenatide to metformin and a sulfonylurea if:

 BMI >= 35 kg/m  in people of European descent and there are problems 
associated with high weight, or 
 BMI < 35 kg/m and insulin is unacceptable because of occupational 
implications  or weight loss would benefit other comorbidities. 
350

172 
  Advantages 
 typically result in weight loss , in contrast to many medications such as insulin, 
sulfonylureas and thiazolidinediones.   
 promote approximately 3% weight loss over a 6 month period.  
 weight loss of approximately 6% at 6 months can be achieved with liraglutide 1.8  
mg.

mg. 
 improving glycaemic control, with modest weight loss, without increasing the risk 
of hypoglycaemia compared with uptitration of insulin.  
 reduce HbA1c by similar levels to basal insulin, without increasing the risk of 
hypoglycaemia,  
 Advantages of liraglutide over exenatide  
 liraglutide is only needs to be given once a day (long-acting ). 
 exenatide must be given by subcutaneous injection within 60 minutes before the

morning and evening meals. It should not be given after a meal. 
 liraglutide can be used in renal impairment with an estimated glomerular filtration 
rate [eGFR] as low as 30 mL/min/1.73 m2. 
 exenatide  are not recommended in patients with severe renal impairment  
 Administration 
 administered subcutaneously.  
 Combination of GLP-1 and DPP- 4 inhibitors  
 trials of DPP- 4 inhibitor and GLP-1 together suggest no added efficacy 
versus GLP-1 alone.

versus GLP-1 alone. 
 Both exenatide and liraglutide may be combined with metformin and a sulfonylurea.  
 Standard release exenatide is also licensed to be used with basal insulin alone or with 
metformin .  
 Ongoing prescription of GLP-1 mimetics  
 NICE like patients to have achieved a 1% reduction in HbA1c and 3% weight loss after 
6 months to justify the ongoing prescription of GLP-1 mimetics. 
 nice advice that this should only be continued if after six months HbA1c reduces

by at least 11 mmol/mol 
 Adverse effects  
 nausea and vomiting (the major adverse effect). 
 severe pancreatitis  in some patients. 
 Liraglutide  is associated with an approximately 7 beats per minute increase in heart 
rate versus control in diabetes  
 
The preferred pathway for glucose management according to the NICE guidelines is to a dd insulin to 
the combination of metformin and a sulphonylurea. However, where weight is of particular concern

(BMI >35), exenatide may be considered as an alternative . It can also be used where insulin 
would interfere with a patient's occupation . 
 
 351

173 
  
When to choose exenatide as an alternative to insulin or sulphonylurea  as first choice add-
in options to metformin?   
 morbid obesity  
 or risk of hypoglycaemia, ( eg : HGV drivers ) 
 
Current NICE guidance suggests the use of GLP-1 mimetics only if BMI is above 35 and there are

specific medical or psychological problems associated with high body weight.  
 
Dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. Vildagliptin, sitagli ptin)  
 
 Members 
 Vildagliptin, Sitagliptin, Saxagliptin, Linagliptin and Alogliptin 
 Action 
 Dipeptidyl peptidase-4 (DPP-4) inhibitors  
 induce Glucose dependent glucagon suppression 
 only recommended as second-line  therapy with metformin  if patients are at

significant risk of hypoglycaemia or its consequences (e.g. older patients, those 
working at heights or heavy machinery, isolated patients) or if a sulphonylurea is not 
tolerated or contraindicated.  
 NICE guidelines on DPP-4 inhibitors 
 continue DPP-4 inhibitor only if there is a reduction of > 0.5 percentage points in HBA1c 
in 6 months 
 NICE suggest that a DPP-4 inhibitor might be preferable to a thiazolidinedione if f urther

weight gain would cause significant problems, a thiazolidinedione is contraindicated o r 
the person has had a poor response to a thiazolidinedione 
 oral preparation 
 well tolerated with no increased incidence of hypoglycaemia 
 do not cause weight gain 
 We can use them all in CKD but with dose adjustment ( Only linagliptin  does not need 
dose adjustment in any stage of CKD ) 
 Side effects

 GI disturbance  is reported across a range of sitagliptin studies, including nausea, 
flatulence, diarrhoea and constipation. 
 This is not surprising given that GLP-1, the degradation of which is blocked by 
sitagliptin, a DPPIV inhibitor, delays gastric emptying. 
352

174 
 ____________________________________________________________
SGLT2 inhibitors   (- gliflozin)  
 Examples include cana gliflozin , dapa gliflozin  and empa gliflozin 
 Mode of action 
 reversibly  inhibit sodium-glucose co-transporter 2 (SGLT2) in the renal proximal

convoluted tubule  to reduce glucose reabsorption and increase urinary glucose 
excretion.  
 Advantages  
 promotes greater weight loss ( modest calorie spillage into the urine)  
 there for it is better than gliptins in obese patient who not achieve control 
by metformin  
 has positive effects on blood pressure control.  
 Sodium loss   the most likely cause of the fall in blood pressure  some four 
weeks after therapy initiation . 
 associated with positive cardiovascular outcomes.

 reduce uric acid, which may over the longer term reduce nephropathy progression 
 glycosuria  
 urine dip sticks will test positive for glucose.  
 Ĺ glucose in the urine  predispose to bacterial growth. 
 recurrent urinary infections  
 genital infection  
 these medications are contra-indicated in patients with 
recurrent thrush .  
 diabetic ketoacidosis 
 may contribute to developing diabetic ketoacidosis 
 patients may present with euglycaemic ketoacidosis

 increased risk of bone fracture  
 SGLT-2 inhibitors   ĹPTH  Ĺbone turnover Ĺ risk of bone fracture. 
 SGLT-2 inhibitors   Ĺ fibroblast growth factor (FGF- 23)  Ļvitamin D   Ļbone 
mineralisation.  
_____________________________ _______________________________  
Alpha-glucosidase inhibitors  
 These are acarbose  and miglitol.   
 MOA 
 inhibits intestinal α -glucosidase , which therefore delays the digestion and 
absorption of starch and sucrose.

absorption of starch and sucrose. 
 has a modest effect on the absorption of sugars from the gut, 
 Advantage of acarbose 
 in impaired glucose tolerance:  
 reduction in risk of new onset type 2 diabetes of 25%  
 reduction in cardiovascular events of 49%   
 Side effect s  353

175 
  They can lead to diarrhea, abdominal pain, bloating, and flatulence  in much the same 
way as lactose intolerance. 
 MECHANISM OF DIARRHEA WITH GLUCOSIDASE INHIBITORS  
 When acarbose and miglitol block glucose absorption, the sugar remains in the

bowel, available to bacteria. When bacteria eat the glucose, they cast off gas an d 
acid. Using glucosidase inhibitors is like making a person lactose intolerant. 
Diabetic ketoacidosis (DKA)  
 Approximately 25% of patients with type 1 diabetes will first present in diabetic 
ketoacidosis 
 What is the primary cause of ketoacidosis in type 1 diabetes? 
 Lipolysis

 Lipolysis  
 Precipitating factors leading to diabetic ketoacidosis (DKA) are: 
 Infection (30-40%)   The most common precipitating factor 
 Non-compliance with treatment (25%) 
 Alterations to insulin dose (13%) 
 Newly diagnosed diabetes (10-20%) 
 Myocardial infarction (< 1%)  
 
 The drugs implicated in precipitating diabetes as well as diabetic ketoacidosis. 
 atypical antipsychotics such as olanzapine  
 thiazide diuretics 
 beta sympathomimetics, and 
 steroids. 
Features

Features  
 abdominal pain 
 polyuria, polydipsia, dehydration 
 Kussmaul respiration (deep hyperventilation) 
 Acetone-smelling breath ('pear drops' smell) 
 serum sodium  is falsely low  due to the osmotic load of glucose.  
 
 354

176 
  
Diagnostic criteria  
American Diabetes 
Association (2009) Joint British Diabetes 
Societies (2013) Nice guidelines (2015) 
 glucose > 13.8 
mmol/l 
 pH < 7.30 
 serum bicarbonate 
<18 mmol/l 
 anion gap > 10 
 ketonaemia 
  glucose > 11 mmol/l or 
known diabetes 
mellitus 
 pH < 7.3 
 bicarbonate < 15

mellitus 
 pH < 7.3 
 bicarbonate < 15 
mmol/l 
 ketones > 3 mmol/l or 
urine ketones ++ on 
dipstick  acidosis (indicated by blood 
pH <  7.3 or bicarbonate < 
18 mmol/l)  and 
 ketonaemia (indicated by 
blood beta-hydroxybutyrate  > 
3 mmol/l ) or ketonuria ≥ ++  
 Diagnose severe DKA if pH < 
7.1. 
 
A raised amylase in the absence of frank pancreatitis is common in patients with diabetic 
ketoacidosis (DKA), No specific management is required and amylase falls with rehydration and

control of blood glucose.  
 
Very high glucose artificially drops sodium level  Pseudohyponatremia 
 
Mechanism of hyperkalemia in DKA 
 Hyperkalemia is from transcellular shift of potassium out of the cell in exchange for hyd rogen 
ions going into the cell. The cells “suck up acid ” as a way of compensating for the severe  
metabolic acidosis and release potassium in exchange.  
 Also, insulin drives potassium into cells with glucose.

 Although plasma potassium is significantly elevated in DKA, total body potassium stores are 
depleted. This is due to transcellular shift of potassium from intracellular sites to the  plasma, 
resulting in excess loss of solutes with water in the urine, which may lead to hypovolemic 
shock.  
 Note that acidemia can also cause hyperkalemia via exchange of potassium for protons in th e 
serum. The mechanism for this is not entirely clear.

Cause of hyperkalemia   transcellular shift of potassium out of the cell in exchange for 
hydrogen. 
 Cause of Ļ total body K stores  excess loss of solutes with water in the urine. 
 Cause of hypokalemia during DKA treatment  insulin drives potassium into cells with 
glucose. 
 
 355

177 
  
MECHANISM OF INCREASED ANION GAP  
 In the absence of insulin, glucose can ’t enter, and cells look for an alternate fuel source. The 
alternate fuel is FFA and ketones.  
 Ketones are negatively charged acids, so using them as fuel drives down the level of  
bicarbonate. 
 
Acidosis = Hyperkalemia

Acidosis = Hyperkalemia 
Alkalosis = Hypokalemia 
 
In a patient with DKA, the total body level of potassium is low. Chronic hyperkalemia deplete s the 
potassium of the body. 
 
Parameters indicate severe  DKA:  (suggest  intensive care admission)  
 pH < 7 
 Blood ketone > 6 mmol/L 
 Bicarbonate < 5 mmol/L 
 Anion gap >16 mmol/l 
 Potassium < 3.5 mmol/L on admission 
 Tachycardia or bradycardia 
 Systolic blood pressure <90 mmHg 
 Oxygen saturation <92% on air

 Oxygen saturation <92% on air 
 GCS < 12 
 
 Fluid replacement:  
 Assume a 5% fluid deficit in children and young people in mild or moderate DKA 
(indicated by a blood pH of 7.1 or above)  
 Assume a 10% fluid deficit in children and young people in severe DKA  (indicated b y a 
blood pH below 7.1) 
 
 Most patients with DKA are deplete around 5-8 litres.  The typical fluid deficit 
associated with DKA is approximately 6 litres.  
 Isotonic saline is used initially

 Isotonic saline is used initially 
 The initial half of this amount is derived from intracellular fluid and precedes signs of 
dehydration, while the other half is from extracellular fluid and is responsible f or clinical 
signs of dehydration. 
 Appropriate fluid replacement requires 1 litre of normal saline over the first 1/2  hour, 
then 1 litre over the next hour, then 1 litre over the next two hours followed by 1 litre 
every 4 hours depending on the degree of dehydration. 356

178 
  Nice 2015 recommend: When calculating the fluid requirement for people with DKA, 
assume: 
 a 5% fluid deficit in mild to moderate DKA (indicated by a blood pH of 7.1 or 
above) 
 a 10% fluid deficit in severe DKA (indicated by a blood pH below 7.1).  
 Calculate the maintenance fluid requirement

 Calculate the maintenance fluid requirement  
 if they weigh less than 10 kg, give 2 ml/kg/hour 
 if they weigh between 10 and 40 kg, give 1 ml/kg/hour 
 if they weigh more than 40 kg, give a fixed volume of 40 ml/hour. 
 Aim to replace the fluid deficit over the first 48 hours because faster rehydratio n is 
associated with an increased risk of cerebral oedema.  
 Use 0.9% sodium chloride until the plasma glucose is below 14 mmol/litre.

 all fluids (except any initial bolus) administered with 40 mmol/litre potassium chloride, 
unless they have renal failure.  
 Change fluids to 0.9% sodium chloride with 5% glucose and 40 mmol/litre potassium 
chloride once the plasma glucose concentration falls below 14 mmol/litre  
 JBDS example of fluid replacement regime for patient with a systolic BP on 
admission 90mmHg and over: 
 
Fluid Volume 
0.9% sodium chloride 1L 1000ml over 1st hour 
0.9% sodium chloride 1L with potassium

0.9% sodium chloride 1L with potassium 
chloride 1000ml over next 2 hours 
chloride 1000ml over next 4 hours 
chloride 1000ml over next 4 hours 357

179 
 Fluid Volume 
chloride 1000ml over next 6 hours 
 Note that slower infusion may be indicated in young adults (aged 18-25 years) as t hey 
are at greater risk of cerebral oedema. 
 
 Insulin :  
 Root and dose?

 Insulin :  
 Root and dose? 
 an intravenous  soluble infusion should be started at 0.1 unit/kg/hour.  
 best time for starting? 
 nice 2015 recommend: Start an intravenous insulin infusion 1 –2 hours after 
beginning intravenous fluid therapy   
 Rate?  
 Latest guidance recommends use of a fixed rate insulin regime , not a sliding 
scale . 
 0.1 unit/kg/hr based on estimate of weight 
 50 units human soluble insulin (Actrapid or Humulin S) made up to 50 ml

with 0.9% sodium chloride solution 
 Once blood glucose is < 15 mmol/l an infusion of 5% dextrose should be 
started 
 If patient normally takes long acting insulin analogue (Lantus, Levemir) 
continue at usual dose and time.  
 Guidelines suggest that insulin infusion rate should only be increased if  
blood ketones are not falling at >0.5 mmol/h.  
 Do not give bolus doses of intravenous insulin.  
 
pH >7.3 and ketones <0.3 mmol/L define resolution of DKA, at which time a patient

can be converted back to subcutaneous insulin. 
       
 correction of hypokalaemia 
                               JBDS potassium guidelines          
Potassium level in first 24 
hours (mmol/L)  Potassium replacement in 
mmol/L of infusion solution  
Over 5.5 Nil 
3.5-5.5 40 
Below 3.5 Senior review as additional 
potassium needs to be given 
 358

180 
  Bicarbonate : 
 The role of bicarbonate in DKA is controversial.  
 The acidosis usually corrects itself once the fluid and electrolyte balance is restored. 
 Some physicians administer bicarbonate if there is severe acidosis (pH < 7). However, 
rapid correction of acidosis might impair cardiac function.

 There is no evidence to support bicarbonate use in a patient with a pH greater than 7.0 . 
  Intravenous bicarbonate should be given  if the blood pH is lower than 6.9.  
 In practice for DKA, sodium bicarbonate is only really considered in the peri-arrest 
situation. 
 S/c low-molecular weight heparin 
  DKA  increased risk of venous thromboembolism because of volume depletion, 
hyperglycaemia and their decreased conscious level. 
Complications of DKA and its treatment

Complications of DKA and its treatment 
 gastric stasis 
 cerebral oedema 
 the leading cause of death in children  with DKA  
 The risk is highest in paediatric ( 1% ) and adolescent patients, and is rarer in adults. 
 Exact pathogenic mechanism remains unknown – multifactorial  
 May be iatrogenic due to incorrect fluid therapy  
 Ĺglucose  Ĺosmolar gradient results in water shift fro m the intracelluar fluid (ICF) to

the extracellular fluid (ECF) space and contraction of cell volume. Correction with insulin 
and I.V fluids  rapid reduction in osmolarity  reversal of the fluid shift  cerebral 
edema.   
 Thus the warning signs of cerebral oedema - headache, lethargy, confusion, red uced 
conscious level, incontinence, pupillary changes - must be considered in this patient 
group. 
 early manifestations: 
 headache 
 agitation or irritability 
 unexpected fall in heart rate

 unexpected fall in heart rate 
 increased blood pressure. 
 treatment with mannitol (20%, 0.5 –1 g/kg over 10 –15 minutes) or hypertonic sodium 
chloride (2.7% or 3%, 2.5 –5 ml/kg over 10 –15 minutes). 
 Immediately treat for cerebral oedema if person with DKA develops any of these signs: 
 deterioration in level of consciousness 
 abnormalities of breathing pattern, for example respiratory pauses 
 oculomotor palsies 
 pupillary inequality or dilatation. 
 thromboembolism

 thromboembolism 
 acute respiratory distress syndrome 
 arrhythmias secondary to hyperkalaemia/iatrogenic hypokalaemia 359

181 
  acute kidney injury 
 Prognosis 
 Whilst DKA remains a serious condition mortality rates have decreased from 8% to under 1% 
in the past 20 years. 
 The mortality associated with the modern management of diabetic ketoacidosis  1-2% 
 Specifically, mortality relates to cerebral oedema.

January 2008 exam: A patient weighs 80 kg.  Presented with a feature of DKA. One lit re of 0.9% saline is 
infused and an intravenous insulin pump is set-up. What rate shou ld insulin be initially given?  8 unit / 
hour (The Joint British Diabetes Societies produced guidelines in 2010 recommending startin g the insulin infusion at a 
rate of 0.1 unit/kg/hour)  
 
Hypoglycaemia

 Hypoglycaemia is defined as a plasma glucose concentration < 2.5 mmol/l  
Causes 
 Ĺ Insulin wit h Ļ C-Pepti de level point s to a diagnosis of insulin abuse  
 C-Peptide level Ĺ with Sulfonylu rea abuse  
 insulinoma - increased ratio of proinsulin to insulin 
 self-administration of insulin/sulphonylureas 
If C peptide is undetectable   Exogenous insulin administration ( as the C peptide is 
released with endogenous insulin)  
 liver failure 
 Addison's disease

 Alcohol 
 Glucokinase activators may lead to both enhanced insulin release and glycogen storag e in the 
liver, as such they are known to cause hypoglycaemia. No glucokinase activators have yet 
made it to the clinic.  
 Other possible causes in children  
 nesidioblastosis - beta cell hyperplasia 
 
features  
 nocturnal hypoglycaemia  vivid dreams   REM sleep disruption  daytime weakness 
and somnolence

and somnolence 
Standard work-up for hypoglycaemia should include: 
 Laboratory (not test-strip) blood glucose measurement 
 Liver function tests to rule out significant liver dysfunction 
 Blood alcohol and alcohol history 
 Cortisol levels, with or without Synacthen testing 
 Insulin and C-peptide levels taken during an attack 
 Chest X-ray to exclude occult malignancy  360

182 
  
 For patient who are able to swallow, give fast-acting form of glucose.  
 Large-bore venous access should be achieved and blood samples taken for serum 
glucose, liver function, ethanol, Cortisol, insulin, C-peptide, proinsulin and 
sulphonylurea levels.

sulphonylurea levels.  
 If the patient's Glasgow Coma Score (GCS) is under 13, then 60-80 ml 20% glucose 
should be given intravenously.  
 If a patient's Glasgow Coma Scale Score is reduced oral routes of glucose replacement ar e 
likely to be inappropriate due to the risk of aspiration.  
 50% intravenous dextrose is contra-indicated due to difficulties with intravenous access, the 
intravenous flow of 50% dextrose, and risks of phlebitis.

 The most appropriate treatment to correct hypoglycemia is treatment with 10% 
intravenous dextrose.  
 Glucagon  (1 mg intramuscularly) can be administered if no intravenous access can be 
obtained. 
 Can be given by a family member or friend 
 Glucagon acts mainly on the liver by Activates adenylate cyclase   increases 
glycogenolysis and gluconeogenesis 
 Activation of adenylate cyclase  is responsible for rapid correction of hypoglycaemia

 Glucagon acts also via cyclic AMP to stimulate lipolysis in adipose tissue, producing 
free fatty acids that can act as a major source of energy. 
 
September 2011 exam: An 18-year-old girl is admitted with hypoglycaemia (RBS: 1.9 mmol). 
her father who has type 2 DM describes a number of similar episodes.Insulin15 mg/ml (6- 10 
mg/ml)Proinsulin22% (22-24%) C-peptide 0.15 nmol/l (0.2-0.4 nmol/l).What is the most likely

diagnosis?  Insulin abuse  (The raised insulin with low c-peptide level points to a diagnosis of insulin 
abuse. C-peptide levels would be raised in a patient following sulfonylurea abuse)  
 
Somogyi effect vs Dawn phenomenon  
 Somogyi effect: Nocturnal hypoglycemia leading to a surge of counterregulatory 
hormones, leading in turn to hyperglycemia in the morning. 
 Dawn phenomenon: Nocturnal secretion of GH leading to early-morning hyperglycemia

 Somogyi: high dose insulin  hypoglycemia at midnight  body adjusts it by releasing 
Epinephrine, Norepinephrine, Cortisol, glucagon  Hyperglycemia in the morning  
treatment by insulin dose modification. 
 Dawn phenomenon: normal nocturnal glycemia, but hyperglycemia due to increased GH in 
the morning  no treatment. 
361

183 
 Differentiate between them  by: 
 Nocturnal glycaemia: low  Somogyi, normal is Dawn. Both have hyperglycemia in the 
morning. 
 DECREASE the insulin at night: Then check morning glucose: 
 If the glucose ĹĹ  Dawn Phenomenon. (not enough Insulin or not the right type at 
pm)

pm) 
 If the glucose is normal or ĻĻ  Somogyi.  
(NEVER INCREASE the Insulin dose, because if the patient has Somogyi, we could 
end up putting him in a coma) 
 
Hypoglycaemia unawareness 
 Hypoglycaemia unawareness is more common in patients with intensively controlled  
diabetes  of long duration, but can occur in any person with diabetes as a consequence of 
diminished counter-regulatory responses to recurrent hypoglycaemia.

 Alcohol inhibits gluconeogenesis, decreases peripheral hypoglycaemic responses and 
impairs perception of symptoms of hypoglycaemia. 
 There is no evidence to suggest that beta-blockers cause hypoglycaemia unawareness.  
 Glucose sensing occurs in the hypothalamus, and there is evidence to suggest that ch ronic, 
and recurrent hypoglycaemia may have deleterious effects on higher cerebral function. 
  
 
Factitious hypoglycaemia

  
 
Factitious hypoglycaemia 
 ↑↑ insulin + normal  C -peptide  abuse of exogenous insulin  
 if C-peptide levels also elevated, then the logical next step  urine test for the metabolites of 
sulphonylurea  
 
Hypoglycaemic episodes after regular exercise in patient who takes BD mixed insulin: 
 the most appropriate next step in his management  is  transfer to a basal bolus regime  
 change to a basal bolus regime where he can alter his short acting insulin dose just

prior to planning exercise.  
 
Hyperosmolar hyperglycaemic state (HHS) 
 Hyperosmolar hyperglycaemic state (HHS) is a complication of type 2 diabetes  
 In general there is enough insulin in patients with type 2 diabetes to suppress 
ketogenesis,  but insufficient to prevent hyperglycaemia and the hepatic resistance to 
glucagon. 
 Two-thirds of people with Hyperosmolar hyperglycaemic state are presenting with type 2

diabetes mellitus for the first time. 
 The risk of mortality in HHS is 10-20%, with a strong predilection to thrombotic events.  362

184 
  In general, HHS results in osmotic fluid shift to the intravascular space. 
 Urinalysis reveals increased specific gravity denoting dehydration. 
 
Confirmed by: 
 Osmolality >320mosmol/kg 
 calculated osmolality of mOsm/kg =  [2(Na+K) + glucose + urea]

 Hyperglycaemia >30 mmol/L with pH >7.3, bicarbonate >15mmolL and no significant 
ketonenaemia <3mmol/L 
 Fluid management is essential 
 The initial goal is repletion of extracellular volume; the 1 litre of 0.9% saline  will start to 
restore this, as it remains in the extracellular compartment; this is suggested by the mild 
hypotension and absent postural drop - if these were still persistent that would ind icate 
a need for further volume expansion.

a need for further volume expansion.  
 Once this has been achieved in patients who are hyperosmolar  given the 
hypernatraemia, the appropriate agent is 0.45% saline  which replaces intra and 
extracellular fluid loss, which is similar in composition to the fluid lost during the osmotic 
diuresis. 
 5% dextrose should be added when blood glucose reaches 15 mmol/L.  
 Electrolytes should be checked 2-4 hourly, aiming a decrease of Na of no quicker than

10 mmol/day, and patients managed in a high care environment. 
 Insulin  
 The aim is to reduce glucose levels by approximately 3 mmol/hour.  
 Patients with HONK are often sensitive to insulin replacement and doses can be much 
lower than those required for DKA. 
 insulin replacement of 0.15 IU/kg/hour is recommended as an initial guide. 
 After getting over their episode of hyperosmolar hyperglycaemic state it is likely that

their insulin requirement will fall. Hence as a starting insulin dose it would be most 
sensible to begin with around 2/3rds of the total dose required during the episod e 
of hyperosmolar hyperglycaemic state , split morning and evening. 
Diabetes mellitus: hypertension management  
Antihypertensive therapy is the single intervention most likely to reduce the overall risk of 
both micro vascular and macro vascular events

both micro vascular and macro vascular events  
 Lipid  lowering therapy  prevent macrovascular  events, but has no effect on microvascular 
events. 
 Lowering HbA 1c only resulted in  a significant reduction in microvascular  events 
 
 Hypertension in type 2 diabetes is primarily associated with hyperinsulinaemia and 
insulin resistance 
 
Pathophysiology 363

185 
  Hyperinsulinaemia directly stimulates sympathetic nervous system activity, increasing renal 
sodium reabsorption and promoting vascular smooth-muscle proliferation. 
 Insulin resistance is also associated with the reduced activity of nitric oxide synthase, leadin g

to reduced vasodilation in response to vascular stress.  
 Red cell sodium-lithium countertransport activity abnormalities are associated with the ea rly 
development of hypertension in type 1 diabetes. 
 
NICE recommend the following blood pressure targets for type 2 diabetics:  
 targets for type 2 diabetics   
 if end-organ damage (e.g. renal disease, retinopathy) < 130/80 mmHg 
 otherwise  < 140/80 mmHg

 otherwise  < 140/80 mmHg 
 Patients who were more tightly controlled had a slightly reduced rate of stroke but otherwise 
outcomes were not significantly different. 
 Because ACE-inhibitors have a renoprotective effect in diabetes they are the first-li ne 
antihypertensives recommended for NICE.  
 Patients of African or Caribbean family origin should be offered an ACE-inhibitor plu s either a 
thiazide diuretic or calcium channel blocker.

thiazide diuretic or calcium channel blocker.  
 Further management then reverts to that of non-diabetic patients, as discussed earlier in the 
module. 
 Remember that autonomic neuropathy may result in more postural symptoms in patients 
taking antihypertensive therapy. 
 The routine use of beta-blockers in uncomplicated hypertension should be avoided , particularly 
when given in combination with thiazides, as they may cause insulin resistance, impair insu lin

secretion and alter the autonomic response to hypoglycaemia. 
 
ACE inhibitors are first-line for hypertension in diabetics, irrespective of the patients age 
 
_____________________________ _______________________________ 
 
Diabetes associated with pancreatitis  is due to damage to the endocrine pancreas and associated 
lack of insulin. the patient ’s presentation:   thin, with symptoms of insulinopaenia. As such,  
exogenous insulin replacement is the only appropriate intervention

Diabetic nephropathy 
Basics 
 commonest cause of end-stage renal disease (ESRD) in the western world 
 In type 1 diabetes microalbuminuria usually occurs  5-15 years after the diagnosis of diabetes 
mellitus.  
 The peak incidence of frank albuminuria is 17 years after diagnosis of type 1 diabetes 364

186 
  The majority of patients with diabetic nephropathy have type 2 diabetes, however this is d ue to 
higher prevalence of type 2, rather than higher incidence of nephropathy (as incidence is in 
fact higher in type 1 DM). 
 Diabetic nephropathy develops in approximately 40% of patients with type 1 d iabetes and in

5% to 40% of patients with type 2 diabetes. 
 It is reasonable to expect a fall in the glomerular filtration rate (GFR) of 1 ml/minute per m onth 
once the serum creatinine level has reached around 200 pmol/l.  
 40% of deaths of patients with nephropathy are due to cardiovascular disease. 
 Glomerulosclerosis the most common renal complication of DM 
 Typically, there is thickening of the glomerular basement membrane and

glomerulosclerosis that may be diffuse or nodular (Kimmelstiel-Wilson disease)  
 Kimmelstiel-Wilson disease is characterised by hyaline masses in the mesangial  
core of the glomerular lobules.These masses consist of lipids and fibrin 
 What is the renal biopsy finding would be diagnostic of diabetic related 
kidney injury? 
 Kimmelstiel-Wilson lesion  
 
 Pathophysiology  is poorly understood, however:

 changes to the haemodynamics of the glomerulus is thought to be key, which leads to an 
increased glomerular capillary pressure 
 histological changes  include: basement membrane thickening, capillary obliteration, 
mesangial widening. Nodulular hyaline areas develop in the glomuli - Kimmelstiel-Wilson 
nodules 
 Kimmelstiel-Wilson lesion is the only biopsy finding that is specific & 
diagnostic  to diabetic related kidney  disease.  
MECHANISM OF GLOMERULAR DAMAGE

MECHANISM OF GLOMERULAR DAMAGE  
 Uncontrolled diabetes removes the negative charge from the filtration slits of the glomerular 
basement membrane.  
 Normally, negative charges repel (يمنعthe filtration of albumin, which is also negatively 
charged.  
 Loss of negative charges allows albumin to pass through the glomerulus.  
 ACE inhibitors decrease intraglomerular hypertension by dilating the efferent arteriole. This

protects the glomerulus from the damage caused by intraglomerular hypertension. 
 
Risk factors for developing diabetic nephropathy  
Modifiable Non-modifiable 
Hypertension 
Hyperlipidaemia 
Smoking 
Poor glycaemic control 
Raised dietary protein Male sex 
Duration of diabetes 
Genetic predisposition (e.g. ACE gene polymorphisms) 365

187 
 Screening 
 all patients should be screened annually 
 albumin:creatinine ratio (ACR) in early morning specimen 
 ACR > 2.5 = microalbuminuria 
 
Diabetic nephropathy: stages  occurring in five stages*: 
Stage  Description 
Stage 1   hyperfiltration: increase in GFR 
 may be reversible 
Stage 2

Stage 2 
(silent or latent phase) 
  most patients do not develop microalbuminuria for 10 years 
 GFR remains elevated 
Stage 3 
(incipient 
nephropathy) 
  microalbuminuria (albumin excretion of 30 - 300 mg/day, 
dipstick negative) 
Stage 4 
(overt nephropathy) 
  persistent proteinuria (albumin excretion > 300 mg/day, 
dipstick positive) 
 hypertension is present in most patients 
 histology shows diffuse glomerulosclerosis and focal

glomerulosclerosis (Kimmelstiel-Wilson nodules) 
Stage 5 
  end-stage renal disease, GFR typically < 10ml/min 
 renal replacement therapy needed 
*The timeline given here is for type 1 diabetics. Patients with type 2 diabetes mell itus (T2DM) progress through 
similar stages but in a different timescale - some T2DM patients may progress quick ly to the later stages  
 
Optimal glycaemic and blood pressure control is the most important step

The best therapeutic option to prevent progression of renal disease  Treat with ACEI 
(superior to glycaemic control )  
 
 dietary protein restriction 
 Do not offer low-protein diets (dietary protein intake less than 0.6 –0.8 g/kg/day) to 
people with CKD. [new 2014] nice guidelines   
 The evidence for a low protein diet exists for overt proteinuria but not microalbuminuria . 
 tight glycaemic control 
 The evidence for good glycaemic control in the treatment of microalbuminuria in

patients with type 1 diabetes suggests no clear benefit 
 BP control: aim for < 130/80 mmHg 366

188 
  benefits independent of blood pressure control have been demonstrated for ACE inhibitors 
(ACE-i) and angiotensin II receptor blockers (A2RB).  
 ACEi or  A2RBs are the treatment of choice for hypertension in diabetic nephropathy 
 Combinations of ACE-i and A2RB are not recommended Ĺside effects  worse

outcomes. 
 ACEi   can potentiate the hypoglycaemic effect of insulin and oral antidiabetic agents, 
especially during the first few weeks of use.  
 ACEi should be used under specialist supervision if the creatinine concentration is > 
150 pmol/l, and the renal function and potassium levels should be monitored. 
 Non-dihydropyridine calcium antagonists, eg diltiazem, may have additional effects in reducing 
proteinuria

proteinuria  
 amongst the calcium antagonist class, only diltiazem has been shown to impact 
significantly on proteinuria. 
 control dyslipidaemia e.g. Statins 
Prognosis 
 Without intervention nephropathy is likely to deteriorate with the development of 
macroalbuminuria. In association with the latter, renal function declines about 10% pe r year, 
ending in end-stage renal disease. 
 The deterioration in GFR/year if BP is well controlled is 4 ml/min/year.

 Proteinuria in the absence of reduced GFR is associated with approximately 20% progression 
to nephropathy over five years.  
 End-stage renal failure is said to occur some 7-10 years after diagnosis of albuminuria,  but 
improved management of hyperglycaemia and hypertension might stretch this pe riod a little. 
 33% of patients with type 1 diabetes mellitus have diabetic nephropathy by the age o f 40 years 
 approximately 5-10% of patients with type 1 diabetes mellitus develop (ESRD)

 percentage of diabetics with diabetic nephropathy would be expected to progress to ESRD  
Type 1   50%.  
Type 2  15%  
 
Diabetic retinopathy   
 The most common cause of blindness in adults aged 35-65 years-old. 
  About 80% of patients with type I diabetes will have retinopathy 10 years after 
presentation. By contrast, in type II diabetes, where the time of onset is uncertain, up to

25% of patients will have retinopathy at the time of diagnosis.  
 the most likely cause of blurred vision in a newly diagnosed  diabetic who was 
previously fit and well  is  Osmotic changes in the lens    
 Rapid improvement in blood glucose levels may be associated with worsening of 
diabetic eye disease. 
Pathogenesis  
 Hyperglycaemia  Ĺ retinal blood flow & abnormal metabolism in the retinal vessel walls  
damage to endothelial cells & pericytes 367

189 
  Endothelial dysfunction  Ĺ vascular permeability  exudates (seen on fundoscopy).  
 Pericyte dysfunction   predisposes to the formation of microaneurysms.   
 retinal ischaemia  production of growth factors   Neovasculization  
 
Classification

The earliest sign of diabetic retinopathy is the presence of microaneurysms on 
fluorescein angiography.  
Recently a new classification system has been proposed, dividing patients into those with non-
proliferative diabetic retinopathy (NPDR) and those with proliferative retinopathy (PDR): 
 
Traditional classification New classification 
Background retinopathy 
 microaneurysms (dots) 
 blot haemorrhages (<=3) 
 hard exudates 
 
Pre-proliferative retinopathy

Pre-proliferative retinopathy 
 cotton wool spots (soft 
exudates; ischaemic nerve 
fibres) 
 > 3 blot haemorrhages 
 venous beading/looping 
 deep/dark cluster haemorrhages 
 more common in Type I DM, 
treat with laser 
photocoagulation Mild NPDR 
 1 or more microaneurysm 
Moderate NPDR 
 microaneurysms 
 blot haemorrhages 
 cotton wool spots, venous beading/looping and 
intraretinal microvascular abnormalities (IRMA)

intraretinal microvascular abnormalities (IRMA) 
less severe than in severe NPDR 
Severe NPDR 
 blot haemorrhages and microaneurysms in 4 
quadrants 
 venous beading in at least 2 quadrants 
 IRMA in at least 1 quadrant 
 
Proliferative retinopathy ĺ (urgent referral to an ophthalmologist for pan-retinal photocoagulation ) 
 retinal neovascularisation - may lead to vitrous haemorrhage 
 fibrous tissue forming anterior to retinal disc 
 more common in Type I DM, 50% blind in 5 years

 more common in Type I DM, 50% blind in 5 years 
 Normal visual acuity is seen in proliferative retinopathy  
 urgent referral to an ophthalmologist (seen within one week) is required if there is 
proliferative retinopathy or there is evidence of clinically significant macular oedema 
(hard exudates at the fovea). 
 
Maculopathy 
 based on location rather than severity, anything is potentially serious 
 hard exudates and other 'background' changes on macula

 The exudates can be arranged in a ring (circinate exudates)  surrounding a point of capillary 
leakage.  368

190 
  This can be shown on fluorescein angiography  
 check visual acuity 
 more common in Type II DM 
 responds to laser treatment at the point of leakage. 
 
 Cotton wool spots (CWS) represent infarcts of the nerve fibre layer of the retina , since 
multiple CWS are a pre-proliferative sign.

multiple CWS are a pre-proliferative sign. 
 Haemorrhages (or hard exudates ) close to the fovea represent a risk of macular oedema a nd 
are therefore sight threatening. 
 Hard exudates (HE) are collections of exudated lipid and protein. 
 Macular oedema is associated with micro-aneurysms and hard exudates and is due to fluid 
leakage but is not necessarily a feature pre-proliferative or proliferative retinopathy althou gh it 
may still require laser photocoagulation.

may still require laser photocoagulation. 
 Microaneurysms (MA) are capillary aneurysms. 
 Venous beading, loops and soft exudates (cotton wool spots) are characteristic of the 
ischaemia associated with preproliferative diabetic retinopathy . 
 Soft exudates are a feature of pre-proliferative retinopathy, and despite quite marke d 
new vessel disease the visual acuity may be normal. 
 
 New vessels suggest proliferative retinopathy.

 New vessels suggest proliferative retinopathy. 
 Feature necessitate immediate  referral to the ophthalmologist  
 New vessels anywhere in the fundus  
 
Treatment 
 Achievement of target HbA1c of 47.54 mmol/mol (6.5%) would be associated with 
significantly reduced progression of retinopathy. 
 Progression may be slowed with improved glycaemic and hypertensive control  but the 
latter has been shown to be more effective at reducing progression  
369

191 
  Indications for emergency  referral to ophthalmologist: 
 sudden loss of vision 
 rubeosis iridis 
 pre-retinal or vitreous haemorrhage 
 retinal detachment. 
 
 Indication for urgent referral to the ophthalmologist (seen within one week)

 Hard exudates in the macular region ( evidence of clinically significant macular 
oedema ) 
 proliferative retinopathy 
 Vitreous haemorrhage  
 Laser destroys ischaemic - but viable-   retina to reduce the secretion of angiogenic growth 
factors and allow new vesel regression. it is not applied directly to new vessels as this would 
cause bleeding. 
 
NHS Diabetic Eye Screening Programme (2015):

NHS Diabetic Eye Screening Programme (2015):  
 Screening for diabetic retinopathy is offered to all people aged 12 and over  with type 1 or type 
2 diabetes. 
 For diabetics at low risk of sight loss, the interval between screening tests should change from 
one year to two years. The current one year interval should remain unchanged for the  
remaining people at high risk of sight loss. 
 
Prognosis

Prognosis  
The approximate percentage of eyes that will lose useful vision irretrievably with in 5 years if not 
treated : 
 3% in those with background retinopathy 
  20% for those with exudative  
  30% for those with pre-proliferative,  
  50% for those with proliferative retinopathy.  
 
Asymmetric diabetic retinopathy   
Asymmetric DM Retinopathy ĺ suspect ocular ischemia (carotid artery disease)

 Asymmetric diabetic retinopathy  should always raise the suspicion that there is some 
other cause of ocular ischaemia on the worst-affected side, such as unilateral or 
asymmetrical carotid artery disease  do Carotid Doppler  
 
 370

192 
  
Hypertensive retinopathy. 
 The presence of flame and blot haemorrhages, cotton wool 
spots and blurring of the optic disc margins are typical of the 
retinal changes that are seen in advanced hypertensive 
retinopathy.  
Whilst some of these findings are also observed in diabetic

eye disease (e.g. dot and blot haemorrhages, cotton wool 
spots), the absence of other features (e.g. hard exudates, 
venous beading) should alert the clinician to other possible 
diagnoses.  
  
Diabetic neuropathy 
MECHANISM OF NEUROPATHY IN DIABETES  
 Nerves have a supply of blood vessels. Diabetes damages small blood vessels, starving off 
the nerves

the nerves 
 
 pain and temperature sensation carried through small fibres  affected first  
 Joint position sense and vibration are carried through large fibres , and are therefore affected 
later.  
 Sensory nerves are affected more than motor so often reflexes remain intact . 
 Diabetic peripheral neuropathy  usually goes in parallel with retinopathy and nephropathy.  
 It is also slowly progressive and affects mainly the spinothalamic pathway.

Treatment: NICE updated it's guidance on the management of neuropathic pain in 2013. Di abetic 
neuropathy is now managed in the same way as other forms of neuropathic pain:  
 first-line treatment: amitriptyline, duloxetine, gabapentin or pregabalin 
 Duloxetine  
 Duloxetine is preferred to amitryptiline because it is associated with a 
lower risk of urinary retention. 
 Duloxetine is first line therapy for neuropathy except where it is contraindicated 
due to:

due to: 
 previous hypersensitivity 
 history of glaucoma  
 patients already taking a serotonergic agent, such as tramadol , because 
of the associated risk of serotonin syndrome. 
 Amitriptyline  
371

193 
  Amitriptyline is recommended by NICE as an option for second line therapy in 
patients for whom home duloxetine is unsuitable .  
 Doses of 10-75 mg amitriptyline are usually appropriate, but again is 
contraindicated here due to history of glaucoma.

contraindicated here due to history of glaucoma. 
  glaucoma and left bundle branch block are contraindications to TCA use.  
 Pregabalin or gabapentin  
 Pregabalin or gabapentin can be considered as second or third line 
monotherapy or in combination.  
 However where there is renal impairment, pregabalin is preferable over 
gabapentin.  
 Peripheral neuropathy  with H/O glaucoma  and on tramadol  for chronic back 
pain, what is the best treatment?  
 Pregabalin

 Pregabalin 
 tramadol may be used as 'rescue therapy' for exacerbations of neuropathic pain 
 
Acute painful neuropathy of rapid improvement of blood glucose control

 rapid improvement of blood glucose control  Acute painful neuropathy (self-limiting)  
 Simple analgesics (paracetamol, aspirin) and local measures (bed cradles) are 
recommended as a first step 
 
 Duloxetine is the standard first line therapy for neuropathy   
 The starting dose is 60 mg daily, may be increased up to 120 mg/day.  
 It cannot be used in patients with a history of acute narrow angle glaucoma.

 Amitriptyline is an alternative option to duloxetine if it is contraindicated; a dose of 10 -75 
mg/day is recommended. 
 pregabalin is recommended either as a second line agent or in combination with 
amitriptyline.  
 
September 2009 exam: H/O type 2 DM and benign prostatic hypertrophy (BPH) presents with burning 
pain in his feet. He tried duloxetine but no benefit. What is the most suitabl e initial management?

Pregabalin  (Amitriptyline is first choice but given H/O BPH, it is better to avoid amitriptyli ne due to the risk of urinary 
retention).  
 
Diabetic autonomic neuropathy 
Features 
 marked postural drop (recurrent falls)  
 gastrointestinal tract neuropathy  diarrhoea -  particularly at night - and intractable vomiting. 
 impotence. 
  tachycardia  372

194 
  impaired cardiovascular response to the Valsalva manoeuvre.  
 atonic bladder, painless urinary retention and recurrent urinary tract infections. 
 
Gastroparesis 
 occurs in 10 –20% of diabetics after 10 years.  
 mechanism  
 The major stimulant for gastric motility is “stretch. ”

 In patients with longstanding diabetes, there is impaired ability to perceive stretch in the 
GI tract and impaired motility.  
 symptoms  include  
 erratic blood glucose control,  
 bloating and vomiting 
 abdominal fullness, constipation.  
 diagnosis  
 may be confirmed with a gastric-emptying scan , but this is often unnecessary.  
 Isotope gastric motility studies are the most appropriate way to assess 
gastric emptying  
 management options include

 management options include  
 metoclopramide, domperidone  
 Domperidone is now the initial intervention of choice , with metoclopramide 
having fallen out of favour because of long-term neurological sequelae 
associated with its use. 
 prokinetic drug has the added effects of increasing locally released acetylcholine 
at the myenteric plexus.  
 or erythromycin ( prokinetic agents )  
 Erythromycin increases the release of “motilin, ” a pro-motility GI hormone.

Impotence  
 Autonomic nerve dysfunction is one of the commoner causes of impotence in a person with 
diabetes  
 The combination of DM and hypogonadotrophic hypogonadism (HH) ( low testosterone 
& FSH)) is compatible with a diagnosis of haemochromatosis and measuring ferritin 
would be a reasonable investigation.  
 diabetes and impotence associated with high ferritin  haemochromatosis  
 The next investigation would be measurement of transferrin saturation,

 and then, if elevated (above 45%), genotyping (homozygosity for C282y mutation s) 
would next be considered and would be expected to clinch the diagnosis.  
 hypotestosteronaemia  
 Hypogonadism is not unusual in the obese diabetic  nor indeed in the metabolic 
syndrome and seems to arise as a consequence of a combination of tertiary and 
primary hypogonadism. 373

195 
  Low testosterone + normal TSH and LH 
 In the first instance, to improve sexual function together with libido, it is probably 
worthwhile starting transdermal testosterone, probably gel. 
 the most appropriate treatment for this man's erectile dysfunction  
Transdermal testosterone

Transdermal testosterone   
 If sexual dysfunction persists then sildenafil or any other phosphodiesterase 
inhibitor would be an appropriate adjunct. 
Diabetic amyotrophy 
Leg pain, weakness and reduced knee reflexes with an impaired fasting glucose 
concentration suggests a diagnosis of diabetic amyotrophy  should be confirmed 
with OGTT.  
 Diabetic amyotrophy is also known as proximal diabetic neuropathy.  The latter term is

probably more useful as it describes more accurately the aetiology of the condition. 
 Caused by occlusion of the vasa nervorum of the proximal lumbar plexus and/or femoral 
nerve.  
 It is a mixed motor and sensory proximal neuropathy that can cause severe pain (which is 
responsible for the anorexia and weight loss).  
 Occur most commonly in men in their 50s with type 2 diabetes treated with oral hypoglyca emic 
agents.

agents.  
 Is not uncommonly a presenting feature of diabetes in the elderly.  
 Often associated with poor diabetic control 
 May improve with good control (although it often self-resolves with time). 
 often affects the femoral nerve, lumbosacral plexus or lumbar roots. 
Features  
 pain is usually the first symptom, often in the thigh, hips or buttocks 
 this is followed by weakness, for example difficulty getting out of a chair 
 Often asymmetrical (although it can be bilateral).

 loss of knee reflexes  
 Tender & wasting of proximal muscles with diminished reflexes.  
 The plantars can become extensor, but this is unusual. 
 Plantar responses may be flexor or extensor. 
 There is often little sensory loss. 
 EMG shows multifocal denervation in paraspinous & leg muscles. 
Treatment 
 The mainstay of treatment is supportive care and transference to insulin therapy.  
 
 374

196 
Post prandial pain in diabetics 
 Diabetes, especially Type 2 diabetes, is associated with macrovascular disease. 
 Smoking is a further risk factor for macrovascular atherosclerosis.

 After a meal splanchnic blood flow is increased. If the mesenteric artery is occluded the 
lack of blood flow to the bowel will produce ischaemic type pain. 
Diabetic foot  
2% of patients with diabetes in the community develop new foot ulcers each year  
Diabetic foot ulcers can be divided into: 
1. Neuropathic foot 
 Warm 
 Well perfused with palpable pulses

 Warm 
 Well perfused with palpable pulses 
 sweating is decreased and the skin may be dry and prone to fissures. 
 typical neuropathic ulcer ,  
 callus forming the edge  
 clean base. 
 commonly found on the pressure points (i.e. metatarsal heads and the he el).  
 Painless 
 These ulcers are the result of continuous trauma due to the lack of pain.. 
 10% of people have absent dorsalis pedis pulses. Therefore, their absence  does not 
indicate ischaemia. 
2. Ischaemic foot

2. Ischaemic foot  
 cool  
 pulseless 
 thin, shiny skin which often lacks hair 
 There may be atrophy of the subcutaneous tissues, 
 Intermittent claudication and rest pain may be absent due to co-existent neuropathy. 
 Ischaemic ulcers found on the dorsa or edges of the feet.  
 the nails are in poor condition.  
 Arterial ulcers typical present in patients with severe atherosclerosis or peripheral vascular 
disease.

disease.  
 Normally, the ulcer starts as a small injury that doesn ’t heal due to poor blood supply.  
 
 375

197 
  
Other types of ulcers 
 Infected ulcers are mal-odorous and often exude pus.  
 Venous ulcers   
 usually found on the gaiter area of the ankle.  
 Venous stasis ulcers typically present in the area around the ankle and result from venous 
reflux.

reflux.  
 The venous reflux causes congestion and dilated veins, which impair the transport o f 
fresh blood to the area. 
 Multi-layer bandaging  is most useful in reducing lower limb oedema and improving the 
chances of healing of venous ulcers.   
 An ankle brachial pressure index (ABPI) measurement is essential before 
beginning bandaging , as if there is significant arterial insufficiency, blood supply to 
the lower limb may be threatened. 
 
Manifestations

Manifestations  
(Range in severity from superficial paronychia to deep infection and gangrene) 
 Cellulitis 
 Myositis 
 Necrotising fasciitis  Septic arthritis 
 Tendonitis, and 
 Osteomyelitis. 
 
Risk factors of foot ulceration in diabetics 
 Neuropathy 
 vascular insufficiency  
 reduced neutrophil function  
 
Factors associated with an increased risk of plantar ulceration,  
 neuropathy disability score, loss of 10-g monofilament sensation

 foot deformity  
 However, the strongest predictive factor with respect to future risk of ulceration 
is either active ulceration or a history of a previous ulcer. 
 Callus formation at pressure areas is an important predictor of ulceration 
 Plantar ulceration is usually a consequence of neuropathy and minor skin trauma is 
probably the most common initiating event. 
Local signs of wound infection  
 Granulation tissue that becomes increasingly friable

 Yellow or grey moist tissue at the base of the ulcer 
 Purulent discharge, and 
 An unpleasant odour. 
Pathogens  
 The most common pathogens in acute, previously untreated superficial ulcers in dia betic 
patients are aerobic Gram positive bacteria ( particularly Staphylococcus aureus  and beta-
haemolytic Streptococci ). 376

198 
  In patients who have recently received antibiotics or who have deep tissue involvement,  
infection is usually caused by a mixture of aerobic Gram positive, Gram negative (for 
example, Escherichia coli ,Proteus , Klebsiella ) and anaerobic organisms (for 
example, Bacteroides , Clostridium ).

example, Bacteroides , Clostridium ). 
 Methicillin-resistant Staphylococcus aureus  (MRSA) is more common in patients who have 
been previously hospitalised or who have received antibiotic therapy, although increasingly it is 
community acquired. 
Treatment 
 Many leg ulcers have a mixed etiology so arterial and venous function should also be 
assessed here.  
 If infection is suspected, deep swab and tissue samples should be sent for culture an d broad-

spectrum antibiotics started. The presence of deep infection with abscess, cellulitis gangrene 
or osteomyelitis is an indication for hospitalisation. 
 Indications for urgent surgical intervention are: 
 A large area of infected sloughy tissue 
 Localised fluctuance and expression of pus 
 Crepitus in the soft tissues on radiological examination, and 
 Purplish discolouration of the skin (which indicates subcutaneous necrosis).

 Antibiotic treatment should subsequently be tailored according to the clinical response, cu lture 
results and sensitivity.  
 If osteomyelitis is present, surgical resection should be considered and antibiotics continued 
for four to six weeks. 
 Blood flow is often decreased with autonomic neuropathy hence sympathectomy m ay be 
performed to improve skin blood flow.  
 
 Neuropathic & ischaemic picture: 
neuropathic foot  ischaemic foot  
often warm  Cold foot

often warm  Cold foot  
Painless or abnormal neuropathic pain.  causes rest pain 
bounding pulses  nearly pulseless foot  
ulceration tends to occur on the plantar 
surface  Ulceration tends to be painful and often 
presents in the heal area  
It can be high arched, with toe clawing. there is often gravity- dependent reddening of 
the foot, which disappears on elevation of 
the foot. 
The two conditions can coexist, with a mixed ischaemic/neuropathic picture.  
 377

199 
  
This is a typical neuropathic ulcer , with callus forming the edge and a clean base .  
Adhesive capsulitis  
 Adhesive capsulitis (frozen shoulder) is a common cause of shoulder pain. aetiology of f rozen 
shoulder is not fully understood.

shoulder is not fully understood.   
 Adhesive capsulitis is a recognised musculoskeletal complication of diabetes . 
 40% of diabetic patients developing this problem at some stage. 
 occurs more commonly in women after age 50 
Feature (typically develop over days)  
 Pain (Night pain may interfere with sleep). 
 patients typically have a painful freezing phase, an adhesive phase and a  recovery 
phase

phase 
 Restricted both active and passive movement of the shoulder, usually in the absen ce of 
intrinsic shoulder disease.  
 The restricted active and passive movements confirm that this patient's problems are 
either capsular or articular in origin rather than periarticular tendon problems where 
active movements are generally more restricted than passive movements. 
 external rotation is affected more than internal rotation or abduction  
 The shoulder is tender to palpation,

 The shoulder is tender to palpation, 
 bilateral in up to 20% of patients 
 the episode typically lasts between 6 months and 2 years 
Diagnosis: 
 Radiographs of the shoulder show osteopenia. 
378

200 
  The diagnosis is confirmed by arthrography. 
 
 no single intervention has been shown to improve outcome in the long-term 
 treatment options include NSAIDs, physiotherapy, oral corticosteroids and intra-articular 
corticosteroids 

Charcot's foot (Charcot ’s arthropathy)  
In patients with long-standing diabetes and peripheral neuropathy, a red hot swollen foot  should 
raise suspicion of Charcot neuroarthropathy after exclude infection.  
 A Charcot joint is also commonly referred to as a neuropathic joint.  
 It describes a joint which has become badly disrupted and damaged secondary to  a loss of 
sensation.  
Incidence

Incidence  
 Occur in 1 in 750 people with diabetes mellitus, although this increases to 5 in 100 diab etics 
with documented neuropathy. 
Causes 
 The most common cause  is diabetes mellitus ): 
 Other causes 
 syringomyelia ( 20-40%) 
 long-standing syphilis (tabes dorsalis)  (5-10%) 
 poliomyelitis,  
 rheumatoid arthritis 
Pathophysiology   
 The pathophysiology  is thought to start with peripheral neuropathy. The lack of pain

sensation may mean that patients subject the foot joints (commonly the midfo ot) to stress 
injuries that lead to the Charcot process.  
 Charcot ’s is thought to occur due to increased blood flow as a result of neuropathy. This 
results in increased osteoclast activity and bone turnover; the foot is then susceptible to ofte n 
very minor trauma and destructive changes take place. 
 The pathology of this condition is thought to be due to sympathetic dysfunction,

excessive blood flow to the joint and osteoclast activity 
Feature s 
 The majority of patients are in their 50-60s, and they often present in the latter sta ges of the 
disease.  
 the foot and ankle is typically swollen, red and warm 
 infection is important to exclude.  
 normal C-reactive protein and white blood cell count  make osteomyelitis unlikely  
 typically less painful than would be expected given the degree of joint disru ption due to the

sensory neuropathy. However, 75% of patients report some degree of pain 
 
Stages : Four stages of Charcot neuropathy are recognised: 
 Stage 0  (inflammation): characterised by erythema and oedema, but no structural ch anges 379

201 
  Stage 1  (development): bone resorption, fragmentation and joint dislocation. Swelling, warm th 
and erythema persist but there are also radiographic changes such as debris formation a t the 
articular margins, osseous fragmentation and joint disruption

 Stage 2  (coalescence): bony consolidation, osteosclerosis and fusion are all seen on plain 
radiographs 
 Stage 3  (reconstruction): osteogenesis, decreased osteosclerosis, progressive fusion. Healing 
and new bone formation occur, and the deformity becomes permanent. 
 X-ray :   
 plain radiographs can be normal in the early stages  
 later on they show joint destruction, osteolysis, joint reorganisation and subluxation.

 Although not widely available, an indium-labelled white cell scan is the best way to 
differentiate between infective causes of this clinical presentation and Charcot ’s 
arthropathy.  
 Chronic untreated Charcot's foot results in either  
 'rocker-bottom' foot due to downward displacement and subluxation of the t arsus,  
 or medial convexity due to talonavicular joint displacement  
 or dislocation of the tarsometatarsal joints. 

 the most effective treatment is a period of immobilisation in a specially made cast  
 Immobilisation in a cast for 3 –6 months is the treatment of choice  
 this is thought to be complemented by use of bisphosphonates.  
 The reduction in bone reabsorption associated with bisphosphonates is thought to 
accelerate healing.  
 In stages 0 and 1 the treatment is: 
 immediate immobilisation  
 avoidance of weight-bearing

 avoidance of weight-bearing 
 A total-contact cast is worn until the redness, swelling and heat subside (generally 8- 12 
weeks, changed every 1-2 weeks to minimise skin damage) 
 After this the patient should use a removable brace for a total of four to six months. 
 Intravenous bisphosphonate treatment can benefit some patients. 
 tight glycaemic control, 
 Surgery is reserved for severe deformities that are susceptible to ulceration, and

where braces and orthotic devices are difficult to use.  
 Good control of blood glucose to reduce the risk of microvascular complications is associated 
with decreased incidence of Charcot ’s arthropathy, although once established, it cannot be 
reversed. 
 
 380

202 
Diabetic cheiroarthropathy 
 Diabetic cheiroarthropathy is a condition of limited joint mobility that occurs in subjects 
with diabetes. 
 characterised by thickening of the skin resulting in contracture of the fingers.

 causes limited motion of the fingers that the affected individual is unable to extend the  fingers 
to flatten the hand fully.  
 Typically both hands are affected. 
 reported in over half of patients with insulin-dependent diabetes and approxima tely three 
quarters of those with non-insulin-dependent diabetes. 
 occurs more frequently in those with a longer history of diabetes. 
 Treatment includes pain relief and/or anti-inflammatory drugs, physiotherapy and tight 
glycaemic control.

glycaemic control. 
 
Skin lesions in diabetes  
Necrobiosis lipoidica diabeticorum  
 a disorder of collagen degeneration with a granulomatous response, thickening of blood  
vessel walls, and fat deposition. 
 Causes 
 occurs in patients with type 1 diabetes, 
 It is usually related to diabetes, but can also occur in patients with rheumatoid 
arthritis

arthritis  
 may precede symptoms and signs of diabetes by several months.  
 more common in females 
 presents in young adults or in early middle life.  
381

203 
  Pathophysiology 
 The exact cause is unknown, but the leading theory has focused on diabetic 
microangiopathy. 
 Features 
 typically painless. 
 Beginning as a patch of erythema that spreads across the shin, begins to yellow 
and can then ulcerate.  

 Biopsy reveals granuloma formation with infiltration of lymphocytes, plasma cells and 
eosinophils. 
 Necrobiosis is often mistaken for eczema but rather than responding to steroids may 
actually deteriorate.  
 usually managed with support bandaging and the use of topical steroids. 
 Topical steroids is the most appropriate treatment to the non-atrophied areas

 the areas of already atrophied skin respond poorly to steroid therapy. 
 Small trials support the use of both Ciclosporin and Hydroxychloroquine as second line 
agents. 
 
Acanthosis nigricans  
 Acanthosis nigricans has a characteristic hyperpigmented, velvety surface.  
 Sites of lesions 
 It frequently occurs in the axillae, groins and in the skin fold of the neck and 
occasionally on the dorsum of the hand. 
 Causes

 Causes 
 endocrine disease (acromegaly, Cushing's syndrome, insulin resistant diabetes 
mellitus ) 
 polycystic ovary syndrome, and 
 paraneoplastic phenomenon (usually tumours of the GI tract, especially 
adenocarcinoma of the stomach). 
 Granuloma annulare   
 normally diffuse in diabetes and occurs as a ring of papules. 
 382

204 
  
Necrobiosis lipoidica dibeticorum  
 
Bullous disease of diabetes or ‘bullosis diabeticorum ’  
 Recurrent, dermal blisters containing sterile proteinaceous fluid with no inflammato ry 
component, in patients with diabetes.  
 It is rare, with a prevalence of 0.5%,

 It is rare, with a prevalence of 0.5%,  
 twice as common in males as in females.  
 The cause is unknown, although as they tend to occur on the acral surfaces a numbe r of 
theories are postulated including trauma and microangiopathy.  
 It tends to occur in patients with longstanding diabetes and multiple complications, many of  
whom will have neuropathy and nephropathy.  
 Blisters usually heal spontaneously after 2 –6 weeks , although they often recur in the same

place and can be complicated by secondary infection, which may lead to furthe r complications 
such as ulceration, osteomyelitis, and amputation.  
 Correct management is to leave the blister intact to reduce the risk of secondary 
infection.  
 
383

205 
Diabetes mellitus: Ramadan  
 
If a patient with type 2 diabetes mellitus does decide to fast:  
 they should try and and eat a meal containing long-acting carbohydrates prior to sunri se 
(Suhoor)

(Suhoor) 
 patients should be given a blood glucose monitor to allow them to check their glucose leve ls, 
particularly if they feel unwell 
 for patients taking metformin the expert consensus is that the dose should be split one-
third before sunrise (Suhoor) and two-thirds after sunset (Iftar) 
 expert consensus also recommends switching once-daily sulfonylureas to after sunset. For 
patients taking twice-daily preparations such as gliclazide it is recommended that a larger

proportion of the dose is taken after after sunset 
 no adjustment is needed for patients taking pioglitazone 
May 2012 exam: H/O type 2 diabetes on metformin500 mg tds, asks for advice regard his medication 
because he is due to start fasting for Ramadan soon . What is the most appropriate advice? 500 mg 
at the predawn meal + 1000 mg at the sunset meal  
DVLA: diabetes mellitus  
 
Type 2 vehicles (lorries, HGV)

Type 2 vehicles (lorries, HGV)  
 A recent change in the DVLA guidelines of May 2012 allows HGV drivers to retain their license  
even if taking insulin, providing they are able to meet a stringent set of criteria. 
 Criteria regarding driving for patient on insulin (and also apply to patients using other 
hypoglycaemic inducing drugs such as sulfonylureas): 
1) having no episodes of hypoglycaemia requiring the assistance of another person w ithin 
the preceding 12 months

the preceding 12 months 
2) evidence of good glycemic control - demonstrated by review of 3months of BM 
readings on insulin  
 to demonstrate adequate control, applicants will need to have used blood glucose 
meters with a memory function to measure and record blood glucose levels for at least  3 
months prior to submitting their application 
3) close BM monitoring (at least BD) 
384

206 
 4) full hypoglycaemia awareness,  
5) the ability to manage hypoglycaemia independently. 
6) here are no other debarring complications of diabetes 
 no visual field impairments.  
 From a practical point of view patients on insulin who want to apply for a Group 2 (HGV)

licence need to complete a D2 form. They may will also be required to produce a D4 Medical 
examination report. 
 
Type 1 vehicles (cars, motorcycles)  
 if on insulin then patient can drive a car as long as they: 
 have hypoglycaemic awareness,  
 not more than one episode of hypoglycaemia requiring the assistance of another person 
within the preceding 12 months  
  no relevant visual impairment.  
 Drivers are normally contacted by DVLA

 Drivers are normally contacted by DVLA 
 if on diet controlled alone , tablets or exenatide no need to notify DVLA. 
 
hypoglycaemic episodes  
 If a patient has two or more  episodes  of severe hypoglycaemia  then they need to inform the 
DVLA and not drive.  
 If a patient needs help to correct the hypoglycaemic episode then it is termed severe 
 When the DVLA is informed, the patient should be advised to inform the DVLA

themselves rather than breaking patient confidentiality, but if the patient repeatedly fails 
to follow this advice then the doctor should inform the DVLA  after telling the patient 
that he or she is doing so.  
Jobs that not allowed to subjects with insulin dependent diabetes  
 armed forces, 
 working offshore or aboard ships, 
 air pilot,  
 Police, Fire or driving in the post office (Traffic police driver) 
 driving emergency vehicles.  
 Offshore work (البحرية)

 Offshore work (البحرية)  
 
 Patient with diabetes who have had two hypoglycaemic episodes requiring help needs 
to surrender (تسليمtheir driving licence 
 If a patient needs help to correct the hypoglycaemic episode then it is termed severe 
hypoglycaemia 
 If a patient has two or more episodes of severe hypoglycaemia then they need to inform 
the DVLA and not drive.  
 385

207 
  
Insulinoma  
 
An insulinoma is a neuroendocrine tumour deriving mainly from pancreatic Islets of Langer hans cells  
Basics  
 most common pancreatic endocrine tumour 
  incidence of 1-2/million/year, 
 commoner in women 
 may be associated with the MEN-1 syndrome in around 10%;

 10% malignant, 10% multiple 
 of patients with multiple tumours, 50% have MEN-1 
 90% of them are less than 2 cm in size.  
 More of the insulin released by an insulinoma remains as pro-insulin, so that pro-insuli n levels 
are often raised as a proportion of total insulin levels. 
Features  
Whipple triad  is the clinical presentation of pancreatic insulinomas  and consists of: 
1. fasting hypoglycemia 
2. symptoms of hypoglycemia

2. symptoms of hypoglycemia 
3. immediate relief of symptoms after the administration of IV glucose 
 features of hypoglycaemia: typically early in morning or just before meal, e.g. diplopia, 
weakness , sweating, Tachycardia/palpitations etc 
 Memory loss 
 Seizures 
 Hunger 
 rapid weight gain may be seen 
 Patients eat in an attempt to avoid hypoglycaemia  
 and may avoid physical activity because this is also recognised as a trigger.  
 high insulin, raised proinsulin:insulin ratio

 high insulin, raised proinsulin:insulin ratio 
 high C-peptide 
Diagnosis 
 supervised, prolonged fasting (up to 72 hours) 
 If the patient develops symptoms, then a plasma glucose is measured and if low, insulin 
and C-peptide is then collected and the fast terminated.  
 After a 15 h fast, the cut-off normal limits for glucose are 2.5 mmol/l and 5 mU/l for 
insulin. 
 By 24 h, fasting leads to a detection rate of 78% for insulinoma. If the fast is ex tended to

72 h, this detection rate increases to 98%. 
 CT pancreas 
 To exclude possible drug administration, a sulphonylurea screen should be undertaken . 
386

208 
 Management 
 surgery 
 diazoxide and somatostatin if patients are not candidates for surgery 
September 2010 exam: H/O gained 10 kg in weight in the past 3 months + early morning sweating &  
double vision What is the most likely diagnosis?  Insulinoma

January 2010 exam: H/O weight gain & recurrent 'dizzy' episodes. blurred vision, sweating, 
headaches and palpitations. blood sugar 1.4 mmol/l. What is the single most useful test?  Insulin + C-
peptide levels during a hypoglycaemic episode (∆ insulinoma. Whilst supervised fasting is the investi gation of 
choice, if this option is not given  then insulin + C-peptide levels during an acute hypoglycaemic episode are useful)  
 
Glucagon  
 Action and function 
 stimulates glycogenolysis, at the same time inhibiting glycolysis and activating 
gluconeogenesis. 
 stimulates lipolysis.  
 stimulation of catecholamine secretion. 
 delays gastric emptying  
 reduces pancreatic exocrine secretions. 
Glucagonoma  
 Glucagonomas are small tumours, almost always found in the pancreas, and frequ ently 
malignant.  
 Very rare, with an annual incidence of 1 in 20 million, 
 They present with

 They present with   
 secondary diabetes mellitus 
 Over 90% of glucagonomas are associated with impaired glucose tolerance 
as a result of insulin antagonism   
 weight loss due to protein catabolism.  
 Neuropsychiatric features. 
 venous thrombo-embolism  
 necrolytic migratory erythema   
 in 75% of cases 
 Red, blistering rash. 
 The lesion starts as an indurated erythema at the perineum, face and nose.

  Within a few days blisters will cover the surface of the skin, which then crust 
and heal, leaving hyperpigmented skin.  
 This process takes 7-14 days, with lesions developing in one area while 
others are resolving.  
 At least 50% are metastatic at presentation, so prognosis is poor. 
 Measure plasma glucagon levels 
 Management 387

209 
  surgical cure rate is only 5% because these tumours have often metastasised many 
years before the patient presents.  
  Octreotide improves the skin rash but can have a detrimental effect on glucose 
control.  
 Combination chemotherapy with streptazocin and 5-fluorouracil (5FU) gives good

palliative results, as does hepatic embolisation.  
Maturity-onset diabetes of the young ( MODY)  
 characterised by the development of type 2 diabetes mellitus in patients < 25 yea rs old. 
 It is an important diagnosis as the therapy may be different compared with T1DM and T2DM. 
 MODY3 is particularly important to diagnose as many patients initially treated with 
insulin can in fact be managed with sulphonylurea.

 MODY is the commonest cause of monogenic B-cell dysfunction 
 It is thought that around 1-2% of patients with diabetes mellitus have MODY, and a round 90% 
are misclassified as having either type 1 or type 2 diabetes mellitus. 
Genetic 
 autosomal dominant condition.  
 typically develops in patients < 25 years 
 absence of autoimmune markers,  
 absence of insulin resistance  
 remains C-peptide +ve, even if insulin-treated.

 a family history of early onset diabetes is often present 
 ketosis is not a feature at presentation 
 patients with the most common form are very sensitive to sulfonylureas, insulin is not usu ally 
necessary 
Types 
 MODY 3  (HNF1A-MODY ) 
 the commonest form of MODY, 60% of cases 
 due to a defect in the HNF-1 alpha gene  (hepatic nuclear factor- 1) 
 characterised by: 
 ↑(HDL) cholesterol levels 
 Preserved insulin sensitivity 
 Low renal threshold for glucose (glycosuria)

 Low renal threshold for glucose (glycosuria) 
 Sulphonylureas  is the initial drug of choice  
 MODY 2   (GCK-MODY) 
 The second commonest MODY variant after MODY3 
 20% of cases 
 due to a defect in the glucokinase gene ( GCK  gene)  388

210 
  This gene helps the body to recognise how high the blood glucose level is in the body . 
When this gene isn ’t working properly the body allows the level of blood glucose to be 
higher than it should be.  
 Blood glucose are typically only slightly higher than normal, generally between 5.5-
8mmol/l.

8mmol/l.  
 often picked up through routine testing (eg during pregnancy). 
 90% of MODY2 patients are controlled on diet therapy alone. 
 Patients do not tend to get diabetes complications and do not require treatment. 
 All types of MODY apart from glucokinase carry a risk of the long-term complications of 
diabetes 
 MODY 5   (HNF1B-MODY) 
 Defect in HNF-1 beta gene. 
 associated with renal cysts , uterine abnormalities and gout as well as diabetes.

 Often the renal cysts can be detected in the womb before a baby is born.  
 bilateral renal cysts + Ĺ glucose  MODY related cyst formation  
 insulin treatment is usually necessary 
 
subacute presentation & negative antibodies suggests that  a diagnosis of  MODY most likely 
than type 1 diabetes  
 
September 2011 exam: Which one of the following statements regarding maturity-onset diabetes of 
the young (MODY) is true? There is usually a strong family history

September 2012 exam: A 25-year-old male develops type 2 diabetes mellitus. Which gene is most 
likely to be responsible? HNF-1 alpha  
 
Latent autoimmune diabetes of adulthood (LADA)  
 adult-onset, presence of diabetes associated autoantibodies, and no insulin tre atment 
requirement for a period after diagnosis.  
 constitutes approximately 10% of patients incorrectly labelled as type 2 diabetic.  
Feature

Feature  
 features consistent with type 1 diabetes (eg: weight loss)  
 despite the presence of islet antibodies at diagnosis of diabetes, the progression of 
autoimmune -cell failure is slow.  
389

211 
  In contrast to type 2 diabetes, patients are typically younger and without an incre ased body 
habitus.  
 In contrast to type 1 diabetes, insulin is not usually required in the early stages o f the disease.  
Diagnosis  
  may be aided through a Glutamic Acid Decarboxylase (GAD) Autoantibodies test and

evidence of other autoimmune diseases.   
 
Pregnancy: diabetes mellitus  (NICE 2015)  
The oral glucose tolerance test remains the investigation of choice for gestational diabetes  
 Diabetes mellitus may be a pre-existing problem or develop during pregnancy, gestational 
diabetes.  
 It complicates around 1 in 40 pregnancies.  
Risk factors for gestational diabetes  
1) BMI of > 30 kg/m 
2) previous macrosomic baby weighing 4.5 kg or above 
3) previous gestational diabetes

3) previous gestational diabetes 
4) first-degree relative with diabetes 
5) family origin with a high prevalence of diabetes (South Asian, black Caribbean and Middle  
Eastern) 
Importance of planning pregnancy  
 use contraception until blood glucose is controlled (assessed by HbA1c level)  
 Control  will reduce the risk of miscarriage, congenital malformation, stillbirth and neonata l 
death.  
 glucose target ranges as recommended for all people with type 1 diabetes:

 a fasting plasma glucose level of 5 –7 mmol/litre on waking and 
 a plasma glucose level of 4 –7 mmol/litre before meals at other times of the day. 
 HbA1c level below 48 mmol/mol (6.5%)   
 
Screening for gestational diabetes 
 Women who've previously had gestational diabetes:  
 oral glucose tolerance test (OGTT) should be performed as soon as possible after 
booking and at 24-28 weeks if the first test is normal.

 NICE also recommend that early self-monitoring of blood glucose is an alternative to the  
OGTTs 
 women with any of the other risk factors should be offered an OGTT at 24-28 wee ks 
 Be aware that glycosuria of 2+ or above on 1 occasion or of 1+ or above on 2 or mo re 
occasions detected by reagent strip testing during routine antenatal care may indicate 
undiagnosed gestational diabetes. If this is observed, consider further testing to exclud e 
gestational diabetes.

gestational diabetes. 
Diagnostic thresholds for gestational diabetes 
 these have recently been updated by NICE, gestational diabetes is diagnosed if either: 390

212 
  fasting glucose is ≥ 5.6 mmol/l 
 2-hour glucose is ≥ 7.8 mmol/l 
 If fasting blood glucose between 5.5 and 7.0 mmol/l then proceed to  75-g oral 
glucose tolerance test  
Management of gestational diabetes 
 newly diagnosed women should be seen in a joint diabetes and antenatal cli nic within a week

 women should be taught about self-monitoring of blood glucose 
 advice about diet (including eating foods with a low glycaemic index) and exercise sho uld be 
given 
 Aspirin should also be considered given the increased risk of pre-eclampsia. 
 if the fasting plasma glucose level is < 7 mmol//l: 
 trial of diet and exercise should be offered  
 if glucose targets are not met within 1-2 weeks of altering diet/exercise metformin 
should be started

should be started 
 if glucose targets are still not met insulin should be added to diet/exercise/met formin 
 glibenclamide should only be offered for women who cannot tolerate metformin or th ose 
who fail to meet the glucose targets with metformin but decline insulin treatment. 
 if at the time of diagnosis the fasting glucose level is ≥ 7 mmol/l: 
 insulin should be started 
 if the plasma glucose level is between 6-6.9 mmol/l , and there is evidence of complications

such as macrosomia or hydramnios:  
 insulin should be offered  
  fasting blood glucose  should be checked 6 -13 weeks postpartum  
Management of pre-existing diabetes 
 weight loss for women with BMI of > 27 kg/m^2 
 stop oral hypoglycaemic agents, apart from metformin, and commence insulin 
 folic acid 5 mg/day from pre-conception to 12 weeks gestation 
 detailed anomaly scan at 20 weeks including four-chamber view of the heart and outflow tracts

 tight glycaemic control reduces complication rates 
 treat retinopathy as can worsen during pregnancy 
  It is advised, however, if the patient has not had retinal screening within the last six 
months  to offer this urgently  as there can be rapid development of diabetic retinopathy 
in pregnancy. 
  In diabetes, patients should achieve good diabetic control prior to planning for preg nancy.  
 If this has not been achieved, then NICE advises contraception and to offer terminatio n

if pregnancy does occur due to increased risks in pregnancy.  
 
Patients with diabetes should have increased frequency of retinal screening during 
pregnancy due to increased risk of retinopathy 
 
Targets for self-monitoring of pregnant women (pre-existing and gestational diabetes)  
 391

213 
 Time Target 
Fasting 5.3 mmol/l 
1 hour after meals 7.8 mmol/l, or: 
2 hour after meals 6.4 mmol/l 
Prognosis 
 Abnormal glucose tolerance occurs as a de novo event in around 2 –3% of pregnant women, 
unfortunately their long-term risk of subsequent type 2 diabetes is as high as 40-50%.

 Women should be offered a further glucose tolerance test at the 6 week check, to rule 
out the possibility of continued abnormal glucose tolerance or type 2 diabetes.  
May 2009 exam: H/O 26 weeks pregnant has (OGTT): 14 mmol/l. ultrasound shows that the 
fetus is large for dates. What is the most appropriate management?  Start insulin (due to ĹĹ 
glucose & macrosomia. Aspirin should also be considered as she is at increased risk of pre-
eclampsia)

eclampsia)  
Lipids and obesity problems 
Obesity hormones   
 
Food intake regulation (ghrelin and leptin): 
  ghrelin  "hunger hormone"  
 regulate appetite   stimulates hunger  
 empty stomach  ĹĹghrelin  
 stretched stomach  ĻĻghrelin  
 secreted by GIT(mainly by the fundus of 
the stomach and the pancreas),  acts on 
hypothalamus to ĹĹ hunger, ĹĹgastric

hypothalamus to ĹĹ hunger, ĹĹgastric 
acid secretion and ĹĹGIT motility   
 acts synergistically with GnRH to 
stimulate growth hormone release  
 Leptin - the satiety hormone - has 
opposite effects from ghrelin.  
392

214 
  
Leptin ( the satiety hormone ) 
 synthesised within the adipocyte  
 plasma concentrations are directly related to adipocyte (fat) mass. 
 acts on  receptors within the arcuate nucleus within the hypothalamus  to produce satiety .

 when patients reach a certain peripheral fat mass, leptin acts as a lipostat to reduce f ood 
intake. 
 However, leptin resistance is seen, hence patients can continue to accumulate weight and  
addition of leptin does not curb food intake. 
 
Adiponectin  
Adiponectin —a unique adipokine with anti-atherogenic, anti-inflammatory and insulin-
sensitizing properties

sensitizing properties 
 
 adiponectin is a recently described adipokine  that has been recognized as a key regulator of 
insulin sensitivity  and tissue inflammation.  
 It is produced by adipose tissue (white and brown) 
 Actions 
 improve hepatic insulin sensitivity,  
 via AdipoR2 receptor  
 increase fuel oxidation [via up-regulation of adenosine monophosphate-activated 
protein kinase (AMPK) activity]  
 via AdipoR1 receptor  
 decrease vascular inflammation.

 decrease vascular inflammation. 
 Via T-cadherin (adiponectin-binding protein) 
 In contrast to other adipokines, adiponectin levels are inversely proportional to body fa t 
content.  
 Levels are reduced in  metabolic syndrome, diabetes and coronary artery disease.  
 Adiponectin antagonizes many effects of tumour necrosis factor-alpha(TNF-alpha) an d this, in 
turn, suppresses adiponectin production.

turn, suppresses adiponectin production.  
 adiponectin secretion from adipocytes is enhanced by thiazolidinediones (which also act to 
antagonize TNF-alpha effects).  
 PPAR -gamma upregulates HMW adiponectin and PPAR-alpha upregulates  adiponectin 
receptors (AdipoRs) 
 adiponectin may be the common mechanism by which TNF-alpha promotes, and the 
thiazolidinediones suppress, insulin resistance and inflammation.

 under pathophysiological conditions, such as obesity  and diabetes , only high molecular 
weight (HMW)  adiponectin was decreased ; therefore, strategies to increase only HMW 393

215 
 adiponectin may be a logical approach to provide a novel treatment modality for obesity-lin ked 
diseases, such as insulin resistance and type 2 diabetes. 
Obesity: therapeutic options 
The management of obesity consists of a step-wise approach:

1. conservative: diet, exercise 
 Diet and exercise have been shown to be ineffective over the long term . 
 More than 90% of people who attempt to lose weight gain it all back. 
2. medical 
3. surgical 
 
Dietary fat intake 
 The average daily energy consumption of a male is 2500 kcal and 2000 kcal for a female. 
These values are important when determining the dietary calorie restriction. 
 The current recommendations in the UK for fat intake are that:

 Total fat intake should be restricted to less than 30% of dietary energy. 
 Monounsaturated fats should provide around 12% of dietary energy. 
 Polyunsaturated fats should provide around 6% of dietary energy. 
 Saturated fats should provide no more than 10% of dietary energy.  
anti-obesity drug s 
 Indications: 
 body mass index (BMI) ≥ 30 kg/m2 in whom at least three months  of managed care 
involving supervised diet, exercise and behaviour modification fails.

 BMI ≥ 28 kg/m2 + risk factors  (eg: diabetes mellitus, coronary heart disease, 
hypertension and obstructive sleep apnoea)  
 Discontinuation: Anti- obesity drug treatment should be discontinued : 
  If weight loss is less than 5% after the first 12 weeks. 
 If the individual regains weight at any time whilst receiving drug treatment  
 Contraindications: 
 Combination drug therapy is contraindicated

 Combination drug therapy is contraindicated  
 drugs should never be used as the sole element of treatment (should only be prescri bed 
as part of an overall plan for managing obesity). 
 
Orlistat  
 Action   
 pancreatic lipase inhibitor,   
 blocks the breakdown and hence the absorption of dietary fat.  
 used in the management of obesity. 
  Adverse effects   
 faecal urgency/incontinence and flatulence. 394

216 
  If patients taking orlistat do not maintain a low-fat diet then they can suffer distre ssing, 
oily diarrhoea. This is why it is essential to combine orlistat therapy with an effective 
patient support programme.  
 A lower dose version is now available without prescription ('Alli').

  NICE have defined criteria for the use of orlistat:  
 It should only be prescribed as part of an overall plan for managing obesity in adults 
who have: 
 BMI of 28 kg/m^2 or more with associated risk factors ( (eg: diabetes mellitus, 
coronary heart disease, hypertension and obstructive sleep apnoea)) 
 BMI of 30 kg/m^2 or more in whom at least three months of managed care 

 continued weight loss e.g. 5% at 3 months 
 orlistat is normally used for < 1 year 
Sibutramine 
 withdrawn  January 2010 by the European Medicines Agency due to an increased risk o f 
cardiovascular events 
 centrally acting appetite suppressant (inhibits uptake of serotonin and noradrenaline at 
hypothalamic sites that regular food intake) 
 adverse effects include hypertension (monitor blood pressure and pulse during treatment),

constipation, headache, dry mouth, insomnia and anorexia 
 contraindicated in psychiatric illness, hypertension, IHD, stroke, arrhythmias 
Rimonabant,   
 was withdrawn  in October 2008 after the European Medicines Agency warned of serious 
psychiatric problems including suicide 
  a specific CB1 cannabinoid receptor antagonist, 
NICE recommendations are first to classify the level of obesity. 
Classification BMI kg/m2 
Healthy weight 18.5-24.9 
Overweight 25-29.9 
Obesity I 30-34.9

Obesity I 30-34.9 
Obesity II 35-39.9 
Obesity III 40 or more 
 
395

217 
  
Obesity: bariatric surgery 
 
Benefits 
 It is now recognised that for many obese patients who fail to lose weight with lifestyle a nd drug 
interventions the risks and expense of long-term obesity outweigh those of surgery .

 Reduces cardiovascular mortality   
 
Indications (NICE guidelines):   
 BMI ≥ 40 kg/m^2 ,  
 BMI ≥ 35 kg/m^2 and other significant disease (eg: type 2 DM, hypertension ,  sleep apnea )  
 If all appropriate non-surgical measures have failed to achieve or maintain 
adequate clinically beneficial weight loss for at least 6 months 
 they are receiving or will receive intensive specialist management  
 they are generally fit for anaesthesia and surgery

 they commit to the need for long-term follow- up 
 BMI > 50 kg/m2  
 Consider surgery as a first-line option  for adults with a BMI of more than 50 kg/m2 in 
whom surgical intervention is considered appropriate;  
 consider orlistat before surgery if the waiting time is long 
Types of bariatric surgery:  
 primarily restrictive: laparoscopic-adjustable gastric banding (LAGB) or sleeve gastrectomy

 primarily malabsorptive: classic biliopancreatic diversion (BPD) has now largely been replaced 
by biliopancreatic diversion with duodenal switch 
 mixed: Roux- en-Y gastric bypass surgery 
Which operation? 
 LAGB produces less weight loss than malabsorptive or mixed procedures but as it has fewer 
complications it is normally the first-line intervention in patients with a BMI of 30- 39kg/m^2 
 patients with a BMI > 40 kg/m^2 may be considered for a gastric bypass or sleeve

gastrectomy. The latter may be done as a sole procedure or as an initial procedure prior to 
bypass 
 primarily malabsorptive procedures are usually reserved for very obese patients (e.g. BMI > 60  
kg/m^2) 
Post-operative mortality  
 ranges from 0.1-2%.  
 The rate of post operative complications following bariatric surgery is no greater tha n other 
elective major abdominal operations  
396

218 
 Specific post bariatric complications  deoend on the procedure used: 
 Laparoscopic adjustable gastric band - band slippage, erosion, infection, pouc h dilatation, 
band/tubing leak, megaoesophagus. 
 Laparoscopic roux en y gastric bypass - stomal stenosis, internal hernia, malnutrition.

 Laparoscopic sleeve gastrectomy - reflux, staple line leak, sleeve dilatation and weigh t gain. 
Lipid disorders 
Etiology 
 Congenital (less common) 
 Hyperchylomicronemia  
 Familial hypercholesterolemia  
 Familial Combined Hyperlipidaemia  
 Remnant hyperlipidaemia (dysbetalipoproteinaemia) 
 Familial hypertriglyceridemia  
 Acquired (more common) 
 Obesity 
 Diabetes mellitus 
 Physical inactivity 
 Alcoholism

 Alcoholism 
 Hypothyroidism 
 Nephrotic syndrome  
 Cholestatic liver disease  
 Cushing's disease 
 Drugs:  
 oral contraceptive pill,  
 high-dose diuretic use,  
 metoprolol 
 
Genetic dyslipidemias  
WHO/Fredrickson classification :  
 Classification was devised before the importance of HDL as a prognostic indicator was 
recognized. 
 High triglycerides  are a component of each of these dyslipidemias  except  Fredrickson type

IIa (familial hypercholesterolemia). 
 The 2 most common  dyslipidemias are Fredrickson type II b (familial com bined 
hyperlipidemia) and type IV (familial hypertriglyceridemia). Together, these 2 dyslipide mias 
account for 85% of familial dyslipidemias. 
 
Types: 
WHO/Fredrickson classification:  397

219 
 Classification Name Lipid profile Etiology Notes 
Type 1 Familial Hyper-
chylomicronaemia Ĺ chylomicrons  Deficiency of Apo 
Cll or LPL 
(lipoprotein lipase)  
 typically presents 
with eruptive 
xanthoma  and 
abdominal colic. 
Type 11A Familial 
hypercholesterolaemia  ĹTC > 7.5  
ĹLDL -C > 4.9 LDL-receptor

ĹLDL -C > 4.9 LDL-receptor 
deficiency Heterozygous 
type is  Common 
Associated with  
tendon 
xanthoma  
Type 11B  Familial Combined 
Hyperlipidaemia  Ĺ LDL  
ĹVLDL  
ĹTG overproduction of 
apo B- 100 &(VLDL) 
by the liver  The commonest 
type (two thirds). 
Associated with 
glucose 
intolerance. 
 
Type 111 Remnant hyperlipidaemia 
(dysbetalipoproteinaemia) Ĺ IDL  Abnormal ApoE  palmar 
xanthoma is 
diagnostic 
fibrates are first 
line treatment 
Type 1V  Familial

Type 1V  Familial 
hypertriglyceridaemia  ĹTG 
ĹVLDL  Overproduction 
orĻcatabolism of 
VLDL ( due to ↓ 
LPL) often “polygenic ”. 
Common 
 
Chylomicronaemia  (type I ) 
 The episodes of abdominal pain, eruptive xanthoma and strong family history should 
lead you to think of a form of familial hyperlipidaemia. 
 Chylomicrons  are lipoprotein particles that consist of triglycerides (85 –
92%), phospholipids (6–12%), cholesterol (1–3%), and proteins (1–2%)

 Chylomicrons are formed in  the endoplasmic reticulum in the absorptive cells (enterocytes) of 
the small intestine.  
  The lymphatic vessels carry the chyle to the venous return of the systemic circulation . From 
there the chylomicrons supply the tissue with fat absorbed from the diet. 
 unlike the carbohydrates and proteins, the lipids from the diet bypass the hepa tic portal 
system, meaning the liver does not get "first crack" at them.

 Function : Chylomicrons transport lipids absorbed from the intestine to adipose, cardiac, and 
skeletal muscle tissue, where their triglyceride components are hydrolyzed by the activity o f 
the lipoprotein lipase, allowing the released free fatty acids to be absorbed by the t issues.  
 
 Chylomicronaemia is due to a circulating inhibitor of lipoprotein lipase (type 1c 
hyperlipidaemia ).  398

220 
  It typically presents with eruptive xanthoma and abdominal colic.  
 Associated particularly with severe hypertriglyceridaemia and not with large elevations in 
cholesterol.  
 There is no increased risk of atherosclerotic disease.  
 Complications include  
 retinal vein occlusion,  
  acute pancreatitis,

  acute pancreatitis,  
  steatosis  
 and lipidaemia retinalis.  
 
The following table shows the apolipoproteins present on the surface of various lipoproteins: 
Lipoproteins apolipoproteins  
Chylomicron Apo CII & Apo B48 
Chylomicron remnant Apo E 
VLDL Apo CII & Apo B100 
LDL Apo B100 
IDL Apo E & Apo B100 
HDL Apo A1 
 
Which protein deficiency is most likely to be associated with very high levels of plasma 
chylomicrons?  Apolipoprotein Cll

chylomicrons?  Apolipoprotein Cll  
Familial hypercholesterolaemia (FH)  (type IIa)    
Tendon xanthomata are diagnostic hallmarks of heterozygous familial hypercholesterolaemia 
(FH) 
 
 autosomal dominant  on the short arm of chromosome 19  
 Heterozygous  familial hypercholesterolaemia is one of the most common familial conditions, 
with a prevalence of about 1 in 500.  
 Homozygous familial hypercholesterolaemia is exceedingly rare - most patients die in their

teenage years from a myocardial infarction. 
 Heterozygotes rarely present before age 30. 
 caused by mutations in the gene which encodes the LDL-receptor protein  LDL-receptor 
deficiency  
 manifests by increased low density lipoprotein (LDL) concentrations (not chylomicrons) due to 
constitutional abnormalities and reduced numbers of the LDL receptor. 
 results in high levels of LDL-cholesterol which, if untreated, may cause early cardiovascular 
disease (CVD).

disease (CVD).  
 Tendon xanthomata are characteristic  
 genetic factor mechanisms 
 Failure to produce any LDL receptors 399

221 
  Failure of the LDL receptors to move to the cell surface  
 Abnormal receptor binding to LDL 
 Inability to internalise LDL for metabolism 
 
Clinical diagnosis  is now based on the Simon Broome criteria : 
 in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l or children TC > 6.7

mmol/l and LDL-C > 4.0 mmol/l, plus: 
1. for definite FH : tendon xanthoma  in patients or 1st or 2nd degree relatives or DNA-
based evidence of FH 
2. for possible FH : family history of myocardial infarction below age 50 years in 2nd 
degree relative, below age 60 in 1st degree relative, or a family history of raised 
cholesterol levels 
 
 the use of CVD risk estimation using standard tables is not appropriate in FH as they do not 
accurately reflect the risk of CVD

accurately reflect the risk of CVD 
 the maximum dose of potent statins are usually required 
 first-degree relatives have a 50% chance of having the disorder and should ther efore be 
offered screening. This includes children who should be screened by the age of 10 years if 
there is one affected parent  
 statins should be discontinued in women 3 months before conception due to the risk of 
congenital defects 
400

222 
 
Familial hypercholesterolaemia (FH)  (type IIa)  
 autosomal dominant,  on chromosome 19 
 prevalence  1 in 500 (the second most common). 
 Usually Heterozygous (because homozygous die in teenage years by MI)   
 caused by  LDL-receptor deficiency

 caused by  LDL-receptor deficiency  
 diagnosis  based on the Simon Broome criteria : 
 in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l or children TC > 
6.7 mmol/l and LDL-C > 4.0 mmol/l, plus: 
1. for definite FH : tendon xanthoma  in patients or 1st or 2nd degree relatives or 
DNA -based evidence of FH 
2. for possible FH : family history of myocardial infarction below age 50 years in 
2nd degree relative, below age 60 in 1st degree relative, or a family history of

raised cholesterol levels 
 statin (usually maximum dose) 
 screening for 1st degree (children by the age of 10 years) 
 
Question 
 A Fasting lipid profile shows an elevated cholesterol, reduced HDL-cholesterol, and normal 
triglyceride, in a patient with negative family history for any hereditary lipid disorder. Which  is the most 
likely cause of the observed disturbance in his lipid profile? 
 
401

223 
 Answer    Reduced tissue LDL uptake 
 Serum cholesterol is carried in: 
 In the fasting state  in LDL, VLDL, HDL 
 After a meal  chylomicrons  
 VLDL additionally contains triglyceride.  
 This patient's fasting lipid profile has shown a reduced HDL cholesterol and normal triglyceride .

Therefore, the elevated serum cholesterol in this patient is most likely due to an increase in  the 
level of LDL, not VLDL (because the triglyceride concentration is normal). 
 
Familial Combined Hyperlipidaemia (FCHL)  (type IIB)  
 The commonest type (two thirds) 
 affect around 1 person in every 100. 
 Etiology  
 It is autosomal dominant,  
 More likely it is caused by a combination of genes  working individually or together to affect 
the levels of blood fats.

the levels of blood fats.      
 caused by overproduction of hepatically-derived apo B-100 associated with very  low density 
lipoprotein (VLDL) 
 Apo B levels are strongly correlated with LDL phenotype B in FCHL families 
 Total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels are all 
elevated. 
 Triglycerides and cholesterol may not be raised until the age of 20 or 30. Only 20% of children 
have elevated triglycerides before the age of 25.

 Low levels of HDL-C are often associated with raised TG levels (eg, in familial combined 
hyperlipidaemia and in dyslipidaemia in type 2 diabetes).   
 can be diagnosed only on family studies 
 associated with:  
 Obesity,  
 insulin resistance, 
  hyperinsulinaemia,  
 glucose intolerance, 
  and hyperuricaemia 
 Pattern of raised blood fats 
People with FCH have a unique pattern of raised blood fats which put them at high risk of 
cardiovascular disease.  This includes:

cardiovascular disease.  This includes: 
 raised levels of VLDL particles – these are triglyceride  rich particles produced by the 
liver 
 elevated ApoB levels (each VLDL particle contains one particle of ApoB, so more V LDL 
means more ApoB) 
 fasting  triglyceride levels above 1.5mmol/l 
 LDL cholesterol particles that are smaller and more compact (dense) than normal  
  402

224 
 Large LDL vs small  
 Increased  large  buoyant low density lipoprotein (LDL) is seen in response to increased insulin 
sensitivity. It is thought to be less atherogenic than small  dense LDL. 
 
Which feature suggests a diagnosis of familial combined hyperlipidaemia (FCHL) rather than

heterozygous familial hypercholesterolaemia (FH)? 
 Presence of glucose intolerance  
 
HDL 
 Increased high density lipoprotein (HDL) is seen with exercise and modest alcohol 
consumption. 
 Diabetes causes low HDL 
 They contain apolipoprotein B- 100  
 Increased oestrogen levels, as caused by the contraceptive pill, lead to higher HDL levels.  
 Women have naturally higher HDL levels compared to men, due to higher oestrogen 
levels.

levels. 
 Low levels of HDL are associated with an increased risk of ischaemic heart disease  
 
Familial Combined Hyperlipidaemia (FCHL) (type IIB) 
 commonest type (two thirds)  
 prevalence  1% 
 caused by  Ĺapo B -100 & &(VLDL) 
 associated with: Obesity, glucose intolerance, and hyperuricaemia 
 feature  Ĺ LDL, ĹVLDL, ĹTG  
  premature cardiovascular disease 
 treatment  atorvastatin 
 
Remnant hyperlipidaemia  (type III)

Remnant hyperlipidaemia  (type III)  
A significantly elevated TG, despite normal VLDL and chylomicron concentrations, simply 
implies increased concentrations of IDL and chylomicron remnants. This can be due to apoE 
deficiency which results in the accumulation of IDL and chylomicron remnants in the plasma. 
Normally, these particles have apoE on the surface through which they are taken up by the 
liver. 
 
Palmar xanthomas are pathognomonic of dysbetalipoproteinaemia

(type III hyperlipoproteinaemia).  
Overview 
 rare cause of mixed hyperlipidaemia (raised cholesterol and triglyceride levels) 
 also known as Fredrickson type III hyperlipidaemia , broad-beta disease and 
dysbetalipoproteinaemia. 
Genetic 403

225 
  Autosomal recessive with variable penetrance 
  caused by mutation in apoprotein E  ( apo-e2 homozygosity) 
 usually requires a secondary exacerbating metabolic factor for expression of the phenotype. 
Therefore, secondary causes of hyperlipidaemia such as hypothyroidism, obesity, d iabetes

mellitus, renal insufficiency, unhealthy diet (high-calorie, high-fat diet) or alco hol are often 
encountered at diagnosis, 
 Plasma TG is mainly transported by chylomicron (in the postprandial state) and VLDL (in the 
fasting state) as well as intermediate-density lipoprotein (IDL) cholesterol.  
 After being released into the circulation by the intestinal tract and liver, chylomicron and VLDL

are subject to hydrolysis by capillary lipoprotein lipase (cLPL), mostly in the adipose tissue and 
muscles.  
 By losing its TG content, the chylomicron is converted to chylomicron remnant.  
 VLDL is converted to IDL and then to low-density lipoprotein (LDL) cholesterol.  
 Normally, these particles ( IDL and chylomicron remnants) have apoE on the surface through 
which they are taken up by the liver. 
 Decreased or lack of apolipoprotein E-containing lipoproteins   results in the

accumulation of IDL and chylomicron remnants in the plasma. 
 Remnant hyperlipidaemia is due to a combination of:  
1) abnormal ApoE receptor function  and   
2) metabolic disorder  such as diabetes, obesity or hypothyroidism.  
 Affected homozygotes may be asymptomatic until an additional insult occurs 
affecting lipoprotein metabolism, such as the development of obesity or diabetes  
mellitus. 
Features 
 Yellow palmar creases (palmar xanthoma is diagnostic ) 
 tuberous xanthomas

 tuberous xanthomas   
 Hypercholesterolaemia, typically 8-12 mmol/L 
 Hypertriglyceridaemia, typically 5-20 mmol/L 
 Normal ApoB concentration 
 
Consequences include: 
 premature cardiovascular disease and  
 pancreatitis.  
 
Diagnosis 
 Definitive diagnosis can be made by lipoprotein electrophoresis  or genotyping of 
apoprotein E.  
 fibrates are first line treatment 
 mode of action  Increased lipoprotein lipase activity via PPAR-alpha  404

226 
  The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to 
a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolip oprotein 
(apo)A-V, and to an inhibition of apoC-III expression.  
 The increase in plasma HDL-cholesterol depends partly on an overexpression of

apoA -I and apoA-II. 
 
Familial hypertriglyceridaemia  (type IV)  
 autosomal dominant condition  
 Affects 1 in 300 people.  
 Usually due to polygenic factors 
 May also be due to lipoprotein lipase deficiency  
 can be exacerbated by alcohol, glucocorticoids and thiazide diuretics  
 Features :  
 severe hypertriglyceridemia > 5.6 mmol/l  (>500 mg/dL) may cause pancreatitis  
 eruptive xanthomas   
  1- to 3-mm yellow papules that can erupt anywhere but are usually seen on

the back, chest, and proximal extremities.  
 Lipaemia retinalis   is a sign consistent with isolated hypertriglyceridaemia  : 
 visualization of lipemic blood in the retinal blood vessels  pale pink milky 
appearance to the retinal vessels or even to the retina itself.  
 raised very-low-density lipoprotein (VLDL) and triglyceride levels.  
 total cholesterol and LDL levels are typically normal  
 fibrates are generally used first-line

 fibrates are generally used first-line 
 the best option to reduce triglyceride is fibrate or omega 3 fatty acids  
 statins do reduce triglyceride levels and they may be indicated, particularly if there is mix ed 
hyperlipidaemia 
 Small dense LDL molecules  (LDL is not typically elevated in type 2 diabetes) 
 ĻĻ HDL  
 ĹĹTriglycerides  
 405

227 
  
Eruptive xanthomata  
 
Hypertriglyceridaemia  (NICE 2015)  
 
The commonest cause of a mild hypertriglyceridaemia is obesity secondary to a reduced 
efficacy of lipoprotein lipase activity and overproduction of VLDL. 
 
 Hypertriglyceridaemia may be primary (familial) or secondary.

 Secondary causes  include:  
 high alcohol intake 
 type 2 diabetes mellitus 
 Lipoprotein lipase hydrolyzes triglycerides in chylomicrons and very low-density 
lipoprotein (VLDL), releasing free fatty acids. This pathway is affected in 
diabetes, because lipoprotein lipase requires insulin for full activity.  
 Bad diabetic control (↑↑ H bA1c) leads to  hypertriglyceridaemia . As such 
the first priority in this patient is to improve the glucose control with a 
second oral agent.

second oral agent.  
 Hepatic fat content is a determinant of postprandial triglyceride levels in type 2  
diabetes, and increased hepatic fat is associated with elevated triglyceride levels.  
406

228 
  JBS2 guidelines suggest that all patients with type 2 diabetes should be 
prescribed a statin, even if their cholesterol is within the target range, although 
statin therapy impacts most on low- density lipoprotein (LDL) cholesterol.

 In patients with type 2 diabetes who have hypertriglyceridaemia despite optimal 
glucose control and statin therapy, treatments targeted for triglyceride reduction, 
such as niacin, fibrates or omega-3 fatty supplementation should be considered. 
 High triglycerides and low high-density lipoprotein (HDL) cholesterol are 
the commonest lipid abnormality seen in type 2 diabetes, and both are 
associated with increased cardiovascular risk.

associated with increased cardiovascular risk.  
 Studies indicated that  elevated triglyceride levels are associated with increased 
cardiovascular risk, particularly in the presence of low HDL cholesterol, a 
situation seen most commonly in patients with type 2  
 
hypertriglyceridaemia and raised transaminases are suggestive of increased hepatic fat  
associated with Non-alcoholic steatohepatitis (NASH)  
 
 renal disease 
 drugs (cyclosporin, oestrogens, corticosteroids)

 bulimia nervosa 
 pregnancy 
 Triglycerides above 1.7 are thought to be associated with around a 30% relative 
increase in cardiovascular disease events.  
407

229 
  Triglycerides were seen as the strongest independent risk factor for 
cardiovascular death in a patient with impaired glucose tolerance, ahead of other 
more established risk factors such as smoking, body weight or blood pressure.

 Triglyceride levels greater than 11.2 mmol/l (1000 mg)increase the risk of acute p ancreatitis 
 to prevent pancreatitis  reduce triglyceride levels to < 5.6 mmol/l (500 mg/dL). 
 elevated triglycerides associated with Increased insulin resistance  
 Triglyceride/HDL ratio is most predictive of insulin resistance.  
 TG/HDL can be used to stratify both future risk of the development of cardiovascu lar 
disease and future risk of diabetes mellitus.  
 
For people with a TG concentration > 20 mmol/l that is not a result of excess alcohol or poor 
glycaemic control, refer for urgent specialist review (i.e at a regional lipid clinic).  
 For people with a triglyceride concentration between 10 and 20 mmol/L:  
 Repeat the triglyceride measurement with a fasting test (following a meal, the 
chylomicron level rises in the serum which will lead to a rise in triglyceride levels)

 Review for potential secondary causes of hyperlipidaemia 
 Address lifestyle factors: encourage weight loss, healthy diet and exercise 
 Disordered free fatty acid handling is associated with increased central fat , 
increased cardiovascular risk, and hepatic steatosis. Weight loss is an important 
treatment option in this case.  
 Commence high-potency statins (atorvastatin, rosuvastatin) if unable to address the

triglyceride level through lifestyle measures. Monitor liver function tests and creatine 
kinase in these patients 
 Statins result in only a modest reduction in triglycerides versus their impact on 
LDL cholesterol.  
 Fibrates can also be used (for example fenofibrate). These lower triglycerides through  
increasing the activity of lipoprotein lipase  
 However, fibrates have not been shown to reduce cardiovascular events in the 
presence of diabetes, while statins have. Thus, an isolated

hypertriglyceridaemia in the presence of significant cardiovascular risk 
factors, in a patient not currently on a statin, should be managed with the 
introduction of a statin.  
 Fenofibrate increases HDL-C by 10-15% and reduces plasma TG by 15-20%.  
 Concomitant fibrate-statin use is associated with an increased risk of myopathy 
so evaluation of combination therapy for safety and tolerability is important. 
 Omega-3 -acid ethyl esters and nicotinic acid are other pharmacological options

 Trials of omega 3 supplementation suggest that it is associated with 
triglyceride reduction of up to 38%.  
 OMACOR (omega-3-acid ethyl esters) : Mode of action  Increases 
peroxisomomal beta-oxidation of fatty acids in the liver  
 Nicotinic acid  
 it lower both cholesterol and triglyceride concentrations by inhibiting synthesis 
and increases HDL-cholesterol when used in doses of 1.5-3g daily.  408

230 
  It is recommended for use by specialists in combination with a statin, where a 
statin alone has failed to adequately control dyslipidaemia.  
 Add of nicotinic acid   raise HDL cholesterol level by great amount  
 the value of nicotinic acid is limited by its side-effects (especially vasodilatation)

 may increase blood glucose in some patients.  many mechanisms have 
been suggested for this : 
 Since nicotinic acid inhibits triglyceride synthesis , it may be that the 
increased availability of free fatty acids stimulates hepatic glucose output 
by increasing gluconeogenesis or replacing glucose as the primary 
energy source.  
 Higher levels of fatty acids may also block glucose uptake by skeletal 
muscle.  
 Direct effects on beta-cell function have also been postulated.

 For people with a triglyceride concentration between 4.5 and 9.9 mmol/L, optimize the 
management of other CVD risk factors present.  
 
Lipoprotein lipase deficiency 
Pathogenesis : 
  Dietary triglycerides in cholesterol are packaged by gastrointestinal epithelial cells into large  
lipoprotein particles called chylomicrons.  
 chylomicrons bind to the enzyme lipoprotein lipase, which is located on endothelial sur faces. 
409

231 
   This enzyme is activated by a protein contained in the chylomicron, apolipoprotein Cll, 
liberating free fatty acids and monoglycerides, which then pass through the endo thelial cells 
and enter adipocyte or muscle cells.  
 Complete inactivation of either lipoprotein lipase or apolipoprotein Cll results in an

accumulation of chylomicrons (type I lipoprotein elevation) due to failure of conversion t o the 
chylomicron remnant particle. 
Presentation : 
  usually present in infancy with recurrent attacks of abdominal pain caused by pancre atitis.  
 eruptive xanthomas resulting from triglyceride deposition. 
Treatment  
 life- long  low-fat diet  
 This milky looking serum sample is due to 
hyperchylomicronaemia/hypertriglyceridaemia and is a

consequence of deficiency of lipoprotein lipase (LPL).  
 Causes: 
 primary condition (rare) : autosomal recessive loss of LPL 
 secondary to diseases (more common) such as: 
 Pancreatitis 
 Hypothyroidism 
 Type 1 diabetes 
 Alcoholism, and 
 Cushing's syndrome. 
 Apolipoprotein C- II deficiency (rare autosomal recessive 
hereditary disorder) is an inhibitor to lipoprotein lipase and may 
cause this type of appearance, but is extremely rare and 
manifests in childhood.

manifests in childhood. 
 
Question 
Analysis of a patient  lipoprotein profile shows a deficiency of apolipoprotein C -II. All other lipoproteins 
are normal. 
Which lipid profile is most likely to be shown? 
Answer  Elevated levels of both chylomicrons and VLDLs 
 Apolipoprotein C-II (Apo C-II) is an essential co-factor of lipoprotein lipase, which hydrolyze s 
triglyceride in chylomicrons and VLDLs. 
 
Hyperlipidaemia: xanthomata

Hyperlipidaemia: xanthomata 
 
The presence of tendon xant homata and ĹLDL, ĹT.chol ≡ HDL meet the diagnost ic criteria for 
familial hypercholes terolemia.  
 
410

232 
 Xanthomas 
 Tuboeruptive xanthomas  occur in type III hyperlipoproteinaemia  
 Eruptive xanthomas  are associated with hyperchylomicronaemia (type I and type V 
hyperlipoproteinaemia)  
 Xanthoma tendinosum , which are nodular swellings of tendons, usually occur in type II 
hyperlipoproteinaemia

hyperlipoproteinaemia  
 
Characteristic xanthomata seen in hyperlipidaemia:  
 
Palmar  xanthoma  
 remnant  hyperlipidaemia 
 may less commonly be seen in familial hypercholesterolaemia 
Eruptive  xanthoma  are due to high triglyceride levels and present as multiple red/yellow vesicles on 
the extensor surfaces (e.g. elbows, knees) 
 
Causes of eruptive  xanthoma 
 familial hyper triglycerid aemia 
 lipoprotein lipase deficiency 
 
Tendon  xanthoma , tuberous xanthoma, xanthelasma

 familial hyper cholesterol aemia 
 remnant hyperlipidaemia 
Xanthelasma  
 xanthomas that appear on the eye are called xanthelasmas  
 Xanthelasmas are yellow plaques on the medial aspects of the eyelids and are commo nly 
bilateral.   
 causes 
 familial hypercholesterolemia  
 primary biliary cirrhosis  
 also seen without lipid abnormalities 
 Management of xanthelasma, options include: 
 surgical excision 
 topical trichloroacetic acid 
 laser therapy 
 electrodesiccation 411

233 
  
xanthelasma  
 
___________________________________________________ _________ 
Hyperlipidaemia: secondary causes 
 
Causes of predominantly hypertriglyceridaemia 
 diabetes mellitus (types 1 and 2) 
 obesity 
 alcohol 
 drugs: thiazides, non-selective beta-blockers, unopposed oestrogen

 liver disease 
Causes of predominantly hypercholesterolaemia 
 nephrotic syndrome 
 cholestasis 
 Frank hypothyroidism is said to occur in 4% of patients with dyslipidaemias;  
 a raised thyroid-stimulating hormone (TSH)  & normal free T4 occur in 10% of 
patients with dyslipidaemia  
 Total cholesterol often improves to some degree with thyroxine therapy but statins migh t 
be required as well.  
Hyperlipidaemia: management  (NICE 2014) 
 
412

234 
  
Graphic showing choice of statin. 
 
Statins reduce all-cause mortality (not just cardiovascular mortality) in primary prevention  
Primary prevention - who and how to assess risk  
 A systematic strategy should be used to identify people aged over 40 years who are likely t o

be at high risk of cardiovascular disease (CVD), defined as a 10-year risk of 10% or greater.  
 NICE recommend we use the QRISK2  CVD risk assessment tool for patients aged <= 84 
years. Patients >= 85 years are at high risk of CVD due to their age.  
 QRISK2 should not be used in the following situations as there are more specific guideli nes for 
these patient groups: 
 type 1 diabetics 
 patients with an estimated glomerular filtration rate (eGFR) less than 60 ml/min and/or

albuminuria 
 patients with a history of familial hyperlipidaemia 
 NICE suggest QRISK2 may underestimate CVD risk in the following population groups: 
 people treated for HIV 
 people with serious mental health problems 
 people taking medicines that can cause dyslipidaemia such as antipsychotics, 
corticosteroids or immunosuppressant drugs 
 people with autoimmune disorders/systemic inflammatory disorders such as systemic 
lupus erythematosus 
Measuring lipid levels  
413

235 
  When measuring lipids both the total cholesterol and HDL should be checking to provide th e 
most accurate risk of CVD.  
 A full lipid profile should also be checked (i.e. including triglycerides) before starting a statin . 
The samples does not need to be fasting.

The samples does not need to be fasting. 
 
 When monitoring for dyslipidaemia in people with type 2 diabetes, Confirm d yslipidaemia using 
a repeat sample (fasting or non-fasting) before deciding on further management 
strategies. [new 2015]  
 In the vast majority of patient the cholesterol measurements will be fed into the  QRISK2 tool. If 
however the patient's cholesterol is very high we should consider familial hyperlipidaemia.

 NICE recommend the following that we should consider the possibility of familial 
hypercholesterolaemia and investigate further if the total cholesterol concentration is > 7.5  
mmol/l and there is a family history of premature coronary heart disease.  
 They also recommend referring people with a total cholesterol > 9.0 mmol/l or a non-HDL 
cholesterol (i.e. LDL) of > 7.5 mmol/l even in the absence of a first-degree famil y history of 
premature coronary heart disease.

premature coronary heart disease. 
Interpreting the QRISK2 result  
 Probably the headline changes in the 2014 guidelines was the new, lower cut-off o f 10-year 
CVD risk cut-off of 10%.  
 NICE now recommend we offer a statin to people with a QRISK2 10-year risk of >= 10%  
 Lifestyle factors are of course important and NICE recommend that we give patients the  option 
of having their CVD risk reassessed after a period of time before starting a statin.

 Atorvastatin 20mg should be offered first-line. 
Special situations  
 Type 1 diabetes mellitus 
 NICE recommend that we 'consider statin treatment for the primary prevention of CVD 
in all adults with type 1 diabetes' 
 atorvastatin 20 mg should be offered if type 1 diabetics who are: 
ĺ older than 40 years, or 
ĺ have had diabetes for more than 10 years or 
ĺ have established nephropathy or 
ĺ have other CVD risk factors 
 Chronic kidney disease (CKD)

 Chronic kidney disease (CKD) 
 atorvastatin 20mg should be offered to patients with CKD 
 increase the dose if a greater than 40% reduction in non-HDL cholesterol is not 
achieved and the eGFR > 30 ml/min. If the eGFR is < 30 ml/min a renal specialist 
should be consulted before increasing the dose 
 All patients with CVD should be taking a statin in the absence of any contraindication. 
 Atorvastatin 80mg should be offered first-line. 
 414

236 
  LDL should be treated to the secondary prevention target of <2.0 mmol/L and 
triglycerides to the 1.7 mmol/L target.  
Follow- up of people started on statins  
 NICE recommend we follow-up patients at 3 months 
 repeat a full lipid profile

 repeat a full lipid profile 
 if the non-HDL cholesterol has not fallen by at least 40% concordance and life style changes 
should be discussed with the patient 
 NICE recommend we consider increasing the dose of atorvastatin up to 80mg 
Lifestyle modifications  
Cardioprotective diet  
 total fat intake should be <= 30% of total energy intake 
 saturated fats should be <= 7% of total energy intake 
 intake of dietary cholesterol should be < 300 mg/day

 saturated fats should be replaced by monounsaturated and polyunsaturated fa ts where 
possible 
 replace saturated and monounsaturated fat intake with olive oil, rapeseed oil or sprea ds based 
on these oils 
 choose wholegrain varieties of starchy food 
 reduce their intake of sugar and food products containing refined sugars including fructose 
 eat at least 5 portions of fruit and vegetables per day 
 eat at least 2 portions of fish per week, including a portion of oily fish

 eat at least 4 to 5 portions of unsalted nuts, seeds and legumes per week 
Physical activity 
 each week aim for at least 150 minutes of moderate intensity aerobic activity or 75 minu tes of 
vigorous intensity aerobic activity or a mix of moderate and vigorous aerobic activity 
 do muscle strengthening activities on 2 or more days a week that work all major muscle groups 
(legs, hips, back, abdomen, chest, shoulders and arms) in line with national guidance  for the 
general population

general population 
Weight management 
Alcohol intake : males drink no more than 3-4 units/day and females no more than 2-3 units/d ay 
Smoking cessation 
lipid-lowering agents 
mechanism of action and adverse effects 
The following table compares the side-effects of drugs used in hyperlipidae mia: 
 
Drugs Mechanism of action Adverse effects 
Statins HMG CoA reductase inhibitors Myositis, deranged LFTs 415

237 
 Drugs Mechanism of action Adverse effects 
Ezetimibe Decreases cholesterol absorption in the small 
intestine Headache 
Nicotinic acid Decreases hepatic VLDL secretion Flushing, myositis 
Fibrates Agonist of PPAR-alpha therefore increases 
lipoprotein lipase expression Myositis, pruritus, cholestasis

Cholestyramine Decreases bile acid reabsorption in the small 
intestine, upregulating the amount of 
cholesterol that is converted to bile acid GI side-effects 
 
PPAR- α agonists (The fibrate)   ↓serum triglyceride levels and  ↑ HDL-cholesterol 
PPAR- Ȗ agonists  (the glitazones)  ↓free fatty acid levels  ↓insulin resistance  ↓blood glucose levels 
 
Statins 
 
Action

Statins 
 
Action 
 Statins inhibit the action of HMG-CoA reductase, the rate-limiting enzyme in hepatic 
cholesterol synthesis 
Indication 
 Statins are the first-line therapy for hypercholesterolemia 
 
Metabolism 
 Simvastatin,  atorvastatin  and lovastatin  are mainly metabolized by cytochrome P450 (CYP) 
3A4,  
 fluvastatin  and rosuvastatin  is metabolized by CYP2C9 ,  
 pravastatin  is excreted largely unchanged . 
 myopathy:

 myopathy:  
 includes myalgia, myositis, rhabdomyolysis and asymptomatic raised creatine kinase.  
 It is important to check the CK in all patients with statin related muscle symptoms to 
exclude these serious causes. 
416

238 
  Statins decrease the synthesis of coenzyme Q 10 and impair energy production within 
the muscle  
 Risks factors for myopathy include: 
 advanced age,  
 female sex,  
 low body mass index  
 presence of multisystem disease such as diabetes mellitus.

 Statin-associated myopathy occurs in up to 5% of those treated with statins and may b e 
exacerbated by the co-prescription of other drugs  (see interaction blow) 
 Myopathy is more common in lipophilic statins (simvastatin, atorvastatin) than relatively 
hydrophilic statins (rosuvastatin, pravastatin, fluvastatin) 
 Myalgia (muscle pain): continue treatment as long as creatinine phosphokinase (CK) 
remain normal  
 Statin-associated myopathy 
1. Muscle pain and weakness 
2. Ĺ CK

2. Ĺ CK  
3. May progress to rhabdomyolysis: rare but severe side-effect that may lead to 
myoglobulinuria ĺ AKI (Ĺ BUN and Ĺ creatinine)  
 Management of cardiovascular risk in case of  statin-induced myalgia . 
 Myalgia can gradually improve with time, dose reduction, or changing to an 
alternative statin.  
 Myalgia is a side effect of all statins but the incidence is probably less with 
rosuvastatin and pravastatin.

rosuvastatin and pravastatin.  
 Pravastatin and rosuvastatin are metabolised via different pathways when 
compared to simvastatin and atorvastatin.  
 Pravastatin may be suitable for primary prevention, but in high-risk secondary 
prevention patient, a stronger agent is required such as rosuvastatin.   
 Rosuvastatin can be effective at even low doses (5-10 mg). 
 Starting at a low dose and gradually titrating up can also minimise the risk of

side effects: for example, start at 5 mg of rosuvastatin. 
 
 Hepatotoxicity :  
 (∼ 2% of patients) 
 Ĺ LFTs due to the involvement of cytochrome P450 systems (CYP3A4 and CYP2C9) in 
the breakdown of statins  
 the 2014 NICE guidelines recommend checking LFTs at baseline, 3 months and 12 
months.  
 Treatment should be discontinued if serum transaminase concentrations rise to and 
persist at 3 times the upper limit of the reference range.

 If LFT are raised but less than twice the upper limit of normal.  
 The options are to reduce the dose or consider an alternative statin.  
 NICE advises reducing the dose in the first instance.  417

239 
  Fibrates and ezetimibe are generally not recommended in patients with type 2 
diabetes.  
 NICE suggests referral to a specialist if statins are completely not tolerated. 
 If there is a history of statin-related hepatitis or rhabdomyolysis, statins should generally 
be avoided in the future if possible.

be avoided in the future if possible. 
 statins may increase the risk of intracerebral haemorrhage in patients who've previously had  a 
stroke.  
 This effect is not seen in primary prevention.  
 For this reason the Royal College of Physicians recommend avoiding statins in patients 
with a history of intracerebral haemorrhage 
 
Maintain a high index of suspicion for rhabdomyolysis if muscle pain occurs after 
administering statins  
 
Who should receive a statin?

Who should receive a statin? 
 all people with established cardiovascular disease (stroke, TIA, ischaemic heart disease, 
peripheral arterial disease) 
 following the 2014 update, NICE recommend anyone with a 10-year cardiovascular risk >= 
10% 
 patients with type 2 diabetes mellitus should now be assessed using QRISK2 like other 
patients are, to determine whether they should be started on statinsStatins should b e taken at

night as this is when the majority of cholesterol synthesis takes place. This is especially true 
for simvastatin which has a shorter half-life than other statins 
 
Current guidelines for lipid lowering* 
Total cholesterol 
(mmol/l) LDL cholesterol 
Joint British Societies < 4.0 < 2.0 
National Service Framework for 
CHD < 5.0 < 3.0 
SIGN 2007 < 5.0 < 3.0 
*current NICE guidelines do not recommend a target cholesterol in primary prevention  
 
Drug interactions with statins

Drug interactions with statins 
P450 inhibitors ↑ CK and myopathy  
 
 Other lipid-lowering agents 
 Fibrates and Nicotinic acid 418

240 
  Both agents may also cause myopathy ĺ concomitant use with statins further  
increases the risk of myopathy 
 CYP3A4 inhibitors  
 HIV/HCV protease inhibitors 
 Macrolides (especially erythromycin and clarithromycin) 
 Azole antifungals 
 Cyclosporine

 Cyclosporine  
 azole antifungal 
 Antacid and antifungal agents are known to interact with atorvastatin. 
 Warfarin  and digoxin  have well-recognised interactions with atorvastatin and simvastatin. 
 Antacid  and antifungal  agents are known to interact with atorvastatin. 
 Agents which can precipitate Myopathy or rhabdomyolysis 
 calcium channel blockers ,  
 macrolide antibiotics,(eg:  Erythromycin  )

 macrolide antibiotics,(eg:  Erythromycin  ) 
 fibrates, 
  Amiodarone 
 Grapefruit juice  reducing the CYP3A4-mediated first-pass (a member of the 
cytochrome P450 system.)  Ĺ serum statins. 
 Bergamottin  is a constituent of grapefruit juice and is metabolised by the 
cytochrome p450 3A4 pathway. 
 
What to do in case of atorvastatin intolerance? 
 NICE guidance currently recommends starting high-dose statins in patients with type 2

diabetes and established cardiovascular disease (atorvastatin 80 mg).  
 If patient has been intolerant of atorvastatin at its maximum dose with myalgia or ra ised liver 
function tests (LFT less than twice the upper limit of normal),The options are: 
 NICE advises reducing the dose in the first instance.  
 NICE suggests referral to a specialist if statins are completely not tolerated (LFT ≥ twice 
the upper limit of normal)

the upper limit of normal) 
 Myalgia is a side effect of all statins but the incidence is probably less with rosuvastatin 
and pravastatin.  
 Starting at a low dose and gradually titrating up can also minimise the risk of side 
effects: for example, start at 5 mg of rosuvastatin. 
 
 Normally in pregnancy, cholesterol can increase by up to 50%   
 Omega-3 fatty acids can be used safely in pregnancy as monotherapy, and fu nction to 
decrease maternal TG levels.

decrease maternal TG levels.  
 With the exception of the bile acid sequestrants (BAS) such as cholestyramine , cho lesterol-
lowering medications should be stopped prior to pregnancy 
  (NICE) guidelines recommend stopping cholesterol-lowering medications 3 months b efore 
attempting to conceive. 419

241 
  
Which statin is associated with the lowest risk of rhabdomyolysis? 
 Fluvastatin  
 The lipophilic statins, simvastatin, lovastatin and cerivastatin are all associated with a 
higher incidence of rhabdomyolysis compared to hydrophilic statins.

 It is possible that the lipophilic statins have a greater ability to cross the myocyte cell 
membrane and cause direct effects on intracellular organelles. 
 Cerivastatin has been withdrawn from the market as the risk of rhabdomyolysis was 
considered unacceptably high. 
1. Active liver disease 
2. Muscle disorder 
3. Pregnancy, breastfeeding 
Fibrates  
Agents:  
 bezafibrate, fenofibrate, and gemfibrozil

 bezafibrate, fenofibrate, and gemfibrozil 
Mechanism of action:  
 activation of  the peroxisome proliferator-activated receptor alpha (PPAR –α) ĺ Ļ LDL, Ĺ HDL, 
ĻĻĻ triglyceride  
 ĹLDL  recept or-mediated clearance of LDL   Ļ LDL  
 increase high-density lipoprotein (HDL) synthesis.  
 This leads to a corresponding fall in triglycerides due to a fall in very low-den sity 
lipoprotein (VLDL), and a rise in HDL.  
 enhance lipoprotein lipase activity,

 enhance lipoprotein lipase activity,  
 fibrates inhibit the secretion of triglycerides from the liver and stimulates the clearanc e 
of triglycerides by activating lipoprotein lipase. 
 In total, they reduce triglycerides by 20 –60%, LDL by 5 –25%, and increase HDL by 15 –30%.  
Indication:  
 second-line drug of choice in hyperlipidemia, most effective for lowering triglycerides  
 Renal insufficiency  
 Liver failure 
 Gall bladder diseases 
Side effects

 Dyspepsia 
 Myopathy  
 Cholelithiasis (Cholesterol gallstones)  
 Ĺ LFTs  (hepatotoxicity) 
Interactions:  
 enhance the effect of other drugs by inhibiting hepatic CYP450 (e.g., sulfonylureas, warfarin)  420

242 
  
__________________________________________________________________  
Ezetimibe   
Ezetimibe  reduces the absorption of cholesterol through the gut. 
 selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesterol 
transporter NPC1L1) ĺ  Ļ LDL

transporter NPC1L1) ĺ  Ļ LDL   
 blocks cholesterol reabsorption at small intestine brush border via inhibiting 
NPC1L1 in the gut lumen. 
 Monotherapy: in contraindications or statin intolerance 
 When used as a monotherapy at a dose of 10 mg daily, ezetimibe reduces LDL 
cholesterol by around 20%. Increasing the dose further generally does not improve 
efficacy. 
 Combination therapy (statin and ezetimibe): in insufficient LDL cholesterol reduction by statins

 When used in conjunction with statins much greater LDL cholesterol reductions are 
seen. 
Side effects  (especially in combination therapy, otherwise rare):  
 Ĺ liver enzymes,   
 angioedema,  
 diarrhea,  
 myalgia 
Contraindication:  
 coadministration with a statin during active liver disease 
Nicotinic acid  (niacin ) 
 
Mechanism of action:

 inhibits lipolysis and fatty acid release in adipose tissue ĺ Ļ triglyceride and LDL synthesis, Ĺ 
HDL 
 Niacin lowers LDL-C and increases HDL-C by:  
 Ļ hepatic VLDL synthesis and secretion into circulation,  
 Ļ lipolysis in peripheral adipose tissue.  
Indication :  
 high LDL cholesterol and lipoprotein(a) levels (> 50 mg/dL) despite statin and ezetimibe 
therapy (or if statins are contraindicated)

therapy (or if statins are contraindicated) 
 Nicotinic acid is highly effective at raising high density lipoprotein (HDL) cholesterol   
 
421

243 
 Adverse effects  
 Flushing 
 NSAIDs (e.g., aspirin , ibuprofen) taken 30–60 minutes before niacin can 
prevent flushing by inhibiting prostaglandin synthesis.  
 Aspirin  is commonly given as a pretreatment to alleviate niacin-induced flushing.

 Alternatively, the use of an extended-release niacin formulation, which is associated with  
less flushing, can considered. 
 This flushing is thought to be mediated by prostaglandin release. 
 sometimes accompanied by paresthesias such as tingling or itching.  
 The flushing typically begins within an hour of niacin intake.  
 Niacin-induced flushing often subsides over a few weeks as a result of tachyphy laxis. 
 Hyperglycemia  (impaired glucose tolerance)

 Hyperglycemia  (impaired glucose tolerance) 
 Nicotinic acid  may increase blood glucose  ↑ HA1c in diabetics 
 suggested mechanisms for this: 
 nicotinic acid ↓ triglyceride synthesis  ↑free fatty acids: 
 ↑free fatty acids stimulates hepatic glucose output by increasing 
gluconeogenesis or replacing glucose as the primary energy source.  
 ↑free fatty acids  block glucose uptake by skeletal muscle.  
 Direct effects on beta-cell function have also been postulated.

 irritates the gastric mucosa, exacerbates gastroesophageal reflux. 
 It is contraindicated in patients with active peptic ulcer disease  
 Myositis 
 Hyperuricemia   precipitates acute gout 
 Ĺ LFTs  
 
Contraindications  
 Gout 
 Hemorrhage 
 Gastric ulcer 
 Cardiovascular instability 
 
Cholestyramine 
 bile acid sequestrant

 bile acid sequestrant  
 bind bile acids in the intestine to prevent reabsorption and recycling 
 forces liver to consume cholesterol in the process of making more bile salts 
 binds bile acids in the intestine   ĺ interruption of enterohepatic circulation (Ļ bile acid 
absorption and Ĺ bile acid excretion)  ĺ lowers chole sterol 
 The main effect on lipid profile  reduce LDL cholesterol (Ļ unbound LDL), 422

244 
  causes Ĺ in LDL -receptor synthesis 
 management of hyperlipidaemia. 
 Combination treatment with statins in hypercholesterinemia 
 Digitoxin overdose 
 Pruritus associated with elevated bile acid levels (cholestasis) 
 Bile acid diarrhea 
 Bowel obstruction

 Bowel obstruction 
 occasionally used in Crohn's disease for treatment resistant diarrhoea. 
 abdominal cramps and constipation 
 decreases absorption of fat-soluble vitamins (e.g: vitamin D absorption will be reduced ) 
 cholesterol gallstones 
 Ĺ LFTs  
 Myalgia 
 may raise level of triglycerides 
 Hypertriglyceridemia  > 300 –500 mg/dL 
 Hypertigylceridemia-induced pancreatitis 
Drug interactions

Drug interactions   
 warfarin, digoxin, fat-soluble vitamins 
OMACOR (omega-3-acid ethyl esters)  Increases peroxisomomal beta-
oxidation of fatty acids  
 omega-3 fatty acids make up only 30–50% of many fish oil supplements, whereas Omacor has 
90% omega-3 fatty acids. 
Action 
 decreased serum triglyceride concentrations by 25-30%.

 The synthesis of triglycerides is inhibited through reduced production of triglyce rides in the 
liver, as EPA and DHA are poor substrates for the enzymes responsible for triglyceride 
synthesis. 
 EPA and DHA also inhibit esterification of other fatty acids.  
 Omacor increases peroxisomomal beta-oxidation of fatty acids in the liver. 
unwanted effects  
 Ĺ LDL -C levels 
 
 423

245 
Tangier disease  
 Tangier disease is an extremely rare autosomal recessive metabolic disorder. 
 Characteristics of Tangier disease include: 
 Decreased levels or even a complete absence of high-density lipoproteins (HDL)

concentrations in the plasma 
 Low cholesterol levels in the plasma 
 Increased cholesteryl esters in the tonsils, spleen, liver, skin and lymph nodes. 
 One easily seen characteristic usually found in children with Tangier disease is the 
presence of enlarged, yellow-orange tonsils. 
Abetalipoproteinemia 
 rare autosomal recessive  disorder  
  the microsomal triglyceride transfer protein is absent.

 Deficiency of apolipoprotein B-48 and B-100 .  
 both necessary for chylomicron formation and fat absorption. 
 leads to deficiency of LDL, VLDL and chylomicrons.  
Features 
 fat malabsorption (chylomicrons accumulate in intestinal villi and prevent absorption)  
 deficiency of fat-soluble vitamins (A,D,E,K) .  
 low calcium and phosphate levels, suggestive of vitamin D deficiency. 
 frothy or foul-smelling stools (Steatorrhoea) 
 Fatty liver.

 Fatty liver. 
 neurologic symptoms : ataxia, cognitive decline  
 deficiency of vitamin E, especially, is responsible for the  neurologic symptoms   
 crucial substance for myelin formation and antioxidant  properties 
 Hypocholesterolaemia syndrome resembling Friedreich's ataxia 
 low visual acuity, caused by:  
 Retinitis pigmentosa  
 fundoscopy reveals retinitis pigmentosa. 
 Vitamin A deficiency. 
 acanthocytosis,

 acanthocytosis,  
 seen in the peripheral smear (irregularly distributed spicule in red blood cells).  
 hemolytic anemia 
 failure to thrive  
 muscle weakness. 
Treatment 
 high-dose vitamin E  and  
 restriction of long-chain fatty acids. 
 424

246 
  
Gynaecomastia 
 Gynaecomastia describes an abnormal amount of breast tissue in males and is usuall y caused 
by an increased oestrogen: androgen ratio .

by an increased oestrogen: androgen ratio .  
 It is important to differentiate the causes of galactorrhoea (due to the actions of prolactin o n 
breast tissue) from those of gynaecomastia   
Causes of gynaecomastia  
 physiological: normal in puberty 
 syndromes with androgen deficiency: 
Kallman's, Klinefelter's (47, XXY 
karyotype)  
 testicular failure: e.g. mumps 
 liver disease  testicular cancer e.g. seminoma  
secreting hCG 
 ectopic tumour secretion 
 hyper thyroidism

 hyper thyroidism 
 haemodialysis 
 starvation/refeeding 
 drugs: see below 
 
Drug causes of gynaecomastia ( 10-25% of cases)  
Relatively Common causes 
 spironolactone (most common drug 
cause) 
 cimetidine 
 digoxin 
 cannabis 
 diamorphine 
 cyproterone 
 finasteride 
 gonadorelin analogues e.g. Goserelin, 
buserelin 
 oestrogens, anabolic steroids Very rare drug causes of gynaecomastia 
 tricyclics 
 calcium channel blockers

 calcium channel blockers 
 heroin 
 busulfan 
 methyldopa 
 
 September 2010 exam: H/O developed excessive amounts of breast tissue bilaterally. Which 
one of the following drugs is most likely to be responsible? Goserelin (Zoladex)  
Pregnancy: physiological changes – endocrine 
pregnancy  Ĺ oestradiol & prolactin + Ļ LH/FSH .

The elevated oestradiol with suppressed luteinising hormone/follicle-stimulating hormon e (LH/FSH) 
and an elevated prolactin concentration. With the recent amenorrhoea ,  the most likely diagnosis is 
pregnancy. 
Progesterone 425

247 
  during the first 2 weeks stimulates the fallopian tubes to secrete the nutrien ts the 
zygote/blastocyst requires 
 placenta starts production at 6 weeks and takes over at 12 weeks 
 progesterone inhibits uterine contractions by: 
 Inhibiting production of prostaglandi ns 
 Decreasing sensitivity to oxytocin

 Decreasing sensitivity to oxytocin 
 stimulates development of lobules and alveoli 
Oestrogen 
 oestriol is major oestrogen (not oestradiol) 
 stimulates the continued growth of the myometrium 
 stimulates the growth of the ductal system of the breasts 
Prolactin 
 increase during pregnancy probably due to oestrogen rise 
 initiates and maintains milk secretion of the mammary gland 
 essential for the expression of the mammotropic effects of oestrogen and progesterone

 oestrogen and progesterone directly antagonises the stimulating effects of prolactin on milk 
synthesis 
hCG 
 secreted by syncitiotrophoblast, stimulated by GnRH produced in adjacent cytotrophoblast 
 can be detected within 9 days, peak secretion at 9 weeks 
 mimics LH, thus rescuing the corpus luteum from degenerating and ensuring early o estrogen 
and progesterone secretion 
 stimulates production of relaxin 
 may inhibit contractions induced by oxytocin

 may inhibit contractions induced by oxytocin 
 Beta-HCG has a degree of thyroid stimulating activity  ↓↓ (TSH).  No intervention is 
necessary  
 
Thyroid hormones 
 Elevated total T4 is a normal finding at third trimester  of pregnancy due to increased 
thyroid binding globulin. 
  Elevated thyroid hormones with suppression of TSH may be considered a normal varian t in 
the early stages of pregnancy if there is a history of hyperemesis.

  TSH falls in the first and second trimester, and increases in the third trimester.  
 Thyroid binding globulin increases during pregnancy.  
 There is an increases in triiodothyronine (T3) and thyroxine (T4), but free T4 and T 3 fall in the 
third trimester.  
 Also 
 Relaxin: suppresses myometrial contractions and relaxes the pelvic ligaments and pubic 
symphysis 
 Human placental lactogen  (hPL): has lactogenic actions (insignificant with respect to

prolactin) - antagonises insulin, therefore making less glucose available to the mother - 
enhances protein metabolism 426

248 
 Telogen phase 
 The telogen phase is the resting phase of the hair follicle.  
 Due to extreme stress  shedding of hair leading to loss of thickness  loss of hair.  
 It occurs as a normal phenomenon one to three months after pregnancy.

 No treatment is required ( only reassurance ) and hair thickness eventually recovers without 
further intervention.  
Physiological effects of LH, FSH, and sex hormones 
 ♀: Ovaries  
 FSH:  follicular maturation ĺ  ↑ estrogen  (see effects of estrogen and associated 
diseases) 
 LH: Ĺ estrogen, ovulation , and ↑ progesterone   
 ♂: Testicles  
 FSH:  production of sperm, ↑ inhibin

 FSH:  production of sperm, ↑ inhibin  
 LH: stimulation of Leydig cells ĺ ↑ production  of testosterone  
 Effects of testosterone 
 Development of male sexual characteristics during puberty 
 Spermatogenesis 
 Increased libido  
 Anabolic effects  
 Bone formation, growth  
 Muscle-building effects 
 
427

249 
Dihydrotestosterone (DHT) 
 Testosterone is a steroid hormone and can be converted to oestradiol. 
 It binds to intracellular receptors  and is mostly bound to sex-hormone binding globulin.

 LH stimulates testosterone production and FSH spermatogenesis  
 Testosterone is responsible for the development of internal genitalia and sperma togenesis.  
  It is converted to dihydrotestosterone (DHT) in the body by the enzyme 5α -reductase.  
 DHT is a more active compound than testosterone and is involved in the expression of 
male secondary sex characteristics. 
 The absence of 5α -reductase or the absence of DHT receptors leads to testicular feminisation.

 Dihydrotestosterone (DHT) is responsible for the differentiation of the penis, scrotum an d 
prostate during fetal development and early life.  
 In late adulthood, DHT is responsible for prostate growth, male pattern baldness, and 
sebaceous gland activity.  
 Testosterone is converted by the enzyme 5α-reductase to DHT to allow for the development of 
male external genitalia. Patients with 5α -reductase deficiency will have ambiguous genitalia at

birth until they reach puberty, when the testosterone surge causes growth of external ma le 
genitalia, however, these patients are otherwise healthy.  
 obesity  lowered sex hormone binding globulin (SHBG) concentrations low 
testosterone 
 insulin downregulates SHBG expression and secretion and thus the hyperinsulinae mia 
of obesity leads to lower SHBG levels .  
 Measurement of his SHBG would confirm low levels and imply that free testosterone 
concentrations are normal

concentrations are normal  
 some people use a ‘free androgen index ’ for the calculated free testosterone though 
there is debate about its utility in this situation. 
 Ļ testosterone is due to either  
1. Ļ free level 
 Due to Ļ production (Leydig and pituitary dysfunction) 
 Lead to Ĺ synthesis of SHBG 
2. Ļ activity at receptor 
 often due to androgen receptor deficiency 
 testosterone therapy: side effects 
 Erythrocytosis leading to elevated haematocrit

 Erythrocytosis leading to elevated haematocrit 
 Haematocrit should be measured 3-6 months after initiating therapy and yearly 
thereafter.  
 Guidelines suggest that if haematocrit is increased and no other underlying 
cause is found, the dose should be down-titrated. 
 PSA, haematocrit, LFTs, and lipid levels need to be monitored serially. 
  Androgen replacement therapy is contraindicated in patients with prostate cancer and 
breast cancer. 
 428

250 
 testosterone secreting tumour  of either ovarian or adrenal origin would typically cause a 
testosterone concentration above 7 nmol/L and would switch off LH/FSH with consequent hy po-
oestrogenism. 
Hormonal changes in weight-restricting adults 
 ↑↑ GH

 ↑↑ GH 
 ↓↓ LH 
 Normal Prolactin  
 T3 and T4 are often low-normal, with a normal (TSH). 
 ↑↑ Cortisol , often fail to suppress with dexamethasone. 
 The most likely reason for the elevation in Cortisol is a stress response related to starvation. 
 Weight gain will lead to a restoration of the normal menstrual cycle.  
___________ _________________________________________________ 
Polycystic ovarian syndrome (PCOS)

Polycystic ovarian syndrome (PCOS) 
 
 PCOS is a complex condition of ovarian dysfunction thought to affect between 5-20 % of 
women of reproductive age. 
  The aetiology of PCOS is not fully understood. Both hyperinsulinaemia  and high levels of 
luteinizing hormone are seen in PCOS and there appears to be some overlap with the 
metabolic syndrome. 
Features  
 Oligo/amenorrhoea 70% 
 hirsutism, acne (due to hyperandrogenism)   60% 
 obesity  35%  
 subfertility and infertility 30%.

 subfertility and infertility 30%.  
 Chronic anovulation is the mechanism for infertility 
 acanthosis nigricans  (due to insulin resistance) 
  psychological symptoms  
 Clitoromegaly is seen occasionally in PCOS but is normally associated with very high 
androgen levels. If clitoromegaly is found then further investigations to exclude an 
ovarian or adrenal androgen secreting tumour are required.  
 pelvic ultrasound: multiple cysts on the ovaries

 transvaginal ultrasound is said to have 91% diagnostic sensitivity  
 The presence of more than eight follicular cysts of less than 10 mm and increase d 
ovarian stroma is sufficient to make the diagnosis. 
429

251 
  FSH, LH, prolactin, TSH, and testosterone are useful investigations: 
  FSH will be normal or low, while LH will be elevated. 
 Increased LH causes hyperplasia of ovarian theca cells. 
 Increased LH  causes increased testosterone and androstenedione

 Raised LH:FSH ratio is a 'classical' feature  but is no longer thought to be useful in 
 LH/FSH ratio is normally about 1:1 in premenopausal women, but with PCOS a 
ratio of greater than 2:1 or 3:1 may be considered diagnostic.  
 Prolactin may be normal or mildly elevated. 
 10% of patients with PCOS have hyperprolactinaemia, the aetiology of which is 
uncertain 
 Testosterone  may be normal or mildly elevated  however,  if markedly raised 
consider other causes

consider other causes  
 The appropriate initial biochemical investigation  
 Normal or elevated testosterone, but with a low sexhormone-binding globulin 
(SHBG) level, resulting in a high free androgen index. 
 The significance of the sex hormone binding protein is that Sex hormone 
binding globulin is lower in PCOS. The reasons include that androgens 
reduce the globulin production, whereas oestrogen promotes production.  
It is a protein for transport of hormones in the blood.

 hyperestrogenism  
 Increased androstenedione/testosterone in PCOS can be peripherally converted 
in adipose tissue to estrone by aromatase. 
  increased circulating levels of estrone  endometrial hyperplasia  which is 
a precursor to endometrial carcinoma 
 
 check for impaired glucose tolerance 
 hyperinsulinaemia  (insulin resistance  high circulating insulin levels due to 
peripheral insulin resistance).  
 10% develop frank type 2 diabetes mellitus.

 10% develop frank type 2 diabetes mellitus. 
 
long term complication of PCOS: 
 risks of diabetes  (due to peripheral insulin resistance),  
 sleep apnoea,  
 endometrial cancer, 
 mental health disorders.  
 
 According to the Rotterdam Consensus,  two of the following three criteria are required for the 
diagnosis of the PCOS: 
1. oligo-/anovulation 
2. hyperandrogenism 
 clinical (hirsutism or less commonly male pattern alopecia) or 430

252 
  biochemical (raised free androgen index or free testosterone) 
3. polycystic ovaries on ultrasound. 
 
General 
 Weight reduction  
 the gold-standard treatment for PCOS , and improves ovulation, androgen levels, 
hirsuitism and metabolic features associated with insulin resistance.

 A loss in weight of only 5% reduces hirsuitism by up to 40%. 
 if a women requires contraception then a combined oral contraceptive (COC) pill may help 
regulate her cycle and induce a monthly bleed (see below) 
Hirsutism and acne 
 For associated hirsutism  Dianette® (cyproterone acetate) combined oral 
contraceptive pill (COC) is the most effective,  along with cosmetic treatments like waxing, 
shaving, plucking or electrolysis.

shaving, plucking or electrolysis.  
 Possible options include a third generation  COC  which has fewer androgenic effects 
or co-cyprindiol  which has an anti-androgen action. Both of these types of COC may 
carry an increased risk of venous thromboembolism 
 Co-cyprindrol  because it contains cyproterone, an anti-androgen, may be more 
effective than the COCP  in controlling acne and hirsuitism and acne in PCOS. 
 if doesn't respond to COC then topical eflornithine may be tried

 spironolactone, flutamide and finasteride may be used under specialist supervisio n 
  used for its anti-androgenic properties 
 A Cochrane meta-analysis has suggested that metformin is not effective in controlling  
hirsuitism and acne versus other options such as the COCP or co-cyprindrol 
Infertility 
 NICE guidelines from 2013 recommend weight loss as the most important initial  step.  
 anti-oestrogen therapies such as clomifene   the most effective treatment

 work by occupying hypothalamic oestrogen receptors without activating them. This 
interferes with the binding of oestradiol and thus prevents negative feedback inhibition 
of FSH secretion 
 metformin is also used, either combined with clomifene or alone, particularly in patients who  
are obese but is not a first line treatment  
 gonadotrophins : usually reserved for patients who are resistant to clomifene  
Other notes

Other notes  
 Surgical intervention with wedge ovarian resection can reduce  androgen secretion and 
symptoms. 
 
May 2009 exam: H/O infertility with PCOS. Apart from advising her to lose weight, which 
intervention is most effective in increasing her chances of conceiving? Clomifene (if 
clomifene – the first line -   is not an option, metformin – the second line - is the right answer)  
 
September 2009 exam: Which finding is most consistently seen in polycystic ovarian

253 
  
January 2012 exam: What is the mechanism of action of metformin in PCOS?  Increases 
peripheral insulin sensitivity  
 
Hirsutism and hypertrichosis 
 hirsutism is often used to describe androgen-dependent hair growth in women

 hypertrichosis used for androgen-independent hair growth 
Hirsutism 
 Excessive male pattern hair growth in women (e.g., on the chin, above the upp er lip, 
and around the umbilicus) 
 causes 
 idiopathic (the  most common ) 
 excess androgen (10% of cases) 
 Although hirsutism is generally associated with hyperandrogenemia, one-half of 
women with mild symptoms  have normal androgen levels . 
 Polycystic ovarian syndrome is the most common causes of hirsutism

 accounting for three out of every four cases. 
 Cushing's syndrome 
 congenital adrenal hyperplasia 
 androgen therapy 
 obesity: due to peripheral conversion oestrogens to androgens 
 adrenal tumour 
 androgen secreting ovarian tumour 
 Rapid onset of hirsutism 
 Virilization (e.g., clitoromegaly, increased muscle mass, loss of female 
body contour) 
 Palpable abdominal or pelvic mass 
 Early morning total testosterone level greater than200 ng per dL (6.94 
nmol per L) 
 drugs

nmol per L) 
 drugs 
 
 Features of hyperandrogenemia  
 hirsutism, 
 could be asymptomatic  
 acne,  
 menstrual dysfunction,  
 alopecia,  
 Assessment of hirsutism 
 Ferriman-Gallwey scoring system: 9 body areas are assigned a score of 0 - 4, a score > 
15 is considered to indicate moderate or severe hirsutism 
 Work- up 432

254 
  evaluation is focused on testing for endocrinopathies and neoplasms, such as polycystic 
ovary syndrome, adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and 
androgen-secreting tumors. 
 Women with mild hirsutism and normal menses do not require laboratory workup and 
can be treated empirically.

can be treated empirically. 
 Any patient with rapid onset of hirsutism, obvious signs of virilization, or a palpable 
abdominal or pelvic mass should undergo a thorough workup for a possible androgen 
secreting tumor. 
 For patients with moderate or severe symptoms,  
 an early morning total testosterone  level should be obtained,  
 if moderately elevated, it should be followed by a plasma free testosterone  
level.

level.  
 A total testosterone level greater than 200 ng per dL (6.94 nmol per L) 
should prompt evaluation for an androgen-secreting tumor.  
 Further workup is guided by history and physical examination, and may include: 
 thyroid function tests,  
 prolactin level,  
 17-hydroxyprogesterone level, and  
 corticotropin stimulation test.  
 Management of hirsutism 
 advise weight loss if overweight 
 hair removal  
 Shaving is effective but needs to be repeated often.

 Evidence for the effectiveness of electrolysis and laser therapy is limited.  
 cosmetic techniques such as waxing/bleaching - not available on the NHS 
 pharmacologic measures  
 combined oral contraceptive pills 
 first-line pharmacologic treatment  in patients who are not planning a 
pregnancy 
 such as co-cyprindiol (Dianette) or ethinylestradiol and drospirenone 
(Yasmin).  
 Co-cyprindiol should not be used long-term due to the increased risk of 
venous thromboembolism

venous thromboembolism 
 facial hirsutism: topical eflornithine - contraindicated in pregnancy and breast-
feeding 
 Treatment response should be monitored for at least six months before making 
adjustments. 
Hypertrichosis  
 excessive hair growth above the normal  for the age, sex and race of an individual, in 
contrast to hirsutism , which is excess hair growth in women  following a 
male distributionpattern.   
 
 Causes of hypertrichosis 
 drugs:  433

255 
  phenytoin  
 minoxidil  (antihypertensive vasodilator. also used to treat androgenic alopecia 
 slows hair loss and promotes hair regrowth) 
 ciclosporin  
 diazoxide 
 congenital hypertrichosis lanuginosa, congenital hypertrichosis terminalis 
 metabolic disorders: 
 thyroid dysfunction,

 thyroid dysfunction,  
 porphyria cutanea tarda 
 anorexia nervosa 
 Hair removal  
Amenorrhoea 
Primary amenorrhoea  
 failure to start menses by the age of 16 years  
 Causes 
 testicular feminisation 
 congenital adrenal hyperplasia 
 congenital malformations of the genital tract 
 
Secondary amenorrhoea  

 absence of menses for more than 3 months (in women with previously regular cycles) 
or 6 months (in women with previously irregular cycles) 
 Causes  
 Pregnancy ĺ most common cause of secondary amenorrhea  
 hypothalamic amenorrhoea (e.g. Stress, excessive exercise )  Ļ FSH 
 Weight-related amenorrhoea 
 amenorrhoea can even be seen at the lower end of the normal range. 
  often seen in ballet dancers, who maintain a low weight  and undergo

periods of extreme physical exercise. 
 Gaining body weight to above the 50th centile for height normally results 
in the restoration of menstruation, but if this cannot be achieved 
oestrogen replacement might be considered. 
 polycystic ovarian syndrome (PCOS) 
 hyperprolactinaemia 
 premature ovarian failure  Ĺ FSH 
 thyrotoxicosis (hypothyroidism may also cause amenorrhoea) 
 Hypothyroidism (Ļ T3/T4 ĺ Ĺ TRH ĺ Ĺ prolactin ĺ Ļ GnRH ĺ Ļ estrogens) 434

256 
  Sheehan's syndrome 
 Asherman's syndrome (intrauterine adhesions) 
Initial investigations 
 exclude pregnancy with urinary or serum bHCG 
 gonadotrophins: low levels indicate a hypothalamic cause where as raised levels suggest an 
ovarian problem (e.g. Premature ovarian failure) 
 prolactin

 prolactin 
 androgen levels: raised levels may be seen in PCOS 
 oestradiol 
Primary ovarian failure  means that the patient never has a normal menstrual cycle, and has the 
triad of   
1- amenorrhea,  
2- hypergonadotropinism,  
3- and hypoestrogenism. 
Premature ovarian failure  (Premature ovarian insufficiency)

The history of prolonged cessation of menses with a normal weight, normal thyroid function t ests 
and a history of coeliac disease is pointed to a diagnosis of premature ovarian failure  
Criteria for diagnosi s  (NICE guidelines: November 2015)  
1. age under 40 years 
2.  menopausal symptoms (including no or infrequent periods) 
3.  and elevated FSH levels on 2 blood samples  taken 4 –6 weeks apart. 
 It occurs in around 1 in 100 women.  
Causes

Causes 
 idiopathic - the most common cause 
 chemotherapy 
 autoimmune 
 Autoimmune disease is responsible for 20% of cases. 
 It occurs in 10% of women with Addison's disease 
 and in 25% of women with autoimmune thyroid disease. 
 radiation 
Features   
 prolonged amenorrhoea  
 climacteric symptoms: hot flushes, night sweats 
 infertility 
 secondary amenorrhoea 
 raised FSH, LH levels 
 ↑↑ (FSH), + ↓↓oestradiol  435

257 
  FSH levels above 30 IU/L are generally considered post menopausal.   
 Levels above 12 are considered raised in a woman still having periods. 
 sex hormone releasing hormones would be elevated in an attempt to drive LH a nd follicle-
stimulating hormone (FSH) release.

stimulating hormone (FSH) release. 
 Testosterone levels vary in women and are increased in women who are overweig ht because 
of peripheral conversion to androgens in fat, and in patients with polycystic ovarian syndrome. 
Treatment 
 Spontaneous recovery of fertility is unlikely (occurs in only 5%). 
 Require hormone replacement therapy (HRT) to protect against osteoporotic fracture . 
 HRT or a combined hormonal contraceptive

 HRT or a combined hormonal contraceptive 
 HRT may have a beneficial effect on blood pressure when compared with a combined 
oral contraceptive 
 both HRT and combined oral contraceptives offer bone protection 
 HRT is not a contraceptive. 
Menopause  (NICE guidelines: November 2015) 
 
Definitions of perimenopause and menopause 
 Peri-menopause  aged over 45,vasomotor symptoms and irregular periods

 menopause  aged over 45, no period for at least 12 months and are not using hormona l 
contraception 
Symptoms associated with menopause 
 vasomotor symptoms (for example, hot flushes and sweats) 
 hot-flashes occur due  to erratic vasodilation of blood vessels in the skin, resulting in 
intense sweating. 
 Hot flashes are caused by low oestrogen which results in dysfunction of 
thermoregulation in the hypothalamus.

thermoregulation in the hypothalamus.  
 inappropriate peripheral vasodilatation and sweating lead to rapid heat loss an d a drop 
in core temperature leading to shivering.  
 musculoskeletal symptoms (for example, joint and muscle pain) 
 effects on mood (for example, low mood) 
 urogenital symptoms (for example, vaginal dryness) 
 vaginal atrophy can lead to vaginal dryness and dyspareunia as well as loss of libido 
and low mood. 
 Sexual difficulties (for example, low sexual desire).

 Women with obesity  tend to suffer from fewer symptoms  in menopause due to peripheral 
conversion of androgens to estrogen in adipose tissue. 
 
 436

258 
  
Consequences of menopause  
 ĻĻ bone mineral density  osteoporotic fractures. 
  ischaemic heart disease, 
 ĻĻ insulin sensitivity  
 ĹĹ thrombotic tendency.  
 Increased possibility of developing Alzheimer's dementia 
 Oestrogen deficiency might play a role in the development of dementia. 

 androstenedione is produced by ovarian stromal cells and the adrenal g lands.  
 Ļ HDL (high-density lipoprotein) + Ĺ total cholesterol levels 
 Ĺ FSH and LH 
 Ļ estradiol + Ĺ GnRH 
 Decreased estradiol release by the ovaries in menopause results in  increased release 
of gonadotropin-releasing hormone from the hypothalamus. 
 Estrone  is the dominant form of estrogen in menopausal women as it is produced 
by aromatase from androstenedione in adipose cells. 
 
 Vasomotor symptoms  hormone replacement therapy (HRT) 
 women with a uterus  oestrogen and progestogen 
 Women without a uterus  Oestrogen alone. 
 Oestrogen only replacement is only appropriate for patients whose uterus has 
been removed due to the increased risk of endometrial cancer.  
 Psychological symptoms   low mood or anxiety  HRT & CBT  
 women with low sexual desire   testosterone supplementation if HRT alone is not 
effective.

effective. 
 Urogenital atrophy  vaginal oestrogen (including those on systemic HRT), also in whom 
systemic HRT is contraindicated.  
 If vaginal oestrogen does not relieve symptoms of urogenital atrophy, consider 
increasing the dose  
Hormone replacement therapy (HRT) 
 
437

259 
  
 Hormone replacement therapy (HRT) involves the use of a small dose of oestrogen, com bined 
with a progestogen (in women with a uterus), to help alleviate menopausal symptoms. 
 
Unopposed oestrogen therapy is most appropriate for patient who had a hysterectomy  and combined

hormone replacement therapy (HRT) is unnecessary. 
  
Indications  
 vasomotor symptoms such as flushing, insomnia and headaches ( The main indication ) 
 Premature menopause: should be continued until the age of 50 years. Most impo rtant reason 
is preventing the development of osteoporosis 
 The other indications such as reversal of vaginal atrophy should be treated with other ag ents 
as first-line therapies 
 
Advantages of hormone replacement therapy (HRT)

Advantages of hormone replacement therapy (HRT)  
1. improvement in menopausal symptoms 
2. protection against fractures of the wrist, spine and hip secondary to osteoporosis.  
3. reduced incidence of colorectal cancer  
4. reductions in the incidence of Alzheimer's  
 
 Hormone replacement therapy and effects on bone mass  
 Reduction in total-body bone mass begins in women in their late twenties  
 This loss is accelerated at the menopause

 This loss is accelerated at the menopause 
 Both trabecular bone loss at the level of the vertebrae and cortical bone loss at the 
radius are prevented by oestrogen therapy 
 The risk of osteoporotic fractures is reduced, but not eliminated, by oestrogen the rapy 
 If the uterus has been removed in a patient, there is no need for additional 
progesterone therapy 
 The effect of oestrogens on bone loss may be reduced after 10 years of 
oestrogen therapy 
 
Combined OCP:

Combined OCP:  
↑ Risk of breast cancer  
↑ Risk of DVT  
↓ Risk of endometrial ca.  
 
 438

260 
  
HRT long term adverse effects (NICE guidelines: November 2015)  
 Venous thromboembolism (VTE)  
 Ĺ risk of (VTE)  
 VTE risk is greater for oral than transdermal preparations 
 the risk associated with transdermal HRT given at standard therapeutic doses is no 
greater than baseline population risk.

greater than baseline population risk. 
 Consider transdermal rather than oral HRT for menopausal women who are at 
increased risk of VTE, including those with a BMI over 30 kg/m2. 
 Risk of DVT is 2 –4 times higher in women on HRT 
 Cardiovascular disease 
 HRT does not increase cardiovascular disease risk when started in women aged under 
60 years  
 HRT with oestrogen alone  is associated with no, or reduced, risk of coronary heart 
disease

disease 
 HRT with oestrogen and progestogen  is associated with little or no increase in the 
risk of coronary heart disease. 
 taking oral (but not transdermal) oestrogen  is associated with a small increase in the 
risk of stroke . 
 increased risk of ischaemic heart disease if taken more than 10 years after menopause  
 
 Breast cancer (increased by the addition of a progestogen) 
 HRT with oestrogen alone  is associated with little or no change in the risk of breast 
cancer

cancer  
 HRT with oestrogen and progestogen  can be associated with an increase in the risk  
of breast cancer and reduces after stopping HRT. 
 the increased risk relates to duration of use 
 breast cancer incidence is higher in women using combined preparations compared to 
oestrogen-only preparations 
 the risk of breast cancer begins to decline when HRT is stopped and by 5 years it 
reaches the same level as in women who have never taken HRT

 Women with mutated BRCA genes or existing breast cancer should not receive 
hormone replacement therapy during menopause. 
 Endometrial cancer  
 increased risk of endometrial cancer: reduced by the addition of a progestogen but not 
eliminated completely. The BNF states that the additional risk is eliminated if a 
progestogen is given continuously 
 
 439

261 
 Combined treatment with oestrogen and progesterone  increases the risk of VTE, stroke, breast 
cancer, and cardiovascular disease. Protective effects include reduction in osteoporosis and 
colorectal cancers.  
 
Short term Side-effects  
 Nausea 
 breast tenderness 
 fluid retention and weight gain

 fluid retention and weight gain 
 unscheduled vaginal bleeding is a common side effect of HRT within the first 3 months o f 
treatment  
 
Effects of reducing and stopping of HRT 
 gradually reducing HRT may limit recurrence of symptoms in the short term  
 gradually reducing or immediately stopping HRT makes no difference to their symptoms  in the 
longer term . 
 
synthetic oestrogen - ethinyl oestradiol, for oestrogen replacement  is not detectable on the

traditional oestradiol assay.  So this is why the oestradiol concentration is unrecordable and is also 
the reason why oestradiol should not be requested (but unfortunately is) whilst patients are taking  the 
combined OCP. 
Selective Estrogen Receptor Modulators (SERMs) 
  
Raloxifene  
 Mechanism of action 
 estrogen antagonist  in breast and endometrium  
 (preventing endometrial/breast hyperplasia).

 (preventing endometrial/breast hyperplasia). 
 It differs from tamoxifen in this regard, because tamoxifen (another SERM) acts 
as a partial agonist at the endometrium, so can promote endometrial hyperplasia. 
 agonist  in bone 
 to increase mineralisation  
 Clinical use 
 osteoporosis in menopausal women 
 breast cancer prevention in women high risk for breast cancer 
 Toxicity 
 Ĺ risk of  venous thromboembolism 
 induces menopause 440

262 
  hot flashes 
 
Tamoxifen  
 estrogen antagonist  in breast  
 estrogen agonis t in endometrium and bone  
 estrogen and progesterone receptor positive breast cancer 
 Toxicity

 Toxicity 
 Ĺ risk of venous thromboembolism   
 ↑ risk of endometrial cancer   
 secondary to agonist activity 
 induces menopause 
 hot flashes 
Androgen insensitivity syndrome  
The testosterone which is in the male range, the history of hernias as a baby and absence of 
acne or secondary sexual hair are all pointers towards androgen insensitivity syndrome.

The presence of breast development  in the absence of secondary sexual hair , with a history of 
hernias  as a child is suggestive of a diagnosis of androgen insensitivity syndrome . It is likely that 
the hernias were related to undescended testes . The vagina is blind ended, and there are no 
ovaries. 
 
 X-linked recessive  
  due to end-organ resistance to testosterone causing genotypically male children (46 XY) to 
have a female phenotype.

have a female phenotype.  
 Complete androgen insensitivity syndrome is the new term for testicular feminisation syndrome 
Features  
 primary amennorhoea 
 undescended testes causing groin swellings ,  Crypt orchidism (absence of one or both testes 
from the scrotum)  
 External genitalia ranges from normal female, to female with clitoromegaly, to under-d eveloped 
male (hypospadias).  
 Associated with abdominal hernias .

 Associated with abdominal hernias . 
 breast development may occur as a result of conversion of testosterone to oestradiol 441

263 
  The feminisation  is a consequence of:  
 increased testicular secretion of oestradiol  
 peripheral conversion of androgens to oestradiol .  
Diagnosis  
 high levels of LH  
 borderline/elevated levels of testosterone (with lack of virilization)

 buccal smear  or chromosomal analysis to reveal 46XY genotype 
 counselling - raise child as female 
 bilateral orchidectomy (increased risk of testicular cancer due to undescended testes) 
  typically performed after puberty  
 oestrogen therapy 
Azoospermia  
 absence of spermatozoa after centrifugation of complete semen  
 causes of Azoospermia: 
1. reproductive tract obstruction (Obstructive azoospermia)

 congenital (absence of the vas deferens, idiopathic epididymal obstruction) or  
 acquired (from infection, vasectomy, trauma). 
2. inadequate production of spermatozoa. 
  hormonal analysis (FSH, testosterone) to define the cause of azoospermia. 
 provide a >90% prediction of the type of azoospermia (obstructive v. non-
obstructive).  
  testicular biopsy  
 Couples in whom the man has congenital reproductive tract obstruction  should

have cystic fibrosis gene mutation analysis  for both partners, as there is a high risk 
of the male being a CF carrier. 
 Acquired obstruction of the genital tract  
 can be treated using microsurgical reconstruction. 
  Alternatively, sperm can be retrieved from the testes and subsequently used for 
assisted reproduction. 
 The cause of non-obstructive azoospermia needs to be identified prior to any 
treatment. 

Erectile dysfunction 
 Erectile dysfunction occurs in approximately 10% of all men and in > 50% of men o ver 
the age of 70 years.  
 Common causes 
  psychological factors (20%),  
 drugs (25%) and  442

264 
  endocrine causes. 
 the commonest cause in healthy younger age group is  Psychological factors 
Menstrual cycle 
The menstrual cycle may be divided into the following phases: 
Follicular phase (proliferative phase)

Follicular phase (proliferative phase) 
(from day 1 until day 14) Luteal phase (secretory phase) 
(From day 15 until day 28)  
Ovarian 
histology   A number of follicles develop. 
 One follicle will become dominant 
around the mid-follicular phase  Corpus luteum 
Endometrial 
histology   Proliferation of endometrium  Endometrium changes to 
secretory lining under influence 
of progesterone 
Hormones   A rise in FSH results in the development 
of follicles which in turn secrete

of follicles which in turn secrete 
oestradiol 
 When the egg has matured, it secretes 
enough oestradiol to trigger the acute 
release of LH. This in turn leads to 
ovulation  
 Graafian follicle  is a large 
mature tertiary follicle containing 
an oocyte that is ready to be ovulated.  
 Ovulation occurs 14 days before 
menses, regardless of cycle length. 
 estradiol stimulates the growth of 
the endometrium. 
 Progesterone levels are low 
 FSH activates aromatase within

 FSH activates aromatase within 
granulosa cells, increasing estradiol 
 The main hormone controlling 
the follicular phase is estradiol, secreted 
by Granulosa cells.   corpus luteum produces (3 
hormones) estrogen, inhibin, 
and progesterone. 
 progesterone   is significantly 
higher than in other phases of 
the menstrual cycle. 
 If fertilisation does not occur the 
corpus luteum will degenerat e 
and progesterone levels fall 
Cervical

Cervical 
mucus   Following menstruation the mucus is 
thick and forms a plug across the 
external os 
 Just prior to ovulation the mucus 
becomes clear, acellular, low viscosity.  Under the influence of 
progesterone it becomes thick, 
scant, and tacky 443

265 
 Follicular phase (proliferative phase) 
It also becomes 'stretchy' - a quality 
termed spinnbarkeit 
Basal body 
temperature   Falls  prior to ovulation due to the 
influence of oestradiol  Rises  following ovulation in

response to higher 
progesterone levels 
  
 The normal menstrual cycle typically lasts 28 to 35 days.  
 The length of the follicular phase can vary, but the luteal phase lasts for 14 d ays 
following ovulation.  
 Endometrial biopsy  
 Endometrial biopsy is still performed as an indicator of ovulation and adequate 
progesterone secretion in the luteal phase.  
 The presence of proliferative endometrium indicates that ovulation has not 
occurred.

occurred. 
 Proliferative endometrium is seen in the follicular phase before ovulation.  
 Secretory endometrium is the hallmark of ovulation: the endometrium thickens and 
contains more tortuous glands that secrete mucus. 
 Aplastic cells would be seen in neoplasia of the endometrium.  
 In pregnancy, the secretory endometrium would be much thicker (decidua). 
 Anovulation   
 is the failure of the ovary to release ova .  
 common causes is:

 common causes is: 
  hypothalamic dysfunction, characterized by failure of the pituitary gland to  produce  LH 
and FSH hormones needed for ovulation. This is common in women who are: 
 underweight,  
 exercise excessively , or  
 have delayed menarche. 
 Diagnosis of anovulation is difficult and is often done by temperature char ting or 
measuring hormone levels. 
 Follicle stimulating hormone (FSH) 
 In women ,

 In women ,  
 FSH stimulates folliculogenesis during the follicular stage of the menstrual cycle 
to prepare for the next ovulation cycle.  
 FSH also stimulates granulosa cell hypertrophy and cell division as well as the 
enzyme aromatase within the granulosa cells, which converts androstenedione to 
estradiol. 
 In men ,  
 binds to receptors on the basal membrane of Sertoli cells , leading to increased 
cAMP levels and activation of protein kinase. This, in turn, causes the Sertoli

cells to increase production of androgen binding proteins .  444

266 
  FSH also stimulates spermatogenesis.  
 Men without or with low levels of FSH are unable to produce sperm and can be 
diagnosed with secondary hypogonadism. 
 
Which hormone levels would be most likely to indicate the occurrence of ovulation? 
 Luteinising hormone

 Luteinising hormone 
 
At which point in the menstrual cycle do progesterone levels peak? 
 Luteal phase 
 Progesterone is secreted by the corpus luteum following ovulation.  
 
Which mechanism is most likely responsible for the missed period in early pregnancy? 
 Syncytiotrophoblast produces human chorionic gonadotropin (hCG), which 
stimulates progesterone production by the corpus luteum.  
 
Ovarian hyperstimulation syndrome (OHSS) 
 potentially life-threatening conditions that occurs as a result of fertility medications 
enlarging the ovaries and causing a fluid shift.  
 Causes 
 clomiphene treatment or  
 following in-vitro fertilization(IVF), but pathogenesis does not occur unless a dose 
of injectable hCG is given.   
 Effectively, OHSS results from disruption of the hypothalamic-pituitary-ovarian

feedback system of the normal menstrual cycle.  
 Neovascularization due to follicular production of VEGF creates highly permeable 
vessels. These leaky vessels allow fluid to escape, leading to third-spacing in 
the abdomen. This third-spacing can manifest as ascites, edema, and perica rdial 
effusion.  
 Risk factors: 
 prior episodes of OHSS,  
 larger or more numerous follicles,  
 polycystic ovarian syndrome (PCOS).  
 typically begin within 10 days of treatment,

 typically begin within 10 days of treatment,  
 nausea, vomiting,  
 bloating,  
 sudden weight gain.  445

267 
  Signs of severe OHSS  include:  
  severe pain,  
 shortness of breath,  
 arterial and venous thromboembolisms, and  
 reduced liver function.  
Hypogonadism 
Primary hypogonadism ( Hypergonadotropic hypogonadism ) 
 Definition :

 insufficient sex steroid production in the gonads 
 gonadal insufficiency ĺ insufficient sex steroid production (Ļ testosterone, Ļ estrogen) 
ĺ increased gonadotropin secretion (Ĺ FSH and Ĺ LH) from the anterior pituitary ĺ lack 
of negative feedback from the impaired gonads ĺ further Ĺ FSH and Ĺ LH levels  
 Causes 
 Congenital abnormalities: (Primary gonadal insufficiency):  
 Turner syndrome (females), 
 webbed neck, short stature

 webbed neck, short stature 
 Klinefelter syndrome (males), 
 gynecomastia 
 androgen insensitivity syndrome ,  
 Mutation in the FSH and LH receptor genes 
 Cryptorchidism 
 Varicocele 
 Myotonic dystrophy. 
 Acquired diseases: (Secondary gonadal insufficiency) (damage to leydig cells or 
ovarian tissue): 
 Medications (Radiation, chemotherapy, Ketoconazole, Glucocorticoids, 
Environmental toxins)  
 trauma/surgery,  
 autoimmune disease, 
 infections ( mumps , tuberculosis)

 infections ( mumps , tuberculosis) 
 Testicular tumour, infiltration  
 Chronic systemic illnesses (eg: Hepatic cirrhosis , Chronic renal failure) 
 Ageing 
 primary testicular failure ( idiopathic failure ). 
 Investigations  
 (Ĺ(LH) & (FSH) + Ļ testosterone + Ļ sperm count )  
 loss of negative feedback of testosterone results in Ĺ LH  
 FSH levels are variable based on presence of inhibin 
 Ĺ FSH if seminiferous tubule dysfunction is also present

 inhibin normally released by Sertoli cells to inhibit FSH 
 if damaged that feedback is lost 446

268 
  normal FSH if dysfunction is limited to Leydig cells 
 Ļ function of Leydig cells  Ļ testosterone  synthesis 
 any dysfunction isolated to Sertoli cells/seminiferous tubules does not 
result in Ļ testosterone synthesis  
 if testes are cryptorchid, testosterone production is normal because Leydig

cells are not affected by Ĺ temperature  
 Testicular ultrasound  
 ultrasonic evaluation of the testes is the most appropriate investigation. 
 
Andropause is the term for the gradual decrease in serum testosterone concentration with 
age, but does not occur, usually, until after the age of 50. 
 
Secondary hypogonadism  (hypogonadotrophic hypogonadism )  
 insufficient gonadotropin-releasing hormone (GnRH) and/or gonadotropin release at the 
hypothalamic-pituitary axis

hypothalamic-pituitary axis 
 In Kallmann syndrome:  
 impaired migration of GnRH cells and defective olfactory bulb ĺ Ļ GnRH in 
hypothalamus ĺ Ļ FSH and Ļ LH ĺ Ļ testosterone and Ļ estrogen  
 In hypothalamic and/or pituitary lesions:  
 Ļ pituitary gonadotropins (Ļ FSH and Ļ LH) ĺ Ļ testosterone and Ļ estrogen  
 Causes 
 Genetic disorders 
 Kallmann's syndrome 
 congenital GnRH deficiency  
 Other associated abnormalities include anosmia ,  midline defects

particularly cleft palate, colour blindness, and deafness. 
 Idiopathic hypogonadotropic hypogonadism (IHH): genetic disorder characterized 
by a defect in GnRH production/action in the absence of anosmia 
 Prader-Willi syndrome 
 muscular hypotonia, short stature, facial dysmorphia 
 Gaucher's disease 
 hepatomegaly, splenomegaly, painful bone crisis 
 Hypothalamic and/or pituitary lesions due to: 
 Neoplasm (e.g. prolactinoma, craniopharyngioma, astrocytoma)

 Trauma, surgery, irradiation 
 Infection 
 Eating disorders 
 associated with type 2 diabetes and obesity.  
 serum testosterone  and sperm count  are subnormal  + normal or reduced LH and 
FSH  447

269 
  Prolactin level  
 Hyperprolactinaemia may be associated with a hypogonadotrophic 
hypogonadism   and signs such as galactorrhoea may be present. This should 
be excluded.  
 measure of free testosterone   
 as total testosterone can be low due to SHBG being decreased in obesity and 
with ageing.

with ageing. 
 pituitary MRI would be the best imaging technique to exclude other pituitary patholo gy. 
 
Clinical features 
 Delayed puberty  
 ♂ 
 Testicular hypoplasia 
 Ļ Body  hair growth (e.g., absent facial hair) 
 High-pitched voice 
 Smooth skin (no acne) 
 Ļ Lean  body mass 
 ♀: primary amenorrhea 
 Developmental abnormalities with genitalia (undescended testes, hypospadias) 
 Infertility (Ļ sperm  count), impotence, and/or Ļ libido  
 Secondary amenorrhea

 Secondary amenorrhea 
 
Routine tests  
 Ļ Serum  testosterone levels and Ļ serum  estrogen levels (in females) 
 Determine if the source is primary or secondary hypogonadism. 
 Hypergonadotropic hypogonadism: Ĺ GnRH, Ĺ LH/FSH 
 Hypogonadotropic hypogonadism: Ļ GnRH, Ļ LH/FSH 
 Bone scan may support the diagnosis of hypogonadism (Ļ bone  density (osteoporosis ) or 
delayed epiphyseal closure). 
 
Further tests : based on suspected etiolo gy

Further tests : based on suspected etiolo gy 
 Genetic testing (for Klinefelter syndrome, Turner syndrome, Kallmann syndrome) 
 Serum prolactin (Ĺ in prolactinoma) 
 Pelvic ultrasound (e.g., gonadal dysgenesis in Klinefelter syndrome) 
 Brain MRI (for CNS lesion or Kallmann syndrome ) 
 Adrenocorticotropic hormone stimulation test (ACTH stimulation test): to exclude congenital 
Treatment

Treatment 
 Treat underlying cause: e.g., surgical excision of tumors, pharmacotherapy for prolactinoma s 
 Hormone replacement therapy 
 
Tip to remember 
Testosterone and LH levels can help distinguish between different causes of abnormal sexual 448

270 
 development: 
 High testosterone and high LH: defective androgen receptor (androgen insensitivity synd rome) 
 High testosterone and low LH: testosterone-secreting tumor 
 Low testosterone and high LH: primary hypogonadism 
 Low testosterone and low LH: hypogonadotrophic hypogonadism

Contraception  
Mechanisms of action:  
 Estrogen 
 Hypothalamus: Ļ release  of GnRH 
 Pituitary: Ļ LH ĺ inhibits ovulation,  Ļ FSH ĺ prevents ovarian folliculogenesis  
 Progestin 
 Endometrial atrophy, changes in cervical mucus (Ļ volume  and Ĺ viscosity), and 
impaired fallopian tube peristalsis ĺ inhibition of sperm ascension and egg  implantation

 Inhibits follicular maturation; ovulation may be suppressed (not consistent). 
449

271 
  Antiprogestin   
 inhibits or delays ovulation by inhibiting the progesterone receptor 
  
Emergency contraception 
 Most effective when taken within 3 days of intercourse 
 Typically administered as a single dose or as two doses over one day

 Significantly less effective in patients who are obese or overweight  
 What is the action of emergency contraception in preventing conception following 
unprotected sexual intercourse.? 
 Decreasing tubal motility and ciliary activity  thereby preventing sperm from reaching 
the oocyte in the ampulla of the tube.  
(levonorgestrel 1.5 mg) 
 The rate of pregnancy is ≤ 3.0%  if emergency contraception is taken within 72

hours  after unprotected sexual intercourse. The earlier it is takes, the lower the likelihood 
of pregnancy 
 
Side-effects of the oral contraceptive pill 
 Breakthrough bleeding is most commonly associated with low-dose combined oral 
contraceptive pills, especially those containing 20 micrograms ethinylestradiol. 
  Nausea and vomiting are less with this dose. 
  Migraine can occur in susceptible women, irrespective of the dosage.

 There is no appreciable increase in clotting risk or pregnancy rate with these pills. 
Contraindications to the combined oral contraceptive pill 
As well as age > 35 years, other absolute contraindications to the combined oral contraceptive pill 
(OCP) include a history of: 
 Heart disease 
 Pulmonary hypertension 
 Arterial or venous thrombosis 
 Cerebrovascular disease  Liver disease 
 Severe migraine 
 Breast or genital tract cancer

 Breast or genital tract cancer 
 
Studies have shown that women taking estrogen-  progestin combination OCPs before 
menopause have an increased risk of cervical carcinoma but a decreased risk of endometrial 
and ovarian carcinoma . 
 
Progestin-only pills 
 women who are unable to take regular oral contraceptives due to their side-effects or t o 
the exacerbation of existing conditions like migraine. 
 breastfeeding women:

 breastfeeding women: 
 estrogen-containing combined contraceptives should be avoided in 
early postpartum period : 
 estrogen  inhibition of prolactin activity  reduce breast milk 
production.  450

272 
  Estrogens  increased risk of thromboembolic events in the 
early postpartum period.  
 Action 
 Main contraceptive mechanism  thickens the cervical mucus, preventing the 
entry of sperm. 
 Although it decreases tubal motility, this is more related to the occurrence of 
ectopic pregnancy.

ectopic pregnancy. 
 The dose of progesterone is not sufficient to inhibit ovulation or reduce lutein ising 
hormone (LH) secretion. 
 
An entirely normal 16-year-old girl is very tall and would like to stop growing. What is the most 
appropriate treatment for her? 
 Oral contraceptive pill  
 The oral contraceptive pill used in this context would be associated with fusion of 
long-bone growth plates, and subsequent cessation of longitudinal growth.

 Although ideally she should be encouraged not to receive medical intervention at all , in 
this situation use of the OCP represents the lowest-risk option. 
Puberty  
Physiology:  
 The primary event of puberty is the initiation of a pulsatile secretion patte rn of gonadotropin-
releasing hormone.  
 unknown initial trigger ĺ Ĺ activators and/or Ļ inhibitors of GnRH secretion ĺ Ĺ GnRH pulsing  
ĺ Ĺ FSH and Ĺ LH levels

ĺ Ĺ FSH and Ĺ LH levels  
 
Puberty in girls 
 The sequence of pubertal events in girls: 
1. breast development  (thelarche) usually marks the first stage of puberty and is 
indicated by the presence of breast budding.  
 This begins between the ages of 9 years and12 years and continues to 12- 18 
years. 
2. Thelarche is typically followed by pubic hair growth (pubarche) secondary to production 
of adrenal androgens (adrenarche).

of adrenal androgens (adrenarche).  
 Pubic hair growth occurs at ages 9-14 years, and is complete at 12-16 years. 
 Adrenarche, the appearance of pubic and axillary hair during female puberty, 
depends on increased levels of adrenal androgens.  
3. Thelarche and pubarche are followed by acceleration of growth to maximum g rowth rate 
(growth spurt),  
 Peak height velocity is reached earlier (10-13 years) and growth is completed 
much earlier than in boys

much earlier than in boys 
4. finally the onset of menses (menarche). 
 Menarche occurs relatively late (age 11-15 years). 
 Started with irregular menses (usually related to anovulatory cycle) 451

273 
 The first visible sign of puberty in males is testicular enlargement , while in females it is 
breast development . 
 
Precocious puberty 
Central precocious puberty has a central cause (e.g., hypothalamic lesions) and high GnRH

levels; precocious pseudopuberty has a peripheral cause (e.g., germ cell tumors), without 
elevated GnRH levels 
 
 Definition:  
 the appearance of secondary sexual characteristics before the age of 8 years  in 
girls and 9 years in boys  
 Classification 
 Central precocious puberty  (gonadotropin-dependent precocious puberty, true 
precocious puberty) 
 Peripheral precocious puberty  (gonadotropin-independent precocious 
puberty, peripheral pseudopuberty, peripheral precocity)

 Clinical features 
 Precocious puberty may manifest with either development of all the secondary  sexual 
features or occasionally as isolated premature thelarche, adrenarche, or menarche. 
 Accelerated growth and early skeletal maturity  
 Central precocious puberty (CPP): Premature sexual development typically follows the 
normal pattern of puberty, except that it is early.  
 Peripheral precocious puberty: may not follow the normal developmental pattern; ma y

exhibit possible features of underlying condition (e.g., café- au-lait spots in 
neurofibromatosis, testicular mass in Leydig cell tumor) 
Central precocious puberty 
 precocious puberty with elevated GnRH levels 
 Etiology 
 Idiopathic or constitutional (most cases) 
 CNS lesions 
 midline hamartoma of the hypothalamus. 
 Pituitary gonadotropin-secreting tumors (rare) 
 Systemic conditions: tuberous sclerosis, neurofibromatosis

 Obesity-related precocious sexual development due to increased levels of leptin 
in obesity 
 Obesity causes compensatory hyperinsulinemia (due to increased insulin 
resistance) and higher levels of leptin, which both lead to earlier development of 
sexual characteristics. 
 Pathophysiology:  
 premature activation of the hypothalamo-hypophyseal axis ĺ abnormally early initiation 
of pubertal changes ĺ early development of secondary sexual characteristics 
and gonadarche 452

274 
 Laboratory tests 
 Basal LH and FSH ( The best initial  lab test  ): increased  
 GnRH stimulation test ( gold standard ): Gonadotropin (LH a nd FSH) levels 
increase after intravenous administration of GnRH.  
 Sex hormones 
 ♂: Ĺ serum  testosterone 
 ♀: Ĺ serum estradiol  
 Imaging

 Imaging 
 Brain MRI/CT with contrast  
 X-ray of the left hand  
 Therapy 
 GnRH agonist (e.g., leuprolide, buserelin), with close monitoring of therapy  
 Manage underlying cause 
Peripheral precocious puberty 
 precocious puberty without elevated GnRH levels  
 Etiology 
 Ĺ Androgen production, e.g.: 
 Ovarian cyst (most common cause) 
 Congenital adrenal hyperplasia (CAH) 
 Virilizing ovarian and adrenocortical tumors

 Virilizing ovarian and adrenocortical tumors 
 Leydig-cell tumor 
 Ĺ Estrogen production, e.g.: 
 HCG -secreting germ cell tumors (e.g., granulosa cell tumor) 
 Rarely: adrenal gland tumors that produce estrogen 
 McCune-Albright syndrome  
 McCune-Albright syndrome  is established on clinical grounds, with the 
presence of: 
 precocious puberty,  
 bony fibromas leading to possible pathological fractures,  
 thyrotoxicosis, and  
 café au lait spots 
 Ĺ β-HCG  production: e.g.,

 Ĺ β-HCG  production: e.g.,  
 Hepatoblastoma 
 pinealoma  
 Pinealoma is a tumor of the pineal gland.  
 The pineal gland produces the hormone melatonin which plays a role in 
regulating circadian rhythms.  
 can lead to paralysis of conjugate vertical gaze by the compression of 
superior colliculi , resulting in vertical gaze palsy  
 present as precocious puberty in males due to increased beta-human 
chorionic gonadotropin production 
 Primary hypothyroidism

 Primary hypothyroidism 
 Obesity-related precocious sexual development due to compensatory hyperinsulin emia 
(caused by increased insulin resistance in obesity) 453

275 
 Imaging: ultrasound  of the pelvis, testicles, and abdomen 
 Ĺ Estrogen/testosterone (depending on the tumor), Ļ FSH, Ļ LH 
 Tests to detect primary underlying causes: e.g., TSH, FT3, β-HCG , CT/MRI 
 Therapy

 Therapy 
 Precocious puberty caused by excessive hormonal production from a tumor in the b ody: 
surgical removal 
 Precocious puberty caused by CAH: cortisol replacement  
 Ovarian cysts: No intervention is necessary, as spontaneous resolution of ovarian 
cysts is common. 
__________ _________________________________________________ 
Delayed puberty  
 Causes 
 Constitutional growth delay ( most common cause of delayed puberty ) 
 Definition:

 Definition:  
 a temporary delay in growth and onset of puberty that is not caused by 
any pathological process  
 Etiology:  
 may be inherited as an autosomal dominant, recessive, or X-linked trait  
 Diagnosis:  
 X-ray showing a bone age that is less than the individual's chronological 
age  
 No treatment is needed, as catch-up growth eventually occurs and the 
individual reaches a normal adult height. 
  hypogonadotrophic causes such as:

  hypogonadotrophic causes such as: 
 low weight / malnutrition, 
 Kallman's syndrome 
 hypergonadotrophic causes such as Turner's syndrome. 
 Other causes include: 
 pituitary lesions like craniopharyngioma,  
 co-morbidities such as severe asthma, or inflammatory bowel disease. 
 Signs of delayed puberty in girls include:  
 Absence of breast development by age 14 years 
 Pubic hair absent by age 14 
 More than five years between the start and completion of breast growth

 Menarche has not occurred by age 16. 
 Signs of delayed puberty in boys include: 
 No testicular enlargement by age 14 years 
 Pubic hair absent by age 15 
 More than five years between the start and completion of growth of the genita lia. 
 X-ray of the hand 
 Allows association between skeletal maturation and chronological age 454

276 
  Shows delayed bone age 
 Basal LH and FSH 
 In the case of primary amenorrhea ĺ also measure TSH and prolactin  
 Therapy 
 Treatment of the underlying disease 
 Watchful waiting: careful serial growth measurements at frequent intervals ∼ every 6 
months 
 When pubertal delay is severe: gonadal steroids

Multiple endocrine neoplasia 
Genetic inheritance  
 autosomal dominant disorder, high penetrance 
 
The table below summarises the three main types of multiple endocrine neoplasia (ME N) 
455

277 
  
 MEN 1 MEN 2 
MEN 2A MEN 2B 
Wermer syndrome Sipple syndrome 
Genetics  Altered menin  protein 
expression  Altered expression of the RET proto-oncogene  ĺ 
elevated tyrosine kinase activity 
Main disease  Primary 
hyperparathyroidism  
(∼ 90% of cases)  Medullary thyroid carcinoma  (95–100% of cases)

Further  Endocrine pancreatic  Pheochromocytoma  (∼ 40% of cases) 
456

278 
  MEN 1 MEN 2 
manifestations tumors  (∼ 50–80% of 
cases) such 
as gastrinoma (60%)   
(most common )  
and insulinoma (30%)  
 Pituitary adenoma   
(∼ 30–50% of cases) 
 Carcinoid tumors ( ∼ 
10–15% of cases)  
  Primary 
hyperparathyroidis
m(∼ 20–30% of

 Primary 
m(∼ 20–30% of 
cases)  Marfanoid habitus   
(> 95%) 
 Multiple neuromas   
(mucosal neuroma , 
intestinal 
ganglioneuromatosis ) 
 
Mnemonics  3 "P"s = Parathyroid, 
Pancreas, Pituitary gland 
 1 "M", 2 "P”s 
= Medullary thyroid  
carcinoma , Pheochrom
ocytoma , Parathyroid  2 “M”s, 1 “P” = Medullary 
thyroid carcinoma, Marfanoid 
habitus/Multiple neuromas, 
Pheochromocytoma  
Management  Parathyroidectomy  
 Excision of pancreatic 
tumor 
 Transsphenoidal

tumor 
 Transsphenoidal 
surgery for  pituitary 
adenoma  Thyroidectomy including cervical lymph nodes 
 Pheochromocytoma should first be ruled out 
(e.g., measuring urine metanephrines) or 
treated before undergoing surgery  
 If pheochromocytoma removal ( adrenalectomy ) 
 If hyperparathyroidism: ( parathyroidectomy ) 
Type 1 multiple endocrine neoplasia (MEN 1)  
 Genetic 
 Menin is a tumor suppressor gene implicated in multiple endocrine neoplasia 1.

 The MEN1  gene  on chromosome 11  codes for the tumor suppressor protein menin , 
 Features 
 Hyperparathyroidism is the most common manifestation in MEN 1(or Werner 
syndrome). 
 Prolactinomas are most common in the pituitary gland.  
 The pancreas is the second most commonly involved organ in MEN 1.  
 60% of pancreatic endocrine tumours are gastrinomas (most common). 
 About 30% of pancreatic tumours are insulinomas.

 Somatostatinoma, ViPoma and glucagonomas are much rarer than the two 
commonest types. 
 Duodenal microgastrinomas may also occur, and can be multiple, although they  
make up less than 10% of MEN-1 related pancreatic tumours. 
 Pancreatic tumours  are associated with:  
 pancreatic polypeptide (75-85%) 457

279 
  gastrin (Zollinger —Ellison syndrome ) - recurrent peptic ulcers 
 insulinoma - hypoglycaemia 
 glucagonoma - hyperglycaemia and skin rash (necrolytic migratory 
erythema) 
 VIPoma (vasoactive intestinal peptide-secreting tumour) - Verner-Morrison 
syndrome or watery diarrhoea hypokalaemia achlorhydria (WDHA

Type 2 multiple endocrine neoplasia (MEN 2) 
When differentiating between MEN 2A and 2B, it is worth remembering that MEN 2B has 
similar characteristics as MEN 2A (Thyroid carcinoma's, Adrenal tumours, Parathyroid 
hyperplasia) but in addition typically have a Marfanoid appearance and mucosal 
neuromas, as well as the absence of hyperparathyroidism.  
 
 A point mutation in the RET oncogene  
 The RET oncogene encodes a receptor tyrosine kinase

 mutation on the long arm of chromosome 10 (mutations at 10q11) 
 Subtypes  
 MEN Type 2a  
 also called Sipple syndrome  
 associated with parathyroid hyperplasia, pheochromocytoma and medullary 
thyroid cancer. 
 medullary thyroid carcinoma in MEN-2a tends to be less aggressive than in 2b 
 young- onset hypertension with feature of hyperparathyroidism ( ↑ Ca  & ↓ P) 
 MEN Type 2a 
 MEN- 2b  
 MEN-2b present earlier than 2a

 MEN- 2b  
 MEN-2b present earlier than 2a   
 MEN-2 is strongly associated with a family history of unexplained death in 
childbirth  
 Feature of MEN-2b: 
 Intestinal ganglioneuromatosis affects around 75% of cases.  
 Neuromas involve the autonomic nerves of both the myenteric and 
submucosal plexi and can cause poor suckling with failure to thrive, 
constipation, diarrhoea, recurrent pseudo-obstruction and toxic 
megacolon.

megacolon. 
 marfanoid habitus, visceral and intestinal ganglioneuromas (which can 
occur around the lips and tongue) 
 Adrenal tumours leading to Cushing syndrome and phaeochromocytoma 
(70% bilateral) can occur. 
 For underlying phaeochromocytoma. 458

280 
  full alpha blockade with an agent such as phenoxybenzamine is essential  
whilst investigations are undertaken to rule out medullary thyroid carcinoma (as 
part of MEN) as a cause of her hypercalcaemia. 
 the most appropriate additional medication to control blood pressure is  
phenoxybenzamine

phenoxybenzamine 
 Beta blockade without first alpha blocking raises the possibility of rebound 
hypertension due to unopposed action of the alpha vasoconstrictors; as such it is 
inadvisable to consider bisoprolol or atenolol. 
 Screening  in case of family history  
 Biochemical screen with annual calcium, calcitonin and urinary metaphrines, and 
MRI adrenals every three years are needed 
 The best screen for phaeochromocytoma is 24-hour urinary catecholamine 
estimation.

estimation. 
 Screening is recommended for people with MEN 2: 
 The pentagastrin test is used to screen for medullary thyroid carcinoma.  
 (Total thyroidectomy in childhood is often recommended for those with a 
known gene defect.) 
 Annual testing of calcium and PTH from the age of 10 is recommended for 
child with family history of MEN-2 
 the 10-year survival rate is around 65%. 
 
Which of the manifestations of MEN-2 has the most malignant potential?

 C cell hyperplasia  
 C cell hyperplasia eventually undergoes malignant transformation, leading to  
medullary carcinoma of the thyroid.  
 If patients with MEN- 2 are not identified by screening, often at the time of 
presentation medullary thyroid carcinoma with metastases to cervical lymph 
nodes has already occurred.  
 
Which finding in a blood test will be the most characteristic in  (MEN 2B) patient? 
 Elevated metanephrines

 Elevated metanephrines  
 
Multiple endocrine neoplasia type II is due to mutation in which sort of receptor? 
Membrane-bound tyrosine kinase receptor  
 
January 2008 exam: A 25-year-old man with a family history of multiple endocrine neoplasia type 1 is 
reviewed in clinic. What is the single most useful investigation to monit or such patients? Serum 
calcium  
 
459

281 
 Autoimmune polyendocrinopathy syndrome (APS) (Polyglandular 
syndrome)  
Type Polyglandular syndrome type 1  Polyglandular syndrome type 2 
Also called (Schmidt's disease) 
inheritance  autosomal recessive 
 caused by mutation of  AIRE1  gene 
on chromosome 21  polygenic inheritance 
 linked to HLA DR3/DR4.

 linked to HLA DR3/DR4.  
Epidemiology   rare 
 usually begins in childhood.  more common  
feature  Mucocutaneous candidiasis (100%) 
 Hypoparathyroidism (in around 
90%) 
 Adrenal insufficiency (in around 
60%) 
 gonadal failure 
 Primary hypothyroidism 
 Hypopituitarism/diabetes insipidus 
(rarely) 
 There might be associated 
malabsorption, pernicious anaemia, 
chronic active hepatitis or vitiligo.  Adrenal insufficiency (in all 
patients) 
 Type-1 diabetes

patients) 
 Type-1 diabetes 
 Gonadal failure 
 Diabetes insipidus (rare) 
 Associated conditions include 
vitiligo, myasthenia gravis, 
alopecia, immune 
thrombocytopenic purpura and 
pernicious anaemia. 
diagnosis (2 out of 3 needed) 
1. chronic mucocutaneous 
candidiasis (typically first feature 
as young child) (100%) 
2. primary 
hypoparathyroidism (90%), 
3. Addison's disease (60%) Patients have Addison's disease  plus  
either: 
1. type 1 diabetes mellitus

either: 
1. type 1 diabetes mellitus 
2. autoimmune thyroid disease 
 
Primary HYPOparathyroidism is usually the first endocrine manifestation of type 1 
autoimmune POLY endocrinopathy syndrome. While (MEN) ĺ hyperparathyroidism is a 
common finding 
 
 Tryptophan hydroxylase autoantibodies  may be found in autoimmune polyendocrine 
syndrome associated with an autoimmune malabsorption.  
 
May 2005 exam: H/O recurrent painful oral ulceration. Examination reveals signs of

oral Candida l infection. Which one of the following would most suggest type 1 polyglandular 
syndrome? Hypocalcaemia  
 460

282 
  
Somatostatin 
 
Source  Action  Regulation  Notes  
 D cells  
(pyloric antrum, 
and duodenum 
mucosa) 
 delta cells 
(pancreas) 
 ventromedial 
nucleus of 
the hypothalamus.
   Ļ gastric H+ and 
pepsinogen secretion 
 Ļ pancreatic and small

 Ļ pancreatic and small 
intestine fluid secretion 
 Ļ gallbladder 
contraction 
 Ļ insulin and glucagon 
release 
 Ļ GH release  Ĺ by H+ 
 Ļ by vagal 
stimulation  Inhibitory hormone 
 Antigrowth hormone effects 
(digestion and absorption of 
substances needed for growth) 
 Produce vasoconstriction of 
the splanchnic system . 
 Somatostatin is treatment 
for VIPoma and carcinoid 
tumors 
 
 Mechanism of action

tumors 
 
 Somatostatin receptor is linked to adenylyl cyclase by Gi protein, which 
inhibits cAMP production and reduces secretion of  hormones. 
 
Somatostatinoma 
 Annual incidence  1 in 40 million. 
 Associations: 
 Impaired glucose tolerance 
(IGT) or diabetes mellitus 
(95%) 
 Gallstones (68%) 
 Weight loss (25%)  Anaemia (14%) 
 Multiple endocrine neoplasia type 1 
(7%) 
 Diarrhoea 
 
 Diagnosis :

(7%) 
 
 Diagnosis :  
 The tumours are often multisecretory  ↑↑ Somatostatin, adrenocorticotropic 
hormone (ACTH) and calcitonin  
 Contrast spiral computed tomography scanning is effective for detecting the prima ry 
tumour in only 50% of cases;  
 Radiolabeled octreotide or endoscopic ultrasound scanning are often be required. 
 Treatment :  
 surgery is rarely possible due to presence of metastases, 
 hepatic embolisation can be helpful for symptom control. 
 
 461

283 
 ___________________________________________ _________________ 
Carney complex 
 Caused by an inactivating mutation of protein kinase A on chromosome 17. 
 Carney complex is diagnosable if there are two features out of the following: 
1. Spotty skin pigmentation 
2. Myxoma

2. Myxoma 
3. Endocrine tumours: 
 the commonest is primary pigmented nodular adrenocortical disease,  
 others 
 Sertoli cell tumours,  
 growth hormone- or prolactin-producing pituitary adenomas,  
 thyroid adenomas  
 ovarian cysts 
4. Psammomatous melanotic schwannoma (PMS) 
 It is also diagnosable in the presence of one feature and an affected first-degree rela tive. 
 
 462

Cardiology 
 
Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  1 
  
By
 
Cardiology
 
Updated 
 
2017
 
Contains: 
 
 463

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  2 
 Anatomy of the heart 
 The right ventricle lies anterior to the left ventricle 
 The tricuspid valve is the most anterior valve of the heart and is the most common to be 
injured during a stabbing attack  
 The left atrium is the most posterior chamber of the heart, the right atrium is just anterio r and to

the right of the left atrium. 
 The left atrial appendage is not readily seen on transthoracic echocardiography and requ ires 
transoesophageal echocardiography. 
 The aortic valve is tricuspid  
Arterial anatomy 
 internal thoracic artery arises from the subclavian artery. 
 The subscapular artery arises from the axillary  and is its largest branch, eventually 
anastomosing with the lateral thoracic and intercostal arteries. 
Anatomical relations

Anatomical relations 
 descending aorta lies behind (posterior to) the left main bronchus.  
 ascending aorta is anterior to the pulmonary trunk. 
 left pulmonary artery is anterior to the left main bronchus. 
 right main bronchus should be beside the left following bifurcation of the trachea. 
 superior vena cava can be found next to the ascending aorta. 
 oesophagus is also a posterior structure to the left main bronchus. 
Valvular anatomy

Valvular anatomy 
 left atrial enlargement can result in mitral regurgitation by affecting which leaflet? 
 posterior leaflet 
 anterior leaflet is not affected, because of its attachment to the root of the a orta. 
Coronary arteries  
 Basic understanding of coronary anatomy is important as this is predictive of problems following  
MI. For example:

MI. For example: 
 the right coronary artery  supplies the AV node, so heart block following inferior MI is 
common. However, heart block following anterior MI is a grave prognostic marker as 
this indicates a large anterior wall infarct.  
 The right coronary system also supplies the right ventricle, hence problems relatin g to a 
right ventricular infarct are commonly associated with an inferior MI.

 right coronary artery supplies the inferior myocardium and occlusion causes ST eleva tion 
in II, III and aVF. 
 
 Posterior descending artery  
 a branch of the right coronary artery in 85% of people (a branch of the circumflex in the 
remaining population).  
 The concept of coronary dominance  refers to which coronary artery supplies 
the posterior descending coronary artery.  
 85% of patients having a dominant right coronary artery

 15% of patients having a dominant left circumflex.  
 supplies the posterior left ventricular myocardium  
 occlusion causes posterior MI  (ST depression in V1-V4 with a dominant R wave in V1).  
 Circumflex : lateral 
 Occlusion produces ST elevation in V5, V6, I and aVL. 
 Left anterior descending : anterior and septum 
 Occlusion  ST segment elevation in leads V1- V4 
 Right bundle branch block in acute anterior myocardial infarction suggests

obstruction prior to the first septal branch of the left anterior descending coronary 
artery  
 Left main stem :  
 branches into the left anterior descending artery and circumflex and supplies most of the 
left ventricle.  
 Complete left main stem occlusion is invariably fatal. 
 Occlusion of the left main stem has the same effect as occlusion of the left circumflex and 
anterior descending simultaneously (given that they are both branches of the abov e). It 464

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  3 
 would produce extensive ST elevation across all the chest leads, I and aVL an d possibly 
aVR, too. 
 Obtuse marginal : one of the branches of the circumflex and supplies the 'high lateral' region of 
the left ventricle (ECG leads I and aVL). 

Coronary circulation 
Arterial supply of the heart 
 left aortic sinus ĺ left coronary artery (LCA)  
 right aortic sinus ĺ right coronary artery (RCA)  
 LCA ĺ LAD + circumflex  
 RCA ĺ posterior descending  
 RCA supplies SA node in 60%, AV node in 90% 
 The sinus node artery is a branch of the right coronary artery in 60% of cases. 
Venous drainage of the heart 
 coronary sinus drains into the right atrium 

 Adenosine  is an important mediator of metabolic vasodilatation   
 Adenosine has a particularly short half-life,  
 acts on specific adenosine cell surface receptors (A1 and A2)  
 inactivated by adenosine deaminase.  
 It results in coronary vasodilatation and depression of sinus node automaticity and AVN 
conduction. 
 Coronary blood flow is dependent on myocardial oxygen consumption and is pretty 
independently maintained throughout the ranges of blood pressure.

 Increasing O2 demands are met by increased blood supply facilitated by vasodilatation b rought 
about by adenosine production. 
 
Pulmonary circulation 
The normal pulmonary circulation is characterised by: 
 low pressures,  
 low flow rates,  
 high compliance vessels.  
___________________________________________________ _______________________________  
 Internal jugular vein  
 originates at the jugular foramen.

 originates at the jugular foramen. 
 It initially lies posterior to the carotid artery, as it descends in the carotid sheath it lies late ral first 
to the internal then the common carotid artery within the carotid sheath. 
 Lies lateral to the common carotid artery  
 It passes anterior to the subclavian artery to join the subclavian vein and then form the 
brachiocephalic vein; the left and right brachiocephalic veins unite to form the superio r vena 
cava.

cava. 
 The internal jugular vein receives a lymphatic trunk at its union with the subclavian vein. 
Waveforms of the jugular venous pressure 
 
465

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  4 
  
Jugular venous pulse 
As well as providing information on right atrial pressure, the jugular vein waveform may provide clue s to 
underlying valvular disease. A non-pulsatile JVP is seen in superior vena caval obstructio n. Kussmaul's

sign describes a paradoxical rise in JVP during inspiration seen in constrictive pericarditis. 
 
'a' wave  = atrial contraction 
 large if atrial pressure e.g. tricuspid stenosis, pulmonary stenosis, pulmonary hypertension 
466

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  5 
  absent if in atrial fibrillation 
Cannon 'a' waves 
 caused by atrial contractions against a closed tricuspid valve 
 are seen in complete heart block, ventricular tachycardia/ectopics, nodal rhythm, single chamber 
ventricular pacing 
'c' wave 
 closure of tricuspid valve 
 not normally visible 
'v' wave

'v' wave 
 due to passive filling of blood into the atrium against a closed tricuspid valve 
 giant v waves in tricuspid regurgitation 
'x' descent  = fall in atrial pressure during ventricular systole 
'y' descent  = opening of tricuspid valve 
JVP: cannon waves 
Caused by the right atrium contracting against a closed tricuspid valve. May be subdivided int o regular 
or intermittent

or intermittent 
Regular cannon waves  
 ventricular tachycardia (with 1:1 ventricular-atrial conduction) 
 atrio-ventricular nodal re-entry tachycardia (AVNRT) 
Irregular cannon waves 
 complete heart block 
Subclavian vein  
 Each subclavian vein is a continuation of the axillary vein and runs from the outer border

of the first rib  to the medial border of anterior scalene muscle. From here it joins with the 
internal jugular vein to form the brachiocephalic vein (also known as "innominate vein"). The 
angle of union is termed the venous angle. 
 The subclavian vein follows the subclavian artery and is separated from the subclavian artery b y 
the insertion of anterior scalene. Thus, the subclavian vein lies anterior to the anteri or scalene

while the subclavian artery lies posterior to the anterior scalene (and anterior to the midd le 
scalene).  
 The subclavian and internal jugular vein unite to form the brachiocephalic vein, subsequen tly the 
left and right brachiocephalic veins unite to form the superior vena cava. 
 The thoracic duct enters the left subclavian. 
 Right or left subclavian is regarded as the cleanest site for central venous access. It also 
the most tolerated by patients.

the most tolerated by patients. 
 However the incidence of subclinical pneumothorax even in the hands of experienced  clinicians 
has led to it falling out of favour. 
  Compared with femoral site access, internal jugular or subclavian access was associated with a 
lower risk of catheter-related bloodstream infections (CRBSIs) in earlier studies, but subsequent 
studies (since 2008) found no significant differences in the rate of CRBSIs between t hese three 
sites.

sites.  
 The subclavian approach remains the most commonly used blind approach for subclavian  vein 
cannulation. Its advantages include consistent landmarks, increased patient comfort, an d lower 
potential for infection or arterial injury compared with other sites of access. 
 
467

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  6 
  
which vessel would become important for transporting blood from the lower to upper parts of 
the body in the event of complete occlusion of the inferior vena cava?  
 Ascending lumbar vein  
 
A left sided internal jugular central venous catheter has been inserted and you are reviewing

the chest radiograph to check the position of the tip of the catheter.  What is the safest 
position to leave the catheter tip?   
 In the lower superior vena cava 
 If the catheter tip is above the carina on a post-procedure radiograph then it is generall y 
accepted that the catheter lies outside the right atrium in the lower superior vena cava 
(SVC).  
 It is also recommended that the catheter tip should lie in the long axis of the SVC 
without acute abutment to the vein wall.

without acute abutment to the vein wall. 
 Left sided catheters are more likely to erode the vessel wall if they lie in the innominate 
veins or the upper SVC due to the abutment of the catheter tip to the vessel wall.  
 They are also more likely to cause pain on injection, thrombosis and infection if the tip  
lies in the innominate veins. 
 It is considered negligent to site the catheter tip in the right atrium as this may lead to

arrhythmias, tricuspid valve disfunction and placement in the coronary sinus. 
 
Subclavian steal syndrome 
 
 characterized by retrograde flow  into the vertebral or internal thoracic arteries, due 
to stenosis and/ or occlusion of the subclavian artery.  
Symptoms: 
 Many patients are asymptomatic. 
 Upper extremity symptoms include fatigue, aching, coolness of the affected arm and num bness.

 The most common symptoms  of subclavian steal syndrome are those related to upper 
limb ischemia.  
 arm pain and numbness, especially during exertion. 
 Neurological symptoms 
 occur in around 25% of patients. 
 may include vertigo, diplopia, decreased vision, nystagmus and gait unsteadiness  
 blood pressure is different between the upper limbs by at least 15 mmHg.  
 can present with the manifestations of cardiac ischemia in patients with internal 
mammary bypass graft .

mammary bypass graft .  
 Symptoms may be precipitated by: 
  extreme exercise on the affected side, such as cricket bowling, use of an unde rarm crutch 
or painting a wall . 
Pathophysiology: 
 Subclavian steal produces symptoms by  flow-related phenomena  rather than embolic. 
 atherosclerotic lesion  in the proximal subclavian artery  significant stenosis,  collateral 
vessels enlargement from subclavian artery distal to obstruction

 The upper extremity becomes dependent on these collaterals  
 The collateral vessels serve as points of re-entry for blood flowing retrograde into the arm  from 
the head, shoulder and neck, thereby providing the extremity with adequate perfusi on. 
 When the arm is exercised,  the blood vessels dilate to enhance perfusion to the ischaemic 
muscle, thus lowering the resistance in the outflow vessels.

 Blood is siphoned from the head, neck and shoulder through collateral vessels to sup ply this l ow-
resistance vascular bed, satisfying increased oxygen demand by the exercising muscles of th e 
upper extremity. 
 This results in posterior cerebral circulation neurological symptoms . 
 What is the most likely mechanism that maintains blood flow to the affected extremity? 
468

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  7 
  Blood from the contralateral vertebral artery  is shunted away from the basilar artery 
(away from the brainstem ) and retrograde into the ipsilateral vertebral artery  to supply 
the affected arm .  
Diagnosis 
 non-invasive arterial flow studies, Doppler and arteriography.

 Duplex ultrasound  is the best initial  radiological test   
 The most accurate  test is angiography of the subclavian vessels. 
Management: 
 Most patients require no intervention,  
 surgical reconstruction may be required where symptoms are severe. 
 
Physiological notes  
 The sinoatrial node  has the fastest firing rate  of all potential pacemakers in the heart.

 Sinoatrial node impulses must occur at a rate slower than 200 impulses per minute  to be 
considered in normal sinus rhythm. 
 Endothelin  
 preferentially constricts renal  afferent  arterioles.  
 Efferent arteriole vasoconstriction is particularly mediated by angiotensin- II, to 
defend GFR in states of generalised vasoconstriction and reduced blood flow. 
 efferent arteriole vasodilation will occur when angiotensin-II levels fall.

 Stimulates the renin-angiotensin-aldosterone system 
 Leads to release of atrial natriuretic peptide 
 Inhibits the action of vasopressin 
 Two types of endothelin receptor have been characterised, A and B.  
 Binding of endothelin to the A receptor induces vasoconstriction,  
 binding to the B receptor leads to nitric oxide release and hence vasodilatation. 
Pulses 
Pulsus parodoxus

Pulses 
Pulsus parodoxus 
 greater than the normal (10 mmHg) fall in systolic blood pressure during inspiration ĺ faint or 
absent pulse in inspiration 
 severe asthma, cardiac tamponade 
Slow-rising/plateau 
 aortic stenosis 
Collapsing 
 
 aortic regurgitation 
 patent ductus arteriosus 
 hyperkinetic (anaemia, thyrotoxic, fever, exercise/pregnancy) 
Pulsus alternans 
 
 regular alternation of the force of the arterial pulse 
 severe LVF

 severe LVF 
 It is found in association with a third heart sound 
Bisferiens pulse 
 'double pulse' - two systolic peaks 
 mixed aortic valve disease 
'Jerky' pulse 
 hypertrophic obstructive cardiomyopathy* 
*HOCM may occasionally be associated with a bisferiens pulse 
Atrial natriuretic peptide 
Basics 
 secreted mainly from myocytes of right atrium and ventricle in response to increased bloo d 
volume

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  8 
  secreted by both the right and left atria (right >> left)  
 synthesis increased by thyroid hormones, glucocorticoids, endothelin-1, angiotensin-II, an d 
tachycardia, independent of the haemodynamic effects of these factors. 
 28 amino acid peptide hormone, which acts via cGMP 
 degraded by endopeptidases 
 
Actions

Actions 
 natriuretic, i.e. promotes excretion of sodium 
 lowers BP 
 reduced pre-load due to relaxing effects on vascular smooth muscle.  
 antagonises actions of angiotensin II, aldosterone  
B-type natriuretic peptide 
 
 B-type natriuretic peptide (BNP) is a hormone produced mainly by the left ventricular 
myocardium in response to strain. 
Causes of raised BNP levels

Causes of raised BNP levels  
 heart failure is the most obvious cause  
 The stimulus for BNP release is myocyte stretch, rather than transmural pressure load. 
 any cause of left ventricular dysfunction such as myocardial ischaemia or valvular disease  
 chronic kidney disease (due to reduced excretion) .  
 BNP synthesis is increased by thyroid hormones as well as glucocorticoids, endothelin-1, 
angiotensin-II, and tachycardia, independent of the haemodynamic effects o f these factors.

Factors which reduce BNP levels 
  treatment with ACE inhibitors, angiotensin-2 receptor blockers and diuretics.  
Effects of BNP  
 Vasodilator 
 arterial and venous smooth muscle vasodilatation 
 BNP  relaxing effects on vascular smooth muscle (vasodilatation)  reduced pre-load 
 reduced blood pressure, 
 Diuretic and natriuretic 
 In the kidney, BNP causes increased glomerular filtration rate (GFR) and inhibition of 
sodium reabsorption, leading to natriuresis and diuresis.

 suppresses both sympathetic tone and the renin-angiotensin- aldosterone system 
Clinical uses of BNP  
 Diagnosing patients with acute dyspnoea 
 a low concentration of BNP(< 100pg/ml) makes a diagnosis of heart failure unlikely, b ut 
raised levels should prompt further investigation to confirm the diagnosis 
 Levels >400 pg/ml warrant urgent specialist assessment and echocardiography;  
 intermediate levels (100-400 pg/ml) should be investigated within six weeks.

 NICE currently recommends BNP as a helpful test to rule out a diagnosis of heart failure 
 Prognosis in patients with chronic heart failure 
 initial evidence suggests BNP is an extremely useful marker of prognosis 
 Guiding treatment in patients with chronic heart failure 
 effective treatment lowers BNP levels 
 Screening for cardiac dysfunction 
 not currently recommended for population screening 

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  9 
  T tubules and calcium channels 
 tubular network formed by the invagination of the sarcolemma of the myocyte  
 Sarcolemmal calcium channels are located on the T tubules  
 There are two main types of channels  
 T (transient) channels do not interact with conventional calcium-channel blockers

 L-type calcium channels do interact with calcium-channel blockers 
 Titin 
 Titin tethers the myosin molecule to the Z line, and its elasticity explains the stress-strain 
elastic relation of striated muscle  
  It is the largest protein molecule yet described 
 Tropomyosin 
 The thin actin filaments intertwine and are carried on a heavier tropomyosin molecule  that 
functions as a backbone  
  At regular intervals along this structure is a group of three regulatory proteins called the

'troponin complex', which is composed of troponin C, I and M 
Cardiovascular physiology 
 The basic muscle unit of the myocardium  Sarcomere  
 What is the normal resting cell membrane potential of a cardiac myocyte?  - 90 mV  
 
Left ventricular ejection fraction (LV EF) 
 The left ventricle pumps only a fraction of the blood it contains.

 The ejection fraction is the amount of blood pumped (stroke volume) divided by the amount of 
blood the ventricle contains (end diastolic volume). 
 ejection fraction = ( Stroke volume /end diastolic volume ) * 100%  
 stroke volume = end diastolic volume − end systolic volume  
 normal ejection fraction is more than 55% of the blood volume.  
 in systolic dysfunction, EF is low. 
 In diastolic dysfunction, EF is normal (called HF with preserved LV EF)

 e.g: hypertrophy heart failure occur due to diastolic dysfunction. heart muscle is 
big, so less blood can come to the heart during the diastole. say 40 ml of blood 
can come to the heart (40 ml is the total blood volume end of the diastole) but 
heart pump 30 ml in each beat. so EF 30/40=75%.  
 Which echocardiographic measures is mandatory  in calculating ejection fraction?   
 Left ventricular end diastolic diameter

 Left ventricular end diastolic diameter  
 One way of measuring ejection fraction (EF) is estimated by the ratio between the M-mod e 
readings of the left ventricular end diastolic volume (EDV) and the end systolic volume (ESV), 
using the formula [(EDV - ESV) / EDV] x 100 = EF (%). 
Cardiac output (CO) 
 The Cardiac output measure how much blood ejected by the heart in one minute. 
 CO= Stroke volume (SV) (volume pumped in each beat) x Heart rate (HR) 
 Changes in CO

 Changes in CO 
 Ļ SV in ventricular tachycardia 
 if HR is too high, diastolic filling is incomplete and CO decreases 
 exercise  
 CO maintained by SV in early  stages of exercise 
 CO maintained by HR in late stages of exercise 
 cardiac output  studies  
 PiCCO (pulse contour cardiac output)  
 PiCCO gives indications of cardiac output, extravascular lung water, intravascular 
filling  
 only requires a central line and a PiCCO femoral arterial line and as such is

relatively simple to use. 
Stroke Volume (SV)  
 SV = CO/HR = End-Diastolic Volume (EDV) - End-Systolic Volume (ESV) 
 volume of blood ejected per heart beat 
 SV ~ 70 mL 
Pulse pressure  
 Pulse pressure = Systolic Pressure - Diastolic Pressure 
 Factors which increase pulse pressure  471

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  10 
  less compliant  aorta (this tends to occur with advancing age) 
 increased stroke volume 
 Factors which reduced pulse pressure 
 Reduced stroke volume,  
 high aortic compliance,  
 reduced venous return, and  
 reduced peripheral resistance  

Cardiovascular physiology response to blood loss 
Stroke volume (SV) is decreased because of hypovolaemia 
The compensation mechanisms to sudden hypovolaemia include: 
 Cardiac output (CO) can increase, decrease, or stay the same (CO = HR × SV).  
 Heart rate (HR) can increase due to decreased  (parasympathetic ) vagal stimulation and 
enhanced sympathetic stimulation with adrenaline . 
 Total peripheral resistance can increase due to increased sympathetic drive . This causes

peripheral vasoconstriction and preserves blood flow to essential organs, such as the  brain, heart 
and kidneys. 
 Venous return increases if sympathetic output increases, and this is related to the pe ripheral 
vasoconstriction. Less blood can pool in the peripheral vessels so it is transported back to the 
central circulation quickly. This increases venous return and maximises stroke volume. 

Physiological C.V changes during pregnancy 
 Heart rate: 
  increases by 10-20 bpm 
 cardiac output   
 cardiac output and blood volume increase from the second month up to the t hirtieth week 
to 30 - 50% above the normal levels. 
 The average increase in blood volume during pregnancy amounts to 1600 ml 
 The increase in cardiac output is mediated via increase in both stroke volume  and to a 
lesser extent heart rate , along with a dramatic fall in total peripheral vascular

resistance . 
 stroke volume and cardiac output increase  
 venous pressure  
 venous pressure should remain the same due to a 25% reduction in systemic and 
pulmonary vascular resistance. 
 Blood pressure: 
  should drop in the first and second trimester and then climb to pre-pregnan cy levels by 
the third trimester. 
 Lowered diastolic blood pressure due to vasodilatation : this is responsible for the 
fading of the aortic regurgitation murmur

fading of the aortic regurgitation murmur  
 The increase in blood volume and increased cardiac output lead to all stenosic murmurs 
becoming more prominent (there is increased flow across the valve, with more turbulence and 
pressure gradient, leading to a louder sound).  
 Typically, an ASD  is associated with fixed splitting of the second heart sound; if a murmur is 
present it has arisen from increased pulmonary valvular flow , and hence is increased during 
pregnancy.

pregnancy.  
 metabolic workload  
 there is also an increased metabolic workload 
 apex beat  
 The apex beat is displaced, because of cardiomegaly and a raised diaphragm 
 The increased blood flow may produce a pulmonary systolic murmur  and a third heart 
sound . 
 
Which murmur is diminished during pregnancy? 
 Aortic regurgitation  
 The fall in diastolic blood pressure during pregnancy leads to a reduction in the murmur o f 
aortic regurgitation.

aortic regurgitation.  
 Murmurs follow pressure gradients – if the blood pressure is lower, then the difference 
between the aortic pressure and LV pressure is less, making the murmur quieter. 
 
___________________________________________________ _____________________________ 472

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  11 
 Valsalva manoeuvre 
The Valsalva manoeuvre describes a forced expiration against a closed glottis. This leads  to increased 
intrathoracic pressure which in turn has a number of effects on the cardiovascular system. 
Uses  
 to terminate an episode of supraventricular tachycardia 
 normalizing middle-ear pressures

 normalizing middle-ear pressures 
Stages of the Valsalva manoeuvre 
 1. Increased intrathoracic pressure 
 2. Resultant increase in venous and right atrial pressure reduces venous return 
 3. The reduced preload leads to a fall in the cardiac output (Frank-Starling mechanism)  
 4. When the pressure is released there is a further slight fall in cardiac output due to incre ased 
aortic volume 
 5. Return of normal cardiac output

 5. Return of normal cardiac output 
Cardiac action potential 
Cardiac action potential  
 
Phase Description Mechanism 
0 Rapid 
depolarisation Rapid sodium influx 
These channels automatically deactivate after a few ms 
1 Early repolarisation Efflux of potassium 
2 Plateau Slow influx of calcium 
3 Final repolarisation Efflux of potassium 
4 Restoration of ionic

4 Restoration of ionic 
concentrations Resting potential is restored by Na+/K+ ATPase 
There is slow entry of Na+ into the cell decreasing the potential difference 
until the threshold potential is reached, triggering a new action potential 
NB cardiac muscle remains contracted 10-15 times longer than skeletal muscle 
 
473

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  12 
  
Conduction velocity 
Site Speed 
Atrial 
conduction Spreads along ordinary atrial myocardial fibres at 1 m/sec 
AV node 
conduction 0.05 m/sec 
Ventricular 
conduction Purkinje fibres are of large diameter and achieve velocities of 2-4 m/sec (this allows a 
rapid and coordinated contraction of the ventricles

Which physiological change associated with age  during exercise ? 
 Reduced tachycardic response  
 There is a reduced tachycardic response during exercise associated with age.  
  The heart has to compensate by increasing stroke volume and failure to do so will 
reduce aerobic capacity.  
 Some fit, healthy elderly men can compensate for this by increasing left ventricular 
filling and thus stroke volume (Starling's law).

Physiological changes associated with age. They occur, irrespective of whether a patient 
exercises or not.   
 Decrease elasticity and compliance of the aorta  increased resistance to ejection of blood from 
the left ventricle  increased ventricular afterload.   
 Diastolic dysfunction and reduced stroke volume  
 ↓↓diastolic pressure (the pressure responsible for subendocardial perfusion )  subendocardial

ischemia and interstitial fibrosis. (These changes are related to an increase in the magnitude of 
the L-type Ca++)  
 Higher systolic arterial pressure and increased impedance to left ventricular ejection   
 ↑ systolic + ↓ diastolic  ↑ pulse pressure  
 Increased sino-atrial conduction time  
  Because of the delayed LV relaxation and the stiffer left ventricle, the force o f left atrial 
contraction increases and the contribution of the atrial contraction to LV end-diastolic

volume increases  
 There is apoptosis of atrial pacemaker cells with a loss of 50%-75% of cells by age 50. The 
number of atrioventricular nodal cells is preserved and there is fibrosis and cellular loss in the His 
bundle  
 Left ventricular hypertrophy 
Heart sounds 
First heart sound (S1)  
 Caused by closure of mitral and tricuspid valves 
 Causes of a loud S1  
 mitral stenosis 
 left to right shunts

 left to right shunts 
 short PR interval, (  shortened diastole) atrial premature beats  
 hyperdynamic states 
 Causes of a quiet S1  
 mitral regurgitation 
 long PR 
Second heart sound (S2)  
  
474

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  13 
  The second heart sound consists of the closure of the aortic valve (A 2) followed by the closure of 
the pulmonary valve (P 2).  
 splitting during inspiration is normal 
 inspiration causes negative intrathoracic pressure, increasing return of blood from the

body into the right atrium and ventricle. This slightly prolongs systole in the right ventricle 
and therefore delays closure of the pulmonary valve, causing an appreciably split second 
heart sound. 
 Causes of a loud S2 
 hypertension: systemic (loud A2) or pulmonary (loud P2) 
 atrial septal defect without pulmonary hypertension 
 Causes of a soft S2 
 aortic stenosis 
 Causes of fixed split S2 
 atrial septal defect (ASD)

 atrial septal defect (ASD) 
 ASD Ĺ blood volume in the right atrium,  overloads the right ventricle,  
delayed closure of the pulmonary valve.  
 As the flow of blood from the left to the right is relatively unaffected by respiration, it 
results in a fixed, widely split second heart sound. 
 right heart failure 
 Right bundle-branch block with heart failure 
 right bundle-branch block widens the split, and heart failure makes the split fix ed.  
 pulmonary hypertension

 pulmonary hypertension 
 Causes of a widely split S2 
 deep inspiration 
 S2 is split during inspiration, and synchronous during expiration.  
 This is because during inspiration there is increased venous return to the right 
heart, which delays the closure of the pulmonary valve (P2) relative to the aortic 
valve (A2). 
 RBBB 
 RBBB (delayed electrical activation of the right ventricle)  delayed pulmonary 
valve close  wide physiological splitting of S2 
 pulmonary stenosis

 pulmonary stenosis 
 severe mitral regurgitation 
 Causes of a reversed (paradoxical) split S2 (P2 occurs before A2) 
 LBBB 
 severe aortic stenosis 
 hypertrophic obstructive cardiomyopathy  
 right ventricular pacing 
 WPW type B (causes early P2) 
 patent ductus arteriosus 
 
475

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  14 
 Third heart sound (S3) 
 
 caused by diastolic filling of the ventricle 
 The mechanism of an S3 gallop is rapid ventricular filling during diastole. As soon a s the mitral 
valve opens, blood rushes into the ventricle, causing a splash sound 
 considered normal if < 30 years old (may persist in women up to 50 years old)

 heard in left ventricular failure (e.g. dilated cardiomyopathy), constrictive pericarditis (called a 
pericardial knock) 
 
Fourth heart sound (S4) 
 caused by atrial contraction  against a stiff ventricle 
 P wave on ECG  
 It is heard just before S1  
 occurs with: (any type of left ventricular hypertrophy): 
 aortic stenosis, 
 HOCM,  
 in HOCM a double apical impulse may be felt as a result of a palpable S4 
 
476

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  15 
  
Murmurs 
Most murmurs of stenosis or regurgitation are exaggerated during squatting and get so fter with the 
Valsalva manoeuvre. The exceptions are HOCM where the opposite occurs ( Ĺ by valsalva & Ļ

by squatting) and mitral valve prolapse where the murmur gets longer. 
 
Relation between murmurs intensity and respiration: 
 Murmurs that increase in intensity with inspiration  originate from the right side of the heart  
(tricuspid or pulmonary) 
 Murmurs that increase in intensity with expiration  originate from the left side of the heart  
(mitral or aortic). 
Mnemonic: RILE (Right Inspiration, Left Expiration) 
 
Ejection systolic 
 aortic stenosis, HOCM 
 pulmonary stenosis

 pulmonary stenosis  
 ASD 
 ( ASD with pulmonary hypertension  prominent left precordium  with an 
ejection murmur  ) 
 Fallot's 
Holosystolic (pansystolic) 
 mitral/tricuspid regurgitation (high-pitched and 'blowing' in character) 
 VSD ('harsh' in character) 
Late systolic 
 mitral valve prolapse 
 coarctation of aorta 
Early diastolic 
 aortic regurgitation (high-pitched and 'blowing' in character)

 Graham-Steel murmur (pulmonary regurgitation, again high-pitched and 'blowing' in character)  
Mid-late diastolic 
 mitral stenosis ('rumbling' in character) 
 Austin-Flint murmur  (severe aortic regurgitation, again is 'rumbling' in character) 
477

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  16 
  It is a low frequency mid/late diastolic murmur which may show pre-systolic 
accentuation  and is virtually indistinguishable from that of mitral stenosis. 
 It is due to partial closure of the anterior leaflet of the mitral valve by the regurgitant jet.  
Continuous machine-like mumur 
 
478

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  17 
  
Murmurs in pregnancy  
 The intensity of Aortic regurgitation murmur diminishes during pregnancy.  
 Diastolic blood pressure is lower due to vasodilatation, and this is responsible for the fad ing of 
the aortic regurgitation murmur 
 All stenotic murmurs become more prominent

 All stenotic murmurs become more prominent  
 
 Mitral murmurs are heard best during expiration and while the patients lies on the left side.  
 
 All right-sided heart murmurs are intensified during deep inspiration.  
 
Syncope  (Nice guidelines 2014) and (ESC guidelines 2009)  
 Syncope is a transient loss of consciousness due to transient global cerebral hypoperfusion ,

characterised by rapid onset, short duration, and spontaneous complete recovery.   
 in the majority of patients, the cause of syncope is relatively benign, and a strategy b ased on 
patient education and prevention of recurrences is sufficient.  
 Syncope can be classified as  
1. neurally-mediated (reflex syncope) 
2. secondary to orthostatic hypotension  
3. secondary to cardiac causes. 
 In older patients, non-cardiovascular causes (such as vasovagal or orthostatic episodes) are

twice as common as cardiovascular causes (such as arrhythmias or ischaemia). 
 situational syncope : provoked by straining during micturition (usually while standing) or by 
coughing or swallowing. 
 The initial evaluation after T-LOC consists of: 
 a careful history 
 physical examination, including orthostatic blood pressure measurements  
 electrocardiogram (ECG). 
 Based on these findings, simple additional examinations such as, carotid sinus massage,

echocardiogram, ECG monitoring or orthostatic challenge can be indicated. 
 The initial evaluation can define the cause of syncope in 23-50% of patients and  should answer 
three key questions: 
 Is it a true syncopal episode or not? 
 Has the aetiological diagnosis been determined? 
 Are there findings suggestive of a high risk of cardiovascular events or death?  
 It is important to distinguish exercise-induced syncope occurred during exercise  (when a

cardiac arrhythmic cause is probable) from those whose syncope occurred shortly after 
stopping exercise  (when a vasovagal cause is more likely). 
 For people who have experienced syncope during exercise : 
  offer urgent (within 7 days) exercise testing, unless there is a possible contraindication 
(such as suspected aortic stenosis or hypertrophic cardiomyopathy requiring initial 
assessment by imaging).

assessment by imaging).  
 Advise the person to refrain from exercise until informed otherwise following further 
assessment. 
 If the mechanism for exercise-induced syncope is identified by exercise testing, c arry out 
further investigation or treatment as appropriate in each individual clinical context.  
479

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  18 
  Otherwise, carry out further investigations assuming a suspected cardiac arrhythmic 
cause. 
 For people with a suspected cardiac arrhythmic cause of syncope, offer an ambulatory ECG and  
do not offer a tilt test as a first-line investigation.

 For all people with unexplained syncope  offer ambulatory ECG. Do not offer a tilt test before 
the ambulatory ECG. 
 The type of ambulatory ECG offered should be chosen on the basis of the person's history and 
frequency of TLoC. 
 TLoC at least several times a week ,  offer Holter monitoring (up to 48 hours) 
 If no further TLoC occurs during the monitoring period,  offer external event 
recorder that provides continuous recording with the facility for the patient to

indicate when a symptomatic event has occurred. 
 TLoC every 1 –2 weeks   offer an external event recorder.  
 If the person experiences further TLoC outside the period of external even t 
recording,  offer an implantable event recorder. 
 TLoC infrequently (less than once every 2 weeks)   offer an implantable event 
recorder. A Holter monitor should not usually be offered unless there is evidence of a 
conduction abnormality on the 12-lead ECG.

conduction abnormality on the 12-lead ECG. 
 For people with suspected carotid sinus syncope and for people with unexplained syncope 
who are aged 60 years or older,  offer carotid sinus massage as a first-line investigation.  
 This should be conducted in a controlled environment, with ECG recording, and with 
resuscitation equipment available. 
 Diagnose carotid sinus syncope if carotid sinus massage reproduces syncope due to 
marked bradycardia/asystole and/or marked hypotension.

 Do not diagnose carotid sinus syncope if carotid sinus massage causes asymptomatic 
transient bradycardia or hypotension 
 tilt test  
 Do not offer a tilt test to people who have a diagnosis of vasovagal syncope on initial 
 For people with suspected vasovagal syncope with recurrent episodes of TLoC  
adversely affecting their quality of life, or representing a high risk of injury,  consider a 
tilt test only to assess whether the syncope is accompanied by a severe

cardioinhibitory response (usually asystole).  
 If a person has persistent TLoC, consider psychogenic non-epileptic seizures (PNES)  or 
psychogenic pseudosyncope  if: 
 the nature of the events changes over time 
 there are multiple unexplained physical symptoms 
 there are unusually prolonged events. 
 Driving 
 must not drive while waiting for a specialist assessment.  
 Following specialist assessment report the TLoC event to (DVLA) 
 
Implantable loop recorder (ILR)

Implantable loop recorder (ILR)  
 subcutaneous, single-lead, (ECG) monitoring device  
 used for diagnosis in patients with recurrent unexplained episodes of palpitations or syn cope,  
 The device is typically implanted in the left parasternal region and is capable of storing  ECG 
data automatically in response to a significant bradyarrhythmia or tachyarrhythmia or in 
response to patient activation.

response to patient activation.  
 It is particularly useful either when symptoms are infrequent (and thus not amenabl e to 
diagnosis using short-term external ECG recording techniques) or when aggregate long-term 
data (eg, burden of AF) are required. 
 
Vasovagal syncope  (VVS)  
 Vasovagal syncope (VVS) is the most common type of syncope. 
Causes 
 features suggestive of uncomplicated vasovagal syncope ( the 3 'P's ):

 Posture – prolonged standing, or similar episodes that have been prevented by lying down  
 Provoking factors (such as pain or a medical procedure) 
 Prodromal symptoms (such as sweating or feeling warm/hot before TLoC). 
 Vasovagal syncope  is common during dental procedures, mainly induced by pain (as the 
dentist started drilling).  480

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  19 
 Feature 
 VVS is usually preceded by a prodrome of symptoms such as dizziness, nausea, and  
diaphoresis. 
  The syncope lasts briefly, but nausea, warmth and sweating may persist for some time. 
 Twitching and jerking are often seen with vasovagal or cardiac syncope, which can be

differentiated from rhythmic jerking of all the limbs in tonic-clonic seizures. 
 It is common to have jerking of limbs due to brain hypoxia. 
 Incontinence of urine can occur, but not biting of the tongue . 
Diagnosis 
 Recover very quickly supports the diagnosis of syncope.  
 ECG is always normal. 
 Tilt table test  is a useful test to support  the diagnosis 
 If structural heart disease is excluded and syncope is reproduced on tilt table testing along

with fall in blood pressure and heart rate, then this is diagnostic of vasovagal syncope. 
Treatment 
 Midodrine may be indicated in patient with VVS refractory to life style management 
 Midodrine is a prodrug of Desglymidodrine  
 a sympathomimetic (alpha receptor agonist) that acts on the blood vessels to raise blood 
pressure. 
 
Postural hypotension  
 Causes: mnemonic ( HANDI ) 
 H = Hypovolemia, Hypopituitarism (dehydration, bleeding )  
 A = Addison's disease

 A = Addison's disease  
 N = Neuropathy (autonomic due to diabetics, amyloidosis )  
 D = Drugs ( Vasodialators, TCA, antipsychotic, Diuretics etc. )  
 I = Idiopathic orthostatic hypotension  
 Management of postural hypotension 
 if the standing BP is clearly acceptable (110 systolic ) , the most obvious first step is 
stopping the causative drug (eg: indapamide)   and monitoring his blood pressure 
over the subsequent 2-4 weeks.

over the subsequent 2-4 weeks.  
 If he still has significant postural hypotension then the next steps  would be to add 
elastic stockings, then fludrocortisone.  
 The history of pre-syncope is much more suggestive of changes in blood pressure 
rather than changes in blood glucose. 
 
Sudden cardiac death  
 The most common cause of sudden cardiac death in those aged greater than 35 years, is

ischemic heart disease.  
 Up to 80% of individuals who suffer sudden cardiac death have coronary heart disease.  
 In those under the age of 35 years of age, HOCM is the most common cause of su dden cardiac 
death, coronary artery disease being the second most common cause. 
 In competitive athletes <35 years of age HOCM is by far the most common cause of sudde n 
cardiac death (prevalence is 1 in 500). 
 arrhythmogenic right ventricular dysplasia (ARVD).

 the second most common cause of sudden cardiac death in the young after HOCM .  
 Catecholaminergic polymorphic ventricular tachycardia (CPVT) 
 an autosomal dominant inherited cardiac disease 
 prevalence of around 1:10,000. 
 Brugada syndrome  
 an autosomal dominant inherited cardiovascular disease.  
 prevalence of 1:5,000-10,000. 
 more common in Asians. 
Exercise: physiological changes

Exercise: physiological changes 
Blood pressure 
 systolic increases, diastolic decreases 
 Diastolic BP remains the same and may decrease slightly  
 leads to increased pulse pressure 
 in healthy young people the increase in MABP is only slight 481

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  20 
 Cardiac output 
 increase in cardiac output may be 3-5 fold 
 results from venous constriction, vasodilation and increased myocardial contractibility, as well  as 
from the maintenance of right atrial pressure by an increase in venous return 
 heart rate up to 3-fold increase 
 stroke volume up to 1.5-fold increase.

 stroke volume up to 1.5-fold increase. 
 
arrhythmias in athletes 
 A variety of arrhythmias occur in athletes, most of which are benign and do not requ ire further 
evaluation.  
 Sinus pauses and arrests less than 3 seconds are common and do not necessarily indicat e an 
underlying structural heart disease.  
 Wandering atrial pacemaker and atrial ectopics are common and reflect high resting vagal tone.

 Atrial flutter in the absence of Wolf-Parkinson-White syndrome is rare and should be eva luated 
further.  
 Sustained or non-sustained VT is never normal and almost always occurs in the context 
of underlying structural heart disease. 
Exercise tolerance tests 
Indications: Exercise tolerance tests (ETT, also exercise ECG) are used for a variety of indications:

 assessing patients with suspected angina - however the 2010 NICE Chest pain of recent onse t 
guidelines do not support the use of ETTs for all patients 
 risk stratifying patients following a myocardial infarction 
 the best predictor of mortality post-STEMI  exercise capacity 
 Above average exercise capacity  good prognosis after a STEMI 
 assessing exercise tolerance 
 risk stratifying patients with hypertrophic cardiomyopathy

Sensitivity and specificity of ETT: ( high number of false positives and false negatives) 
 ETT has a sensitivity of around 80% and a specificity of 70% for ischaemic heart disease . 
Thus, a negative test may not necessarily be true and further testing may be adv iced.  
 Exercise ECG testing has a relatively high sensitivity but only moderate specificity 
for the diagnosis of CAD.  
 Diagnostic accuracy is poor in women and this may relate to smaller heart size. 
Heart rate :

Heart rate : 
 maximum predicted heart rate = 220 - patient's age 
 the target heart rate is at least 85% of maximum predicted to allow reasonable interpr etation of a 
test as low-risk or negative 
Contraindications   
 myocardial infarction less than 7 days ago 
 unstable angina 
 uncontrolled hypertension (systolic BP > 180 mmHg) or hypotension (systolic BP < 90 mmHg) 
 Any condition where left ventricular output is reduced - eg, aortic stenosis or hypertrophic

obstructive cardiomyopathy (HOCM). 
 Abnormal baseline ECG (eg, bundle branch block patterns or left ventricular hypertrophy); these 
make interpretation of the ETT difficult. 
Stop if:  
 exhaustion / patient request 
 'severe', 'limiting' chest pain 
 > 3mm ST depression 
 > 2mm ST elevation.Stop if rapid ST elevation and pain 
 systolic blood pressure > 230 mmHg 
 systolic blood pressure falling > 20 mmHg 
 attainment of maximum predicted heart rate

 attainment of maximum predicted heart rate 
 heart rate falling > 20% of starting rate 
 arrhythmia develops 
Interpreting the exercise tolerance test 
 The patient is normally considered to have been adequately 'stressed' if they achieve 85 % or 
more of their maximum heart rate (calculated as 220 - age in years for men and 2 10 - age for 
women).  
 If ECG criteria for inducible ischaemia (chest pain is not mandatory).The next step is  
Coronary angiography

Coronary angiography  
 this will define the coronary anatomy and give a better guide to prognosis. 482

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  21 
  If an inadequate test was performed, further non-invasive investigations may be  indicated, such 
as myocardial perfusion scanning, cardiac MRI, or stress echocardiogram.  
Notes 
 Beta-blockers and digoxin can interfere with the results so are usually stopped befo re the ETT.

 If ETT performed on beta blocker and there is an adequate rise in heart rate  (85% of 
(220 − age))   so there is no indication for stopping beta blocker and repeat the test 
 
PiCCO (pulse contour cardiac output)  
Which method is an appropriate of measuring adequate intravascular filling? 
 PiCCO (pulse contour cardiac output)

 PiCCO (pulse contour cardiac output) 
 PiCCO gives indications of cardiac output, extravascular lung water, intravascular 
filling and only requires a central line and a PiCCO femoral arterial line and as such is 
relatively simple to us e.  
 
Cardiac enzymes and protein markers 
 
Myoglobin rises first following a myocardial infarction 
 
Key points for the exam 
 myoglobin is the first to rise

 myoglobin is the first to rise 
 CK-MB is useful to look for reinfarction as it returns to normal after 2-3 days (troponin T rem ains 
elevated for up to 10 days) 
 
Begins to rise Peak value Returns to normal 
Myoglobin  1-2 hours 6-8 hours 1-2 days 
CK-MB 2-6 hours 16-20 hours 2-3 days 
CK 4-8 hours 16-24 hours 3-4 days 
Trop T  4-6 hours 12-24 hours 7-10 days 
AST  12-24 hours 36-48 hours 3-4 days 
LDH  24-48 hours 72 hours 8-10 days 
  
Troponin

Troponin 
Troponin C: Binds to calcium to activate actin: myosin interaction 
Troponin T: Binds to tropomyosin 
Troponin I: Blocks or inhibits actin: myosin interaction 
 
 Troponin is a component of thin filaments  (along with actin and tropomyosin), and is the 
protein to which calcium binds to accomplish this regulation. 
 Troponin has three subunits, TnC, TnI, and TnT. 
 When calcium is bound to specific sites on TnC, the structure of the thin filament cha nges in

such a manner that myosin (a molecular motor organised in muscle thick filaments) attaches to 
thin filaments and produces force and/or movement. 
 In the absence of calcium, tropomyosin interferes with this action of myosin, and therefore 
muscles remain relaxed. 
 Both troponin I and T are highly sensitive and specific for cardiac damage, and a re of equal 
clinical value.    
 Baseline troponin (I or T) should be done on admission. This troponin is not used  immediately for

interpretation of the cause of chest pain, but can be used to show a rise in patients w ho have an 
elevated baseline troponin (for example those with renal impairment). 483

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  22 
  A second blood sample is taken for troponin I or T 10-12 hours after the onset of sym ptoms. A 
myocardial infarct can be diagnosed when there is a rise and/or fall of troponin (with at lea st one 
value abouve the 99th percentile of the upper reference limit)

 The 99th percentile thresholds for troponin I and T may differ between  sexes. 
 There is probability of chronically elevated troponin levels in some people  
  Diagnosis of ischaemia 
 What is the significant level? 
 A level of > 0.1 ng/ml is considered as a significant rise 
 What is the next step after detecting a high level before confirming the diagnosis o f ACS? 
 a detectable troponin on the first high-sensitivity test  does not necessarily 
indicate that they have had an MI.

indicate that they have had an MI. 
 perform a second high-sensitivity troponin test   if the first troponin test at 
presentation is positive. 
 When a raised troponin level is detected in people with a suspected ACS, reassess 
to exclude other causes for raised troponin (for example, myocarditis, aortic 
dissection or pulmonary embolism) before confirming the diagnosis of ACS. 
 What is the time for increasing after event? 
 Levels rise about 4 hours after the onset of chest pain

 100%  of patients are positive for troponin at 12 hours after the onset of pain  
 Levels act as a prognostic factor following an acute coronary syndrome  
 Other causes of an elevated troponin are: 
 Trauma 
 Cardioversion 
 Rhabdomyolysis 
 Pulmonary embolism 
 Pulmonary hypertension 
 Hypotension, especially with arrhythmias 
 Hypertrophic obstructive cardiomyopathy 
 Myocarditis including Kawasaki's disease 
 Sepsis 
 Burns

 Sepsis 
 Burns 
 Subarachnoid haemorrhage and stroke 
 Infiltrative/autoimmune disorders including sarcoidosis, amyloidosis, haemochromatosis 
and scleroderma. 
 Drugs including  
 Adriamycin, Herceptin  and 5-fluorouracil. 
 
Serum creatine kinase 
 Creatine kinase (CK) rises to a peak at about 24 h after a myocardial infarction and usua lly 
returns to baseline by72 h 
 serum CK activity in Afro-Caribbean people is often up to three times the upper limit of

normal for white populations 
 other causes of high CK: hypothyroidism, heavy exercise and statins  
 
 LDH-1 isoenzyme is predominantly found in cardiac muscle so a high LDH-1:LDH-2 ratio c an 
indicate myocardial damage.  
 Glycogen phosphorylase isoenzyme BB (GPBB)  
 GPBB exists in heart and brain tissue. 
 rise significantly by three hours post mi. As such it is an  appropriate marker for 
early cardiac muscle injury.  
 Rise earlier than myoglobin

 Rise earlier than myoglobin 
 GPBB levels increase 1–3 h after the event. 
 Myoglobin levels increase significantly 2 h after ischaemia. 
 Cardiac enzymes may be elevated in pulmonary embolism (PE), aortic dissection, renal fail ure 
and sepsis. 
 
 484

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  23 
  
ECG: axis deviation 
Left axis deviation (LAD) 
 Left axis deviation ( ≥ - 30 degrees) is the most common "abnormality" in adults occurring in over 
8%. It can be part of the criteria for LVH but in isolation it has little significance.

 Marked LAD ( ≥ - 45 degrees) is called left anterior hemiblock or left anterior fascicular block. 
 Recommendations : If left axis deviation is present:  
 Exclude  hypertension. If borderline  ambulatory BP monitoring.  
  check for borderline indicators of LVH (i.e., the voltage criteria and left atrial 
enlargement).  
 Note whether diagnostic inferior Q waves are present since an inferior MI can cause LA D. 
 Causes of left axis deviation (LAD) 
 left anterior hemiblock

 left anterior hemiblock 
 left bundle branch block 
 Wolff-Parkinson-White syndrome* - right-sided accessory pathway 
 hyperkalaemia 
 congenital: ostium primum ASD, tricuspid atresia 
 minor LAD in obese people 
Right axis deviation (RAD) 
 QRS axis between +90° and + 180° 
 Causes of right axis deviation (RAD) 
 right ventricular hypertrophy 
 left posterior hemiblock 
 chronic lung disease ĺ cor pulmonale  
 pulmonary embolism 
 ostium secundum ASD

 ostium secundum ASD 
 Wolff-Parkinson-White syndrome* - left-sided accessory pathway 
 *in the majority of cases, or in a question without qualification, Wolff-Pa rkinson-White 
syndrome is associated with left axis deviation 
 normal in children or thin adults 
 normal in youngsters (less than 21 years of age) and in athletes.  
 minor RAD in tall people 
 
ECG: coronary territories

ECG: coronary territories 
The table below shows the correlation between ECG changes and coronary territories: 
 
ECG changes Coronary artery 
Anteroseptal  V1-V4 Left anterior descending 
Inferior  II, III, aVF Right coronary 
Anterolateral  V4-6, I, aVL Left anterior descending or left circumflex 
Lateral  I, aVL +/- V5-6 Left circumflex 
Posterior  Tall R waves V1-2 Usually left circumflex, also right coronary ECG  485

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  24 
  
high lateral wall MI  
 ST segment elevation in leads I and aVL  High lateral wall MI 
 usually due to occlusion of the first diagonal branch of the left anterior descending a rtery, 
though occlusion of other arteries like branches of the left circumflex or a short left anterior 
descending artery may cause the same picture.

Postero-lateral MI   prominent R wave in lead V1 and ST depression in V1-V3 + ST elevation 
in leads V5 and V6. 
 
posterior MI  (ESC guidelines 2017)  
 posterior wall (now termed inferobasilar), usually supplied by the posterior descen ding 
artery — a branch of the right coronary artery  in 80% of individuals.  
 isolated ST- segment depression ≥ 0.5 mm in leads V 1–V3 represents the dominant finding. 
These should be managed as a STEMI.

These should be managed as a STEMI.  
 The use of additional posterior chest wall leads [elevation V 7–V9 ≥ 0.5 mm (≥1 mm in men , 
40 years ol d)] is recommended.  
 
The presence of ST depression ≥ 1 mm in six or more surface  leads, coupled with ST-segment 
elevation in aVR and/or V 1, suggests multivessel ischemia  or left main coronary artery 
obstruction , particularly if the patient presents with haemodynamic compromise. (ESC guidelines 2017)  
 
Left main stem (LMS)

Left main stem (LMS) 
 LMS occlusion typically presents dramatically with cardiogenic shock.  
 ECG findings include ST elevation in aVR with diffuse ST depression in other leads. 
 
Which ECG changes may be seen earlier in ischaemia ? 
 hyper-acute T-waves , which may precede ST-segment elevation.  
 
ECG criteria for STEMI   (ESC guidelines 2017)  
 ST-segment elevation (measured at the J-point) is considered suggestive of ongoing coro nary

artery acute occlusion in the following cases:  
 Numbers of leads : at least two contiguous leads with ST-segment elevation 
  ST-segment elevation: 
 ≥ 2.5 mm in men < 40 years,  
 ≥ 2 mm in men ≥ 40 years, or 
 ≥ 1.5 mm in women in leads V 2–V3 and/or   
 ≥ 1 mm in the other leads  
 In patients with inferior MI,  it is recommended to record right precordial leads (V 3R and 
V4R) seeking ST-segment elevation, to identify concomitant right ventricular (RV) 
infarction.

infarction.  
 Likewise, ST-segment depression in leads V 1–V3 suggests myocardial ischaemia, 
especially when the terminal T-wave is positive (ST-segment elevation equivalent), and  
confirmation by concomitant ST-segment eleva tion ≥ 0.5 mm recorded in leads V 7–
V9 should be considered as a means to identify posterior MI  (circumflex occlusion ). 
 
ECG: digoxin 
ECG features

ECG features 
 down-sloping ST depression ('reverse tick') 
 flattened/inverted T waves 
 short QT interval 
 arrhythmias e.g. AV block, bradycardia 
 
 486

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  25 
 ___________________________________________________ _____________________________ 
ECG: hypothermia 
The following ECG changes may be seen in hypothermia 
 
 bradycardia 
 'J' wave - small hump at the end of the QRS complex 
 first degree heart block 
 long QT interval 
 atrial and ventricular arrhythmias

 atrial and ventricular arrhythmias 
ECG: left bundle branch block 
 The diagram below shows the typical features of left bundle branch block (LBBB): 
 
 The ECG would show: 
 broad QRS complex (>120ms),  
 tall R waves in the lateral leads (I, V5-6) and deep S waves in the right precordial leads 
(V1-3)  
 usually leads to left axis deviation.

 usually leads to left axis deviation.   
 One of the most common ways to remember the difference between LBBB an d RBBB is 
WiLLiaM  MaRRoW  
 WiLLiaM : in LBBB there is a 'W' in V1 and a 'M' in V6 
 MaRRoW : in RBBB there is a 'M' in V1 and a 'W' in V6 
 
ECG showing typical features of LBBB 
 
 Causes of LBBB 
 ischaemic heart disease 
 cardiomyopathy 
 rare: idiopathic fibrosis, digoxin toxicity, hyperkalaemia

Right bundle branch block (RBBB) 
 Patients with MI and right bundle branch block (RBBB) have a poor prognosis. (ESC 
guidelines 2017)  
 It may be difficult to detect transmural ischaemia in patients with chest pain and RBBB. 
487

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  26 
  Therefore, persistent ischaemic symptoms  occur in the presence of RBBB  primary 
PCI strategy (emergent coronary angiography and PCI if indicated) should be  
considered  
 
Trifascicular block

Trifascicular block 
 
The evidence of trifascicular block (RBBB, LAD and prolongation of the PR interval) in the conte xt of 
dizziness and collapses. This is an indication for dual chamber (DDDR) pacing for likely complete 
heart block. 
 
 trifascicular block is not strictly an ECG diagnosis but is a term used for the combination of: 
1. right bundle branch block,  
2. left hemiblock (typically left anterior hemiblock (LAHB) )  (LAHB is diagnosed because the

net QRS deflection in lead II is negative). 
3. long PR interval. 
 the site of the lesion AV node and Purkinje fibres  
 The most common pattern referred to as “trifascicular block ” is the combination of bifascicular 
block with 1st degree AV block.   
 It implies that the bundle branches (Purkinje fibres) are blocked in the right bundle a nd one of the 
left hemibundles.  
 The 'third' bundle is also delayed or partially blocked hence the name. However, the d elay (long

PR interval) is usually at the AV node. 
 Clinically it means there is extensive disease of the conduction system and, in a patie nt such as 
this, would be an indication for permanent pacemaker. 
ECG: normal variants 
The following ECG changes are considered normal variants in an athlete: 
 sinus bradycardia 
 junctional rhythm 
 Wenckebach phenomenon

 Wenckebach phenomenon 
ECG: PR interval 
Causes of a prolonged PR interval  
 ischaemic heart disease 
 digoxin toxicity 
 hypokalaemia* 
 *hyperkalaemia can rarely cause a prolonged PR interval, but this is a much less comm on 
association than hypokalaemia 
 rheumatic fever 
 aortic root pathology e.g. abscess secondary to endocarditis 
 sarcoidosis 
 myotonic dystrophy

 A prolonged PR interval may also be seen in athletes 
 
short PR interval  is seen in Wolff-Parkinson-White syndrome 
 
ECG: ST depression 
Causes of ST depression 
 secondary to abnormal QRS (LVH, LBBB, RBBB) 
 ischaemia 
488

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  27 
  digoxin 
 hypokalaemia 
 syndrome X 
Q waves  
 A Q wave is any negative deflection that precedes an R wave on the ECG. 
 The evolution of Q waves is the most suggestive of an infarct. (more specific than ST elevation 
and cardiac enzyme for MI )

and cardiac enzyme for MI )  
 the most specific for a diagnosis of myocardial infarction 
 Small Q-waves are normal in most leads, and they can be prominent in leads III an d aVR as a 
normal variant, but should not be seen in leads V1-V3.  
 They are considered pathological if  they are: 
 more than 1mm wide,  
 more than 2mm deep,  
 more than 25% of the depth of the QRS complex, or  
 seen in leads V1-V3.

 seen in leads V1-V3.  
 Such pathological Q-waves usually indicate prior full thickness myocardial infarct.  
 
ECG: ST elevation 
Causes of ST elevation 
 myocardial infarction 
 pericarditis 
 normal variant - 'high take-off' 
 left ventricular aneurysm 
 Prinzmetal's angina (coronary artery spasm) 
 rare: subarachnoid haemorrhage, part of spectrum of changes in hyperkalaemia

TQ Interval 
 The TQ interval is the time between the end of the T wave and the onset of  the next QRS  
complex.  
 It represents the ventricular diastole 
 T wave corresponds with ventricular repolarization (when contraction stops) and QRS 
corresponds with ventricular depolarization (when it contracts). 
 which phase of the cardiac cycle shortens the most with increasing heart rate?: it is diastole.

 Diastole is usually the longest portion of the cardiac cycle, and its duration diminishes the m ost 
(more than the reduction seen in the duration of systole) with increasing heart rate. 
 Which ECG interval will show the greatest reduction during ECG stress test? 
 TQ interval 
 
ECG: Junctional escape rhythm 
 Junctional escape rhythm describes an abnormal heart rhythm that arises within the AV n ode or 
from an adjacent area.  
 There is a slow, regular pulse rate.

 There is a slow, regular pulse rate.  
 Common after a pause in the underline rhythm  
 ECG shows absent P waves, narrow QRS complexes, and a heart rate of 40 to 60 bp m.  
 Retrograde P waves, which appear immediately before or after the QRS complex may be seen. 
 
Cardiac amyloidosis  
 
Amyloid 
489

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  28 
  Low-voltage EKG  
 Speckled pattern on echo 
 
 Cardiac amyloidosis most commonly presents as restrictive cardiomyopathy.  
 The clinical findings are those of right heart failure, i.e. jugular venous distension and peri pheral 
oedema, whereas orthopnoea and paroxysmal nocturnal dyspnoea are typically ab sent.

 In more advanced stages, systolic dysfunction also occurs. Postural hypotension can occur as a  
result of poor ventricular filling or associated autonomic neuropathy.  
 The combination of low-voltage ECG and thickened ventricular walls is one of the 
characteristic features of cardiac amyloidosis.  
 echocardiographic abnormalities include atrial dilatation, thickened interatrial septum, diastolic 
dysfunction and small-volume ventricles.

dysfunction and small-volume ventricles.  
 The most distinctive feature of cardiac amyloidosis is a sparkling, granular appearance of t he 
myocardium, but this is a relatively insensitive feature occurring only in about 25% of cases. 
 
 The history of rheumatoid arthritis and the echocardiographic finding of bi-atrial dilatatio n, 
ventricular hypertrophy and a speckled appearance to the myocardium make amyloidosis the 
most likely underlying cause.

most likely underlying cause.  
 Digoxin is contraindicated in amyloid patients as the digoxin binds irreversibly to the 
amyloid fibrils.  
The ECG typically shows low-voltage complexes with poor R wave progression in the chest leads (a 
pseudoinfarction pattern). 
 
Cardiac amyloidosis is associated with a 'global speckled' pattern on echo. 
ECG: Wrong leads

ECG: Wrong leads  
 They are normally labelled red (right arm) and yellow (left arm). The other leads are green (left 
leg) and black (right leg). 
 If the wires to the right and left arms have been accidentally swapped over  It gives the 
appearence of abnormal T wave inversion in the lateral leads I and aVL. 
 The clue to recognising it is the inverted P waves in lead I  and the upright aVR which  are both 
highly unusual for a 12-lead ECG.

highly unusual for a 12-lead ECG. 
  The correct course of action  Repeat the ECG again  
Early repolarization variant  
 It is expresses as an early uptake of the ST segment before the descending limb of the R wave 
has reached the baseline .   
 Features of early repolarization variant are: 
 Classically the ST segment elevation during early exercise returns to normal as 
heart rate increases further 
490

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  29 
  It is common in black males 
 Clinical evaluation is entirely normal 
 ST elevation is usually seen in the precordial leads 
ECG: U wave 
 Causes of prominent U waves are: 
 Hypokalaemia

 Hypokalaemia 
 Cardiovascular drugs, e.g. digitalis, quinidine, amiodarone 
 Psychotropic drugs, e.g. phenothiazines, tricyclic antidepressants. 
 
Cardiac cathe terisation and oxygen saturation levels 
 Questions regarding cardiac cath eterisation and oxygen saturation levels can seem daunting at 
first but a few simple rules combined with logical deduction can usual produce the answer.

Let's start with the basics: 
 deoxygenated blood returns to the right side of the heart via the superior vena ca va (SVC) and 
inferior vena cava (IVC). It has an oxygen saturation level of around 70%. The right atrium (RA), 
right ventricle (RV) and pulmonary artery (PA) normally have oxygen saturation levels of ar ound 
70% 
 the lungs oxygenate the blood to a level of around 98-100% . The left atrium (LA), left ventricle

(LV) and aorta should all therefore have oxygen saturation levels of 98-100% 
 
Some examples: 
Diagnosis & notes RA RV PA LA LV Aorta  
Normal  70% 70% 70% 100% 100% 100% 
Atrial septal defect (ASD)  
 
The oxygenated blood in the LA mixes with the 
deoxygenated blood in the RA, resulting in intermediate 
levels of oxygenation from the RA onwards 85% 85% 85% 100% 100% 100% 
Ventricular septal defect (VSD)  
 
The oxygenated blood in the LV mixes with the

The oxygenated blood in the LV mixes with the 
deoxygenated blood in the RV, resulting in intermediate 
levels of oxygenation from the RV onwards. The RA blood 
remains deoxygenated 70% 85% 85% 100% 100% 100% 
Patent ductus arteriosus (PDA)  
 
Remember, a PDA connects the higher pressure aorta with 
the lower pressure PA. This results in only the PDA having 
intermediate oxygenation levels 70% 70% 85% 100% 100% 100% 
VSD with Eisenmenger's  70% 70% 70% 100% 85% 85%

VSD with Eisenmenger's  70% 70% 70% 100% 85% 85% 
PDA with Eisenmenger's  70% 70% 70% 100% 100% 85% 
ASD with Eisenmenger's  70% 70% 70% 85% 85% 85% 
 Cardiac investigations  491

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  30 
  
Guidelines for the Interpretation of Cardiac Catheter Data 
 Right-heart saturations do not exceed 75%. Saturations more than this are suggestive of 
a left- to-right shunt.  
 Atrial septal defect (ASD) : The oxygen saturation in the RA and SVC should be the same.

But in ASD there is a step-up in oxygen saturation at the level of the RA.  This can only result 
from the addition of oxygenated blood to the deoxygenated blood in th e right heart circulation, 
that is, an abnormal connection between the right and left sides of the heart.  
 Primum ASD :  
 The location of the step-up is suggestive of a primum defect since these lesions 
occur low down in the A-V septum, lying immediately above the 
atrioventricular valves.

atrioventricular valves.   
 These lesions can affect the function of the anterior leaflet of the mitral valv e, 
causing mitral regurgitation. 
 high pressures of Right ventricular are more likely to occur with primum 
ASDs . 
 Patent ductus arteriosus (PDA)  
 unexpected step-up in oxygen saturation between the RV and PA. 
 high pulmonary artery pressures  
 high wedge pressure.  
 The change in O 2 saturation between the ascending and descending aorta strongly

suggests the presence of a patent ductus.  
 Unfortunately the extremely elevated right sided pressures are indicative of advanced 
disease, not amenable to surgical correction. In late disease the machinery murmur said 
to be characteristic of the disease may well not be audible.  
 Left-heart saturations vary from 96 –98%. Saturations less than this are suggestive of a right- to-
left shunt.  
492

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  31 
  In right- to-left shunts, the arterial saturations do not change with inspired high-conc entration 
oxygen. 
 Ventricular septal defect (VSD) 
 There is a step-up in the oxygen saturation between the RA and RV.  This can only 
occur when there is an abnormal connection between these two chambers, that is, via a  
VSD.

VSD. 
 This is confirmed by the raised right ventricular pressures.  
 VSD with Eisenmenger's syndrome 
 the pressures in the RV and PA are markedly elevated , but RA pressure is 
normal.  
 The left ventricular oxygen saturation is low , which raises the possiblity of a 
right to left cardiac shunt mixing desaturated RV blood with LV saturated blood 
(due to right ventricular pressures exceeding left ventricular pressure).

 post-MI VSD and papillary rupture are difficult to distinguish clinically.  
 The diagnosis is established by demonstration of a left to right shunt. 
 if there is  a step-up in the oxygen saturation between the RA and PA  
VSD 
  if there is no step-up,  papillary muscle rupture.  
 Fallot's tetralogy  
1. VSD:  step-down in oxygen saturation between LA and LV, indicating right to left shun t at 
the level of the ventricles.

the level of the ventricles. 
2. Pulmonary stenosis : there is ↑mmHg gradient across the pulmonary valve (RV systolic - 
PA systolic). 
3. RVH : Right ventricular pressures are high and there is a right to left shunt, which indicated 
by the oxygen saturations. 
4. Over-riding aorta :  
 there is a further step-down in oxygen saturation between the LV and aorta.  
 This could occur in either Fallot's or with a patent ductus arteriosus with right to left 
shunting.

shunting.  
 However, given the other features of Fallot's, this is most likely to be caused by  an 
over-riding aorta with reduced saturations due to a mixture of deoxygenated  blood 
from the RV entering the left heart circulation. 
 The over-riding aorta recieves a mixture of blood from the left and right ventricl es 
as is formed above a VSD. 
 Pulmonary hypertension does not occur in Fallot's tetralogy due to narrowing of the righ t

ventricular outflow tract/ subpulmonary valve stenosis.  
 A VSD with a right- to-left shunt and pulmonary stenosis can be differentiated from Fallot ’s 
tetralogy by examining the oxygen saturation in the left ventricle and the ascending aorta.  
 In the case of a VSD , the saturations in the left ventricle and the aorta will both be low 
and very similar.  
 In the case of Fallot ’s tetralogy , the aortic oxygen saturation will be much lower than

the oxygen saturation in the left ventricle because the right ventricle pumps most of the 
deoxygenated blood into the overriding aorta.  
 A pulmonary artery pressure exceeding 35 mmHg is suggestive of pulmonary hypertension . 
 A pressure drop of more than 10 mmHg across the aortic or pulmonary valve is sugge stive of 
aortic or pulmonary stenosis , respectively.  
 The diagnosis of mitral regurgitation  cannot be made unless you are given the PCWP ‘v-wave ’.

A v-wave higher than 20 mmHg is highly suggestive of mitral regurgitation. 
 The right and LVEDP and the left and right atrial pressures are roughly equal in pericardial 
constriction 
 When interpreting right heart catheter data, remember the saturation should decrease g radually 
as the venous blood reaches the pulmonary capillary wedge saturation, which should be equal to 
arterial blood. 
 In Ebsteins anomaly there should be elevated RA pressure due to significant tricuspid

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  32 
  Left ventricular pressures are high with a steep drop-off between the LV and aortic 
systolic pressures.  
 Anomalous pulmonary venous drainage to SVC 
 normally oxygenation in the superior vena cava should always be lower than the in ferior 
vena cava, due to the high oxygen demands from the brain.

 If SVC sats is markedly higher than the IVC, sugest a diagnosis of anomalous pulmonary 
venous drainage  of more highly oxygenated blood into the SVC (left to right shunt). 
What is meaning of Ȑvalve gradient ȑ? 
 The valve ’s gradient describes the severity of the narrowing of the valve by the increase in 
pressure behind it.  
 It helps to measure the amount of blood that is able to pass through the valve.

 It also indicates whether the “velocity ” (or speed of movement) of the blood flow is increased 
because of the increased pressure behind the narrowed valve. 
Diagnosis of tricuspid stenosis 
 mean gradient by echocardiogram or cardiac catheterisation of 2 mmHg or greater, but is usually 
found to be >7 to 10 mmHg in severe TS  
Diagnosis of pulmonary hypertension  
 If the pulmonary arterial pressure is greater than the normal one-fifth of systolic measu rements

 pulmonary hypertension is present.  
Diagnosis of right ventricular failure 
 The right atrial pressure is grossly elevated, with a normal wedge pressure.  
 Normal right atrial pressure =  (4 –8) mmHg. 
 Normal indirect left atrial mean pressure (wedge) = (5 –10) mmHg. 
 normal wedge pressure excludes acute left ventricular failure or acute mitral 
regurgitation.  
Diagnosis of aortic stenosis

Diagnosis of aortic stenosis 
 a greater than 25mmHg gradient across the aorta valve, demonstrating moderate aortic steno sis. 
 systolic gradient of  ↑ mmHg across the aortic valve (LV systolic pressure - aortic systolic 
pressure), indicating critical aortic stenosis. 
 Hypertrophic cardiomyopathy may result in similar pressure differences, but given the clinical 
information, aortic stenosis is far more likely than hypertrophic obstructive cardiomyopathy

(HOCM) in an old patient. 
 A guide to determining the severity of aortic stenosis is given below: 
Severity of aortic 
stenosis Severity Valve area 
(cm2) Mean gradient 
(mmHg) 
Mild >1.5 <25 
Moderate 1.0-1.5 25-50 
Severe <1.0 >50 
Critical <0.7 >80 
 
Diagnosis of mitral stenosis  
 A normal mitral valve expects less than 5mmHg pressure difference.  
 Using these inferences, the mitral valve gradient is calculated by the capillary wedge pressure o f

mmHg (same as the left atrial pressure) minus the diastolic left ventricular pressure of mmHg: 
the mmHg difference more than 5 demonstrates mitral stenosis . 
 The PCWP is equal to the LVEDP. When the PCWP exceeds the LVEDP, the di agnosis of mitral 
stenosis  should be considered. 
 The gradient across the mitral valve (LA pressure - LV end diastolic pressure); it is usual 
to use the PCWP as a surrogate for LA pressure.

to use the PCWP as a surrogate for LA pressure.  
 There is also evidence of right ventricular hypertrophy, with markedly elevated RV pressures  
due to secondary pulmonary hypertension .  494

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  33 
  The severity of mitral stenosis can be graded: 
 
Severity of mitral stenosis Severity Valve area (cm2) Gradient (mmHg) 
Mild 1.6-2.0 <5 
Moderate 1.0-1.5 5-10 
Severe <1.0 >10 
 
Aortic incompetence  
 Aortic regurgitation is diagnosed by a wide pulse pressure in the aortic pressure. 
 There is a wide pulse pressure in the aorta

 There is a wide pulse pressure in the aorta  
 accompanied by a very high left ventricular end-diastolic pressure (LVEDP).LVEDP greater than 
20 mmHg is suggestive of irreversible LV dysfunction.  
 All left heart valve diseases can ultimately cause elevated right heart pressures 
coarctation of the aorta 
 There is a steep systolic gradient between the left ventricle and the femoral artery 
 
Pulmonary artery floatation catheter findings:

Pulmonary artery floatation catheter findings: 
 if  the pulmonary artery occlusion pressure is low with a relatively low cardiac index, 
suggesting the patient is hypovolaemic,  even  in spite of high right atrial pressure .  
 A fluid challenge should be performed and values re-measured to assess response . 
 In a fluid replete patient the occlusion pressure would be higher (usually >13 mmHg)

 if the Pulmonary artery occlusion pressure is high and cardiac index low (i.e. <2.5 L/min/m2) 
this would be more suggestive of cardiogenic shock.   
 
Hyperthyroidism and cardiac catheterisation: 
 Cardiac catheterisation requires the use of an iodine-containing contrast. 
 This may worsen hyperthyroidism caused by toxic multinodular goitre, whereas it may improve 
the symptoms in patients with Grave ’s disease (Wolff –Chaikoff effect).

 The most reliable diagnostic method is a radionuclide (99Tcm, 123I or 131I) scan of the 
thyroid, which will distinguish the diffuse, high uptake of Grave ’s disease from nodular 
thyroid disease. 
 If a toxic multinodular goitre or toxic adenoma is detected, the patient should receive an 
antithyroid drug before undergoing catheterisation. 
 The antithyroid medication must be continued for at least 2 weeks after the procedure.

Pulmonary capillary wedge pressure 
 Pulmonary capillary wedge pressure (PCWP) is measured using a balloon tipped Swan-Gan z 
catheter which is inserted into the pulmonary artery.  
 The pressure measured is similar to that of the left atrium (normally 6-12 mmHg). 
 The PCWP provides an indirect measurement of the left atrial pressure, and since the  left atrial

pressure is increased, the PCWP will also be increased.  
 One of the main uses of measuring the PCWP is determining whether pulm onary oedema is 
caused by either heart failure or acute respiratory distress syndrome. 
 In many modern ITU departments PCWP measurement has been replaced by non -invasive 
techniques. 
 
 PiCCO (pulse contour cardiac output)

 PiCCO (pulse contour cardiac output)  
 PiCCO gives indications of cardiac output, extravascular lung water, intravascular filling 
and only requires a central line and a PiCCO femoral arterial line and as such is 495

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  34 
 relatively simple to use.  
 
Cardiac imaging: non-invasive techniques excluding echocardiography  
 
Nuclear imaging  
 These techniques use radiotracers which are extracted by normal myocardium.  
 Examples include: 
 Thallium 
 Nuclear isotopes are picked up by the Na/K ATPase of normal myocardium.

 If cardiac tissue is alive and perfused, it will pick up the nuclear isotope.  
 To the myocardium, thallium looks like potassium. 
 Decreased uptake = Damage 
 technetium (99mTc) sestamibi:  
 a coordination complex of the radioisotope technetium-99m with the lig and 
methoxy-iso-butyl isonitrile (MIBI), used in 'MIBI' or cardiac Single Photon Emission 
Computed Tomography (SPECT) scans 
 fluorodeoxy glucose (FDG):  
 used in Positron Emission Tomography (PET) scans

 Cardiac PET is predominately a research tool at the current time 
 
SPECT  
 The primary role of SPECT is to assess myocardial perfusion and myocardial viability.  
 Two sets of images are usually acquired. First the myocardium at rest followed by  images of the 
myocardium during stress (either exercise or following adenosine / dipyridamole).  
 By comparing the rest with stress images any areas of ischaemia can classified as reversible or

fixed (e.g. Following a myocardial infarction).  
MUGA  
 Multi Gated Acquisition Scan, also known as radionuclide angiography 
 radionuclide (technetium-99m) is injected intravenously 
 the patient is placed under a gamma camera 
 may be performed as a stress test 
 can accurately measure left ventricular ejection fraction .  
 Typically used before and after cardiotoxic drugs are used 
 
Cardiac Computed Tomography (CT)

Cardiac Computed Tomography (CT)  
 Cardiac CT is useful for assessing suspected ischaemic heart disease , using two main 
methods: 
 calcium score:   
 there is known to be a correlation between the amount of atherosclerotic plaque 
calcium and the risk of future ischaemic events.  
 Cardiac CT can quantify the amount of calcium producing a 'calcium score' 
 contrast enhanced CT :  
 allows visualisation of the coronary artery lumen

 If these two techniques are combined cardiac CT has a very high negative predictive value  for 
ischaemic heart disease . 
 The updated NICE guidelines recommends that cardiac CT  is the first-line investigation  for 
patients presenting with new-onset chest pain due to suspected CAD .  
 
Cardiac MRI  
 Cardiac MRI (commonly termed CMR) has become the gold standard for providing structural 
images of the heart .  
 It is particularly useful in: 
 assessing congenital heart disease,

 assessing congenital heart disease,  
 determining right and left ventricular mass and  
 differentiating forms of cardiomyopathy.  
 Myocardial perfusion can also be assessed following the administration of gadolinium.  
 Currently CMR provides limited data on the extent of coronary artery disease.  
 
 496

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  35 
  
Mitral stenosis 
Causes: 
 Common  rheumatic fever 
 Rheumatic valve disease is increasing uncommon in the UK, but can still be seen in other 
parts of the world.  
 The physiological stress of pregnancy can exacerbate the features of rheumatic mitral 
stenosis.

stenosis. 
 Rare   mucopolysaccharidoses, carcinoid and endocardial fibroelastosis 
 
Features  
 tapping apex beat 
 mid-late diastolic murmur (with pre-systolic accentuation ) (best heard in expiration) 
 loud S1 
 opening snap  
 suggests that the mitral valve is mobile  
 opening snap is not heard when the mitral valve is heavily calcified  
 snap occurs when the superior systolic bowing of the  anterior mitral valve leaflet is

rapidly reversed towards the left ventricle in early diastole , owing to the high left atrial 
pressur 
 low volume pulse 
 malar flush 
 leads to left atrial enlargement, but the left ventricle is usually small. 
 enlarged left atrium may lead to pressure posteriorly on the oesophagus. 
Features of severe MS 
 length of murmur increases 
 opening snap becomes closer to S2.  
 opening snap is characteristically lost with heavy valvular calcification

Chest x-ray 
 left atrial enlargement may be seen 
Echocardiography 
 the normal cross sectional area of the mitral valve is 4-6 sq cm. A 'tight' mitral stenosis i mplies a 
cross sectional area of < 1 sq cm 
 Valvular diseases  497

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  36 
  
Chest x-ray from a patient with mitral stenosis. This patient has had a sternotomy and a prosthetic mitral valve. 
There is splaying of the carina with elevation of the left main bronchus, a double right hear t border and

cardiomegaly. The features are those of left atrial enlargement. Although the entire heart is enlarged, a double 
contour is seen through the right side of the heart. The more medial l ine is the enlarged left atrium (white dotted 
line) and the heart heart border is more lateral (blue dotted line). 
Mitral stenosis in pregnancy: 
 Mitral stenosis is poorly tolerated in pregnancy due to volume overload. 
 Pregnancy can unmask previously undiagnosed obstructive valvular heart disease and

intervention should be performed with adequate shielding of the fetus.  
 Pregnant women with mitral stenosis may develop symptoms in the second trimes ter, when the 
demand for cardiac output increases by around 70%.  
 A diuretic is given to control mild symptoms.  
 Percutaneous mitral balloon valvuloplasty (PMBV) should be carried out for severe mitral 
stenosis in patients who remain symptomatic despite medical therapy . 
MECHANISM OF OPENING SNAP EARLIER IN WORSENING MS

 The mitral valve opens when LA pressure > LV pressure. Worse MS = Higher LA pressure. 
Higher LA pressure pushes the mitral valve open earlier. 
 
Lutembacher syndrome 
 characterised by both mitral stenosis and atrial septal defect (ASD).  
 Both conditions may be congenital and occur concurrently, or the mitral stenosis may occu r as 
a result of rheumatic fever or some other cause.  
 Incidence is higher in women due to the greater incidence of congenital ASD.

 Cardiac signs are mixed due to the two concurrent lesions.  
 Presentation is typically in later life, with fatigue or atrial fibrillation.  
 mid-diastolic tricuspid murmur  fits with increased tricuspid valve flow, consistent with a 
shunt because of an ASD 
 Ideally, surgery should be performed as early as possible due to the risks of Eisenm enger 
syndrome in untreated patients. 
 
Mitral regurgitation (MR)  
 Myxomatous degeneration  of the mitral valve is by far the most common cause of MR in 
the United Kingdom.  
Features 
 pan-systolic murmur 
 soft S1, split S2 
498

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  37 
 Which feature suggests more severe mitral regurgitation? 
 As mitral regurgitation becomes more severe, the left ventricle enlarges and the  apex beat 
displaces and a systolic thrill  can develop. 
Mitral valve prolapse (MVP)  

 common, occurring in around 5-10 % of the population.  
 more common in females.  
Causes  
 usually idiopathic  
 congenital heart disease: PDA, ASD 
 Marfan's syndrome,  
 Fragile X 
 osteogenesis imperfecta 
 pseudoxanthoma elasticum 
 Wolff-Parkinson White syndrome 
 long-QT syndrome 
 Ehlers-Danlos Syndrome 
 polycystic kidney disease 
Features

Features 
The late systolic murmur with mid systolic click is indicative of mitral valve prolapse where 
the posterior leaflets bulge during systole. 
 patients may complain of atypical chest pain or palpitations 
 mid-systolic click (occurs later if patient squatting) 
 late systolic murmur (longer if patient standing) 
Complications:  
 mitral regurgitation,  
 arrhythmias (including long QT),  
 emboli,  
 sudden death 
Treatment

 emboli,  
Treatment 
 mild to moderate mitral regurgitation 
 follow-up in clinic with repeat echocardiograms to monitor progression. 
 Mitral valve replacement is only indicated in: 
 severe mitral regurgitation or  
 if there are signs of concomitant LV compromise (reduced ejection fraction or new 
dilatation of the LV).  
  if a surgical mitral valve replacement are indicated, coronary angiogram should be part of  the

pre-op work-up for potential concomitant coronary artery bypass grafting. 
Aortic dissection 
 
 It is most common between the ages of 50-70, being rare below the age of 40 . 
 
Stanford classification 
 type A - Ascending aorta,  (immediately above of the aortic valve)  2/3 of cases  
 type B - descending aorta, (after the aorta arch) distal to left subclavian origin,  1/3 of cases 
DeBakey classification

DeBakey classification 
 type I - originates in ascending aorta, propagates to at least the aortic arch and possibly b eyond 
it distally 
 type II - originates in and is confined to the ascending aorta 
 type III - originates in descending aorta, rarely extends proximally but will extend distall y 
499

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  38 
  
 hypertension (The most common risk factor ) 
 trauma (direct blunt chest trauma)  
 collagens: Marfan's syndrome, Ehlers-
Danlos syndrome   bicuspid aortic valve 
 Turner's and Noonan's syndrome 
 syphilis 
 Drugs (such as cocaine) 
Complications of backward tear

Complications of backward tear 
 aortic incompetence/regurgitation 
 MI: inferior pattern often seen due to right coronary involvement 
Complications of forward tear 
 unequal arm pulses and BP 
 stroke 
 renal failure 
Stanford type A / DeBakey type I  
Stanford type A / DeBakey type II 
 
Stanford type B / DeBakey type III 
  
 The best investigation is a CT chest with IV contrast  (CT aortogram)  because the IV

contrast will be able to best demonstrate the size and extent of the false lumen.  
 Chest X-ray:  
 is a useful first line  investigation because its readily available it is, and useful for ruling 
out many other conditions.  
 The chest X-ray may show a widened mediastinum,  
500

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  39 
   but unfortunately it is not a sensitive or specific investigation as 20% of patients present 
with normal chest X-ray and there are many causes of a widened mediastinum.  
  Looking for a separation of the intimal calcification from the outer aortic soft tissue  border 
by 10 mm is an indication of the presence of a dissection.

 In a man with low blood pressure and vague abdominal pain, always be mindful of the 
possibility of dissection or aneurysmal rupture.  
 Occasionally, there is involvement of the right coronary artery in the dissection process giving 
rise to the acute electrocardiographic changes.  
 MRI has the best sensitivity (98%) and specificity (98%) for aortic dissection. 
 Whilst an echocardiogram might identify disruption of the aortic root in a backw ards tear, it would

not identify more distal aortic pathology. 
 
This chest X-ray shows a widened mediastinum 
 
 This computerised tomography (CT) scan 
demonstrates an obvious flap in the thoracic 
aorta indicating aortic dissection.  The flap is in 
the middle of the descending aorta (the dark line) 
which separates the true lumen anteriorly from 
the intimal flap posteriorly. The aortic regurgitant 
murmur would alert the examiner to this and 
mediastinal widening may be seen on x ray.

mediastinal widening may be seen on x ray. 
 
Differential diagnosis   
501

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  40 
  Myocardial infarction and aortic dissection: an important differential diagnosis   
 The ECG changes of inferior myocardial infarct suggest that the aneurysm has dissected  
the right coronary artery at its ascending aortic ostium.  
 An inferior myocardial infarct is high in the differential; however thrombolysis will kill a

patient with an aortic dissection.  (delayed diagnosis and surgical treatment)  
 up to 85% of patients with dissections may not receive appropriate medical treatment in 
the first hours of treatment due to an incorrect diagnosis 
 pain onset 
 pain in aortic dissection is abrupt in onset and maximal at the time of onset.  
 pain associated with MI starts slowly and gains in intensity with time.  
 Pain character

 Pain character  
 In dissection although tearing is the classical description, the pain is described as 
sharp more often than tearing, ripping, or stabbing. 
 In MI it is usually more oppressive and dull. 
 Pain site 
 with distal dissections the pain location is between the scapulae and in the back.  
 Oesophageal rupture  
 Features that favor oesophageal rupture over aortic dissection include: 
 The history of onset while eating 
 Blood pressure equal in both arms

 Blood pressure equal in both arms 
 No diastolic murmur 
 Good peripheral pulses, and 
 Presence of a pleural effusion. 
 
the history of chest pain radiating to the back  is concerning., early diastolic murmur  suggesting 
aortic valve regurgitation, ECG changes in the inferior territory  and indicating occlusion of the right 
coronary artery. These features combined suggest that the aortic dissection has tracked back to

the heart itself. The enlarged heart on chest X-ray may suggest a haemopericardium , and the 
patient should be assessed for cardiac tamponade  given his low blood pressure . This patient is 
highly unstable and requires urgent cardiothoracic involvement .  the most appropriate next step in 
the management  Bedside echocardiogram and urgent cardiothoracic review  
 
 Type A  
 surgical management, but blood pressure should be controlled to a target systolic of 100-

120 mmHg whilst awaiting intervention 
 The most appropriate management strategy is to provide adequate analgesia a nd urgently 
reduce the blood pressure with intravenous antihypertensives: beta-blockers first line, and 
then nitroprusside. Then the cardiothoracic surgeons should be contacted. 
 perioperative management of patients undergoing high risk vascular surgery  
 prophylactic beta blockers for high risk vascular surgery (including those patients 
with COPD).

with COPD).  
 Bisoprolol is the best clinical choice 
 Atenolol is next best choice ; it is cardioselective and long acting, reducing 
risk of postoperative myocardial ischaemia and tachycardia. 
 Type B* 
 conservative management 
 bed rest 
 reduce blood pressure IV labetalol to prevent progression 
 *endovascular repair of type B aortic dissection may have a role in the future 
 
Complication  
 haemopericardium and cardiac tamponade

 haemopericardium and cardiac tamponade 
 If the dissection (involving the ascending aorta (Stanford type A) results in a te ar of the 
tunica externa, aortic blood can leak into the pericardium.  
 Management of aortic dissection complicated by haemopericardium and cardiac 
tamponade 
 acute type A aortic dissection complicated by haemopericardium and cardiac 
tamponade: 
 Relatively stable patient   immediate surgical repair and surgical 
evacuation of haemopericardium. 502

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  41 
  Pericardiocentesis in these patients can increase the intra-aortic pressure 
and reopen the closed communication between false lumen and 
pericardium. This can lead to recurrent cardiac tamponade that may be 
lethal.  
 marked hypotension or electromechanical dissociation  pericardiocentesis  
Prevention

 The management of patients with predisposing inherited diseases such as Marfan's sy ndrome 
and Ehlers-Danlos syndrome should include: 
 Periodic aortic diameter screening. 
 Lifelong beta-blockade. 
 Consideration of prophylactic replacement of the aortic root if dilated. 
 Moderate restriction of physical activity. 
 
Prognosis 
 Mortality for untreated aortic dissection is 25 –30% at 24 h and 65 –70% at 2 weeks

 dissections confined to the descending aorta are associated with better survival (80%). 
 
Aortic aneurysms (NICE 2009)  
 
The nice guidelines state that an aortic aneurysm of greater than 5.5 cm in diamete r should be 
treated. Below this size, the risk of dissection is outweighed by the risk of surgery.  
  
 Most common cause of aneurysms  atherosclerosis

 most common site of aneurysms  lower part of the abdominal aorta, below the kidney (infra-
renal).  
 abdominal aortic aneurysm (AAA) 
 Definition 
 enlargement of the aorta of at least 1.5 times its normal diameter or greater than 
3 cm diameter in total.  
 Incidence 
 more common in men than in women (3:1) 
 Risk factors 
 increasing age 
 high blood pressure,  
 smoking  
 family history 
 Features

 smoking  
 Features  
 most are asymptomatic (detected by chance during clinical investigation (for 
example, ultrasound or X-ray)) 
 pulsating sensation in the abdomen,  
 back pain and abdominal pain that may spread to the back.  
 Investigations  
 diagnostic gold standard  Ultrasound 
 the best modality to determine anatomy and size  CT 
 for definitive diagnosis  Aortogram  
 Elective surgery is recommended for   
 aneurysms > 5.5 cm

 aneurysms > 5.5 cm  
 aneurysms > 4.5 cm that have increased by > 0.5 cm in the past 6 months.  
 Endovascular stent-grafts are recommended as a possible treatment if:  the 
aneurysm is below their kidney and has not burst. 
 Follow up 
 symptomatic aneurysms  < 4.5 cm  ultrasonography every 6 months. 
 aneurysms of 4.5 –5.5 cm  every 3 or 6 months. 
 prognosis 503

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  42 
  without surgery the 5-year survival rate for patients with aneurysms larger than 
5 cm is about 20%.  
 aneurysms larger than 6 cm in diameter have an annual risk of rupture of 25%.   
 Among patients with a ruptured AAA the mortality rate is about 80%; even when

they undergo emergency surgery, only about half survive beyond 30 days.  
 
Peri-operative management of patients undergoing high-risk vascular surg ery  
 The ESC guidelines in 2009 for peri-operative management of patien ts undergoing high risk 
vascular surgery recommends prophylactic beta-blockers for high risk vascular surgery (including 
those patients with COPD). 
 Bisoprolol is probably the best clinical choice in this case, but is not available, atenolol is

the best alternative  - it is cardio-selective and long acting - reducing risk of postoperative 
myocardial ischaemia and tachycardia. 
 
 This CT reveals leakage of a large aortic 
aneurysm with contrast extravasating into the 
mural thrombus of the aortic aneurysm. 
The aortic aneurysm has not yet ruptured. 
The likely cause of this is atherosclerotic 
 
Aortic regurgitation ( AR) 
 
Causes

Causes   
 due to valve disease  
 bicuspid aortic valve 
 the most common cause of chronic AR in a young patient is a congenital 
bicuspid valve.  
 Bicuspid valve is also a common cause of early-onset aortic stenosis. 
 infective endocarditis 
 the vegetations prevent the valve from creating a proper seal to prevent backflow 
during diastole.  
 rheumatic fever 
 connective tissue diseases e.g. RA/SLE 
 due to aortic root disease 
 aortic dissection

 aortic dissection 
 Spondyloarthropathies (e.g. ankylosing spondylitis ) 
 Ankylosing spondylitis is strongly associated with aortic regurgitation (occurs in 4% 
of cases).  
 An aortitis leads to aortic root dilatation with subsequent failure of leaflet coaptation.  
 syphilis 
 Marfan's,  
 Ehler-Danlos syndrome 
 
Causes of  acute aortic regurgitation: 
 ascending aortic dissection, 
 infective endocarditis,  
 collagen vascular disorders such as Marfan ’s

 collagen vascular disorders such as Marfan ’s  
 trauma,  
504

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  43 
  dehiscence of a prosthetic valve.  
 
Features 
 early diastolic murmur 
 heard along the left sternal border  
 heard best while the patient is leaning forward on deep expiration. 
 collapsing pulse 
 wide pulse pressure 
 mid-diastolic Austin-Flint murmur  
 It is a low frequency mid/late diastolic murmur

 due to partial closure of the anterior mitral valve cusps caused by the regurgitation 
streams.  
 There is no correlation between the presence of murmur and severity of AR, or aetio logy. 
 Note that there is often an aortic systolic flow murmur because there is an increased v olume of 
blood in the LV due to the regurgitation. 
 Isolated LV dilatation (other chambers are normal) on ECHO due to volume overload  
 (AS, HOCM & Ĺ BP  hypertrophy and a smaller LV cavity)

 Pulsus bisferiens; increased pulse pressure; visible, forceful, and bounding peripheral p ulses 
(water hammer) 
 Corrigan's pulse - visible and vigorous arterial pulsations in neck 
 Musset's sign - Bobbing of the head , due to the arterial pulsations in the neck  
 Quincke's sign - Capillary pulsations of the nail bed 
 Muller's sign - Pulsations of the uvula 
 Traube's sign - Loud systolic sound over femoral arteries ('pistol-shot' femorals)

 Duroziez sign - diastolic murmur proximal to femoral artery compression (due to flow reversal).  
 
Severity is indicated by the presence of: 
 collapsing pulse,  
 a wide pulse pressure and 
 pulmonary oedema. 
 
 Echocardiogram (the most important test)   
 Echocardiographic markers of severe AR  
 Regurgitant volume of >60 mL/beat  
 pressure half time of <250 ms . 
 Cardiac catheterisation

 Cardiac catheterisation  
 may be performed if there is doubt over the severity of the regurgitation;  
 severity is estimated by the degree of contrast that fills the ventricles after injection into 
the aortic root. 
 
Treatment 
 asymptomatic  ACEI  
 ACEI  improve the prognosis in asymptomatic left ventricular dysfunction.  
 Beta blockers should be avoided as these prolong diastole and therefore would increase the 
regurgitant fraction.

regurgitant fraction. 
 Surgery is indicated in symptomatic patients with severe aortic regurgitation.  
 Indications for surgery in asymptomatic aortic regurgitation  are: 
 LV ejection fraction under 50% 
 LV end diastolic diameter greater than 7 cm 
 LV end systolic diameter greater than 5 cm. 
 
Under current ACC/AHA guidelines , aortic valve surgery is recommended for patients with chronic 
severe AR under the following circumstances; 
 Patient is symptomatic

 Patient is symptomatic 
 Patient is asymptomatic, with a resting EF of < 55% 
 Patient is asymptomatic, with LV dilatation (LV end-systolic dimension >55 mm) 
 Additional circumstances in which aortic valve surgery may be reasonable include the 
 Patient has moderate AR and is undergoing coronary artery bypass surgery or other 
surgery involving the ascending aorta 
 Patient has severe AR with no symptoms, normal EF, and less severe LV dilation (LV 505

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  44 
 end-systolic dimension >50 mm or LV end-diastolic dimension >70 mm) 
 if the patient experiences: 
 progressive LV dilation on serial imaging studies;  
 deteriorating exercise tolerance, or  
 abnormal hemodynamic responses to exercise, such as inability to augment 
blood pressure during a treadmill study

blood pressure during a treadmill study 
  
Aortic stenosis 
 
 Aortic stenosis (AS) is the most common valve problem  in the United Kingdom.  
Causes  
 degenerative calcification (tricuspid aortic valve calcification) 
 most common cause in older patients > 65 years 
 congenital bicuspid aortic valve (BAV) 
 most common cause in younger patients < 65 years

 BAV is the most common form of congenital heart disease in adults (1-2% of populat ion). 
 The European Society of Cardiology states that there is an estimated 10% chance of a 
first degree relative being affected, which increases to 20-30% if you consider aortopathy . 
NOTCH1 gene mutations may be responsible. 
  It is possible that up to a third of relatives of patients with a bicuspid valve have 
valve or aortic abnormalities (often a dilated aorta).

 NOTCH1 gene mutations may be responsible. 
 most helpful in establishing a diagnosis of congenital bicuspid valve as the 
aetiology is  Systolic ejection click  (best heard at the apex)  
 aortic valve replacement is eventually likely to be required  
 Only 15% of patients with a bicuspid aortic valve will have a normally functioning 
valve in the fifth decade, and this often continues to deteriorate with age.  
 William's syndrome (supravalvular aortic stenosis)

 post-rheumatic disease   fibrosis  Commissural fusion on ECHO 
 subvalvular: HOCM 
 
 Pathophysiological response in aortic stenosis  
 The LV hypertrophies increase (in the size of myocytes) in a concentric  - rather than 
an eccentric (asymmetric) - manner in response to the increase in afterload. 
 There is also an increase in interstitial collagen and little fibrosis 
  
The triad of angina, left ventricular failure and syncope is classical to aortic stenosis.

Features  of severe aortic stenosis  
 Symptoms 
 heart failure  
 SAD  
 Syncope 
 Angina or chest pain (most common) 
 Dyspnea 
 Physical exam 
 ejection systolic murmur (ESM) 
506

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  45 
  crescendo-decrescendo murmur 
 typically a mid-systolic ejection murmur 
 heard best with the diaphragm of the stethoscope in the 2nd intercostal space in a 
patient who is sitting upright leaning forward.  
 in the elderly the more high frequency components of aortic stenosis may be

heard best at the apex, the so called (Gallavardin phenomenon) 
 may have ejection click 
 radiates to carotid arteries (left often louder than right). radiate to the right neck  
 decreases with standing, Valsalva, or handgrip 
 increases with amyl nitrate, squat, or leg raise 
 The intensity of the systolic murmur  does not correspond to the severity of 
aortic stenosis ; 
 As LV contractility decreases in critical AS, the murmur becomes softer and

shorter. The intensity of the murmur may therefore be misleading in these 
circumstances. 
 the timing of the peak and the duration of the murmur correspond to the 
severity of aortic stenosis.  
 The more severe the stenosis, the longer the duration of the murmur and the 
more likely it peaks at late systole. 
 S4 heart sound 
 from stiff or hypertrophic ventricle 
 S2 (Character of S2)  
 soft/absent S2 
 paradoxical splitting of S2  
 heard on expiration  rather than inspiration

 heard on expiration  rather than inspiration 
 pulse  
 narrow pulse pressure 
 slow rising pulse 
 pulsus parvus et tardus 
 weak pulses with a delayed peak 
 thrill 
 
Associated conditions 
 
In a patient with aortic stenosis, what will lead to an overestimation of the severity of the 
problem when assessed by echocardiography?  
 Aortic regurgitation 
  due to large volumes of blood passing over the valve at high velocities

Which condition is most associated with quietening of the aortic stenotic murmur? 
 Atrial fibrillation  
 Where the R-R interval is particularly short, such as in atrial fibrillation, flow across the 
valve is reduced, as such the intensity of the murmur is variable and may be signi ficantly 
reduced. 
 Aortic regurgitation has no effect on the intensity of the murmur, such that in p atients with 
mixed aortic valve disease, the stenotic murmur is still clearly audible.

Conditions which leads to accentuation of the murmu r  increased flow across the murmur. 
 High output cardiac failure  
 severe thyrotoxicosis  
 
The predominant component of mixed aortic valve disease is determined by the murmur that is 
louder (ejection systolic murmur in aortic stenosis and mid diastolic murmur for aortic 
regurgitation). 
 
Evaluation 
 Severe AS is defined by a valve area of less than 1.0 cm2.

 distinguish patients with true severe (AS) with secondary LV dysfunction from those who 
have a falsely low calculated aortic valve area because of low cardiac output.  
 calculated valve area in patients with severe left ventricular (LV) dysfunction can be falsely 
low because low cardiac output reduces the valve opening forces.  507

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  46 
  It is important to distinguish patients with true severe (AS) with secondary LV dysfunction 
from those who have a falsely low calculated aortic valve area because of low cardiac 
output.  
 An important method of distinguishing between the two conditions is to assess the

haemodynamics after increasing the cardiac output by dobutamine infusion during 
echocardiography or cardiac catheterisation.  
 Patients with truly severe AS manifest an increase in trans-aortic pressure gradient 
while the valve surface area remains the same during dobutamine infusion;  
 those with falsely low calculated valve area manifest an increase in calculated 
valve surface area.  
 Dobutamine echocardiography is also important to assess LV contractile reserve.

 Patients who have 20% or more increase in stroke volume after dobutamine 
infusion have a much better prognosis after surgery compared to those who do not 
have LV contractile reserve. 
 
What is the difference between aortic stenosis and  aortic sclerosis? 
 Both aortic stenosis and aortic  sclerosis  is : 
 senile degeneration of the valve  
 there is an ejection systolic murmur ,  
 Unlike aortic stenosis, aortic sclerosis  have: 
 Occur in > 25% of > 65 year of age

 Occur in > 25% of > 65 year of age  
 Aortic stenosis occur in > 2% of > 65 year of age  
 Absence of stenosis  
 no carotid radiation ,  
 normal pulse  (character and volume)  
 normal S2 . 
 
 Echocardiography  
 transthoracic echocardiogram (TTE) initially 
 transesophageal echocardiogram (TEE) is more accurate 
 Left heart catheterization 
 most accurate diagnostic test 
 to assess pressure gradient across the valve

 to assess pressure gradient across the valve 
 only indicated to confirm the diagnosis if echocardiography is unclear 
 findings 
 elevated pressure gradient ( > 30 mmHg) 
  In the context of poor LV function, the aortic valve gradient may be no rmal 
or only mildly raised in the presence of a severely narrowed aortic valve 
area.  
 The next step in management after diagnosis  Coronary angiography 
 Coronary artery disease (CAD) is common in patients with AS

 Progressing straight to aortic valve replacement is not advised; significant coronary artery 
disease should be ruled out first, as CABG may be required at the same time as valve 
 
Patients undergoing open surgical valve replacement should first undergo coronary 
angiography to exclude any coronary stenosis that could simultaneously be treated with bypass 
grafting. 
 
  
 if asymptomatic then observe the patient is general rule

 if symptomatic then valve replacement  
 The patient's symptomatology   is the most important determinant in terms of the 
decision to operate  
508

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  47 
  
There are three important factors to consider regarding management of aortic stenosis: 
 
 1. Presence of symptoms 
 2. The gradient across the valve on echocardiogram 
 3. Evidence of left ventricular dysfunction. 
 
 Symptomatic patient 
 Fit for surgery  aortic valve replacement

 Fit for surgery  aortic valve replacement 
 the best treatment option in an older person who can undergo the surgery. 
 Not fit for aortic valve replacement   
 Transcatheter aortic valve implantation (TAVI) 
 The catheter-delivered device produces similar one-year survival as aortic 
valve replacement but a higher risk of stroke, TIAs and vascular 
 Balloon valvuloplasty 
 Balloon aortic valvuloplasty is a palliative procedure prone to restenosis for

patients unsuitable for other interventions.  
 Asymptomatic patient 
 with severe stenosis ( transvalvular gradient  > 50 mmHg , valve area <1 cm ² ) but 
has an ejection fraction of less than 50%.  
 should be referred for aortic valve replacement or TAVI if unsuitable. 
 with severe stenosis but has an ejection fraction is greater than 50%. 
 Exercise testing would be recommended  
 If pass exercise testing then  reviewed in six months.

What is the most appropriate treatment for a pregnant lady with symptomatic congenital bicuspid 
aortic valve, If s he wishes to start a family ?  
 Refer for a porcine  valve replacement before pregnancy  
 metal valve replacements require warfarinisation, and warfarin is teratogenic in early 
pregnancy and not advised in late pregnancy because of the risk of haemorrhage.  
 Presence of a metallic valve would therefore necessitate switching to LMW heparin  at 
some stage in pregnancy.

some stage in pregnancy.  
 This leaves a porcine valve replacement before pregnancy as the best option. 
 Untreated aortic stenosis has an average five-year survival rate of only 40%. 
 
Indicator of poor prognosis 
 Clinical features of left ventricular failure  
 deteriorating LV function (ejection fraction less than 40%)  
 Symptomatology 
 exertional breathlessness or presyncope/syncope 
 Increasing gradient across the valve (above 70 mmHg) 
 Age of patient  
 509

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  48 
  
Heyde ’s syndrome 
 association between microcytic anaemia and calcific aortic stenosis.  
 Heyde syndrome refers to a triad of   
1. aortic stenosis,  
2. acquired coagulopathy (von Willebrand syndrome type 2A) and

3. anaemia due to bleeding from intestinal angiodysplasia or from an idiopathic site.  
 Angiodysplasia most common ly occur in the ascending colon, particularly the 
caecum .  
 the mechanism is thought to be due to destruction of von Willebrand ’s factor as the 
platelets traverse the stenosed valve resulting in bleeding per rectum.  
 Investigation  
 The investigation of choice after valve replacement is mesenteric angiography as the

bleeding vessels are poorly visualised on colonoscopy.  
 This would look for the presence of angiodysplasia, which may be associated 
with aortic stenosis.  
 All patients with aortic stenosis should be screened for iron deficiency anaemia. 
 replace the valve 
 Resection of the diseased bowel has also been described as a treatment.  
 There is an association with jaundice and aortic stenosis; this is thought to be due to 
microangiopathic haemolysis.

microangiopathic haemolysis.  
 
Coarctation of the aorta 
510

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  49 
  congenital narrowing of the descending aorta, most commonly at the site of insertion o f the 
ductus arteriosus 
Overview  
 more common in males (despite association with Turner's syndrome) 
 site of coarctation: 
 distal  to the origin of the left subclavian artery 
 The commonest site

 The commonest site 
 The systolic BP in the arms exceeds that in the leg. 
 proximal to the origin of the left subclavian artery  
 occurs in 15% of cases of coarctation  
 if the systolic BP in the right arm is higher than that of the left arm by more 
than 30 mmHg, the left subclavian is involved in the coarctation (ie 
coarctation is proximal to the origin of the subclavian)  
Features 
 Most patients are asymptomatic  
 infancy: heart failure 
 claudication of the calf muscles.

 claudication of the calf muscles.  
 pain in calves is almost certainly due to poor distal blood supply.  
 the  most common  presenting feature in adults 
 headache and nose bleeds occur due to hypertension proximal to the coarctation, 
 differential blood pressures between the right and left arms 
 radio-femoral delay 
 mid systolic murmur,  and thrill  
 maximal over back . 
 continuous  murmur over the thoracic spine usually originates from small, tight

coarctation (< 2 mm).  
 apical click from the aortic valve 
Complications  
 Secondary hypertension 
 development of cerebral aneurysms 
 may present with intracranial haemorrhage from a ruptured berry aneurysm 
 Left ventricular failure, 
 Bacterial endocarditis.  
 Bicuspid aortic valve  
 the commonest associated congenital abnormality 
 occurs  in 50% of the coarctations. 
 patent ductus arteriosus (PDA)  
 Turner's syndrome

 Turner's syndrome 
 Female patients diagnosed with coarctation of the aorta should have a karyotype 
analysis  to rule out Turner syndrome. 
 berry aneurysms 
 neurofibromatosis 
 Radiograph  
 Cardiomegaly  
 Ĺ pulmonary vascular markings  
 rib notching 
 notching of the inferior border of the ribs  (due to collateral vessels ) 
 usually manifests in adults and older children, as it takes time to develop.

 may demonstrate an indentation of the aortic shadow at the site of the coarctation.  
 rib notching is not seen in young children 
 Echocardiography with doppler  (confirmatory test ):  
 location and extent of stenosis;  
 concurrent anomalies 
 
Treatment  
 Balloon angioplasty and stenting is  
 the preferred intervention in adults. 
 surgical correction is indicated  if the pressure gradient across the coarctation is 
above 20 mmHg , even without associated hypertension. 511

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  50 
  Prostaglandin E1 should be administered to neonates with aortic coarctation to keep the ductus 
arteriosus open. 
 
Differences in blood pressure between arms: 
 up to 10 mmHg difference  Normal variant (physiological)  
 difference of greater than 10 mmHg :  abnormal :

 +   radio-radial or radio-femoral delay  (NO Leg claudication )  proximal coarctation  of 
the aorta (involves the left subclavian artery origin)  
 + arm claudication , intermittent vertigo, ataxia or diplopia, or facial sensory symptoms 
(NO Leg claudication ) Subclavian steal syndrome  
 + Leg claudication  (chronic intermittent leg pain, exacerbated by exercise and relieved 
by rest)  Peripheral vascular disease

by rest)  Peripheral vascular disease  
 
Bicuspid aortic valve 
Overview 
 occurs in 1-2% of the population 
 Bicuspid aortic valve tends to be sporadic although there is a reported familial incidence of 
approximately 9%.   
 usually asymptomatic in childhood 
 the majority eventually develop aortic stenosis or regurgitation 
associated with:

associated with:   
 left dominant coronary circulation (the posterior descending artery arises from the circumflex 
instead of the right coronary artery)  
 coarctation of the aorta (around 5% of patients)  
 aortic stenosis/regurgitation as above 
 higher risk for aortic dissection and aneurysm formation of the ascending aorta 
Tricuspid regurgitation 
Signs

Signs 
 giant V waves in JVP 
 pulsatile hepatomegaly 
512

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  51 
  left parasternal heave 
Causes 
 right ventricular dilation 
 pulmonary hypertension e.g. COPD 
 rheumatic heart disease 
 infective endocarditis (especially intravenous drug users) 
 Ebstein's anomaly 
 carcinoid syndrome 
Prosthetic valves

Prosthetic valves 
 
 The most common valves which need replacing are the aortic and mitral valve.  
 There are two main options for replacement: biological (bioprosthetic) or mechanical. 
 
Biological (bioprosthetic) valves Mechanical valves 
Usually bovine or porcine in origin 
 The most common type now implanted is the bileaflet valve. 
Ball-and-cage valves are rarely used nowadays 
advantages :  
not requiring Long-term anticoagulation 
Warfarin may be given for the first 3

Warfarin may be given for the first 3 
months depending on patient factors. 
Low-dose aspirin is given long-term. advantages :  
 
have a low failure rate 
 
disadvantages  
calcification over time.  must be replaced 
within 5 to 10 years. 
 
Most older patients ( > 65 years for 
aortic valves and > 70 years for mitral 
valves) receive a bioprosthetic valve  disadvantages  
↑ risk of thrombosis meaning long-term anticoagulation is

needed. Aspirin is normally given in addition unless there is a 
contraindication. 
 
Target INR 
 aortic: 2.0-3.0 
 mitral: 2.5-3.5 
 
Following the 2008 NICE guidelines for prophylaxis of endocarditis  antibiotics are no longer 
recommended for common procedures such as dental work.  
 
Which pathological findings in the bioprosthesis has most likely led to the need for 
replacement? 
 Calcification with stenosis  
513

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  52 
  
 prosthetic valve thrombosis (PVT)  resulting in shock.  
 occurs in 0.03 –5.5% annually  
  The incidence is higher for mechanical than for biological heart valves (right ‐sided > left ‐
sided, mitral > aortic).  
 Non ‐obstructive thrombi are more frequently observed than obstructive thrombi

 high ‐risk situations  
 early postoperative period,  
 interruption of anticoagulant therapy for non ‐cardiac surgery,  
 pregnancy 
 sub-therapeutic anticoagulation (the most important factor)  
 Diagnosis  
 The initial diagnostic work ‐up includes:  
 transthoracic echocardiogram (TTE) and  
 cinefluoroscopy of mechanical valves.  
 this technique will not be helpful in identifying non ‐obstructive PVT or 
differentiating pannus from thrombus. Hence, additional diagnostic

procedures are often necessary.  
 Suggestive findings  include  reduced or absent leaflet mobility, 
elevated transprosthetic gradients, decreased effective orifice area 
and thrombus visualization  
 TOE will often be performed to complete the investigation.  
 can differentiate thrombi from pannus formation or strands.  
 TOE is also important in guiding treatment  
 first-line   Thrombolysis  
 Tissue plasminogen activator (tPA)

 Tissue plasminogen activator (tPA) 
 Thrombolytic therapy can be a safe alternative to surgery even during 
 If the patient is haemodynamically unwell (ie pulmonary oedema or 
hypotension) and no immediate surgery is available, thrombolytic therapy 
should be given (IV alteplase) .  
 Follow up:  
 When thrombolysis is contemplated, then TEE and Doppler echocardiography are 
the preferred modalities to assess serially the hemodynamic success of 
fibrinolysis.

fibrinolysis.  
 Doppler echocardiography is the most accurate method for detecting and 
quantifying the degree of transvalvar gradient increase and is useful in the follow-
up of patients during thrombolysis.  514

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  53 
  
 OPVT: obstructive prosthetic valve thrombosis; NOPVT: non-obstructive prosthetic valve t hrombosis.  
 
Supraventricular tachycardia (SVT ) 
 Whilst strictly speaking the term supraventricular tachycardia (SVT) refers to any tachycardia that

is not ventricular in origin the term is generally used in the context of paroxysmal SVT. 
Causes 
 atrioventricular  nodal  re-entry tachycardia (AVNRT). 
 the most common supraventricular tachycardia,  
 twice as common in females as in males  
 the incidence is 1 –3 per 1000.  
 Small elevations in troponin are occasionally seen in this situation, but there are no ECG 
changes to suggest a myocardial infarction. 
 atrioventricular re-entry tachycardias (AVRT)

 atrioventricular re-entry tachycardias (AVRT) 
 junctional tachycardias. 
 
Paroxysmal SVT would start and stop suddenly, not gradually. 
Panic attacks  breathlessness and palpitations start and stop gradually.  
 
Acute management 
 vagal manoeuvres: e.g. Valsalva manoeuvre 
 Carotid sinus massage is contraindicated in patients with carotid vascular disease 
 intraveno us adenosine 6mg ĺ 12mg ĺ 12mg  
 contraindicated in asthmatics - verapamil is a preferable option

 electrical cardioversion 
Prevention of episodes 
 beta-blockers 
 Prophylaxis for SVT in pregnancy  Metoprolol ,  
 the most appropriate option for SVT in pregnancy  
 although can cause intra-uterine growth restriction, is seen as the safest as toxicity 
is usually associated with higher doses in treatment of gestational hypertension.  
 It is a short acting β blocker and a TDS regimen is required.  
 radio-frequency ablation 
Arrhythmias  515

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  54 
 SVT in pregnancy 
 Tachyarrhythmias may increase during pregnancy although the causes are not e ntirely clear. 
 Regarding the termination of acute SVT , adenosine appears to be safe in pregnancy.   
 
 In the case of the prevention of recurrent SVT  then verapamil or beta-blockers have data 
supporting their use.

supporting their use. 
 Current AHA/EHA criteria for the treatment of SVTs in pregnancy do suggest using 
metoprolol (level of evidence 1B) rather than verapamil (C), although they recommend 
avoiding the former in the first trimester. 
Sinus arrhythmia   
 The (ECG) shows normal P wave, PR interval, QRS complex and each P wave conducted to 
ventricles.

ventricles.  
 There is a gradual decrease in R –R interval and then an increase again. This slight beat-
to-beat variation (rhythmic and cyclical variation) is termed as sinus arrhythmia . 
  the most common cause is respiration.  
 Respiratory sinus arrhythmia is thus heart rate variability in synchrony with respiration, 
and is normal in children and young adults.  
 The R –R interval decreases with inspiration and increases with expiration.  
 Anxiety reassured.

 Anxiety reassured.  
 
Premature ventricular ectopic (PVEs) 
Beta blockade is the initial treatment of choice for palpitations precipitated by  premature 
ventricular ectopics (PVEs).  
 usually seen in normal hearts;  
 palpitations are described as an early beat with a pause followed by an unus ually strong or 
'pounding' beat, or simply as a 'flip-flop';

'pounding' beat, or simply as a 'flip-flop';  
 Symptoms are usually worse at rest and may disappear with exercise. 
 Symptoms which increase on exercise are more worrying and significant. 
 may be associated with caffeine intake 
 baseline ECG without symptoms: typically normal 
 ambulatory ECG: isolated wide QRS complexes 
 If symptoms are short-lived but frequent (>2-3 times per week), use a 24-ho ur 
Holter monitor

Holter monitor 
 If symptoms are short-lived and infrequent (<1 per week), use an event mon itor or 
transtelephonic recorder 
 Exercise stress testing 
 the relation of extrasystoles to exercise may have prognostic importance. 
 Echocardiography - to assess LV function and heart structure. 
 For PVE to be significant they have to meet the following criteria: 
 Occurring frequently (6 or more beats/min) 
 PVE in bigeminal rhythm 
 PVE in short runs of ventricular tachycardia

 PVE in short runs of ventricular tachycardia 
 PVE exhibiting R- on-T phenomenon 
516

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  55 
  PVE associated with serious organic heart disease and left ventricular decompensation. 
 Not significant PVE  Reassurance  
  Significant PVE  
 beta-blockers 
 Radiofrequency catheter ablation of the ectopic focus  
 Curative with good outcome

 Curative with good outcome  
 
Ventricular extrasystoles are the most common type of arrhythmia that occurs after myocardial 
 
Management of symptomatic atrial extrasystoles 
 beta-blockers (atenolol or metoprolol). 
 Atrial extrasystoles arising from the pulmonary veins may be treatable by the procedure o f 
pulmonary vein isolation.  
 
___________________________________________________ _______________________________

Arrhythmogenic right ventricular cardiomyopathy (ARVC)  
 Arrhythmogenic right ventricular cardiomyopathy (ARVC, also known as arrhythmogenic right 
ventricular dysplasia or ARVD) is a form of inherited cardiovascular disease which may present 
with syncope or sudden cardiac death. 
 It is generally regarded as the second most common cause of sudden cardiac death  in the 
young after hypertrophic cardiomyopathy.

young after hypertrophic cardiomyopathy. 
  Although ARVC was initially described in the right ventricle, most patients have biventricular 
involvement. 
 
 inherited in an autosomal dominant pattern with variable expression 
 the right ventricular myocardium is replaced by fatty and fibrofatty tissue 
 around 50% of patients have a mutation of one of the several genes which encode co mponents 
of desmosome 
 palpitations 
 syncope 
 sudden cardiac death

 syncope 
 sudden cardiac death 
epsilon potential is seen on the ECG of patients with  Right ventricular dysplasia 
 
 ECG abnormalities in V1- 3: 
 Typically, T wave inversion.  
 An epsilon wave  is found in about 50% of those with ARV - this is best described as a 
terminal notch in the QRS complex 
 
 echo changes are often subtle in the early stages but may show an enlarged, hypokine tic right 
ventricle with a thin free wall

ventricle with a thin free wall 
 magnetic resonance imaging is useful to show fibrofatty tissue 
517

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  56 
  drugs: sotalol is the most widely used antiarrhythmic 
 catheter ablation to prevent ventricular tachycardia 
 implantable cardioverter-defibrillator :  
Naxos disease 
 an autosomal recessive variant of ARVC

 an autosomal recessive variant of ARVC 
 a triad of ARVC, palmoplantar keratosis, and woolly hair 
Atrial fibrillation (AF) 
 
Overview 
 AF is the most commonly encountered cardiac arrhythmia. 
 Hypertension is the most common risk factor for AF. 
 In  15% of cases, AF is idiopathic  
 AF most commonly originates from  the roots of the  pulmonary veins .  (longitudinal

smooth muscle fibres in the pulmonary vein ) 
 
classification  
 
classification of atrial fibrillation (AF): AF classified into 3 patterns: 
1. first detected episode  (irrespective of whether it is symptomatic or self-terminating) 
2. recurrent episodes , when a patient has 2 or more episodes of AF: 
 paroxysmal AF :  
 episodes of AF terminate spontaneously.  
 episodes last less than 7 days (typically < 24 hours).  
 persistent AF    
 the arrhythmia is not self-terminating.

 the arrhythmia is not self-terminating.  
 episodes usually last greater than 7 days 
3. permanent AF   
 there is continuous atrial fibrillation which cannot be cardioverted or if attempts to do so 
are deemed inappropriate.  
 Treatment goals are therefore rate control and anticoagulation if appropriate 
 Symptoms  
 Palpitations 
 Dyspnea 
 chest pain 
 Signs  
 irregularly irregular pulse 
Complications

 AF is poorly tolerated in elderly and often leads to pulmonary oedema  even in the presence of a 
relatively normal left ventricle (LV).  
 
 An ECG is essential to make the diagnosis as other conditions can give an irregular pulse, such 
as ventricular ectopics or sinus arrhythmia.  
 
Treatment 
 There are two key parts of managing patients with AF:  
1. Rate/rhythm control 
2. Reducing stroke risk 
518

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  57 
  Rate vs. rhythm control  
 There are two main strategies in dealing with atrial fibrillation: 
 Rate control :  
 accept that the pulse will be irregular, but slow the rate down to avoid 
negative effects on cardiac function 
 now the majority of patients are managed with a rate control strategy.  
 Rhythm control :

 Rhythm control :  
 try to get the patient back into, and maintain, normal sinus rhythm. This is 
termed cardioversion.  
 Drugs (pharmacological cardioversion) and synchronised DC electrical 
shocks (electrical cardioversion) may be used for this purpose 
 indications of  Rhythm control  : 
 coexistent heart failure,  
 first onset AF or  
 where there is an obvious reversible cause. 
 
Do not use rhythm control therapy in asymptomatic AF patients, nor in patien ts with permanent 
AF.

AF. 
 
Rhythm control has no survival benefit over a rate control strategy 
 
Reducing stroke risk   anticoagulation 
Young man with AF, no TIA or risk factors, no treatment is now preferred to aspirin (NO treatment) 
 
Do not use antiplatelet therapy for stroke prevention in AF. 
 
 Some patients with AF are at a very low risk of stroke whilst others are at a very significant risk.  
 NICE in 2014 suggest using the CHA 2DS2-VASc  score to determine the most appropriate

anticoagulation strategy 
 
Risk factor Points 
C Congestive heart failure 1 
H Hypertension (or treated hypertension) 1 
A2 Age >= 75 years 2 
 Age 65-74 years 1 
D Diabetes 1 
S2 Prior Stroke or TIA 2 
V Vascular disease (including ischaemic heart disease and peripheral arterial 
disease) 1 
S Sex (female) 1 
 
The table below shows a suggested anticoagulation strategy based on the score: 
 
Score Anticoagulation 
0 No treatment 
1 Males: Consider anticoagulation

1 Males: Consider anticoagulation 
Females: No treatment (this is because their score of 1 is only reached due to 519

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  58 
 Score Anticoagulation 
their gender) 
2 or 
more Offer anticoagulation 
 
Atrail fibrilation related to mitral stenosis 
 atrial fibrillation related to valvular heart disease  Warfarin  
 In patients with non-valvular atrial fibrillation , novel oral anticoagulants  have the 
same efficacy as warfarin in preventing stroke.

same efficacy as warfarin in preventing stroke.  
 NICE guidelines suggest that valvular disease have high risk for thromboembolic events, an d 
would benefit from anticoagulation.  
 Mitral stenosis patients were excluded from the studies developing the CHADS-VASC score.  
 None of the ‘novel ’ anticoagulants currently available (rivaroxaban, apixaban, dabigatran) are 
indicated or licensed for atrial fibrillation related to valvular heart disease.

CHADS2-VASc scoring is generally used as a tool to assess need to anticoagulate a patie nt with AF. 
However, the following are conditions that, if present, may trump the decision to anticoagulate:  
1. valvular heart disease 
2. prior peripheral embolism, and 
3. intracardiac thrombus. 
 
The risk of stroke without anticoagulation 
 In order to be counselled correctly on the risks and benefits of anticoagulation, p atients should

be aware of their stroke risk based on their risk factors - as outlined below: 
 
CHA2DS2-VASc Score Ischaemic Stroke Rate (per year) 
0 0.2% 
1 0.6% 
2 2.2% 
3 3.2% 
4 4.8% 
5 7.2% 
6 9.7% 
7 11.2% 
8 10.8% 
9 12.2% 
 
 The MRCP examiners would not expect knowledge of the precise figures, however yo u should 
know that : 
 scores of 0-1 convey an annual risk of <1%,  
 while scores of 2 and above give an annual risk roughly equivalent to the score, 
increasing at scores over 5.

increasing at scores over 5.  
 It is important to know that this risk is annual, rather than 10-year or lifetime. 
 Generally, risk is more readily understood by patients if expressed as a '1 in x' rather than 
a percentage. 
 
Bleeding risk assessment ( using the HASBLED scoring system)  520

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  59 
  NICE recommend that we offer patients a choice of anticoagulation, including warfarin and  the 
novel oral anticoagulants (NOACs).  
 Aspirin is no longer recommended for reducing stroke risk in patients with AF 
 Doctors have always thought carefully about the risk/benefit profile of starting some one on 
warfarin.

warfarin.  
 A history of falls, old age, alcohol excess and a history of previous bleeding are common thing s 
that make us consider whether warfarinisation is in the best interests of the patien t. 
  NICE now recommend we formalise this risk assessment using the HASBLED scoring system. 
 
H Hypertension, uncontrolled, systolic BP > 160 mmHg 1 
A Abnormal renal function (dialysis or creatinine > 200) 
Or 
Abnormal liver function (cirrhosis, bilirubin > 2 times

normal, ALT/AST/ALP > 3 times normal 1 for any renal abnormalities 
 
1 for any liver abnormalities 
S Stroke, history of 1 
B Bleeding, history of bleeding or tendency to bleed 1 
L Labile INRs (unstable/high INRs, time in therapeutic 
range < 60%) 1 
E Elderly (> 65 years) 1 
D Drugs Predisposing to Bleeding (Antiplatelet agents, 
NSAIDs) 
Or 
Alcohol Use (>8 drinks/week) 1 for drugs 
 
1 for alcohol 
 There are no formal rules on how we act on the HAS-BLED score although a score of >= 3

indicates a 'high risk' of bleeding , defined as intracranial haemorrhage, hospitalisation, 
haemoglobin decrease >2 g/L, and/or transfusion. 
 
Atrial fibrillation: post-stroke (NICE guidelines 2006)  
 following a stroke or TIA warfarin should be given as the anticoagulant of choice. 
 Aspirin/dipyridamole should only be given if needed for the treatment of other como rbidities 
 cerebral infarction are subject to the risk of haemorrhagic transformation within the acute perio d ,

so in acute stroke patients, in the absence of haemorrhage, anticoagulation the rapy should be 
commenced after 2 weeks. If imaging shows a very large cerebral infarction then the initia tion of 
anticoagulation should be delayed 
 The use of aspirin and/or low dose heparin/LMWH for venous thromboembolis m (VTE) 
prophylaxis can be considered within 24 hours of symptom onset. 
 
Atrial fibrillation: cardioversion 
Atrial fibrillation - cardioversion:

Atrial fibrillation - cardioversion:  
 if no structural heart disease   flecainide  
 With structural heart disease   amiodarone  
 
offer rate or rhythm control if the onset of the arrhythmia is less than 48 hours, and start rate 
control if it is more than 48 hours or is uncertain  
 
 Cardioversion indications 
 Haemodynamically unstable patient  electrical cardioversion ( DC cardioversion 200J ĺ 
360J ĺ 360J ) 
 Adverse signs necessitating DC cardioversion are:

 Blood pressure (BP) ≤90 mmHg  
 Chest pain 
 Heart failure 521

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  60 
  Impaired consciousness, and 
 Heart rate ≥ 200 bpm.  
 Elective procedure  where a rhythm control strategy is preferred  electrical or 
pharmacological cardioversion  
 Onset < 48 hours  
 Anticoagulation 
 patients should be heparinised.  
 Patients who have risk factors for ischaemic stroke should be put on

lifelong oral anticoagulation.  
 Cardioversion method:  
 electrical - 'DC cardioversion' 
 pharmacology: 
 amiodarone if structural heart disease,  
 flecainide or amiodarone in those without structural heart 
disease 
 Post-cardioversion: 
 further anticoagulation is unnecessary 
 Onset > 48 hours  
 prior to cardioversion:  
 anticoagulation  
 for at least 3 weeks prior to cardioversion. OR 
 exclude a left atrial appendage (LAA) thrombus by

transoesophage al echo (TOE). If excluded patients may be 
heparinised and cardioverted immediately. 
 If there is a high risk of cardioversion failure (e.g. Previous failure or 
AF recurrence) then it is recommend to have at least  4 weeks 
amiodarone or sotalol  prior to electrical cardioversion 
 If the patient has a slow ventricular response of AF  in the absence 
of anti-arrhythmic drugs, cardioversion should be performed after the 
insertion of a temporary transvenous-pacing catheter

 NICE recommend electrical cardioversion, rather than 
pharmacological. 
 The initial shock strength should be 100 J, followed by a second 200-
J shock and a third 360-J shock  
 If AF persists, a second 360-J shock with the paddles in the 
anteroposterior position can be attempted 
 Following electrical cardioversion patients should be anticoagulated 
for at least 4 weeks . After this time decisions about anticoagulation

should be taken on an individual basis depending on the risk of 
recurrence 
 The success of cardioversion depends on: 
 the duration of AF 
 transthoracic impedance 
 left atrial size  
 the age of the patient 
 Catheter AF ablation  
 Radiofrequency pulmonary vein isolation with ablation  
 the treatment of choice for patients who remain poorly controlled despite 
medical therapy,  
 in selected patients as first-line therapy for symptomatic paroxysmal AF

 Anticoagulation for stroke prevention should be continued indefinitely in patients at 
high risk of stroke, even after apparently successful ablation of AF.  
 Surgical AF ablation  
 Ablation can be performed in symptomatic patients during cardiac surgery for other 
reasons, or by stand-alone surgery either using open-chest techniques or by 
thoracoscopy.  
 Anticoagulation for stroke prevention should be continued indefinitely in patients at high

risk of stroke, even after apparently successful ablation of AF. 
 
 522

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  61 
 The enlarged left atrial size suggests that a repeat DC cardioversion is unlikely to work for a 
sustained period. 
H/O AF + enlarged left atrial size with previous DC cardioversions. the best long term 
treatment option  Refer for consideration of atrial fibrillation ablation  longer term good 
result. 
 
AV node ablation:

result. 
 
AV node ablation: 
 AV node ablation is reserved for those patients where pharmacological rate control is 
unsuccessful or not tolerated.  
 The procedure is invasive and requires permanent pacemaker implantation. 
 Patients who are candidates for this therapy include those with  tachycardia induced 
cardiomyopathy despite pharmacologic efforts  at rate control and intolerable symptoms 
despite aggressive attempts at pharmacologic therapy (in some cases, much of the sympt om

burden is due to medications rather than AF itself). 
 
Do not perform cardioversion or catheter ablation without anticoagulation, unless an atrial throm bus 
has been ruled out by transoesophageal echocardiogram. 
 
Amiodarone or vernakalant have been efficient in converting post-operative AF to sinus rhythm. 
 
Vernakalant  
 A Novel agent for the Termination of Atrial Fibrillation 
 blocks sodium channels

 blocks sodium channels  
 more prominent in vernakalant's mechanism of action is its ability to block certain 
potassium channels. 
 Specifically, it blocks the atrial-selective potassium current, I Kur, which is involved in 
atrial repolarization. 
 
Atrial fibrillation: pharmacological cardioversion 
 
 Agents with proven efficacy in the pharmacological cardioversion of atrial fibrillation  
 amiodarone 
 flecainide (if no structural heart disease)

 flecainide (if no structural heart disease) 
 with large doses of oral agents  or with intravenous agents. 
 Large single doses of flecainide (300 mg) or propafenone (450-600 mg) given orally 
have been shown to convert patients to sinus rhythm. 
 Flecainide and propafenone are not used in people with : 
 known or suspected ischaemic heart disease,  
 individuals who are already on antiarrhythmic therapy, 
 those with a prolonged QT interval because these agents may have pro-

arrhythmic effects (torsade de pointes). 
 others (less commonly used in UK): quinidine, dofetilide, ibutilide, propafenone 
 Less effective agents 
 beta-blockers (including sotalol) 
 calcium channel blockers 
 digoxin 
 disopyramide 
 procainamide 
1.  
Atrial fibrillation: rate control and maintenance of sinus rhythm  
 
523

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  62 
 The patient with very recent onset of atrial fibrillation is more likely to stay in sinus rhythm  
 
 Agents used to control rate in patients with atrial fibrillation 
 should be used  first line for rate control.  
 cardioselective beta-blockers should be tried in patients with left ventricular systolic

dysfunction even if they have a diagnosis  of: 
 Chronic obstructive pulmonary disease (COPD) 
 Peripheral vascular disease 
 Diabetes 
 Erectile dysfunction, or 
 Interstitial pulmonary disease. 
 Beta-blockers should not be commenced in the setting of acute exacerbations of 
COPD or cardiac failure 
 If one drug does not control the rate adequately NICE recommend combination 
therapy with diltiazem or digoxin 
 calcium channel blockers (diltiazem) 
 digoxin:

 digoxin: 
 not considered first-line anymore as they are less effective at controlling the he art 
rate during exercise.  
 they are the preferred choice if the patient has coexistent heart failure  
 If  the duration of AF is unknown caution should be used when considering the use of 
drugs which may cardiovert the patient - amiodarone and flecainide. 
 
 Agents used to maintain sinus rhythm  in patients with a history of atrial fibrillation 
 sotalol 
 flecainide

 sotalol 
 flecainide 
 others (less commonly used in UK): disopyramide, dofetilide, procainamide, propafenone, 
quinidine 
 The table below indicates some of the factors which may be considered when considering  either 
a rate control or rhythm control strategy 
 
Factors favouring rate control Factors favouring rhythm control 
 Older than 65 years 
 History of ischaemic heart disease  Younger than 65 years 
 Symptomatic 
 First presentation

 First presentation 
 Lone AF or AF secondary to a corrected precipitant (e.g. Alcohol) 
 Congestive heart failure 
 
Atrial flutter 
 
Overview  
 Atrial flutter is a form of supraventricular tachycardia characterised by a succession of rapid atrial 
depolarisation waves. 
 usually caused by a single macro reentrant rhythm within the atria.

 What is the differences  between  atrial flutter  and focal atrial tachycardia ? 
 Atrial flutter is caused mechanistically by  macro - reentry and has atrial rate ( P 
wave/flutter morphology) usually >250 bpm.   
 Focal atrial tachycardia is caused mechanistically by micro-reentry or increased 
automaticity and has atrial rates of 100-250 bpm. 
 Sex: ♂ > ♀ (5:2)  
 Peak incidence: risk of atrial flutter increases with age 
Etiology:  
 similar to atrial fibrillation 
524

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  63 
 ECG findings  
 Regular, narrow QRS complexes  
 flutter waves, which are a saw-tooth pattern  of atrial activation 
 most prominent in leads II, III, aVF, and V1. 
 as the underlying atrial rate is often around 300/min the ventricular or heart rate is depend ent on

the degree of AV block. For example if there is 2:1 block the ventricular rate will be 150/min 
 flutter waves may be visible following carotid sinus massage or adenosine 
 is similar to that of atrial fibrillation although medication may be less effective 
 atrial flutter is more sensitive to cardioversion however so lower energy levels may be used 
 Anticoagulate patients with atrial flutter similar to AF.

 Catheter ablation  is the definitive treatment  for atrial flutte r.  
 radiofrequency ablation of the tricuspid valve isthmus  is curative for most patients 
Multifocal atrial tachycardia 
 Multifocal atrial tachycardia (MAT) may be defined as a irregular cardiac rhythm caused by at 
least three different sites in the atria, which may be demonstrated by morphologically distinctiv e 
P waves.

P waves.  
 It is more common in elderly patients with chronic lung disease, for example COPD 
 correction of hypoxia and electrolyte disturbances 
 rate-limiting calcium channel blockers are often used first-line 
 cardioversion and digoxin are not useful in the management of MAT 
Atrial myxoma 
 
Overview 
 Benign cardiac tumor  
 the most common primary cardiac tumors in adults.

 (rhabdomyoma is the most common primary cardiac tumor in pediatric patients and 
strongly associated with tuberous sclerosis). 
 75% occur in left atrium ,  arising from a pedicle on the fossa ovalis. 
 Three-quarters of cases of atrial myxoma occur in females 
 Although most cases of atrial myxoma are sporadic, an autosomal dominant  variety may also 
exist within families. 
 10% are inherited 
Features 
 One third present with emboli

Features 
 One third present with emboli 
 One third with systemic inflammation (ESR ĹĹ in 1/3)  
 One third are asymptomatic when detected. 
 constitutional symptoms: 
  fatigue, weight loss, fever, clubbing 
 Dyspnoea,  
 Exertional dyspnoea is present in three-quarters of patients. 
 Dizziness or syncope  
 results from the atrial myxoma obstructing the mitral valve.  
 Mitral valve obstruction is the most likely complication

 Myxomas are more likely to have a stalk and be freely mobile.  
 emboli 
 mid-diastolic  murmur, 'tumour plop' 
 Elevated left atrial pressures cause dilatation.  
 echo: pedunculated heterogeneous mass typically attached to the fossa ovalis reg ion of the 
interatrial septum 
 on histology 
 gelatinous appearance 
 abundant ground substance. 
525

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  64 
 Treatment 
 surgical removal by median sternotomy.  
Prognosis 
 sudden death may occur in 15% of patients. 
 
Carney's complex  is a familial multiple neoplasia and lentiginosis syndrome, associated with 
1. Primary adrenal hypercortisolism 
2. Lentigines and naevi of the skin 
3. Various tumours including myxoma.

3. Various tumours including myxoma.  
 
Heart block  
Types of heart block  
 
First-degree heart block  
 PR interval > 0.2 seconds 
 Causes: 
 Increased vagal tone (such as in trained athletes) 
 Ischaemic heart disease 
 Rheumatic fever 
 Hyperkalaemia 
 Hypokalaemia, and 
 Drug therapy such as digoxin or beta-blockers.

 Drug therapy such as digoxin or beta-blockers. 
 A long PR interval on the ECG may also be caused by structural abnormalities such as an atrial 
septal defect. 
 No treatment is usually required. 
Second-degree heart block 
 type 1 (Mobitz I, Wenckebach):  
 progressive prolongation of the PR interval until a dropped beat occurs 
 Mobitz Type I with symptoms is a relative  indication for a permanent pacemaker 
 Asymptomatic  NO treatment  Discharge him from the clinic

 The risk of progression to complete heart block with Mobitz type I in an 
asymptomatic man is very low, unlike in Mobitz type II. 
 type 2 (Mobitz II):  
 PR interval is constant but the P wave is often not followed by a QRS complex   
 the most appropriate next management step  Transvenous cardiac pacing  
 Mobitz type II or complete heart block does not respond to atropine. Atropine ma y be 
useful for sinus or junctional bradycardia.

useful for sinus or junctional bradycardia. 
 Second-degree heart block with RBBB implies that this patient has a significantly 
increased risk of complete heart block. 
 prior to committing to pacemaker insertion, repeat tape is the most likely next step , 
with an electronic patient diary to see if the recorded arrhythmia corresponds to her 
symptoms.  
 murmurs  
Third degree (complete) heart block 
 there is no association between the P waves and QRS complexes 
526

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  65 
  Complete heart block (whether symptomatic or not) is an absolute  indication for a 
permanent pacemaker 
 
Complete heart block 
 
 Complete heart block is related most to right coronary artery occlusion because this commonly

involves both the AV nodal artery and the right superior descending artery.  
 Prognosis is favourable, and revascularisation normally leads to restoration of sinus 
rhythm.  
 As the AV nodal artery arises proximally from the right ventricular artery, distal 
right coronary artery occlusion is not commonly associated with complete heart 
block. 
 the artery most likely to be affected  Proximal right coronary

 Left coronary artery occlusion leads to anterior myocardial infarction. As it is less commonly 
associated with complete heart block, when it does occur, the prognosis is very poor. 
Features 
 Syncope 
 regular bradycardia (30-50 bpm) that does not vary with exercise  
 JVP: irregular  cannon waves in neck 
 variable intensity of S1 
 compensatory increase in stroke volume with a large-volume pulse and systolic flow

ECG showing third degree (complete) heart block 
 
Treatment 
 Whilst arrangements are being made for temporary pacing , the options to be considered, 
prior to temporary transvenous pacing , in this context are:  
1. Atropine  0.5-1.0 mg intravenous bolus, repeated as required. 
2. Isoprenaline, intravenous infusion at 2-10 microg/min. 
 it is a non-selective β agonist  that is analog of epinephrine (adrenaline) 
3. External cardiac pacing.

3. External cardiac pacing. 
 Intravenous aminophylline is useful in complete heart block, as the heart block is often med iated 
by adenosine which aminophylline inhibits 
 
Carotid sinus hypersensitivity (CSH) 
 CSH demonstrating an exaggerated response to carotid sinus stimulation.  
 The diagnosis is only made after ischaemic heart disease or rhythm disturbance have been  
excluded .

excluded .  
 CSH may be predominantly cardioinhibitory (resulting in bradycardia), vasodilatory (resulting in 
hypotension), or a mixture of the two.  
527

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  66 
  Management: 
 Cardioinhibitory CSH is usually managed with insertion of a dual-chamber 
pacemaker. 
 vasodilatory CSH is managed with support stockings, fludrocortisone and midodrine 
(available on a named-patient basis in the UK). 
Pacemakers

Pacemakers 
 
 A permanent pacemaker is an implanted device that provides electrical stimuli, thereb y causing 
cardiac contraction when intrinsic myocardial electrical activity is inappropriately slow or absent.   
Conditions definitely needs a permanent pacemaker  
 Symptomatic bradycardia due to sinus node dysfunction (sick sinus syndrome)   
 Third-degree heart block  
 second-degree (AV) block  associated with any of the following:  
 symptomatic bradycardia

 symptomatic bradycardia  
 documented periods of asystole of 3 s or more  
 any escape rate less than 40 bpm in awake, asymptomatic patients  
 type II second-degree AV block and a ventricular rate of 45 bpm when awake and 
asymptomatic  
 asymptomatic sinus rhythm resulting in periods of asystole longer than 3.0 seconds  
 asystolic pause causing syncope.  
 dual chamber permanent pacemaker (DDDR).  
 The R in this code stands for responsive, and in an otherwise fit and well 76-

year-old, he should have a responsive element to his PPM (that is, increases 
his heart rate with exercise).  
 Type II second-degree AV block has a high chance of progressing to asystole (35%) 
each year  
 Generally, permanent pacing can be justified for any degree of heart block associate d with 
symptoms of bradycardia.   
 
Indications for a temporary pacemaker 
 symptomatic/haemodynamically unstable bradycardia, not responding to atropine

 post-ANTERIOR MI: type 2 or complete heart block 
 post-INFERIOR MI complete heart block is common and can be managed conservatively 
if asymptomatic and haemodynamically stable 
 trifascicular block prior to surgery 
 Other indications for transvenous pacing in setting of acute MI are: 
 asystole  
 new bundle branch block (BBB) with first-degree heart block  
 an old right BBB with first degree atrioventricular (AV) block and a new fascicular block 
Notes

Notes 
 All modern ICDs also function as pacemakers.  
 Chest pain in Ventricular pacing  
 Pacemaker rhythm may prevent interpretation of ST-segment changes and may req uire 
urgent angiography  to confirm diagnosis .  
 Reprogramming the pacemaker —allowing an evaluation of ECG changes during 
intrinsic heart rhythm —may be considered in patients who are not dependent on 
ventricular pacing, without delaying invasive investigation 
 
 528

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  67 
  
Types of Pacemakers  
 Pacemakers are classified by the nature of their pacing mode using a code of up to five  letters.  
 The NBG Pacemaker code was developed by the North American Society of Pacing  and 
Electrophysiology (NASPE) and the British Pacing and Electrophysiology Group (BPEG): 
I II III IV V 
Chamber(s)

I II III IV V 
Chamber(s) 
Paced Chamber(s) 
Sensed Mode(s) of 
Response Rate Modulation Multisite 
Pacing 
O = None O = None O = None O = None O = None 
A = Atrium A = Atrium T = Triggered R = Rate 
modulation A = Atrium 
V = Ventricle V = Ventricle I = Inhibited   V = Ventricle 
D = Dual (A+V) D = Dual (A+V) D = Dual (T+I)   D = Dual 
(A+V) 
Single-chamber pacemakers 
 utilised for patients in permanent atrial fibrillation.

 VVI means there is one lead in the ventricle  (pacing and sensing the ventricle, indicated by the 
‘VV’).  
 VVI pacemaker will pace and sense the right ventricle. 
 VVI pacemaker  is useful when we are not too concerned about atrial activity (e.g. in patients 
with atrial fibrillation).  
 In the presence or organised atrial activity, a VVI pacemaker may pace the ventricles o ut of 
synch with the atria resulting in pacemaker syndrome.

 Since organised atrial activity is present, a DDI pacemaker  would be preferred, as this 
senses and paces both atria and ventricle to preserve synchrony.  
Dual-chamber pacemakers 
 Have pacing electrodes in both the right atrium and the right ventricle. 
 They allow maintenance of the physiological relationship between atrial and ventricular 
contraction and also allow the paced heart to follow the increase in sinus rate t hat occurs during 
exercise. 
Biventricular pacemakers

exercise. 
Biventricular pacemakers 
 Pacemaker leads are placed in the right atrium, right ventricle and left ventricle. 
 Useful in the management of patients with heart failure who have evidence of  abnormal 
intraventricular conduction (most often evident as left bundle branch block (LBBB) on ECG) 
which causes deranged ventricular contraction or dyssynchrony. 
 In a patient with severe ischaemic heart failure and is on optimal medical therapy. Despit e

this he is still symptomatic  ICD with biventricular pacing   
 very prolonged QRS duration is indicating left dyssynchrony which is an indication for 
biventricular pacing according to NICE guidance. 
 Documented VT in the context of ischaemic LV impairment necessitates the need fo r and 
a secondary prevention ICD. 
 529

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  68 
 Pacemaker complications  
 Pacemaker complications are more common in the period following insertion. 
 can be divided into early complications (<6 weeks) or late (>6 weeks).  
 Most frequent complications are those related to implantation procedure, such as lead 
dislodgement and pneumothorax.

dislodgement and pneumothorax.  
 pneumothorax can occur up to forty-eight hours following pacemaker insertion.  
  It occurs in 1-2% of procedures and most patients will require chest drain insertion.  
 The most common complication is lead dislodgement  (higher rate atrial dislodgment than 
ventricular dislodgment). 
 Lead dislodgement can occur following trauma or sporadically and can be either atrial or 
ventricular.

ventricular. 
 Atrial dislodgment affects up to 3% of people whereas ventricular is less common affecting 1%.  
 If the ECG shows loss of sensing and capture around the QRS complex  ventricular lead 
displacement in a dual chamber pacemaker. 
 What would be the likely ECG findings in ventricular lead displacement? 
 Loss of sensing and capture of the QRS complex  
 Atrial lead displacement would show an ECG with loss of atrial sensing and capture.

 The ECG in atrial lead displacement would show an ECG with loss of atrial sensing 
and capture in a dual chamber or single chamber pacemaker.  
 On occasion lead displacement can be seen on chest X-Ray, however, it may not be seen , in 
this case a lateral chest X-Ray may be of use in this scenario.  
 Pacemaker syndrome  would show AV dyssynchronisation.  
 Subclavian vein obstruction  is a fairly common complication over time but many patients may

remain asymptomatic due to collateral vein formation. It can present with symptoms of s uperior 
vena cava (SVC) obstruction in severe cases. 
 Twiddler's syndrome  is when the patient intentionally or accidentally turns the pacemaker on its 
longitudinal axis which can cause lead dislodgement. 
 Reel's syndrome  is Twiddler's syndrome but on the horizontal axis. 
 Pacemaker lead fracture 
 occurs in 1-4% of pacemakers 
 usually following excessive exercise or direct trauma.

  patient will require lead extraction and replacement.  
 myocardial rupture: 
 incidence is relatively small (<1%) 
 can be divided into early or late rupture with respect to the time it occurs following 
procedure. 
 Delayed perforations are less likely to cause such acute symptoms as well as a reduced 
incidence of tamponade and sudden cardiac death. 
 Risk factors for perforation include physician technique, patient independe nt factor (i.e

obesity or difficult anatomy) and lead design. 
 presenting features :pericardial effusion, haemodynamically compromised following 
pacemaker insertion and is likely to develop cardiac tamponade and needs urgent 
intervention with pericardiocentesis.  
 
Pacemaker syndrome 
 pacemaker syndrome 
 Loss of AV synchrony. 
 Retrograde VA conduction. 
 Absence of rate response to physiological need.

pacemaker syndrome (breathlessness associated with ventricular pacing in the context of normal a trial 
activity). 
 
VVI pacemaker will pace and sense the right ventricle. In the presence or organised atrial activity, a 
VVI pacemaker may pace the ventricles out of sync with the atria resulting in pacemaker synd rome. 
 
 pacemaker syndrome is related to nonphysiologic timing of atrial and ventricular contractions, 
which may occur in a variety of pacing modes

which may occur in a variety of pacing modes  
 also named as "AV dyssynchrony syndrome," 
 typically associated with a  VVI pacemaker  that results in simultaneous atria and 
ventricle conduction.  530

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  69 
  Risk factors 
 Sick sinus syndrome as have preserved AV conduction. 
 Single-chamber ventricular pacing. 
 Features 
 hypotension, tachycardia, tachypnoea,  
 dizziness, palpitations, syncope 
 Ventricular contraction against closed tricuspid and mitral valves can result in: 
 raised JVP (pulsation and fullness in the neck)

 cannon waves 
 Complications of AV dyssynchrony include: 
 atrial fibrillation,  
 thromboembolic events, and  
 heart failure. 
 What are the characteristic ECG findings associated with this syndrome? 
 Small P waves with dissociation from QRS complex 
 In patients with other pacing modes, upgrading the pacemaker to a dual-chamber pacing  
or reprogramming the pacemaker parameters  - eg, AV delay, post-ventricular atrial

refractory period, sensing level, and pacing threshold voltage. 
 
DC cardioversion in patients with pacemakers (eg : in AF)  
 DC cardioversion is not contraindicated in patients with pacemakers 
 Pacemaker function should be checked after cardioversion and antiarrhythmic therapy 
added  
 
Brugada syndrome 
 inherited cardiovascular disease with may present with sudden cardiac death.  
 autosomal dominant

 prevalence   1:5,000-10,000.  
 more common in Asians. 
 
 a large number of variants exist 
 around 20-40% of cases are caused by a mutation in the SCN5A gene which encod es the 
myocardial sodium ion channel protein 
ECG changes 
 convex ST segment elevation > 2mm in > 1 of V1-V3 followed by a negativ e T wave 
 partial right bundle branch block 
 changes may be more apparent following flecainide

ECG showing Brugada pattern, most marked in V1, which has an incomplete RBBB, a down sloping ST 
segment and an inverted T wave 
 
 implantable cardioverter-defibrillator 
531

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  70 
 Catecholaminergic polymorphic ventricular tachycardia (CPVT) 
 (CPVT) is a form of inherited cardiac disease associated with sudden cardiac death.  
 It is inherited in an autosomal dominant fashion  
  has a prevalence of around 1:10,000. 

 the most common cause is a defect in the ryanodine receptor (RYR2) which is found in the 
myocardial sarcoplasmic reticulum 
 uncontrolled calcium release from the sarcoplasmic reticulum 
 induced by adrenergic stress. 
Features 
 exercise or emotion induced polymorphic ventricular tachycardia resulting in syncope 
 symptoms generally develop before the age of 20 years 
 beta-blockers

 There is strong evidence that flecainide is effective when prescribed in addition to beta blockers  
 Left cervical sympathetic denervation 
 All first-degree relatives should be evaluated with ECG, Holter monitoring and exerci se stress 
testing. 
__________________________________________________________________________________________ 
Ventricular tachycardia 
 
 wide QRS complex (duration >120 milliseconds) at a rate greater than 100 bpm, originating f rom 
a ventricular ectopic focus.  
 Whilst a broad complex tachycardia may result from a supraventricular rhythm with 
aberrant conduction, the European Resuscitation Council advise that in a peri-arre st 
situation it is assumed to be ventricular in origin. 
 It has the potential to precipitate ventricular fibrillation and hence requires urgent treat ment.

 Among patients with prior MI  or non-ischaemic cardiomyopathy, VT is usually due to re-entry 
involving regions of slowed conduction adjacent to scar.  
 Post MI ventricular tachycardia (VT)  is most commonly due to scar tissue.  
 The definitive investigation would be  Electrophysiological study (EPS)  
 due to the fact that if this were scar related VT, the site could be localised and 
even possibly ablated.

even possibly ablated.  
 If not, then an implantable cardiac defibrillator (ICD) implantation may be 
warranted if left ventricular (LV) dysfunction exists. 
 MADIT-2 trial showed a 5.6% 20 month absolute survival benefit in 
patients with LV dysfunction (EF<30%), post MI, treated prophylactically 
with an ICD. 
 (VT) may also arise from triggered activity due to early after-depolarisations (EADs)  leading to

torsades de pointes, a polymorphic ventricular tachycardia seen in the setting of a prolonged  QT 
interval,  
532

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  71 
  delayed after-depolarisations (DADs),  which are seen in: 
  idiopathic right ventricular outflow tract VT or  
 catecholaminergic polymorphic VT 
 cellular abnormalities of calcium handling  Increased intracellular calcium  
predispose to VT. especially during periods of sympathetic stimulation.

  EADs occur during phase 2 or 3 of the action potential, whereas DADs occur during phase 4.  
 When an EAD or DAD reaches a 'threshold' potential, it can result in triggering of another actio n 
potential.  
 Ventricular tachycardia originates below the bundle of His. 
 
Types  
There are two main types of VT:  
 monomorphic VT:  
 organised, single-morphology QRS arising from one of the ventricles.  
 most commonly caused by myocardial infarction 
 polymorphic VT:

 polymorphic VT:  
 multiple different wide QRS morphologies arising from one of the ventricles.  
  results from abnormal myocardial repolarization. 
 A subtype of polymorphic VT is torsades de pointes  which is precipitated by prolongation 
of the QT interval. The causes of a long QT interval are listed below. 
Other classifications of VT 
 Sustained VT 
 A ventricular rhythm faster than 100 bpm lasting at least 30 seconds  or requiring 
termination due to haemodynamic instability.

termination due to haemodynamic instability.  
 almost always symptomatic. 
 Non-sustained VT 
 A ventricular rhythm faster than 100 bpm lasting for at least 3 consecutive beats but 
terminating spontaneously in less than 30 seconds , and not resulting in significant 
haemodynamic instability. 
 If these do not cause any haemodynamic compromise, treatment is not needed.   
 The most appropriate next step  Check potassium and magnesium levels

  During the GISSI-2 trial it was observed that a serum K+ level of <3.6 mmol/l was 
associated with a twofold increased risk of VF. Therefore serum K+ should be 
maintained >4 mmol/l by oral or intravenous (IV) supplementation in patients with 
acute MI. 
 Concomitant magnesium (Mg2+) deficiency is present in many patients with 
hypokalaemia and also makes correction of hypokalaemia difficult. Hence serum 
Mg2+ levels should also be checked and maintained >1 mmol/l. 
 Idiopathic VT

 Idiopathic VT 
 VT occurring in the absence of apparent structural heart disease  (e.g., ischaemia, prior 
infarction, cardiomyopathy, valvular disease, arrhythmogenic right ventricular 
cardiomyopathy, left ventricular non-compaction, or other disorders of the myocardium), 
known channelopathy  (e.g., long QT syndrome, Brugada syndrome, catecholaminergic 
polymorphic VT, short QT syndrome), drug toxicity , or electrolyte imbalance . 
 Outflow tract VT 
 A form of 'idiopathic' VT

 A form of 'idiopathic' VT  
 typically arises from the right ventricular outflow tract 
 results from cyclic A MP-mediated triggered activity; 
 uniquely sensitive to adenosine.  
 Fascicular VT 
 A common form of idiopathic VT  
 arising from the left ventricle, with re-entrant circuit partially involving the Purkinje fibres,  
 characteristically sensitive to verapamil. 
 
Feature 
 Patients may have a normal cardiac output or may be haemodynamically compromised

 Sustained VT is usually observed in ischaemic cardiomyopathy, but idiopathic VT may  also be 
observed in patients without structural heart disease. 
 jugular veins may show cannon A waves  due to atrioventricular dissociation. 
  
Differential diagnosis  533

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  72 
  Supraventricular tachycardia with bundle-branch block may resemble ventricular tachycardia on 
the ECG 
 Features suggesting VT rather than SVT with aberrant conduction 
 AV dissociation 
 fusion or capture beats 
 positive QRS concordance in chest leads ( (same polarity QRS direction in all chest leads 
V1 -V6)

V1 -V6) 
 marked left axis deviation 
 history of IHD 
 lack of response to adenosine or carotid sinus massage 
 very broad QRS > 160 ms 
 bifid upright QRS with a taller first peak in V1  
 deep S wave in V6  
 
Capture beats 
 intermittent narrow QRS complex owing 
to normal ventricular activation via the 
AV node  
 occurs when a supraventricular and a 
ventricular impulse coincide to produce a 
hybrid complex. 
 It indicates that there are two foci of

 It indicates that there are two foci of 
pacemaker cells firing simultaneously: a 
supraventricular pacemaker (e.g. the 
sinus node) and a competing ventricular 
pacemaker (source of ventricular 
ectopics). 
 Causes: 
 Ventricular tachycardia  
 Accelerated idioventricular rhythm 
(AIVR)  
fusion beats  
(intermediate between ventricular tachycardia 
beat and capture beat) are seen 
 
 VT with pulse  (not respond to medical treatment)  cardioversion (synchronized)

Pulseless VT or VF   DC (asynchronized) 
 
If the patient is unstable , and you can see a QRS-t complex use ( LOW ENERGY ) synchronized 
cardioversion.  
If the patient is pulseless , or if the patient is unstable and the defibrillator will not synchronize, 
use ( HIGH ENERGY ) unsynchronized  cardioversion (defibrillation). 
 
Synchronization avoids the delivery of a LOW ENERGY shock during cardiac repolarization (t-

wave). If the shock occurs on the t-wave (during repolarization), there is a high likelihood that 
the shock can precipitate VF (Ventricular Fibrillation). 534

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  73 
  
 If the patient has adverse signs  (systolic BP < 90 mmHg, chest pain, heart failure or rate > 150  
beats/min) then immediate cardioversion  is indicated.  
 anaesthetist needs to be called to assist with direct current cardioversion (DCCV) which 
should be 'synchronised' to limit the risk of conversion to VF.

 usually at a starting energy dose of 100 J (monophasic; comparable biphasic 
recommendations are not currently available). 
 If deteriorate in the meantime and become pulseless, then a precordial thump should be 
given, followed immediately by DCCV if not successful.  
 In cases of pulseless VT, the electrical cardioversion should be unsynchronized.  
 Amiodarone is the drug of choice for acute VT refractory to cardioversion shock.

 Unstable polymorphic VT is treated with immediate defibrillation. The defibrillator may  
have difficulty recognizing the varying QRS complexes; therefore, synchronization of 
shocks may not occur.  
 In stable patients (absence of adverse signs):  
 stable patients stable patients with monomorphic VT and normal LV function,  
 If LV function is impaired, amiodarone (or lidocaine) is preferred to procainamide

for pharmacologic conversion because of the latter drug ’s potential for exacerbating 
heart failure.  
 restoration of sinus rhythm is typically achieved with  IV pro cainamide , 
amiodarone , or sotalol .  
 If LV function is impaired , amiodarone (or lidocaine) is preferred to procainamide for 
pharmacologic conversion because of the latter drug ’s potential for exacerbating heart 
failure.  
 In the absence of such signs antiarrhythmics may be used. If these fail, then elec trical

cardioversion may be needed with synchronised DC  shocks 
 If medical therapy is unsuccessful, synchronized cardioversion (50-200 J monophasic) 
following sedation is appropriate. 
 prophylactic implantable cardioverter defibrillator implantation is recommended in high-risk 
patients. 
 Polymorphic VT in stable patients 
 typically terminates on its own.  
 
 Unsynchronized Synchronized 
When to deliver electricity At any point in cycle Not during the T-wave

Indications V-fib, pulseless VT Everything except V-fib and pulseless VT 
 
Verapamil is contra-indicated in VT because it can cause a catastrophic fall in blood pressure.  
 
 amiodarone: ideally administered through a central line 
  (i.e. given after the third shock).  If amiodarone is not available lidocaine is a suitable 
alternative. 
 lidocaine: use with caution in severe left ventricular impairment 
 procainamide

 procainamide 
 Adenosine is useful diagnostically when the diagnosis of regular wide complex tachy cardia is in 
doubt. 
 Verapamil should NOT be used in VT 
 
Sotalol is recommended as the first-choice drug to prevent a recurrence of ventricular 
tachycardia (VT) 
 
If drug therapy fails  
 electrophysiological study (EPS) 
 implant able cardioverter-defibrillator (ICD) - this is particularly indicated in patients with 
significantly impaired LV function 
C.V Resuscitation:

C.V Resuscitation:  
 Guidelines from the Resuscitation Council (UK) state that if a patient has a monitored  and 
witnessed VF/VT arrest in hospital, three quick successive (stacked) shocks should be given. 
Chest compressions should be started immediately after the third, with a compression to 
ventilation ratio of 30:2 for 2 minutes. 535

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  74 
  A precordial thump can be successful if given within seconds of the onset of a shockable 
rhythm.  Delivery should not delay calling for help, or accessing a defibrillator, but would be 
indicated here whilst awaiting the defibrillator. Chest compressions should start immediately if it 
is unsuccessful.

is unsuccessful. 
 Intravenous adrenaline would be given every 3-5 minutes once chest comp ressions had started. 
 
P-wave asystole  
 Occasionally, atrial electrical activity continues in the absence of ventricular impulses.  
 This is referred to as P-wave asystole and may respond to electrical pacing.  
 initial treatment of choice   pacing (transvenous, transcutaneous or manual techniques) .

 Transvenous pacing takes longer to instigate, and transcutaneous pacing is therefore 
the initial choice here.  
 Manual pacing is an effective holding measure before more definitive pacing is instituted.  
QT interval 
 
 QT measured from the start of the QRS complex to the end of the T wave 
 represents the duration of activation and recovery of the ventricular myocardium

 Normal duration   should be between 0.33 and 0.44 seconds 
 Corrected QT interval (QTc)  is calculated by dividing the QT interval by the square root of the 
preceding R - R interval. Normal = 0.42 s. 
 
536

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  75 
  
Long QT syndrome 
 Long QT syndrome (LQTS) is an inherited condition associated with delayed repolarization of t he 
 A normal corrected QT interval is less than 430 ms in males and 450 ms ( 0.45 s ) in females. 
 One large box represents 200 ms , one small box represents 40 ms 
Mechanism

Mechanism  
 
 the usual mechanism by which drugs prolong the QT interval is blockage of potassium ch annels 
  delayed repolarization of the ventricles.  
 Most drugs that prolong the QT c interval act by blocking hERG -encoded potassium 
channels , although some drugs modify sodium channels.  
 The most common variants of LQTS (LQT1 & LQT2) are caused by defects in the  alpha subunit 
of the slow delayed rectifier potassium channel.  
 more common in females.

 more common in females. 
 
 LQT1 LQT2 LQT3 
Gene  KCNQ1 KCNQH2/ hERG SCN5A 
Iron  Ks (redifier potassium 
current, slow 
component)  Kr (redifier potassium 
current, rapid component)  Na 
Pathophysiology  Decreased potassium 
outward current Decreased potassium 
outward current excessive sodium inward 
current 
Triger of 
arrhythmia  Exercise stress Emotional stress Rest  
Occurrence  > 50% 34 – 40% 10 – 15% 
 
Causes of a prolonged QT interval

Causes of a prolonged QT interval  
 
Anti-arrhythmics  Antihistamines  Anti-
infectives  Antimalarials  
Amiodarone 
Disopyramide 
Dofetilide 
 Ibutilide  
Procainamide 
Quinidine 
Sotalol 
 Astemizole 
Terfenadine 
 Clarithromycin 
Erythromycin 
Pentamidine 
Sparfloxacin Chloroquine 
Halofantrine 
Antipsychotics  Gastro-intestinal drugs  Opiate 
agonists  Other drugs  
Chlorpromazine 
Haloperidol 
Mesoridazine 
Pimozide 
Thioridazone 
 Cisapride*  
Domperidone Levomethadyl

Cisapride*  
Domperidone Levomethadyl 
Methadone tricyclic 
antidepressants, 
fluoxetine  
Arsenic trioxide 
Bepridil 
Droperidol 
Probuco 
Congenital Other conditions 
537

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  76 
 Jervell-Lange-
Nielsen syndrome 
(includes deafness 
and is due to an 
abnormal 
potassium channel)  
Romano-Ward 
syndrome  (no 
deafness)   Electrolyte s: 
 hypocalcaemia 
 hypomagnesaemia 
 acute myocardial infarction 
  myocarditis 
  hypothermia 
  subarachnoid haemorrhage

  subarachnoid haemorrhage  
 
 *Cisapride have been withdrawn worldwide due to risk of QT prolongation 
 Jervell-Lange-Nielsen syndrome:  
 includes deafness  and is due to an abnormal potassium channel 
 autosomal recessive  
 caused by Mutations in the KCNE1 and KCNQ1 genes  
 Mutations in the KCNE1 and KCNQ1 genes  abnormal potassium channel  
abnormal functions of inner ear  structures and cardiac muscle . 
 Roma no-Ward syndrome :

 Roma no-Ward syndrome : 
 congenital long QT syndrome   
 autosomal dominant   
 involves only cardiac (no deafness ) 
 The human  ether-à- go-go related gene (hERG)  is the gene affected by drugs that lengthen QT 
interval inadvertently; erythromycin, terfenadine, and ketoconazole. 
 a non-sedating antihistamine are classic cause of prolonged QT in a patient, especially if  also 
taking P450 enzyme inhibitor, e.g. Patient with a cold takes terfenadine and erythromy cin at the

same time 
 
Features 
 
 may be picked up on routine ECG or following family screening 
 Long QT1 - usually associated with exertional  syncope , often swimming 
 Long QT2 - often associated with syncope occurring following emotional stress, e xercise or 
auditory stimuli 
 Long QT3 - events often occur at night or at rest 
 
Diagnosis 
 corrected QT interval  
 Diagnosis is based upon the QTc (corrected QT interval),

 QTc may be within the normal range at rest; hence Holter ECG monitoring  is 
recommended. 
 genetic testing of LQTS  
 Identification of an LQTS genetic mutation confirms the diagnosis.  
 However, a negative result on genetic testing is of limited diagnostic value because only 
approximately 50% of patients with LQTS have known mutations. The remaining half  of 
patients with LQTS may have mutations of yet unknown gene.  Therefore genetic testing of

LQTS has high specificity but a low sensitivity. 
 
 may lead to ventricular tachycardia  collapse/sudden death.  
 
Congenital long QT syndrome:  
 Beta-blockers  
 Beta-blockers are first-line  (commonly Propranolol) (The most appropriate initial 
treatment)  
538

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  77 
  Beta blockers alone are enough to abate collapses in up to 70% of patients. 
 Beta blockers act by: 
1. decrease sympathetic activation from the left stellate ganglion,  
2. also decrease the maximal heart rate achieved during exertion and thereby prevent 
exercise-related arrhythmic events that occur in LQTS.

 should be avoided in those congenital cases in which bradycardia is a prominent feature.  
 note sotalol may exacerbate long QT syndrome (due to blockage of K channel). This can 
be a particular risk in individuals with hypokalaemia. Therefore  Sotalol is better to be 
avoided in patients with thiazide diuretics.   
 patients who remain symptomatic despite receiving the maximally tolerated dose of beta -
blockers   Permanent pacing , and can be used in addition to beta-blockers.

 patients who remain refractory to beta-blockade and pacing  High left thoracic 
sympathectomy   
 Implantable cardioverter-defibrillators (ICDs)  are useful in rare instances when torsades still 
continues despite all of these treatments. 
 Beta-blockers should be used along with ICDs because shock can further precipitate torsade s by 
adrenergic stimulation. 
 Left stellate cardiac ganglionectomy  is an invasive procedure and results in Horner ’s

syndrome. It is performed in patients who have symptoms despite βB and have freq uent shocks 
with ICD. 
Acquired long QT syndrome:  
 avoid drugs which prolong the QT interval  and other precipitants if appropriate (e.g. 
Strenuous exercise) 
 Long -term treatment in acquired cases is usually not required because the QT interval r eturns to 
normal once the predisposing factor has been corrected.  
 Correction of any electrolyte disturbance

 Correction of any electrolyte disturbance  
 Due to the pseudo-obstruction  it is very likely that the patient is hypokalaemic and as 
such this is the first reversible aetiology for the non-sustained VT  that needs to be 
investigated  
  Check electrolytes  
 Checking Magnesium would also be an appropriate step. 
 Beta-blockers are contra-indicated in acquired cases  because bradycardia produced by

these agents can precipitate torsades. They should also be avoided in those congenita l cases in 
which bradycardia is a prominent feature. 
 Pacemaker implantation is effective in cases that are associated with heart block or bradycardia. 
 ICDs are indicated in cases that cannot be managed by avoidance of any specific precip itating 
factor. 
 
QT shortening: caused by:  
 Hypercalcaemia  
 Hypermagnesaemia 
 Digoxin 
 Thyrotoxicosis.

 Digoxin 
 Thyrotoxicosis.  
  
January 2013 exam: A patient  develops torsades de pointes shortly after being started on sotalol. 
What effect does sotalol have on the cardiac cell membrane to make this more likely?  Blockage of 
potassium channels  prolonged QT interval.  
 
Torsades de pointes  (TdP) 
 Torsades de pointes ('twisting of the points') is a rare arrhythmia associated with a long QT

interval.  
 It may deteriorate into ventricular fibrillation and hence lead to sudden death 
 In its most typical form, sudden slowing of heart rate (i.e., pauses) invariably precede each b urst 
of TdP, and the recurrent arrhythmia is referred to as “pause-dependent TdP ” 
 Risk factors  539

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  78 
  Female sex  
 causes of QT prolongation, 
 R-on-T phenomenon  
 the R-wave, representing ventricular depolarization, occurs during the relative 
refractory period at the end of repolarization (represented by the latter half of the T-
wave).  
 Long QT intervals predispose the patient to an R- on-T phenomenon,

 R-on-T can initiate torsades.   
 bradycardia,  
 congestive heart failure,  
 digitalis therapy,  
 severe alkalosis  
 recent conversion from atrial fibrillation.  
 Stop all drugs which prolong QT 
 Correct any electrolyte abnormalities 
  IV magnesium sulphate  (MgSo4)  
 the best initial drug 
 Mode of action: MgSo4  ↓ Ca influx Ļ amplitude of the VT and helping 
terminate runs of torsade ’s.

terminate runs of torsade ’s.  
 Dose : 2 gm as bolus over 10 minutes, followed by another bolus in 15 minutes if 
required, or continuous infusion at a rate of 5-20 mg/min. 
 It is effective even when serum magnesium level is normal.  
 Temporary pacemaker/transvenous overdrive pacing (atrial or ventricular)  
 reserved for patients with long QT-related TdP who do not respond to intravenous 
magnesium. 
 Isoproterenol

 Isoproterenol 
 usually used as a temporizing measure prior to pacing in patients who have failed 
to respond to magnesium and are awaiting placement of a temporary 
pacemaker.  
 Action  Strong beta-1 & beta-2  stimulation 
  
Peri-arrest rhythms: tachycardia  (The 2010 Resuscitation Council (UK) guidelines)

 patients are classified as being stable or unstable  according to the presence of any adverse 
signs: 
 shock: hypotension (systolic blood pressure < 90 mmHg), pallor, sweating, cold, clammy 
extremities, confusion or impaired consciousness 
 syncope 
540

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  79 
  myocardial ischaemia 
 heart failure 
 If a patient is unstable  synchronised cardioversion 
 For a broad-complex tachycardia or atrial fibrillation, start with 120 –150 J and 
increase in increments if this fails. 
 Atrial flutter and regular narrow-complex tachycardia will often be terminated by

lower energies: start with 70 –120 J. 
 
 If cardioversion fails : 
 give amiodarone 300 mg IV over 10 –20 min and re-attempt electrical cardioversion.  
 The loading dose of amiodarone may be followed by an infusion of 900 mg ov er 24 
h. 
 If the patient is stable: 
 Regular broad-complex tachycardia  (QRS duration is 0.12 s or greater (3 small squares 
on standard ECG paper speed of 25 mm s-1)  
 ventricular tachycardia (VT)  amiodarone 300 mg IV over 20 –60 min, followed by

an infusion of 900 mg over 24 h  
 or a regular supraventricular rhythm with bundle branch block. 
 assume ventricular tachycardia (unless previously confirmed SVT with bundle 
branch block) 
 
 Irregular broad-complex tachycardia  
 (most likely due to atrial fibrillation (AF) with bundle branch block)  
 Other possible causes: 
 AF with ventricular pre-excitation (in patients with Wolff-Parkinson-White 
[WPW] syndrome),

[WPW] syndrome),  
 or polymorphic VT (e.g. torsade de pointes),  but sustained polymorphic 
VT is unlikely to be present without adverse features. 
 stop all drugs known to prolong the QT interval. 
 Correct electrolyte abnormalities, especially hypokalaemia.  
 Give magnesium sulfate 2 g IV over 10 min (= 8 mmol, 4 mL of 50% 
magnesium sulfate). 
 Do not give amiodarone for definite torsade de pointes. 
 If adverse features are present, which is common, arrange immediate

synchronised cardioversion. 
 Regular narrow-complex tachycardias include:  
 sinus tachycardia 
 In a sick patient it may occur in response to many conditions including pain, 
infection, anaemia, blood loss, and heart failure. 
 Treatment is directed at the underlying cause. 
 Trying to slow sinus tachycardia that has occurred in response to most of 
these conditions will usually make the situation worse. 
 AV nodal re-entry tachycardia (AVNRT) – the commonest type of regular

narrow-complex tachyarrhythmia 
 The usual cause is the presence of dual AV nodal pathways (slow and fast 
pathways within the AV node). 
 Vagal manoeuvres could be attempted to cardiovert the patient. If it fails, the 
use of IV adenosine in the presence of appropriate resuscitation facility 
would be appropriate.  
 Ensure that the patient is being monitored whilst adenosine is given so the 
underlying rhythm canbe captured. This cansometimes uncover underlying

atrial flutter when the rate slows. 
 In cocaine overdos e. 
 Calcium antagonists such as verapamil are the initial pharmacological 
therapy of choice if cardioversion does not work as beta blockade 
may lead to worsening of myocardial ischaemia in the context of 
cocaine overdose. 
 AV re-entry tachycardia (AVRT) – due to WPW syndrome 
 atrial flutter with regular AV conduction (usually 2:1).  
 Typical atrial flutter has an atrial rate of about 300 min-1, so atrial flutter with

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  80 
   Much faster rates (>160 min-1) are unlikely to be caused by atrial flutter with 
2:1 conduction. 
 If the patient is unstable  synchronised electrical cardioversion.  
 It is reasonable to apply vagal manoeuvres and/or give adenosine while 
preparations are being made urgently for synchronised cardioversion.

 In the absence of adverse features:  
 Start with vagal manoeuvres. Carotid sinus massage or the Valsalva 
manoeuvre will terminate up to a quarter of episodes of paroxysmal SVT. 
 If the arrhythmia persists, give adenosine 6 mg as a rapid IV bolus. Use a 
relatively large cannula and large (e.g. antecubital) vein. 
 If there is no response give a 12 mg IV bolus.  
 If there is no response give one further 12 mg IV bolus.

 Apparent lack of response to adenosine will occur if the bolus is given too 
slowly or into a peripheral vein. 
 Termination of a regular narrow-complex tachycardia in these ways (Vagal 
manoeuvres or adenosine) identifies it as being AVNRT or AVRT.  
 Failure to terminate a regular narrow-complex tachycardia with adenosine 
suggests an atrial tachycardia such as atrial flutter (unless the adenosine 
has been injected too slowly or into a small peripheral vein).

 If adenosine is contra-indicated, or fails to terminate a regular narrow-
complex tachycardia without demonstrating that it is atrial flutter, consider 
giving verapamil 2.5 –5 mg IV over 2 min. 
 Irregular narrow-complex tachycardia is most likely to be AF or sometimes atrial flutter 
with variable AV conduction ( ‘variable block ’). 
 most likely due to AF with an uncontrolled ventricular response  
 or, less commonly, atrial flutter with variable AV block.

 If the patient is unstable  start antithrombotic therapy and attempt synchronised 
cardioversion. 
 patients who have been in AF for more than 48 h should not be treated by 
cardioversion (electrical or chemical) until they have been fully anticoagulated for at 
least three weeks, or unless trans-oesophageal echocardiography has shown the 
absence of atrial thrombus. 
 Continue anticoagulation after attempted cardioversion, whether or not it is

successful, which should be a minimum of four weeks 
 If the aim is to control heart rate: 
 the usual drug of choice is a beta-blocker. 
 Diltiazem or verapamil may be used in patients in whom beta-blockade is 
contraindicated or not tolerated. 
 Digoxin or amiodarone may be used in patients with heart failure. 
 Amiodarone may be used to assist with rate control but is more useful in 
maintaining rhythm control.

maintaining rhythm control. 
 management of tachyarrhythmia in pregnancy  Vagal manoeuvres followed by adenosine  
 The most common tachyarrhythmias in pregnancy are AV nodal re-entrant tach ycardia 
 As in the non-pregnant population, vagal manoeuvres should be tried first. 
 If these are unsuccessful, as in approximately 75% of cases, adenosine is the next step.  
 Adenosine is safe in pregnancy  
 Verapamil should not be used in the first trimester.

 Some beta blockers can be used in pregnancy - there is small risk of fetal bradycardia and 
intrauterine growth retardation. 
 Amiodarone should be avoided unless no alternative. 
 
Peri-arrest rhythms: bradycardia 
The 2010 Resuscitation Council (UK) guidelines emphasise that the management of bradycardia 
depends on:

depends on: 
 1. identifying the presence of signs indicating haemodynamic compromise - 'adverse signs' 
 2. identifying the potential risk of asystole 
Adverse signs  
the following factors indicate haemodynamic compromise and hence the need f or treatment: 
 shock: hypotension (systolic blood pressure < 90 mmHg), pallor, sweating, cold, clammy 
 syncope 542

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  81 
  myocardial ischaemia 
Treatment 
 Atropine is the first line treatment in this situation.  
 If this fails to work, or there is the potential risk of asystole then transvenous pacing is ind icated   
 Emergency  temporary transvenous pacing wire is the next most important

treatment  with the situation of inferior MI  until the MI fully resolved. Conduction block 
can recover in the next few days so a permanent pacemaker may not be required 
 
Potential risk of asystole  
the following indicate a potential risk of asystole and hence the need for treatment with  transvenous 
pacing: 
 complete heart block with broad complex QRS 
 recent asystole 
 Mobitz type II AV block 
 ventricular pause > 3 seconds

 ventricular pause > 3 seconds 
If there is a delay in the provision of transvenous pacing the following interventions may b e used: 
 atropine, up to maximum of 3mg 
 transcutaneous pacing 
 Transcutaneous is the same as external pacing (via pads); it is terrible for the patien t and 
should only be used as a holding measure in emergency. transvenous is via the femoral 
or internal jugular vein. 
 adrenaline infusion titrated to response

 adrenaline infusion titrated to response 
 
bradycardia-induced syncope  in a cardiovascularly stable patient: 
if  the diagnosis is not certain in  bradycardia-induced syncope  and  cardiovascularly stable Wha t is 
the most appropriate next step in management?   observation as an inpatient with suitable heart 
rate monitoring is the best answer (Admit and arrange monitored telemetry with printing )  
 Outpatient observation is not appropriate given the syncopal episode.

 Although this patient is likely to require a permanent pacemaker at some stage, 
emergency temporary wire is not indicated unless patient has recurrent syncope due t o 
bradycardia or complete heart block.  
 Because the patient is cardiovascularly stable a temporary wire, atropine or carotid 
sinus massage are not required. 
 
Adult advanced life support

Adult advanced life support 
The joint European Resuscitation Council and Resuscitation Council (UK) 2010 guidelines do no t alter 
significantly from the 2005 guidelines.  
 
Major points include:  
 Immediately after the first shock (and each subsequent shock) chest compressions 
should be restarted immediately and pulse and rhythm reassessed after two minutes. 
 After each shock chest compressions should be restarted immediately before anything 
else is done.

else is done.  
 ratio of chest compressions to ventilation is 30 :2 
 chest compressions are now continued while a defibrillator is charged 
 during a VF/VT cardiac arrest, adrenaline 1 mg is given once chest compressions have 
restarted after the third shock  and then every 3-5 minutes (during alternate cycles of CPR). In 
the 2005 guidelines, adrenaline was given just before the third shock.

 Amiodarone 300 mg is also given after the third shock .  it should be after adrenaline has been 
administered. 
 A 1 mg dose of adrenaline (epinephrine) would be administered with: 
 0.1 ml of 1 in 100,  
 1 ml of 1 in 1000 and  
 10 ml of 1 in 10,000. 
 10 ml of 1 in 10,000 is the recommended dose and concentration  by the UK Resuscitation 
Council. 
 If not able to gain any venous access  Obtain intraosseous access

 Intraosseous access is a safe and effective method of administering drugs in 
cardiac arrest; it provides adequate plasma levels of drugs and allows equivalent 
flow rates to IV access. 543

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  82 
  Therefore if IV access cannot be gained within two minutes, IO access should be 
attempted (if trained). Tibial or humeral sites should be tried first. 
 atropine is no longer recommended for routine use in asystole or pulseless 
 Refractory VF  
 Magnesium sulphate IV is recommended for the treatment of refractory VF , if

there is anything to suggest the patient may be hypomagnesaemic (such as on 
medications which might cause this, that is, thiazides ). 
 There is no indication for increasing doses of adrenaline or amiodarone, or increasing 
shock energy. 
 Amiodarone can be given again but this should be at the reduced dose of 150 mg . 
 Lidocaine is only recommended if amiodarone is unavailable, and/or has not already been  
given. 
 Management of a patient post cardiac arrest

 Management of a patient post cardiac arrest  
 The first step in post-cardiac arrest care is to give aspirin and clopidogrel.  This can 
usually be achieved quickly and easily whilst other investigations and treatments are 
organised. 
 Maintain glucose <10 mmol/L  (due to increased hypoglycaemia). 
 oxygen saturations should be kept at 94-98%, not 100%.  (Hyperoxaemia (and hypoxia) is 
also associated with poor outcomes)

also associated with poor outcomes) 
 The oxygen dissociation curve is shifted to the right in acute acidosis, i.e. 
haemoglobin has a decreased affinity for oxygen. 
 High pulmonary pressures  would be expected after arrest  scenario, as the 
pulmonary arterioles constrict in response to hypoxia.  
 The use of brief periods of echo (FAST scan) (10 seconds) is now supported in an  arrest 
situation (but should be performed at the end of two minutes of compressions).  
 precordial thump

 precordial thump   
 A precordial thump can be successful if given within seconds of the onset of a shockable 
rhythm.  
 Delivery should not delay calling for help, or accessing a defibrillator, but would be 
indicated here whilst awaiting the defibrillator.  
 Chest compressions should start immediately if it is unsuccessful.  
 Only one thump should be delivered over the lower third of the sternum.

 The ulnar edge of a tightly clenched fist is used to deliver a sharp impact from a  height of 
about 20 cm, then retract immediately (thereby creating an impulse-like stimulus). 
  Repeating a precordial thump is not recommended. 
 It is important to remember that a precordial thump has a very low success rate for 
 In general it delivers approximately 7-10 joules of energy, but this is operator depen dent 
and references vary to this regard.

and references vary to this regard. 
  There is more success with pulseless VT than with VF. 
 
Electrical activity (PEA). 
 a single shock for VF/pulseless VT followed by 2 minutes of CPR, rather than a series of 3 
shocks followed by 1 minute of CPR 
544

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  83 
  asystole/pulseless-electrical activity should be treated with 2 minutes of CPR, rather than 3, p rior 
to reassessment of the rhythm 
 (PEA)  pulseless with no respiratory effort .ECG reveals small complexes with a 
normal morphology  CPR + Adrenalin 1mg repeated every 3-5 minutes

 In the presence of a non-shockable rhythm, the use of adrenaline (1mg) every alte rnate 
cycle of CPR is recommended. It should be given once IV or IO access is attained. 
  Adrenaline use is still recommended in pulseless electrical activity (PEA)  and asystole, 
every 3-5 minutes (alternate cycles of cardiopulmonary resuscitation (CPR)), and in 
ventricular fibrillation (VF)/ventricular tachycardia (VT) which is non-responsive to 
shocking, also every 3-5 minutes.

shocking, also every 3-5 minutes. 
 delivery of drugs via a tracheal tube is no longer recommended 
 following successful resuscitation oxygen should be titrated to achieve saturations of 94- 98%. 
This is to address the potential harm caused by hyperoxaemia 
Defibrillation 
 Defibrillation is used to convert ventricular fibrillation to sinus rhythm  
 The recommendation is initially a 360-joule shock 
 
Cardiac arrest in profound hypothermia

Cardiac arrest in profound hypothermia  
 Cardiac arrest in profound hypothermia has several differences from cardiac arrest in 
normothermic patients.  
 Prolonged cardiopulmonary resuscitation is likely to be required 
 At core temperatures of less than 30°C, treatment of ventricular arrhythmia with medical 
therapy is largely ineffective, and electrical cardioversion is less effective than in normotensive

patients. For this reason, a prolonged period of CPR may be required until core temperature is 
above 30ºC. 
 Between 30 –35 °C, the intervals between drug doses should be doubled when compared with 
normothermia intervals.  
 In hypothermic arrest, drugs are less effective - metabolism is slowed and there is the 
possibility of accumulation to toxic levels - and prolonged resuscitation with re-warming 
is the management of choice.

is the management of choice. 
 Recovery with intact neurology has been reported even after very prolonged arrests, there fore 
resuscitation should be continued for far longer than would normally be considered. 
 Hypothermic patients do not respond well to shocks or drugs and if there is no response to 
the first three shocks the patient should be rewarmed to at least 32°C before any drugs 
or shocks are administered.

or shocks are administered.  
 defibrillation can be tried up to three times but should then not be tried until th e 
temperature reaches 30°C. 
 Serious consideration should be given to cardiopulmonary bypass in a patient s uch as this. 
 There is no place for 0.5 mg IV adrenaline in adult cardiac arrest.  
 A half dose of amiodarone is indicated after the fifth, not the third s hock. 
 
Lance-Adams syndrome 
 is a rare condition that can occur following a period of cerebral hypoxia.

 Onset occurs within days to weeks of cardiac arrest .  
 It is characterised by intention myoclonus .  
 Although no trials on effective treatment have been conducted, levetiracetam, clo nazepam 
and valproate have been recommended as first-line treatments. 
 
Management of cold water drowning 
 The management of patients who nearly drown in cold water is quite different fr om that for 
routine cardiopulmonary arrests. 
 Mechanism of circulatory collapse:

 Mechanism of circulatory collapse: 
 Head-out upright immersion in water at body temperature results in a 32 –66% increase in 
cardiac output because of the pressure of the surrounding water 545

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  84 
  Resistance to circulation is suddenly removed as the person leaves the water, which when 
added to venous pooling, can cause circulatory collapse. This is believed to be the  cause 
of death in many individuals 
 To counter this effect, patients should be lifted out of the water in the prone position

 Re-warming  such patients should be undertaken in a hospital that has extracorporeal re-
warming facilities 
 Defibrillation is ineffective if the myocardium is cold. 
 Hypothermia may render the carotid pulse impalpable  so it is important to commence 
chest compression with firm evidence of cardiac arrest. 
 Continuous chest compression should be applied throughout transportation, which is as effectiv e 
as chest compression with expired air resuscitation

 Electrocardiographic monitoring should be available 
 
Wolff-Parkinson White (WPW)  
 congenital accessory conducting pathway between the atria and ventricles leading to a  
atrioventricular re-entry tachycardia (AVRT).  Ventricular pre-excitation  
 due to a congenital accessory cardiac conduction pathway, called the bundle of Kent , that

connects the atria to the ventricles, enabling electrical activity to bypass the atrioventricular 
node.  
 As the accessory pathway does not slow conduction AF can degenerate rapidly to VF 
 Most patients are asymptomatic .  
 WPW presents as SVT that can alternate with ventricular tachycardia (VT).  
 SVT is the most common type of tachycardia seen in a patient with WPW .  
 The other main clue to the diagnosis is  worsening of SVT after the use of calcium blockers or

digoxin  
Possible ECG features includ e: 
 short PR interval 
 wide QRS complexes with a slurred upstroke - 'delta wave' (can be associated with negative  
delta waves in II, III and aVF) 
 ECG in sinus rhythm reveals right bundle-branch block 
 left axis deviation if right-sided accessory pathway* 
 *in the majority of cases or in a question without qualification, Wolff-Parkinson-White synd rome is 
associated with left axis deviation

associated with left axis deviation  
 right axis deviation if left-sided accessory pathway 
 non-specific ST-T changes which are common in WPW and may be mistaken for ischaemia.  
 
ECG showing short PR interval associated with a slurred upstroke (delta wave).  Note the non-specific ST- T 
changes which are common in WPW and may be mistaken for ischaemia. The left axis deviation means that this 
is type B WPW, implying a right-sided pathway 
546

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  85 
  
Differentiating between type A and type B** 
 type A  (left-sided pathway): dominant R wave in V1 
 type B  (right-sided pathway): no dominant R wave in V1 
 In type B pre-excitation, the accessory pathway connects the right atrium to  the right 
ventricle

ventricle 
 **there is a rare type C WPW, WPW in which the delta waves are upright in leads V1-V4 b ut 
negative in leads V5- V6 
Associations of WPW 
 HOCM 
 Ebstein's anomaly  
 thyrotoxicosis 
 secundum ASD 
 Leber's hereditary optic neuropathy (mitochondrial disease) 
 WPW is diagnosed with finding a delta wave on the EKG.  
 The most accurate test is electrophysiologic studies 
 
 asymptomatic : (incidentally found delta wave on ECG)  Reassurance  
 Asymptomatic in high-risk professions (eg pilots) is best managed by catheter ablation of 
the accessory pathway 
 asymptomatic WPW in someone with a family history of sudden cardiac death is another 
indication for radiofrequency catheter ablation 
 definitive treatment: radiofrequency ablation of the accessory pathway 
 first-line therapy  
 Risk of arrhythmia after ablation is 7% over five years.

 medical therapy: flecainide , amiodarone, sotalol***  
 The most appropriate pharmacological management  Flecainide.  
 is a sodium channel blocker (Class Ic anti-arrhythmic) which will reduce the 
excitability of the atrial and ventricular myocardium without AV nodal blockade.  
 ***sotalol should be avoided if there is coexistent atrial fibrillation as prolonging the 
refractory period at the AV node may increase the rate of transmission through the

accessory pathway, increasing the ventricular rate and potentially deteriorating into 
ventricular fibrillation. 
 AV nodal blocking drugs should be avoided ( verapamil (the most contra-indicated )  , 
Adenosine, Beta-blockers) 
547

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  86 
  This is because blocking the AV node may enhance the rate of conduction through 
the accessory pathway, causing atrial fibrillation to degenerate into ventricular 
fibrillation (VF). 
  Digoxin and verapamil are contraindicated  as they increase conduction in the 
bypass tract 
 
Lown –Ganong –Levine (LGL) syndrome:

Lown –Ganong –Levine (LGL) syndrome: 
LGL syndrome is like WPW in the sense that it is a pre-excitation syndrome. However, the ECG 
changes present is only short PR interval without delta waves or abnormal QRS complex. 
 
Implantable cardiac defibrillators (ICD) 
 Congenital long QT with family history of sudden cardiac death at young age.

 hypertrophic obstructive cardiomyopathy (HOCM)  
 previous cardiac arrest due to VT/VF 
 Sustained VT causing haemodynamic compromise   
 previous myocardial infarction with non-sustained VT on 24 hr monitoring, inducible VT on  
electrophysiology testing and ejection fraction < 35% 
 Brugada syndrome 
 Arrhythmogenic right ventricular cardiomyopathy causing cardiac arrest. 
 
Acute pericarditis 
 Pericarditis is one of the differentials of any patient presenting with chest pain. 
 Between 15 and 30% of patients with idiopathic acute pericarditis may have recurrent a ttacks , 
and this is considered to be an autoimmune phenomenon. 
Features  
 Pleuritic chest pain  
 exacerbated by inspiration and lying flat, 
 relieved by sitting up and leaning forwards  
 shoulder pain (referred pain) 
 pericarditis is innervated by phrenic nerve 
 pericardial rub

 pericardial rub 
 the pathognomic feature  
 present in 50% of cases. 
 tachypnoea 
 other symptoms include non-productive cough, dyspnoea and flu-like symptoms 
Types and causes 
 Fibrinous pericarditis  
  the most common type 
 Causes:  
 acute myocardial infarction (MI), 
 more common than dressler syndrome  
 friction rub is more common than pain  
 may be heard within 24 hours and as late as 10 days.

 Aspirin is the only NSAID that can be used in pericarditis complicating MI. 
 post MI (Dressler syndrome),  
  rare 
 autoimmune-mediated phenomenon to myocardial antigens 
 occur 2 – 4 weeks post MI 
 Because of the risk of hemorrhagic pericarditis, anticoagulant therapy should 
be stopped in patients with Dressler syndrome. 
 uremia,  
 radiation,  Pericardial diseases  548

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  87 
  RA, SLE, 
 Trauma, 
 Severe infections  
 Serous pericarditis 
  usually caused by noninfectious inflammation such as: 
 rheumatoid arthritis (RA)  
 systemic lupus erythematosus (SLE).  
 Fibrous adhesions rarely occur. 
 Purulent or suppurative pericarditis

 Purulent or suppurative pericarditis  
 Most commonly caused by staphylococcal and gram-negative species, 
 high percentage of patients develop constrictive pericarditis. 
 Hemorrhagic pericarditis 
 involves blood mixed with a fibrinous or suppurative effusion,  
 most commonly caused by: 
 tuberculosis  
 direct neoplastic invasion.  
 severe bacterial infections  
 bleeding diathesis, 
 cardiac surgery or trauma  
 (may cause tamponade).  
 Caseous pericarditis

 Caseous pericarditis 
 caseation within the pericardial sac is tuberculous in origin, until proven otherwise ,  
 In tuberculous pericarditis, fever, night sweats, and weight loss are commonly noted 
(80%). 
 Untreated, caseous pericarditis is the most common antecedent to chronic 
constrictive pericarditis of a fibrocalcific nature. 
 Approximately 50% of affected patients develop constrictive pericarditis . 
 
 Uremic pericarditis

 Uremic pericarditis  
 result from inflammation of the visceral and parietal layers of the pericardium by metab olic 
toxins 
  blood urea nitrogen (BUN) level is usually greater than 60 mg/dL (22 mmol/L). 
 Hemorrhagic effusions  are more common  and result in part from uremia-induced 
platelet dysfunction.  
 does not present with the classic diffuse ST-elevations seen on ECG as in other types 
of pericarditis.  
 Uremic pericarditis is an indication for urgent hemodialysis.

 2 types of pericarditis in patients with renal failure: 
 uremic pericarditis 
 occurs in patients with uremia who have never received dialysis. 
 dialysis-associated pericarditis,  
 occurs in patients who are already receiving dialysis.  
 The usual cause   inadequate dialysis, because aggressive dialysis often 
leads to resolution. 
 intensive dialysis is the most effective treatment for dialysis-
associated pericarditis 
 Other causes: 
 volume overload

 volume overload  
 bacterial or viral infections 
 
Other causes 
 acute viral pericarditis  
 Viral infection is the most common cause of acute pericarditis 
 The most common viral cause is Coxsackie B virus 
 other causes include adenovirus, echovirus and influenza viruses. 
 wide spread 'saddle-shaped' ST elevation 
 This is followed by the return of ST segments to baseline and flat T waves.

 Which ECG changes would you expect to see in the next week or two? 
 T-wave inversion in all leads 549

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  88 
  PR depression: most specific ECG marker for pericarditis 
 
ECG showing pericarditis. Note the widespread nature of the ST elevation and the PR depre ssion 
 
Diagnosis 
ESC guidelines defined the diagnosis  of acute pericarditis as 2 out of 4 of the following:  
1) pericarditic chest pain;  
2) pericardial rub;

2) pericardial rub;  
3) new widespread ST-elevation or PR depression; and  
4) pericardial effusion (new or worsening). 
 
Treatment 
 Analgesia, observation  and attempts to ascertain a cause as well as ruling out any associated 
pericardial effusions would be appropriate. 
 high dose non-steroidal therapy (eg Aspirin 600mg QDS, ibuprofen 400-800mgs) is 
appropriate.  
 Increasingly oral colchicine  is also used. 
 Colchicine is useful both in acute episode and to prevent recurrence of

pericarditis. 
 If patients are unable to take NSAIDs, colchicine is the alternative.  
 Prednisolon e can be considered in patients who fail to respond to non-steroidal anti-
inflammatory drug and colchicine therapy.  
 recurrent pericarditis post-transplant  Cyclosporine  
 Pericardectomy is only indicated for recurrent pericarditis once medical interventions have 
failed. 
 Treatment duration should be guided by symptoms and blood tests (CRP), but normally it is for

1-2 weeks ’ duration. 
 Patients should be told to reduce physical activity  for a minimum of 3 months  from initial 
onset. 
Prognosis 
 Poor prognostic factors  include: 
 Temperature above 38ºC 
 Subacute disease course 
 Presence of a large effusion or tamponade 
 Unsuccessful therapy with nonsteroidal anti-inflammatory agents 
 Factors associated with complicated pericarditis  include: 
 Early administration of high-dose corticosteroids 
 Lack of colchicine treatment

 Lack of colchicine treatment 
 Elevated levels of high-sensitivity C-reactive protein 
 
Pericardial effusion 
Cause of a pericardial effusion include: 
 infectious pericarditis: viral, tuberculosis, pyogenic spread from septicaemia and pneumonia 
 uraemia 
550

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  89 
  post myocardial infarction (including Dressler's syndrome) 
 trauma  
 CT is the most appropriate investigation 
 provide more information than Echo 
 quicker to obtain than (MRI).

 quicker to obtain than (MRI). 
Constrictive pericarditis 
  
The right sided failure, ascites and pericardial calcification on x ray suggest a diagnosis of 
constrictive pericarditis. 
 Inflammation of the pericardium  fibrosis and constriction 
 previous cardiac surgery 
 previous pericarditis,  
 radiotherapy  
 connective tissue disease  
Causes

Causes 
 Mediastinal irradiation  
 TB :Tuberculous pericarditis is the commonest cause of constrictive pericarditis 
worldwide.  
 any cause of purulent pericarditis 
Features 
 dyspnoea 
 right heart failure: elevated JVP, ascites, oedema, hepatomegaly 
 JVP shows prominent x and y descent 
 pericardial knock - loud S3 
 Kussmaul's sign is positive 
 CXR 
 pericardial calcification 
 can detect effusions only if larger than 250 mL.

 Echocardiography 
 Indication  to assess for pericardial effusion and cardiac tamponade  
  the best diagnostic tool for diagnosing pericardial effusion. 
  shows no increase in the venous return with inspiration. 
 
The key differences between constrictive pericarditis and cardiac  tamponade  are summarized in 
the table below: 
 
Cardiac tamponade Constrictive pericarditis 
JVP Absent Y descent X + Y present 
Pulsus paradoxus  Present Absent 
Kussmaul's sign*  Rare Present

Kussmaul's sign*  Rare Present 
Characteristic features   Pericardial calcification on CXR 
 Kussmaul's sign*   a paradoxical rise in jugular venous pressure (JVP) on inspiration  
 In cardiac tamponade there is pulsus paradoxus (a greater than 10 mmHg fall in systolic BP o n 
inspiration) but this is less commonly seen in constrictive pericarditis, though can still be prese nt 
in both. 551

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  90 
  Kussmaul's sign (a rise in the JVP on inspiration) is more likely to be seen in constrictive 
pericarditis than cardiac tamponade. 
 
Hypotension is the best clinical features that distinguishes cardiac tamponade from constrictive 
pericarditis 
 hypotension is a late feature in constrictive pericarditis.  
 
Treatment

Treatment  
 The first line of treatment of symptomatic constrictive pericarditis is pericardiotomy. 
Cardiac tamponade 
Cardiac tamponade is characterised by Beck's triad  of: 
 hypotension 
 raised JVP (with  absent Y descent ), and 
 muffled heart sounds. 
 
Features 
 dyspnoea 
 raised JVP, with an absent Y descent - this is due to the limited right ventricular filling 
 tachycardia

 Hypotension  
 the best clinical features that distinguishes cardiac tamponade from constrictive 
 hypotension is a late feature in constrictive pericarditis.  
 muffled heart sounds 
 pulsus paradoxus 
 Kussmaul's sign ( rise in JVP on inspiration ) 
 ECG: electrical alternans 
 impalpable apex beat 
 
MECHANISM OF PULSUS PARADOXUS 
 Inhalation increases venous return. Increased venous return expands the right ve ntricle (RV).

Expanded RV compresses the left ventricle (LV). Compressed LV decreases blood pressure. 
Tamponade compresses the whole heart. 
 Inhale = Big RV = Smaller LV = BP drop > 10 mm Hg 
 
Types 
 Essential hypertension ( 95% of patients)  
 causes are multi-factorial with a combination of genetics and environmental factors. 
 Secondary hypertension ( 5% of patients).

 Secondary hypertension ( 5% of patients). 
 
When a question says: ‘What is the most likely diagnosis? ’ think about what is epidemiologically the 
most common cause of hypertension. Therefore the answer is  essential hypertension. The most 
likely cause of hypertension in an obese  is still essential hypertension.  
 
Ref: www.mrcpuk.org/ Acute Medicine Specialty Certificate Examination/ sample questions  
 
Diagnosis

Diagnosis 
Hypertension is defined as systolic blood pressure greater than the 95th centile for age.  
 
Hypertension - NICE now recommend ambulatory blood pressure monitoring to aid diagnosis Hypertension  552

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  91 
  
NICE published updated guidelines for the management of hypertension in 2011. Some of the key 
changes include: 
 classifying hypertension into stages 
 recommending the use of ambulatory blood pressure monitoring (ABPM) and home b lood 
pressure monitoring (HBPM)

pressure monitoring (HBPM) 
 
Flow chart showing simplified schematic for diagnosis hypertension following NICE guidelines 
The use of ambulatory blood pressure monitoring (ABPM) aims to:  
 prevent diagnosing 'white coat hypertension' as having hypertension in patients whose bloo d 
pressure climbs 20 mmHg whenever they enter a clinical setting. 
 ABPM has been shown to be a more accurate predictor of cardiovascular events than clinic 
readings. 
Blood pressure classification

readings. 
Blood pressure classification  
 This becomes relevant later in some of the management decisions that NICE advoca te. 
 
Stage Criteria 
Stage 1 
hypertension  Clinic BP  ≥ 140/90 mmHg and subsequent ABPM daytime average or HBPM average 
BP ≥ 135/85 mmHg 
Stage 2 
hypertension  Clinic BP  ≥ 160/100 mmHg and subsequent ABPM daytime average or HBPM 
average BP ≥ 150/95 mmHg 
Severe 
hypertension  Clinic systolic BP ≥ 180 mmHg, or clinic diastolic BP ≥ 110 mmHg

Diagnosing hypertension ( NICE guidelines ) 
 Firstly, measure BP in both arms  when considering a diagnosis of hypertension.  
 If the difference in readings between arms is more than 20 mmHg  then the 
measurements should be repeated .  
553

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  92 
  If the difference remains > 20  mmHg  then subsequent BP should be recorded from the 
arm with the higher reading . 
 there are pathological causes of unequal blood pressure readings from the arms , such 
as: 
 supravalvular aortic stenosis.  
 listen to the heart sounds  further investigation if a very large difference is

noted. 
 Take a second reading during the consultation , if the first reading is > 140/90 mmHg.  
 The lower reading of the two should determine further management. 
 Offer ABPM or HBPM to any patient with a blood pressure ≥ 140/90 mmHg. 
 If the BP is ≥ 180/110 mmHg: 
 immediate treatment should be considered 
 NICE recommend same day assessment by a specialist if:  
 there are signs of papilloedema or retinal haemorrhages

 phaeochromocytoma is suspected (labile or postural hypotension, headache, 
palpitations, pallor and diaphoresis) 
Ambulatory blood pressure monitoring (ABPM) 
 at least 2 measurements per hour during the person's usual waking hours (for exa mple, between 
08:00 and 22:00) 
 use the average value of at least 14 measurements 
 If ABPM is not tolerated or declined HBPM should be offered. 
Home blood pressure monitoring (HBPM)

Home blood pressure monitoring (HBPM) 
 for each BP recording, two consecutive measurements need to be taken, at least 1 minute apart 
and with the person seated 
 BP should be recorded twice daily, ideally in the morning and evening 
 BP should be recorded for at least 4 days, ideally for 7 days 
 discard the measurements taken on the first day and use the average value of  all the remaining 
measurements 
 
Interpreting the results  
 ABPM/HBPM ≥ 135/85 mmHg (i.e. stage 1 hypertension)

 treat if < 80 years of age AND  any of the following apply: 
 target organ damage,  
 established cardiovascular disease,  
 renal disease,  
 diabetes 
 10-year cardiovascular risk equivalent to 20% or greater 
 ABPM/HBPM ≥ 150/95 mmHg (i.e. stage 2 hypertension) 
 offer drug treatment regardless of age 
Management (NICE guidelines 201)  
 
the key changes include: 
554

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  93 
  calcium channel blockers are now considered superior to thiazides 
 bendroflumethiazide is no longer the thiazide of choice 
 
Managing hypertension  
 Lifestyle advice should not be forgotten and is frequently tested in exams: 
 Of all the lifestyle modifications , weight reduction produces the greatest reduction 
in BP.

in BP.  
 A 10 kg weight loss is expected to decrease BP by 15 –20 mmHg 
 a low salt diet is recommended,  
 aiming for less than 6g/day, ideally 3g/day.  
 The average adult in the UK consumes around 8-12g/day of salt.  
 A recent BMJ paper showed that lowering salt intake can have a significant effect 
on blood pressure. For example, reducing salt intake by 6g/day can lower systolic 
blood pressure by 10mmHg 
 caffeine intake should be reduced

 caffeine intake should be reduced 
 the other general bits of advice remain: stop smoking, drink less alcohol , eat a balanced 
diet rich in fruit and vegetables, exercise more, lose weight 
 If a patient on antihypertensive and drink alcohol  Reduction of alcoho l 
intake is the next step in treatment. 
 Non-pharmacological  manoeuvres are paramount and first line  in 
hypertension management  
 relaxation therapies have been shown to reduce blood pressure ( Meditation is currently

advocated measures to reduce blood pressure ) 
 For patients < 40 years  consider specialist referral to exclude secondary causes. 
 
Flow chart showing the management of hypertension as per current NICE guideliness 
 
Step 1 treatment 
 patients < 55-years-old: ACE inhibitor (A) 
 patients  ≥  55-years-old or of Afro-Caribbean origin: calcium channel blocker 
 If a Calcium channel blocker is not suitable, for example because of oedema or

intolerance, or if there is evidence of heart failure or a high risk of heart failure, offer a 
thiazide-like diuretic.  
 ≥ 55 year old + HTN + history of MI    (ACE) inhibitor is the antihypertensive of 
choice  
 ACE inhibitors and ARBs have beneficial effects on mortality after an acute MI.  
555

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  94 
  
Step 2 treatment 
 ACE inhibitor + calcium channel blocker (A + C) 
Step 3 treatment 
 add a thiazide diuretic (D, i.e. A + C + D) 
 NICE now advocate using either chlorthalidone (12.5-25.0 mg once daily) or indapam ide (1.5 mg 
modified-release once daily or 2.5 mg once daily) in preference to a conven tional thiazide diuretic

such as bendroflumethiazide 
 NICE define a clinic BP  ≥ 140/90 mmHg after step 3 treatment with optimal or best tolerated 
doses as resistant hypertension. They suggest step 4 treatment or seeking expert advice  
Step 4 treatment  
 consider further diuretic treatment 
 if potassium < 4.5 mmol/l add spironolactone 25mg od 
 if potassium > 4.5 mmol/l add higher-dose thiazide-like diuretic treatment

 if further diuretic therapy is not tolerated, or is contraindicated or ineffective, consider an alpha - 
or beta-blocker 
 Patients who fail to respond to step 4 measures should be referred to a specialist. NICE  
recommend:  seek expert advice . 
 
 hypertensive with benign prostatic hyperplasia  alpha-blockers  
 hypertensive with heart failure or angina  beta-blockers 
 hypertensive post myocardial infarction either a beta blocker or ACE inhibitor would be 
the agent of choice. 
.

.  
 
Use of multiple anti-hypertensives at low doses is preferable to having fewer tablets at higher 
doses, in view of the synergistic effectiveness of targeting several mechanisms of 
hypertension. 
 
Screening criteria for target end organ damage:  
 Any patient with hypertension should prompt a search for markers of end organ dam age and risk 
factors for cardiovascular disease: 
 From history-taking  (headache, epistaxis, visual disturbance)

 Clinical examination  (fundoscopy, site and character of apex beat)  
 Investigations :  
 Electrocardiogram screens for hypertensive left ventricular hypertrophy  
(Sokolow-Lyon criteria: S1 +V5 or V6 >3.5 mV).  
 Renal function tests  
 
Blood pressure targets 
 
Clinic BP ABPM / HBPM 
Age < 80 years  140/90 mmHg 135/85 mmHg 
Age > 80 years  150/90 mmHg 145/85 mmHg 
 
Recommendations for BP target differ slightly among different guidelines .

 British Hypertension Society Guidelines for Hypertension Management (BHS-IV) recommend a  
goal BP of less than 130/80 mmHg for patients with diabetes , renal impairment and 
established  cardiovascular disease ;  
 while a Joint Negotiating Committee (JNC) 8 report and American College of 
Cardiology/American Heart Association Guidelines recommend a target BP of less than 
140/90  mmHg in non-diabetic patients with cardiovascular disease.  
556

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  95 
  
Hypertensive crisis 
Hypertensive crisis: 
 Hypertensive emergency  systolic BP  ≥ 180 or diastolic BP  ≥ 110 + end organ damage 
 Hypertensive urgency  systolic BP  ≥ 180 or diastolic BP  ≥ 110 +  NO end organ damage

 The most common clinical presentations of hypertensive emergencies  are: 
 cerebral infarction  (24.5%), 
 pulmonary edema (22.5%), 
 hypertensive encephalopathy (16.3%), 
 congestive heart failure (12%). 
 Other presentations include intracranial hemorrhage, aortic dissection, and eclampsia as 
well as acute myocardial infarction. 
  (NICE) recommends same day referral  for: 
1. accelerated hypertension with papilloedema and/or retinal haemorrhages,  or

2. for patients suspected of having a phaeochromocytoma (labile or postural 
hypotension, headache, palpitations, pallor and sweating). 
 Hypertensive emergency:   
 The initial target is to lower the mean arterial pressure (MAP) by no more than 25%, 
or reduce the diastolic blood pressure by one-third  
  (MAP) = diastolic blood pressure + [(systolic blood pressure - diastolic blood pressure)/3]  
 Or MAP = (2x diastolic + systolic)/3

 Or MAP = (2x diastolic + systolic)/3 
 Even in the presence of heart failure or hypertensive encephalopathy, a controlle d 
reduction, to a level of about 150/90 mmHg, over a period of 24-36 hou rs is ideal  
 
 In most patients, blood pressure can be brought down with bed rest and oral medication   
 Intravenous labetalol (2 mg/min to a maximum of 200 mg), intravenous glyceryl trinitra te 
(0.6-1.2 mg/h), intravenous sodium nitroprusside (0.3-1.0 mg/kg per min) and

intramuscular hydralazine (5 or 10 mg repeated at half-hourly intervals) are all effective 
but require close monitoring 
 Labetalol has both alpha- and beta-adrenoreceptor antagonistic activity and 
is the first choice for hypertensive crises where the aetiology is initially 
unclear .  
Malignant hypertension 
 
 A patient with malignant hypertension always has retinal papilledema

 The term malignant hypertension  is usually reserved for cases where papilloedema  is present 
 The pathologic hallmark of malignant hypertension  is fibrinoid necrosis of the 
arterioles , which occurs systemically, but specifically in the kidneys.  
 
Basics 
 severe hypertension (e.g. >200/130 mmHg) 
 occurs in both essential and secondary types 
 fibrinoid necrosis of blood vessels, leading to retinal haemorrhages, exudates, and p roteinuria,

haematuria due to renal damage (benign nephrosclerosis). 
 can lead to cerebral oedema ĺ encephalopathy  
Features 
 classically: severe headaches, nausea/vomiting, visual disturbance 
 however chest pain and dyspnoea common presenting symptoms 
 papilloedema 
 severe: encephalopathy (e.g. seizures) 
557

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  96 
  reduce diastolic no lower than 100mmHg within 12-24 hrs.  
 BP should not drop initially more than 25 per cent of presenting. 
 bed rest 
 most patients: oral therapy e.g. atenolol 
 if severe/encephalopathic: IV sodium nitroprusside/labetolol 
 The major risk of any oral agent used for hypertensive emergencies is ischaemic

symptoms (for example myocardial infarction, angina pectoris or stroke) due to an 
excessive and uncontrolled hypotensive response usually due to lowering of  BP to below 
the autoregulatory threshold.  
 Therefore the use of oral agents should generally be avoided in the treatmen t of 
hypertensive emergencies if parenteral drugs are available.  
 Sublingual nifedipine is minimally and unpredictably absorbed. Therefore should b e 
avoided

avoided  
 
The diagnosis of accelerated hypertension  requires the finding of fundal haemorrhages and 
exudates , with or without papilloedema , as manifestations of fibrinoid necrosis.  
 
Prognosis 
 These patients develop fatal complications if untreated, and more than 9 0% will not survive 
beyond 1-2 years. 
 
Hypertension: secondary causes 
 Primary hyperaldosteronism , including Conn's syndrome (5-10% of hypertensive patients)

 the single most common cause of secondary hypertension  
  (↑BP + ↓  K+ + ↑ Aldosterone )  
 CT or MRI of the abdomen identifies a secretory adrenal adenoma  
 Renal diseases: include  
 glomerulonephritis 
 Reflux-associated scarring is the commonest renal disease.  
 This will cause  abnormalities on dimercapto succinic acid (DMSA) scan . 
 adult polycystic kidney disease 
 renal artery stenosis 
 
 Endocrine disorders  (other than primary hyperaldosteronism):

 phaeochromocytoma 
 Cushing's syndrome 
 Liddle's syndrome  ( ĹBP + ↓ K+ + ↑ Na+) 
 hypokalaemic hypertension  
 metabolic alkalosis  
 low plasma renin and aldosterone (called pseudo-hyperaldosteronism). 
558

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  97 
  congenital adrenal hyperplasia (11-beta hydroxylase deficiency) 
 acromegaly 
 Fibromuscular dysplasia ,  
 a rare cause of hypertension and hypokalaemia,  
 more common in women.  
 It causes hyperreninaemic hyperaldosteronism.  
 Liquorice ingestion   
 causes a primary aldosterone type picture.

 causes a primary aldosterone type picture.  
 It is caused by glycyrrhizic acid  contained in liquorice, blocking the enzyme 11b 
hydroxysteroid dehydrogenase. This prevents the inactivation of cortisol, which in turn 
activates mineralocorticoid receptors in the kidney.  driving hypokalaemic metabolic 
alkalosis with hypertension. 
 Other causes  include: 
 NSAIDs 
 coarctation of the aorta ( the commonest non-renal cause ) 
 the combined oral contraceptive pill

 the combined oral contraceptive pill 
 steroids 
 MAOI 
MRCPUK- part 2- March 2017 : A 28-year-old woman of Afro-Caribbean ethnic origin c/o difficult- to-
manage hypertension, despite taking maximal-dose amlodipine and indapamide . The GP trialled an 
ACE inhibitor, but this was discontinued due to a rise in serum creatinine. Renin and aldosterone are 
both Elevated. K is 3.1 mmol. Which of the following is the most likely diagnosis? 
 Fibromuscular renal artery dysplasia

 Fibromuscular renal artery dysplasia  
 This patient ’s age and ethnicity suggest that her hypertension is related to fibromuscular 
dysplasia rather than to atherosclerotic renal artery stenosis.  
 The renin and aldosterone elevation, coupled with hypokalaemia and deterioration in 
renal function on starting ACE inhibitors, are consistent with the diagnosis. 
 
Hypokalaemia and hypertension

 For exams it is useful to be able to classify the causes of hypokalaemia in to those ass ociated 
with hypertension, and those which are not  
 The first step in case of (Ĺ BP + Ļ K+) should be further simple investigations  Plasma renin 
and aldosterone levels  
 Cushing's & Conn's   high aldosterone and a low renin,  
 renal artery stenosis  high renin and aldosterone 
 Liddle's  low renin and aldosterone.  
Hypokalaemia with hypertension

Hypokalaemia with hypertension  
 Cushing's syndrome   
 Conn's syndrome (primary hyperaldosteronism)  
 Liddle's syndrome 
  autosomal dominant disorder that mimics hyperaldosteronism 
 renal artery stenosis 
 11-beta hydroxylase deficiency* 
 *21-hydroxylase deficiency, which accounts for 90% of congenital adrenal hyperplasia cases, is 
not associated with hypertension 
 Carbenoxolone, an anti-ulcer drug, and liquorice excess can potentially cause hypokalae mia

associated with hypertension  
 
Hypokalaemia without hypertension  
 diuretics 
 GI loss (e.g. Diarrhoea, vomiting) 
 renal tubular acidosis (type 1 and 2**)  Bartter's syndrome 
 Gitelman syndrome 
**type 4 renal tubular acidosis is associated with hyperkalaemia 
Isolated systolic hypertension(ISH) 
559

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  98 
   isolated systolic hypertension (systolic greater than 160 and diastolic below 90 mmHg). 
 (ISH) is common in the elderly, affecting around 50% of people older than 70 years old.   
 treating ISH reduced both strokes and ischaemic heart disease.

 Evidence from studies such as Systolic Hypertension in the Elderly Program and Syst-Eur  
indicate that both thiazides and calcium antagonists are the drugs of choice in terms of reducing 
morbidity and mortality in this patient group. 
 the 2011 NICE guidelines  recommends treating ISH in the same stepwise fashion as standa rd 
 The incontinence may be exacerbated by the diuretic therapy and a calcium antagonist 
may be more appropriate.

may be more appropriate. 
Hypertension in pregnancy  (NICE guidance 2010)  
 
 Women who are at high risk of developing pre-eclampsia should take aspirin 75mg od from  12 
weeks until the birth of the baby.  
 High risk groups include: 
 hypertensive disease during previous pregnancies 
 autoimmune disorders such as SLE or antiphospholipid syndrome 
 type 1 or 2 diabetes mellitus

 type 1 or 2 diabetes mellitus 
 The classification of hypertension in pregnancy is complicated and varies. Remember, i n normal 
pregnancy: 
 blood pressure usually falls in the first trimester (particularly the diastolic), and continues 
to fall until 20-24 weeks 
 after this time the blood pressure usually increases to pre-pregnancy levels by term 
 Hypertension in pregnancy in usually defined as: 
 systolic > 140 mmHg or diastolic > 90 mmHg

 systolic > 140 mmHg or diastolic > 90 mmHg 
 or an increase above booking readings of > 30 mmHg systolic or > 15 mmHg diastolic 
 After establishing that the patient is hypertensive they should be categorised into o ne of the 
following groups 
 
Pre-existing hypertension Pregnancy-induced hypertension  
(PIH, also known as gestational 
hypertension) Pre-eclampsia 
A history of hypertension 
before pregnancy or an 
elevated blood pressure > 
140/90 mmHg before 20 
weeks gestation

weeks gestation 
 
No proteinuria, no oedema  
 
Occurs in 3-5% of 
pregnancies and is more 
common in older women Hypertension (as defined above) 
occurring in the second half of pregnancy 
(i.e. after 20 weeks) 
 
Occurs in around 5-7% of pregnancies 
 
Resolves following birth (typically after 
one month). Women with PIH are at 
increased risk of future pre-eclampsia or 
hypertension later in life Pregnancy-induced hypertension

in association with proteinuria 
(> 0.3g / 24 hours) 
 
Oedema may occur but is now 
less commonly used as a criteria 
 
Occurs in around 5% of 
pregnancies 
Hypertension risk factors in women  
Hypertension has classically been described in a male population, though relevant risk factors hav e 
been more recently identified in women. 
These include: 
 Multiple previous pregnancies 
 Menopause 
 Hysterectomy, and 
 Hormone replacement therapy.

 Hormone replacement therapy. 
 
Target blood pressure in patients with pre-existing hypertension  
560

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  99 
  The target blood pressure in patients with pre-existing hypertension is under 150/100 
mmHg,  or 140/90 mmHg in the presence of end organ failure. 
 In patients with longstanding hypertension aggressive blood pressure control may compromise 
placental function, so diastolic blood pressure should be preserved above 80 mmHg.

Pre-eclampsia 
 
 Pre-eclampsia is a condition seen after 20 weeks gestation characterised by pregnancy-induced 
hypertension in association with proteinuria (> 0.3g / 24 hours).  
 Oedema used to be third element of the classic triad but is now often not included in the 
definition as it is not specific 
Pre-eclampsia is important as it predisposes to the following problems

 fetal: prematurity, intrauterine growth retardation 
 eclampsia 
 haemorrhage: placental abruption, intra-abdominal, intra-cerebral 
 cardiac failure 
 multi-organ failure 
 > 40 years old 
 nulliparity (or new partner) 
 multiple pregnancy 
 body mass index > 30 kg/m^2 
 pregnancy interval of more than 10 years 
 family history of pre-eclampsia 
 previous history of pre-eclampsia

 previous history of pre-eclampsia 
 pre-existing vascular disease  such as  hypertension  or renal disease 
There is some evidence to suggest that pre-eclampsia is actually less common in smokers 
Features of severe pre-eclampsia 
 hypertension: typically > 170/110 mmHg and proteinuria as above 
 proteinuria: dipstick ++/+++ 
 headache 
 visual disturbance 
 RUQ/epigastric pain 
 hyperreflexia 
 platelet count < 100 * 106/l, abnormal liver enzymes or HELLP syndrome

 consensus guidelines recommend treating blood pressure  > 160/110  mmHg although many 
clinicians have a lower threshold 
 oral labetalol  is now first-line  following the 2010 NICE guidelines. Nifedipine and hydralazine 
may also be used 
 Beta blockers may restrict foetal growth but are sometimes used.  
 delivery of the baby is the most important and definitive management step.  The timing depends 
on the individual clinical scenario

on the individual clinical scenario 
Eclampsia 
Eclampsia 
may be defined as the development of seizures in association pre-eclampsia. To  recap, pre-eclampsia 
is defined as: 
 condition seen after 20 weeks gestation 
 pregnancy-induced hypertension 
 proteinuria 
Magnesium sulphate is used to both prevent seizures in patients with severe pre-eclampsia and treat

seizures once they develop. Guidelines on its use suggest the following: 
 should be given once a decision to deliver has been made 
561

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  100 
  in eclampsia an IV bolus of 4g over 5-10 minutes should be given followed by  an infusion of 1g / 
hour 
 urine output, reflexes, respiratory rate and oxygen saturations should be monitored d uring 
treatment 
 treatment should continue for 24 hours after last seizure or delivery (around 40% of s eizures 
occur post-partum)

occur post-partum) 
Other important aspects of treating severe pre-eclampsia/eclampsia include fluid restriction to avoid the 
potentially serious consequences of fluid overload 
 
Pulmonary arterial hypertension (PAH) 
Definition   
 sustained elevation in mean pulmonary arterial pressure of greater than 25 mmHg at rest o r 30 
mmHg after exercise.  
 
 more common in females,

 more common in females,  
 typically presents at 20-40 years old 
 
Classification & causes 
 PAH has recently been reclassified by the WHO:  
 
1. Group 1: idiopathic pulmonary arterial hypertension (IPAH)  
 Idiopathic  (previously termed primary pulmonary hypertension (PPH) 
 10% are familial (autosomal dominant)  
 diagnosed when no underlying cause can be found  
 endothelin thought to play a key role in pathogenesis

2. Group 2: Pulmonary hypertension with left heart disease  
 congenital heart disease with systemic to pulmonary shunts,  
 left-sided atrial, ventricular or valvular disease such as left ventricular systolic and 
diastolic dysfunction, mitral stenosis and mitral regurgitation  
3. Group 3: Pulmonary hypertension secondary to lung disease/hypoxia  
 COPD 
 interstitial lung disease  
 sleep apnoea  
 high altitude  
4. Group 4: Pulmonary hypertension due to thromboembolic disease

5. Group 5: Miscellaneous conditions  
 lymphangiomatosis e.g. secondary to carcinomatosis or sarcoidosis  
 collagen vascular disease,  
 HIV (the mechanism by which HIV infection produces pulmonary hypertension 
remains unknown)  
 sickle cell disease  
 drugs and toxins,  
 cocaine and anorexigens (e.g. fenfluramine)  
 
Increased pressure in pulmonary circuit ĺ elevated right ventricular  afterload ĺ

dilatation and/or  hypertrophy of the right heart ĺ  right heart failure and arrhythmias 
 
 Increased pulmonary vascular resistance 
 Occlusive vasculopathy 
 idiopathic pulmonary  arterial hypertension (IPAH) ,  
 connective tissue diseases 
 pulmonary embolism 
 Perivascular parenchymal changes (e.g. interstitial lung disease) 
 Hypoxic pulmonary vasoconstriction (e.g., COPD)  
 Increased pulmonary venous pressure 562

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  101 
  Volume or pressure overload from left-sided heart disease (e.g. mitral valve 
regurgitation) 
 Increased pulmonary blood flow 
 Left-to-right shunt (e.g., Eisenmenger's syndrome) 
 haemoglobinopathy- associated pulmonary hypertension  
 eg: 
 Sickle cell anemia   
 thalassemia

 eg: 
 thalassemia 
 Release of hemoglobin and arginase from lysed red cells causes scavenging of 
nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO 
synthase. The resulting impairment in NO bioavailability is associated with 
pulmonary vasoconstriction, endothelial dysfunction  
 The pathophysiology of PAH in haemoglobinopathies is multifactorial, but 
epidemiological and biochemical data support a prominent role for intravascular

hemolysis  inducing a state of vascular dysfunction. 
 
Features 
 
 Symptoms 
 exertional dyspnoea is the most frequent symptom 
 progressive SOB 
 chest pain and syncope may also occur 
 On examination: 
 cyanosis 
 Nail clubbing 
 raised JVP with prominent 'a' waves,  
 left parasternal heave (due to right ventricular hypertrophy) 
 loud P2 
 tricuspid regurgitation 
 
 Doppler echocardiography   
 the initial investigation of choice

 the initial investigation of choice   
 the jet associated with tricuspid regurgitation can be visualised adequately ( tricuspid 
regurgitant jet velocity ) 
 right heart catheterization  
 confirmatory test 
 the gold standard for the diagnosis 
 
 Treatment of the underlying cause for example: 
 anticoagulants for PE 
 bronchodilators and inhalation corticosteroids for COPD,  
 CPAP for patients with obstructive sleep apnea

 CPAP for patients with obstructive sleep apnea 
 Acute vasodilator testing  is central to deciding on the appropriate management strategy. 
 Acute vasodilator testing aims to decide which patients show a significant fall in pulmonary 
arterial pressure following the administration of vasodilators such as intravenous 
epoprostenol or inhaled nitric oxide 
 If there is a positive response  oral calcium channel blockers 
 If there is a negative response:

 If there is a negative response: 
 prostacyclin analogues: treprostinil, iloprost 
 endothelin receptor antagonists: bosentan 
 phosphodiesterase inhibitors: sildenafil 
 
563

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  102 
  diuretics if right heart failure 
 heart-lung transplant 
 
Whilst only 10-15% of patients appear to have a pulmonary vascular tree responsive to 
calcium antagonism, these agents still constitute the initial therapy of choice according to 
guidelines, but only in those patients who show a response to vasodilator testing.

 Cor pulmonale:  
 altered structure (hypertrophy, dilation) or impaired function of the right ventricle cause d 
by pulmonary hypertension resulting from a primary disorder of the respiratory or 
pulmonary artery system  
 
Atherosclerosis

Atherosclerosis 
Atherosclerosis is a complex process which develops over a number of years. A number of chan ges 
can be seen: 
 initial endothelial dysfunction is triggered by a number of factors such as smoking, hypertension  
and hyperglycaemia 
 this results in a number of changes to the endothelium including pro-inflammatory, pro- oxidant, 
proliferative and reduced nitric oxide bioavailability 
 fatty infiltration of the subendothelial space by low-density lipoprotein (LDL) particles

 monocytes migrate from the blood and differentiate into macrophages. These macrophages  then 
phagocytose oxidized LDL, slowly turning into large 'foam cells'. As these macrophages die t he 
result can further propagate the inflammatory process. 
 macrophages play a greater role in the initial development of the plaque.  
 smooth muscle proliferation and migration from the tunica media into the intima resu lts in 
formation of a fibrous capsule covering the fatty plaque.

Complications of atherosclerosis  
 
Taking the coronary arteries as an example, once a plaque has formed a number of complications can 
develop:  
 the plaque forms a physical blockage in the lumen of the coronary artery. This may cause 
reduced blood flow and hence oxygen to the myocardium, particularly at times of increased 
demand, resulting clinically in angina 
 the plaque may rupture, potentially causing a complete occlusion of the coronary artery. This

may result in a myocardial infarction 
 
January 2016 exam:  Which cell type is most implicated in the development of coronary artery plaques? 
Macrophages  
 
Chest pain: assessment of patients with suspected cardiac chest pain 
NICE issued guidelines in 2010 on the 'Assessment and diagnosis of recent onset chest p ain or 
discomfort of suspected cardiac origin'.

discomfort of suspected cardiac origin'. 
 
The NICE guideline update (2016) makes three key changes to the 2010 version. 
1. clinical assessment of the likelihood of CAD, based on the typicality of the chest pain into typ ical, 
atypical or non-cardiac, instead of the previous PTP RS *.  
2.  zero calcium score is no longer used to rule out CAD in patients with low PTP.  
3. all patients with new onset chest pain with atypical or typical anginal features, as well as those

with non-cardiac chest pain and an abnormal resting ECG, should first be investigated w ith 
CTCA using a 64-slice (or above) CT scanner.  
 Functional imaging tests are now reserved for:  Ischemic heart disease 564

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  103 
  the assessment of patients with chest pain symptoms who are known to 
have CAD and  
 for patients where the CTCA has been non-diagnostic or has shown CAD of 
uncertain significance.  
*the pre-test probability (PTP) risk score (RS), which – based on the Duke clinical score – was calculated using age, gender,

typicality of chest pain and the presence of cardiovascular risk factors 
 
 What is the  next investigation for a patient presenting with atypical chest pain against a 
background of known coronary artery disease? 
 The next investigation would ideally be a low-risk procedure that can demonstrate contin ued 
patency of the previously stented coronary artery.  
 Dobutamine-atropine stress echocardiography , thallium perfusion scanning and myocardial

contrast perfusion echocardiography are all capable of localising areas of myocardial 
ischaemia.  
 This is the ideal investigation in that it is non-invasive, providing information on myoca rdial 
ischaemia as well as functional information (dobutamine stress if needed). 
 In this patient with atypical chest pain, we would ideally aim for an investigation with lower r isk 
but with sufficient sensitivity to exclude ischaemia as a cause for his symptoms.

Angina pectoris :  
 
Non-atherosclerotic angina  would be associated with conditions such as 
 Thyrotoxicosis 
 Aortic regurgitation 
 Aortic stenosis 
 Hypertrophic cardiomyopathy 
 Anaemia 
Anginal pain is: 
1. constricting discomfort in the front of the chest, or in the neck, shoulders, jaw, or arms 
2. precipitated by physical exertion 
3. relieved by rest or GTN within about 5 minutes.

 Three of the features above are defined as typical angina.  
 Two of the three features above are defined as atypical angina.  
 One or none of the features above are defined as non-anginal chest pain.  
 
Features which make a diagnosis of stable angina unlikely are when the chest pain is: 
 continuous or very prolonged and/or  
 unrelated to activity and/or  
 brought on by breathing in and/or

 brought on by breathing in and/or  
 associated with symptoms such as dizziness, palpitations, tingling or difficulty swallowing. 
Consider causes of chest pain other than angina (such as gastrointestinal or musculoskeletal 
pain). 
 
 First-line : 64-slice CT coronary angiography 
 Second-line : non-invasive functional testing ( if CTPA is non-diagnostic.) 
 MPS with SPECT or 
 stress echocardiography or 
 first-pass contrast-enhanced magnetic resonance perfusion or

 MRI for stress-induced wall motion abnormalities. 
 Third-line : invasive coronary angiography ( when the results of non-invasive functional 
imaging are inconclusive) 
 
565

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  104 
  In the context of risk factors for ischaemic heart disease (hypertension, hypercholesterolae mia, 
smoking), the clinical diagnosis should be confirmed with non-invasive functional scanning such as 
myocardial perfusion scanning with SPECT. 
 
 High-risk patients  with classic angina symptoms  should proceed directly to coronary

 Offer 64 ‑slice (or above) CT coronary angiography if: 
1. clinical assessment indicates typical or atypical angina or 
2. clinical assessment indicates non-anginal chest pain but 12 ‑lead resting ECG has been 
done and indicates ST ‑T changes or Q waves. 
 Low-risk patients  can be evaluated with non-invasive stress imaging.  
 Offer non-invasive functional imaging for myocardial ischaemia if 64-slice (or above) CT corona ry

angiography has shown CAD of uncertain functional significance or is non-diagnostic. 
 non-invasive functional testing for myocardial ischaemia 
1. myocardial perfusion scintigraphy  with single photon emission computed 
tomography (MPS with SPECT) 
 Use adenosine, dipyridamole or dobutamine as stress agents  
2. stress echocardiography 
 Use exercise or dobutamine for stress echocardiography or MR 
imaging for stress-induced wall motion abnormalities.

3. first-pass contrast-enhanced magnetic resonance (MR) perfusion 
 use adenosine or dipyridamole as stress agents  
4. MR imaging for stress-induced wall motion abnormalities 
 Take account of locally available technology and any contraindications (for examp le, 
disabilities, frailty, limited ability to exercise) when deciding on the imaging method.  
 Offer invasive coronary angiography as a third-line investigation when the results of non- invasive 
functional imaging are inconclusive.

functional imaging are inconclusive. 
 Treadmill exercise is no longer recommended in the work-up of new-onset chest p ain. 
 
 Definition of significant coronary artery disease (CAD) 
 CT coronary angiography is: 
  ≥ 70% diameter stenosis of at least one major epicardial artery segment or   
 ≥ 50% diameter stenosis in the left main coronary artery 
  
Factors intensifying ischaemia 
 Such factors allow less severe lesions (for example,  ≥ 50%) to produce angina:

 reduced oxygen delivery: anaemia, coronary spasm 
 increased oxygen demand: tachycardia, left ventricular hypertrophy 
 large mass of ischaemic myocardium: proximally located lesions 
 longer lesion length. 
Factors reducing ischaemia which may render severe lesions (≥  70%) asymptomatic: 
 Well-developed collateral supply. 
 Small mass of ischaemic myocardium: distally located lesions, old infarction in the territory of  
coronary supply.  
 
ESC guidelines 2017

ESC guidelines 2017  
 A reduction in chest pain after nitroglycerin (glyceryl trinitrate) administration can be m isleading 
and is not recommended as a diagnostic manoeuvre 
 In cases of symptom relief after nitroglycerin administration, another 12-lead ECG mus t be 
obtained.  
 A complete normalization of the ST-segment elevation after nitroglyceri n 
administration, along with complete relief of symptoms, is suggestive of coronary

spasm, with or without associated MI. In these cases, an early coronary angiography 
(within 24 h) is recommended.  
 In cases of recurrent episodes of ST-segment elevation or chest pain, immediate 
angiography  is required. 
  
Drug management 
The management of stable angina comprises lifestyle changes, medication, percuta neous coronary 
intervention and surgery. NICE produced guidelines in 2011 covering the manage ment of stable angina 566

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  105 
  
Medication  
 all patients should receive aspirin and a statin in the absence of any contraindication 
 sublingual glyceryl trinitrate to abort angina attacks 
 NICE recommend using either a beta-blocker or a calicum channel blocker first-line based o n 
'comorbidities, contraindications and the person's preference'

 if a calcium channel blocker is used as monotherapy a rate-limiting one such as verapamil or 
diltiazem should be used. If used in combination with a beta-blocker then use a lon g-acting 
dihydropyridine calcium-channel blocker (e.g. modified-release nifedipine). Remember tha t beta-
blockers should not be prescribed concurrently with verapamil (risk of complete heart block)  
 if there is a poor response to initial treatment then medication should be increased to  the

maximum tolerated dose (e.g. for atenolol 100mg od) 
 if a patient is still symptomatic after monotherapy with a beta-blocker add a calcium channe l 
blocker and vice versa 
 if a patient is on monotherapy and cannot tolerate the addition of a calcium channel blocker or a 
beta-blocker then consider one of the following drugs: a long-acting nitrate, ivabradin e, nicorandil 
or ranolazine 
 if a patient is taking both a beta-blocker and a calcium-channel blocker then only add  a third drug

whilst a patient is awaiting assessment for PCI or CABG 
 The FREEDOM trial demonstrated that in diabetic patients CABG was superior to PCI  in that 
it significantly reduced rates of death and myocardial infarction. 
Nitrate tolerance 
 many patients who take nitrates develop tolerance and experience reduced e fficacy 
 the BNF advises that patients who develop tolerance should take the second dose of  isosorbide

mononitrate after 8 hours, rather than after 12 hours. This allows blood-nitrate levels to  fall for 4 
hours and maintains effectiveness 
 this effect is not seen in patients who take modified release isosorbide mononitrat e 
 the explanation for nitrate tolerance  generation of reactive oxygen species  
 chronic nitrate therapy  ↑vascular oxidative stress  ↑ degradation of nitric oxide (NO) 
 reduced bioavailability  
Ivabradine

Ivabradine 
 a new class of anti-anginal drug which works by reducing the heart rate 
 acts on the I f ('funny') ion current which is highly expressed in the sinoatrial node, reducing 
cardiac pacemaker activity 
 adverse effects: visual effects, particular luminous phenomena, are common. Bradycardia, due  to 
the mechanism of action, may also be seen 
 there is no evidence currently of superiority over existing treatments of stable angina

Ulceration of an atheromatous plaque of the abdominal aorta is the most common source of 
emboli in old man presented with acute pain, pallor and absent pulses in his leg. 
 
Coronary artery bypass graft (CABG) 
 There are two main approaches.  
1. In one, the left internal thoracic artery (internal mammary artery) is diverted to the left 
anterior descending branch of the left coronary artery.

2. In the other, a great saphenous vein is removed from a leg; one end is attach ed to 
the aorta or one of its major branches, and the other end is attached to the ob structed 
artery. 
 CABG is superior to PCI in multivessel coronary disease. 
 indicated when coronary arteries have a 50% to 99% obstruction.  
 CABG guidelines state CABG is the preferred treatment for: 
 Disease of the left main coronary artery (LMCA). 
 Disease of all three coronary arteries (LAD, LCX and RCA).

 Diffuse disease not amenable to treatment with a PCI. 
  high-risk patients such as those with severe ventricular dysfunction (i.e. low ejection 
fraction), or diabetes mellitus. 
 Benefits  
  relief of angina  
 no survival benefit with bypass surgery vs. medical therapy in stable angina  
 Bypass surgery does not prevent future myocardial infarctions. 
 Complications 567

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  106 
  The incidence of acute coronary syndrome within 30 days of CABG is high, at 
around 17.5%.  
 Aneurysms are a rare and late complication of CABG. 
Cardiac syndrome X 
 consist of:  
 angina-like chest pain during exertion

 angina-like chest pain during exertion 
 characteristic ECG changes during exercise testing  
 normal coronary arteries on cardiac catheterisation  
 no inducible coronary artery spasm during catheterisation  
Acute coronary syndrome : Prognostic factors  
 
Poor prognostic factors 
 age 
 development (or history) of heart failure 
 peripheral vascular disease 
 reduced systolic blood pressure

 reduced systolic blood pressure 
 Killip class* 
 initial serum creatinine concentration 
 elevated initial cardiac markers 
 cardiac arrest on admission 
 ST segment deviation 
*Killip class  - system used to stratify risk post myocardial infarction 
 
Killip class Features 30 day mortality 
I No clinical signs heart failure 6% 
II Lung crackles, S3 17% 
III Frank pulmonary oedema 38% 
IV Cardiogenic shock 81% 
 
Clinical factors which are good indicators of ACS:

 These include typical pain lasting at least 15 minutes, associated nausea , and 
sweating.  
 Response to GTN should not  be used as indicator of ACS  
 
ACS referral: 
Refer people to hospital as an  emergency  if: 
 they currently have chest pain or 
 they are currently pain free, but had chest pain in the last 12 hours , and a resting 12-lead ECG is 
abnormal or not available. 
Refer people for urgent same-day assessment  if:

Refer people for urgent same-day assessment  if: 
 they had chest pain in the last 12 hours, but are now pain free with a normal resting 1 2-lead 
ECG or 
 the last episode of pain was 12–72 hours ago . 
 
Referral 
 current chest pain or chest pain in the last 12 hours with an abnormal ECG: emergency 
admission 
 chest pain 12-72 hours ago: refer to hospital the same-day for assessment 
 chest pain > 72 hours ago: perform full assessment with ECG and troponin measu rement

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  107 
  
Myocardial infarction 
 
 The most specific feature, which suggests that the pain is myocardial ischaemia, is the 
radiation to the jaw , which is relatively specific for pain of myocardial ischaemia.

 The clinical classification of MI includes: (NICE 2010) 
 Type 1 : ischaemia due to a primary coronary event such as plaque, fissuring or dissection. 
 Type 2 : ischaemia due to either increased oxygen demand or decreased supply, such as 
coronary spasm, coronary embolism, anaemia, arrhythmias, hypertension, or hypotension.  
 
The diurnal variation of myocardial ischaemia 
 There is a diurnal variation in presentation of myocardial ischaemia.

 Which physiological process is responsible for this?   Vasospasm  
 The peak incidence of STEMI  and the peak incidence of death due to ischaemic heart disease 
both coincide at around 8-9 am.  
 The early morning is associated with several physiological and haematological factors 
which predispose to vasospasm, infarction and death. 
 There is 
 ↑ adrenergic activity 
 ↑plasma fibrinogen levels 
 ↑ inhibition of fibrinolysis and 
 ↑ platelet adhesiveness.

 ↑ platelet adhesiveness. 
 Interestingly, NSTEMIs are not associated with this degree of diurnal rhythm.  
 Precipitating factors for an infarct include: 
 physical exertion 
 Rest , Sleep 
 Surgical procedure 
 Emotional stressors. 
 
Perioperative Myocardial Infarction (PMI) 
  most PMIs start within 24 to 48 hours of surgery during the greatest postoperative st ress. 
 The highest prevalence of myocardial infarction is 72 hours post operation 
(onexamination).

(onexamination).  
 ST elevation occurred in <2% of postoperative ischemic events and was a rare cause of P MI. 
Hence, prolonged, ST-depression –type ischemia is the most common cause of PMI. 
 Two distinct mechanisms  may lead to PMI 
 Acute Coronary Syndrome (Type 1 PMI) 
  Myocardial Oxygen Supply-Demand Imbalance (Type 2 PMI) in the presence of stable 
coronary artery disease (CAD)  
 Most common than type 1

 Most common than type 1  
 Tachycardia is the most common cause of postoperative oxygen supply-demand imbalance 
 Heart rates >80 or 90 bpm in patients with significant CAD whose preoperative resti ng heart rate is 
50 to 60 bpm can lead to prolonged ischemia and PMI  
 In meta-analyses, trials achieving the most effective heart rate control were associated wi th less 
PMI 
569

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  108 
  
 Early mortality after PMI ranges from 3.5% to 25% and is higher among patients with marked 
troponin elevation compared with patients with minor troponin elevation 
 cardiac biomarkers (eg, troponin T improve prediction of adverse cardiac events in the imm ediate 
postoperative period after major noncardiac surgery

http://circ.ahajournals.org/content/119/22/2936  (2009)  
 
The highest prevalence of myocardial infarction is 72 hours post operation. Patients with diabetes may 
not have chest pain due to autonomic dysfunction.  
 
Features 
 
Myocardial infarction: management 
 
570

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  109 
 Management  
Immediate management of suspected acute coronary syndrome (ACS) 
 glyceryl trinitrate 
 Sublingual glyceryl trinitrate and intravenous morphine + metoclopramide should b e given to 
help relieve the symptoms. 
 ongoing pain despite the use of sublingual G TN is suggestive of continuing

myocardial ischaemia/infarction  IV GTN 
 aspirin 300mg.  
  the initial drug therapy 
 Aspirin 300mg should be given to all patients (unless contraindicated). 
  It is safe in the post-surgical patient with no signs of bleeding  at three days post 
operation. 
 A second antiplatelet is normally given, usually ticagrelor, clopidogrel or prasurgel (all are 
antagonists of the P2Y 12 adenosine diphosphate receptor).

 NICE do not recommend giving other antiplatelet agents (i.e. Clopidogrel) outside of 
hospital 
 The dose of clopidogrel is 300 mg in ACS. 
 Other treatments that may be given include bivalirudin (a direct thrombin inhibitor, usually  given 
alongside aspirin + clopidogrel) and a form of heparin (either low-molecular weight or 
unfractionated). 
 Heparin in Non-STEMI ( has no benefit in ST elevation MI). 
 do not routinely give oxygen, only give if sats < 94%*

 *NICE suggest the following in terms of oxygen therapy : 
 do not routinely administer oxygen, but monitor oxygen saturation using pulse oximetry as 
soon as possible, ideally before hospital admission. Only offer supplemental oxyg en to: 
 people with oxygen saturation (SpO2) of less than 94% who are not at risk of 
hypercapnic respiratory failure, aiming for SpO2 of 94-98% 
 people with chronic obstructive pulmonary disease who are at risk of hypercapnic

respiratory failure, to achieve a target SpO2 of 88-92% until blood gas analysis is 
 ESC guidelines 2017 state that : routine oxygen is not recommended when 
SaO 2 is ≥ 90%.  
 perform an ECG as soon as possible but do not delay transfer to hospital. A normal ECG does 
not exclude ACS 
 percutaneous coronary intervention (PCI)  
 is the first-line and the gold-standard treatment  management to revascularise the 
myocardium.

myocardium. 
 but is not available in all centres. Thrombolysis should be performed in patients witho ut 
access to primary PCI 
 offer primary PCI to patients who present within 12 hours of onset of symptoms, i f it can 
be delivered within 120 minutes of the time when fibrinolysis could have been g iven.  
 A practical example may be a patient who presents with a STEMI to a small district 
general hospital (DGH) which does not have facilities for PCI. If they cannot be

transferred to a larger hospital for PCI within 120 minutes then fibrinolysis should 
be given. If the patient's ECG taken 90 minutes after fibrinolysis failed to show  
resolution of the ST elevation then they would then require transfer for PCI. 
 
Percutaneous coronary intervention (PCI) 
 (PCI) is a technique used to restore myocardial perfusion in patients with ischaemic heart 
disease, both in patients with stable angina and acute coronary syndromes.

 Stents are implanted in around 95% of patients - it is now rare for just balloon angioplast y to be 
performed  
 Following stent insertion migration and proliferation of smooth muscle cells and fibroblasts  occur 
to the treated segment. The stent struts eventually become covered by endoth elium. Until this 
happens there is an increased risk of platelet aggregation leading to thrombosis.  
 Following insertion the most important factor in preventing stent thrombosis is antiplatelet

therapy. Aspirin should be continued indefinitely. The length of clopidogrel treatme nt depends on 
the type of stent, reason for insertion and consultant preference  
 How long should he continue dual antiplatelet therapy following stent insertion?  
 12 months  571

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  110 
  When dual therapy is maintained for less than 12 months, early cessation of clopidogrel is 
associated with an increased risk of further ischaemic events.  
 Thrombosis of a drug-eluting stent is associated with high morbidity (42%) and mortality

(71%). For this reason, dual antiplatelet therapy (usually aspirin and clopidogrel) is 
continued for at least twelve months following the insertion of this type of sten t. 
 elective surgery should be postponed for twelve months when it is considered safe to 
stop clopidogrel and continue with aspirin.  
 
Complications:  Two main complications may occur  
1. Stent thrombosis :  
 due to platelet aggregation as above.  
 Occurs in 1-2% of patients, most commonly in the first month.

 Usually presents with acute myocardial infarction 
 Treated by primary angioplasty.  
2. Restenosis :  
 due to excessive tissue proliferation around stent.  
 Occurs in around 5-20% of patients, most commonly in the first 3-6 months.  
 Usually presents with the recurrence of angina symptoms.  
 Risk factors include diabetes, renal impairment and stents in venous bypass grafts 
 In patients with type-2 diabetes, uncoated coronary stents are liable to re-

stenosis at a rate of 40 –50% by the end of a 6-month 
 Drug eluting stents have been shown to reduce the relative risk of re-stenosis by around 
80%, but only where dual anti-platelet therapy with clopidogrel and aspirin is continu ed for 
at least 1 year. 
Types of stent 
 bare-metal stent (BMS) 
 drug-eluting stents (DES): stent coated with paclitaxel or rapamycin which inhibit local tissue 
growth. Whilst this reduces restenosis rates the stent thrombosis rates are increased as the

process of stent endothelisation is slowed 
 
Thrombolysis  
Thrombolysis is no longer indicated except in the context of STEMI where PCI is not available within 
90 minutes of first medical contact. 
 
 ECG criteria for thrombolysis  within 24 hours of typical pain include: 
 ST elevation of more than 1 mm in in two adjacent limb leads. 
 ST elevation more than 2 mm in in two adjacent anterior chest leads. 
 new left bundle branch block.

 new left bundle branch block. 
 Pre-hospital thrombolysis  is indicated if the time from the initial call to arrival at hospital is likely 
to be over 30 minutes.  
 When primary percutaneous coronary intervention cannot be provided within 120 minu tes 
of ECG diagnosis, patients with STEMI should receive immediate (p re-hospital or 
admission) thrombolytic therapy 
 (NICE) recommends using intravenous bolus  (reteplase  or tenec teplase ) rather than

an infusion for pre-hospital thrombolysis 
 Thrombolics 
 tissue plasminogen activator (tPA)  has been shown to offer clear mortality benefits over 
streptokinase 
 streptokinase  
 mechanism of action Combining with plasminogen to form a complex 
 Streptokinase forms a 1:1 complex with plasminogen that induces structural 
changes in the protein that activates it without direct cleavage of the Arg-Val 
bond. it is not specific for fibrin-bound plasminogen. 
 alteplase

 alteplase  
 Unlike streptokinase, alteplase activates plasminogen bound to fibrin without 
activating unbound plasminogen proteins. 
  it is not associated with hypotension or allergic reactions like streptokinase.  
 It has a much shorter half-life of only 3-4 minutes compared to 18 minutes for 
streptokinase. 
 tenec teplase   
 easier to administer 572

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  111 
  has been shown to have non-inferior efficacy to alteplase with a similar adverse 
effect profile 
 ECG should be performed 90 minutes following thrombolysis to assess whether there has b een a 
greater than 50% resolution in the ST elevation 
 if there has not been adequate resolution then rescue PCI is superior to repeat

 for patients successfully treated with thrombolysis PCI has been shown to be beneficial. 
The optimal timing of this is still under investigation 
 Contraindications to thrombolysis  include: 
 Gastrointestinal (GI) bleeding  in the preceding three weeks. 
 Heavy vaginal bleeding 
 Recent stroke or surgery (Ischaemic stroke in last six months) 
 Uncontrolled severe hypertension 
 Previous history of hemorrhagic stroke

 Previous history of hemorrhagic stroke 
 Prolonged cardiopulmonary resuscitation (CPR) (more than half an hour). 
 Known or suspected aortic dissection 
 Known bleeding disorder 
 Major surgery or serious trauma within two weeks. 
 Lumbar puncture in the preceding week. 
 
 Relative contraindications 
 Proliferative diabetic retinopathy,  
 allergy and  
 oral anticoagulants  
 Risk factors for bleeding  
 Advancing age 
 Renal impairment 
 Low body weight  and

 Low body weight  and 
 Known bleeding problems. 
 
Management of hyperglycaemia in acute coronary syndromes  
  the most appropriate treatment for his glycaemic control  Commence intravenous 
insulin infusion and stop metformin  
 metformin  increased risk of lactic acidosis. 
 Nice in 2011  recommends using a dose-adjusted insulin infusion  with regular monitoring of 
blood glucose levels to glucose below 11.0 mmol/l

 The Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study  
demonstrated significant reductions in mortality  in subjects with diabetes and myocardial 
infarction (MI) treated with IV insulin infusion (followed by three months of sc insulin) comp ared 
with conventional therapy with their oral hypoglycaemic agents. 
 intensive insulin therapy (an intravenous infusion of insulin and glucose with or without

potassium, sometimes referred to as 'DIGAMI') regimes are not recommended 
routinely  
 
Myocardial infarction: complications 
 
573

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  112 
  
Patients are at risk of a number of immediate, early and late complications follo wing a myocardial 
infarction (MI). 
 
Cardiac arrest  
 most commonly occurs due to ventricular fibrillation  
 The most common cause of death following a MI.  
 Patients are managed as per the ALS protocol with defibrillation.

Cardiogenic shock  
 Infarction of a large part of the ventricular myocardium ĻĻejection fraction cardiogenic shock.  
 Other causes of cardiogenic shock include the 'mechanical' complications such as left ventricular 
free wall rupture.  
 cardiac index would be below 2 l/min/m2.  
 Cardiac index relates cardiac output to body surface area and is calculated by CO/BSA.  
 Normal range is approximately 2.5-4.0 l/min/m2.

 Management : inotropic support with an agent such as dobutamine, and ideally mechanical 
support with the insertion of an intra-aortic balloon pump (IABP). 
 Patients may require inotropic support and/or an intra-aortic balloon pump. 
 in case with hypotension and shock, the most appropriate intervention  Intra-
aortic balloon counter pulsation (IABCP) to support cardiac output.  
 An intra-aortic balloon pump is inserted under echocardiographic guidance. At

which point of the ECG should balloon inflation be timed?  
 Middle of the T wave  
 Balloon inflation is timed with diastole once closure of the aortic valve has 
occurred; this corresponds to the middle of the T wave.  
 For blood to be ejected antegrade to perfuse the tissues and retrograde to perfuse 
the coronaries, the aortic valve must be closed and competent. 
 Aortic regurgitation is therefore a contraindication to placement of an intra-aortic 
balloon pump.

balloon pump.  
 Inotropes such as adrenaline and noradrenaline can significantly increase 
myocardial ischaemia, as such they would only be adjunctive support after IABC P. 
 
Chronic heart failure  
 As described above, if the patient survives the acute phase their ventricular my ocardium may be 
dysfunctional resulting in chronic heart failure.  
 The most important factor predicting outcomes  post-STEMI is the presence of new 
systolic heart failure.

systolic heart failure. 
 Loop diuretics such as furosemide will decrease fluid overload.  
 Both ACE-inhibitors and beta-blockers have been shown to improve the long-term progno sis of 
patients with chronic heart failure. 
Tachyarrhythmias  
574

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  113 
  Ventricular fibrillation, as mentioned above , is the most common cause of death following a 
MI. Other common arrhythmias including ventricular tachycardia. 
Bradyarrhythmias  
 Atrioventricular block is more common following inferior myocardial infarctions.

 Heart block post anterior MI is most likely to occur within the first few days post MI  rather than 
months. 
 pacing wire induced RV perforation. 
 The time course in this situation is vital, as this often occurs through an infarcted 
RV wall which is more friable and thin walled. 
Pericarditis  
 Pericarditis in the first 48 hours following a transmural MI is common (c. 10% of patients).

 The pain is typical for pericarditis (worse on lying flat etc), a pericardial rub may be heard and a  
pericardial effusion may be demonstrated with an echocardiogram. 
 Dressler's syndrome  
 tends to occur around 1-6 weeks following a MI. 
 The underlying pathophysiology is thought to be an autoimmune reaction against 
antigenic proteins formed as the myocardium recovers. 
  It is characterised by a combination of fever, pleuritic pain, pericardial effusion ,  friction

rub on auscultation and a raised ESR.  
 the most appropriate way to treat this patient  Aspirin 650 mg QDS 
 Other NSAIDs such as indomethacin if aspirin isn ’t tolerated. 
 corticosteroids are used in resistant cases, particularly those where pericardiocentesis 
has been required for drainage of pericardial effusion 
 in rare cases up to 1500 ml of fluid is recognised to accumulate in the pericardial 
sac.  
 
Left ventricular aneurysm

sac.  
 
Left ventricular aneurysm  
 The ischaemic damage sustained may weaken the myocardium resulting in aneurysm forma tion. 
  This is typically associated with persistent ST elevation  and left ventricular failure. 
  Thrombus may form within the aneurysm increasing the risk of stroke. Patients are therefo re 
anticoagulated. 
 the most appropriate initial course of action  Observe in the coronary care unit  
proceeding to echo to confirm the diagnosis.

proceeding to echo to confirm the diagnosis. 
Left ventricular free wall rupture  
 This is seen in around 3% of MIs  
 and occurs around 1-2 weeks afterwards. 
  Patients present with acute heart failure secondary to cardiac tamponade (raised JVP , pulsus 
paradoxus, diminished heart sounds). 
 Urgent pericardiocentesis and thoracotomy are required. 
Ventricular septal defect  
 Rupture of the interventricular septum usually occurs in the first week and is seen in aroun d 1-

2% of patients.  
 Features: acute heart failure associated with a pan-systolic murmur.  
 An echocardiogram is diagnostic and will exclude acute mitral regurgitation which presents  in a 
similar fashion.  
 Urgent surgical correction is needed. 
 
Acute mitral regurgitation  
 More common with infero-posterior infarction and may be due to ischaemia or rupture of the 
papillary muscle.  
 Papillary muscle rupture is rarer, with a reported incidence of <1%.

 The posteromedial papillary muscle  is twice as likely to rupture as is the anterolateral papillary 
muscle.  
 This is because the anterolateral papillary muscle is more often supplied by two arterial 
systems (left anterior descending and left circumflex coronary arteries), whereas the 
posteromedial papillary muscle  is frequently supplied by only one coronary arter y 
(usually the right) system.

(usually the right) system. 
 
 Papillary muscle rupture leading to mitral regurgitation (MR) typically occurs 1-14 days aft er a 
myocardial infarction.  
 Severe acute MR can cause abrupt haemodynamic compromise and cardiogenic shock with 
associated high mortality.  575

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  114 
   suddenly develops pulmonary oedema and a loud systolic murmur at the apex  which radiated 
into the axilla with associated pulmonary oedema.. 
 early- to-mid systolic murmur is typically heard.  
 Right heart studies (Right heart catheterisation and oximetry) would provide information

on left atrium (LA) pressures and suggestive information on MV prolapse.  
 Patients are treated with vasodilator therapy but often require emergency surgical repair.  
 
 Primary prevention 
drugs which have evidence for the reduction of risk of developing a cardiac event ? 
 Angiotensin converting enzyme inhibitor 
 The most appropriate treatment to reduce cardiovascular risk should focus on 
adequate blood pressure control

adequate blood pressure control 
 ↓ BP is most important than control of DM  and lipids in CV risk reduction 
 Aspirin 
 treatment of overweight, diabetic patients with metformin, lowers the relative risk of (MI) 
by 40%, as opposed to treatment with sulphonylureas or insulin. 
 Statins 
 
Myocardial infarction:  secondary prevention  
 
NICE produced guidelines on the management of patients following a myocardial in farction (MI) in 
2013. Some key points are listed below

2013. Some key points are listed below 
 
All patients should be offered the following drugs:  
 dual antiplatelet therapy (aspirin plus a second antiplatelet agent) 
 ACE inhibitor 
 beta-blocker 
 statin 
Some selected lifestyle points: 
 diet: advise a Mediterranean style diet, switch butter and cheese for plant oil based p roducts. Do 
not recommend omega-3 supplements or eating oily fish 
 exercise: advise 20-30 mins a day until patients are 'slightly breathless'

 sexual activity may resume 4 weeks after an uncomplicated MI. Reassure patients that sex do es 
not increase their likelihood of a further MI. PDE5 inhibitors (e.g, sildenafil) may be used 6 
months after a MI. They should however be avoided in patient prescribed either nitrates or 
nicorandil 
Clopidogrel  
 since clopidogrel came off patent it is now much more widely used post- MI 
 STEMI: the European Society of Cardiology recommend dual antiplatelets for 12 m onths. In the

UK this means aspirin + clopidogrel 
 non-ST segment elevation myocardial infarction (NSTEMI): following the NICE 2013 Secondary 
prevention in primary and secondary care for patients following a myocardial infarction  guidelines 
clopidogrel should be given for the first 12 months 
Aldosterone antagonists 
 patients who have had an acute MI and who have symptoms and/or signs of hea rt failure and left

ventricular systolic dysfunction, treatment with an aldosterone antagonist licensed for post- MI 
treatment (e.g. eplerenone) should be initiated within 3-14 days of the MI, preferably afte r ACE 
inhibitor therapy 
 
576

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  115 
  
Hyperlipidaemia: management 
See endocrinology 
 
Heart failure 
Types  
 Systolic dysfunction :  
 heart failure with reduced stroke volume and ejection fraction  
 the most common form of HF overall 
 Causes:  
 Decreased contractility (ischemia, MI, chronic mitral regurg),  
 Increased afterload (aortic stenosis, hypertensive crisis) 
 Diastolic dysfunction :  
 heart failure with reduced stroke volume and preserved ejection fraction 
 Causes:  
 Chronic hypertension,  
 hypertrophic cardiomyopathy,  
 aortic stenosis,

 aortic stenosis,  
 coronary disease 
 
Heart failure: NYHA classification 
 
 The New York Heart Association ( NYHA ) classification is widely used to classify the severity of 
heart failure: 
 NYHA Class I  
 no symptoms 
 no limitation: ordinary physical exercise does not cause undue fatigue, dyspnoea  or 
palpitations 
 NYHA Class II 
 mild symptoms 
 slight limitation of physical activity: comfortable at rest but ordinary  activity results 
in fatigue, palpitations or dyspnoea

in fatigue, palpitations or dyspnoea  
 NYHA Class III 
 moderate symptoms 
 marked limitation of physical activity: comfortable at rest but  less than ordinary 
activity results in symptoms  
 NYHA Class IV 
 severe symptoms 
 unable to carry out any physical activity without discomfort: symptoms of heart 
failure are present even at rest with increased discomfort with any physical 
activity 
 
Heart failure: diagnosis (NICE 2010)

Heart failure: diagnosis (NICE 2010)  
 The choice of investigation is determined by whether the patient has previously had a myoca rdial 
infarction or not.  
 Previous myocardial infarction  
 arrange echocardiogram within 2 weeks 
 if  transthoracic doppler 2D echocardiography imaging is poor (eg: in obese) 
consider other imaging methods, such as: 
 radionuclide angiography,  
 cardiac magnetic resonance imaging or  
 transoesophageal Doppler 2D echocardiography. Heart failure

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  116 
  No previous myocardial infarction 
 measure serum natriuretic peptides (BNP) 
 if levels are ' high ' (> 400) arrange echocardiogram within 2 weeks 
 if levels are ' raised ' (100-400 ) arrange echocardiogram within 6 weeks 
 40% of patients with raised BNP will have left ventricular systolic

dysfunction on echo. the remaining will have other cardiac 
abnormalities. 
 if levels are ' normal ' (< 100) hear failure is unlikely (investigate for other 
causes ) 
 
B-type natriuretic peptide (BNP) 
 Source 
 produced mainly by the left ventricular myocardium in response to strain.  
 Effect  
 The net effect of these peptides is:  
 ĻBP (due to the decrease in systemic vascular resistance) and, thus, afterload on 
the heart.

the heart.  
 Ļcardiac output (due to an overall decrease in central venous pressure) and 
preload as a result of the reduction in blood volume that follows natriuresis and 
diuresis.  
 Uses  
 normal level rules out acute heart failure in the emergency setting  
 Very high levels are associated with a poor prognosis.  
 Excretion 
 Less than 5% of BNP is cleared renally whereas NT-proBNP is reliant solely on the kidney

for excretion and hence it is unreliable in patients with coexistent renal dysfunction. 
 
BNP NTproBNP 
High levels  > 400 pg/ml (116 pmol/litre) > 2000 pg/ml (236 pmol/litre) 
Raised levels  100-400 pg/ml (29-116 pmol/litre) 400-2000 pg/ml (47-236 pmol/litre) 
Normal levels  < 100 pg/ml (29 pmol/litre) < 400 pg/ml (47 pmol/litre) 
 
Diagnosis of acute heart failure (Nice guidelines 2014):  
 In people presenting with new suspected acute heart failure:

 rule out the diagnosis of heart failure if : 
 BNP less than 100 ng/litre 
 NT‑proBNP less than 300 ng/litre. 
 new suspected acute heart failure with raised natriuretic peptide levels  perform 
transthoracic Doppler 2D echocardiography (within 48 hours of admission) 
 
Factors, which alter the BNP level: 
Increase BNP levels Decrease BNP levels 
 Aortic stenosis,  
 Ischaemia 
 Tachycardia 
 Right ventricular overload

 Right ventricular overload 
 Hypoxaemia (including pulmonary embolism) 
 GFR < 60 ml/min 
 Sepsis 
 COPD, Cor pulmonale  Obesity 
 Diuretics 
 ACE inhibitors 
 Beta-blockers 
 Angiotensin 2 receptor blockers 
 Aldosterone antagonists 578

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  117 
 Increase BNP levels Decrease BNP levels 
 Diabetes 
 Age > 70 
 Liver cirrhosis 
 Hyperaldosteronism 
 Stable angina, Acute coronary syndromes 
 Atrial fibrillation (AF) 
 
Mechanism of  central sleep apnea (CSA) in HF: 
 Which mechanism is responsible for the patient ’s polysomnography findings in heart

failure? 
 Increased sensitivity to carbon dioxide and stimulation of the vagal receptors.  
 increased sensitivity to PaCO 2 is a protective mechanism from hypercapnia due to heart 
failure. 
 HF  ↑duration of circulation of blood gases from the lungs to the brain.  
 When these blood gases reach the brain, the increased sensitivity to PaCO 2  
higher-than-normal response of hyperventilation  ↓PaCO 2 lower than the apneic 
threshold.

threshold. 
 As soon as the brain detects low PaCO 2 it will cease ventilation with apnea 
(central) so PaCO 2 can rise again.  
 As soon as the PaCO 2 rises again and reaches the brain (longer than normal due 
to heart failure), it will cause another episode of hyperventilatio n.  
 supine position  ↑ venous return  pulmonary congestion  activate vagal receptors  
 hyperventilation. 
 
 Hyponatraemia in patients with CHF 
 Water restriction is the first-line and mainstay of therapy

 Stopping furosemide will not be possible for a patient who has decompensated h eart failure.  
 Similarly, administration of hypertonic saline is only indicated if there is neurological 
manifestation of hyponatremia.  
 Moreover hypertonic or isotonic saline administration will be poorly tolerated in a volume-
overloaded patient. 
 associated with the worst prognosis  
 
Prognostic markers   worse prognosis in heart failure  include  
 High BNP/NT-pro-BNP 
 Anaemia 
 Hyponatraemia

 Anaemia 
 Hyponatraemia 
 Increased uric acid. 
Chest x-ray: pulmonary oedema 
Features of pulmonary oedema on a chest x-ray may include: 
 interstitial oedema 
 bat's wing appearance 
 upper lobe diversion (increased blood flow to the superior parts of the lung) 
 Kerley B lines 
 pleural effusion 
 cardiomegaly may be seen if there is cardiogenic cause 
 
 579

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  118 
  
Kerley A lines (orange arrows), Kerley B lines (blue arrows) and Kerley C lines (green arrows) are  all 
seen, and all represent essentially the same thing; expansion of the interstitial space by fluid. 
 
The most common cause of flash pulmonary oedema is myocardial ischaemia.

Bilateral renal artery stenosis is a less common cause of flash pulmonary oedema.   
 
Heart failure: drug management 
Acute heart failure management (Nice guidelines 2014):  
  Initial pharmacological treatment 
 intravenous diuretics 
 Do not routinely offer opiates 
 Morphine is an ungraded recommendation and is not actually included on 
guidelines as a drug to use in decompensated heart failure, though it is sometim es

prescribed as a means of reducing anxiety and so the work of breathing. 
 Do not routinely offer nitrates 
 Do not offer sodium nitroprusside 
 Do not routinely offer inotropes or vasopressors 
 Consider inotropes or vasopressors in people with acute heart failure with 
potentially reversible cardiogenic shock.  
 Initial non-pharmacological treatment 
 cardiogenic pulmonary oedema with severe dyspnoea and acidaemia consider 
starting non-invasive ventilation

starting non-invasive ventilation  
 in this case it is the most useful next step , before diuretics .  The effect of the 
diuresis comes much later and has a modest overall contribution in managing the 
symptoms of shortness of breath. 
 Consider invasive ventilation in acute heart failure that, despite treatment, is leading to or 
is complicated by: respiratory failure or reduced consciousness or physical exhaustion.

In a person presenting with acute heart failure who is already taking beta-blockers:  
 continue the beta-blocker treatment unless they have a heart rate less than 50 bea ts per 
minute, second or third degree atrioventricular block, or shock. 
 restart beta-blockers once their condition has been stabilised – for example, when intravenous 
diuretics are no longer needed. 
In a person presenting with acute heart failure who is already taking frusemide  80 mg :

 in a patient with evidence of decompensated heart failure and fluid overlo ad. The most 
appropriate initial management is to Increase furosemide and relieve the symptoms of fluid 
overload – pulmonary and peripheral oedema.  
 
Chronic management 
 4 drugs have been shown to improve mortality in patients with chronic heart failure : 
1. ACE inhibitors  
2. spironolactone  
580

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  119 
 3. beta-blockers  
4. hydralazine with nitrates  
 No long-term reduction in mortality has been demonstrated for loop diuretics such as furosemide . 
 In patients with symptoms of heart failure not controlled on ACE inhibitors alone, switching to the

combination of ARB and neprilysin inhibitor can further improve symptoms and quality of li fe.  
 e.g: combination of sacubitril and valsartan reduced cardiovascular death and heart 
failure hospitalisations by 20%.  
 NICE issued updated guidelines on management in 2010, key points  include: 
 first-line treatment for all patients is both an ACE-inhibitor and a beta-blocker 
 With the persisting symptoms despite 80 mg of furosemide, guidelines would

initially suggest the addition of an ACE inhibitor.  
 Although beta-blockers would be of further benefit in this patient, it is 
important first to establish him on ACEi and then introduce beta-blockers like 
carvedilol, metoprolol or bisoprolol in a small dose and gradually increase. 
 second-line treatment is now either an aldosterone antagonist, angiotensin II recept or 
blocker or a hydralazine in combination with a nitrate

 if symptoms persist cardiac resynchronisation therapy or digoxin should be considered 
 digoxin has also not been proven to reduce mortality in patients with heart failure.  
 It may however improve symptoms due to its inotropic properties.  
 Digoxin is strongly indicated if there is coexistent atrial fibrillation 
 There is no evidence that increasing a dose of digoxin above 62.5 µg in a patient in 
sinus rhythm would have any added benefit.

sinus rhythm would have any added benefit. 
 diuretics should be given for fluid overload 
 offer annual influenza vaccine 
 offer one-off  pneumococcal vaccine 
 adults usually require just one dose but those with asplenia, splenic dysfunction or 
chronic kidney disease need a booster every 5 years 
indications of anticoagulation in patients with heart failure 
Anticoagulation should be considered for patients with heart failure and a low eject ion fraction,

particularly in those who have any of the following: 
 A previous thromboembolic event 
 Intracardiac thrombus 
 Left ventricular aneurysm  
 
In a patient with significant heart failure on maximum medical therapy  (ramipril 10 mg OD, 
furosemide 80 mg OD, bisoprolol 10 mg OD and spironolactone 25 mg OD). Despite this, they h ave 
continued to deteriorate but criteria for cardiac resynchronisation therapy (CRT) are not

achieved . What is the most appropriate next step to improve mortality?  
  Ivabradine  
 acts as an inhibitor of the  If current within the myocardium. This current, particularly 
present in the sino-atrial and atrio-ventricular nodes, acts as the cardiac pacemaker.  
 By inhibiting this current, ivabradine reduces the heart rate without impacting the force 
of cardiac contraction.  
 This has been shown to reduce heart failure hospitalisation and mortality in patients

already on maximum medical therapy.  
 Due to its mechanism, ivabradine is only effective in patients in sinus rhythm. 
 
 If known case of heart failure – on 
β-blocker – presented with acute 
pulmonary oedema  Increase 
diuretics, stop β -blockers and 
restart β -blockers when his 
lungs are dry  
 
A significant benefit from using IV iron in patients with heart failure and iron deficiency was 
demonstrated in a study

demonstrated in a study 
 history of heart failure +  iron deficiency.  the first step  correcting iron deficiency  
 
581

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  120 
 Heart failure: non-drug management  
Cardiac resynchronisation therapy (CRT) (biventricular pacing) 
 criteria for resynchronisation therapy   recommended by NICE guidance 
1. They are in sinus rhythm + 
 either with a QRS duration of  ≥ 150 ms estimated by ECG (LBBB)

 or with a QRS duration of 120-149 ms estimated by ECG and mechanical 
dyssynchrony that is confirmed by echocardiography. 
2. They have a left ventricular ejection fraction of ≤ 35%. 
3. They are receiving optimal pharmacological therapy. 
 The echo will show asynchronous contraction of the LV and RV and subsequently 
reduced ejection fraction.  
 improved symptoms and reduced hospitalisation in NYHA class III patients

  Nice guidelines state that patients who are asymptomatic (NYHA class 1) with a LBBB 
and QRS of more 150 ms should be considered for a CRT.  
 the most useful investigation in predicting symptomatic response to cardiac 
resynchronisation therapy is   transthoracic echocardiogram and  ECG  
 When a CRT device is implanted the left ventricular lead is inserted in the coronary sinus. To 
obtain access to the coronary sinus a catheter with an aggressive tip is used. There is a 1% risk

of causing dissection/perforation to the coronary sinus which can lead to cardiac 
tamponade.  
 
Implantable cardioverter defibrillator (ICD)  
 Where there is no LBBB and QRS is between 120-149 ms, ICD is the recommended option 
according to NICE guidelines. This is because of the risk of VT on account of the low 
ejection fraction, (<35%), and symptomatic heart failure. 
 
Exercise training 
 improves symptoms but not hospitalisation/mortality 
 
Tocolysis-associated pulmonary oedema

Tocolysis-associated pulmonary oedema 
 Tocolytics are medications administered for the suppression of premature contractions.  
 Acute pulmonary oedema can occur with administration of β 2 agonists for tocolysis in 
up to 5 –15% of cases.  
 It usually occurs after 24 h of administration of these agents.  
 The chest X-ray reveals pulmonary infiltrates and normal heart size .  
 Concomitant use of corticosteroids that are often administered for lung maturation have als o

been implicated as risk factor for development of tocolysis-associated pulmonary oedem a.  
 Treatment involves stopping the tocolytics, oxygen and careful volume control. 
 Deferential: 
 Peripartum cardiomyopathy: 
 typically presents in the last month of pregnancy and up-to 6 months postpartum. 
 cardiomegaly on chest X-ray.  
 
Cardiac transplantation 
 
 By five years following cardiac transplantation,  nearly all patients have some degree of small

coronary vascular narrowing ( Coronary arteriopathy ). 
 
Hypertrophic obstructive cardiomyopathy (HOCM)  
 
HOCM is the most common cause of sudden cardiac death in the young 
 
 (HOCM) is an autosomal dominant disorder of muscle tissue caused by defects in the genes 
encoding contractile proteins.  Cardiomyopathies  582

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  121 
  The most common defects involve a mutation in the gene encoding β-myosin  heavy chain  
protein or myosin binding protein C.  
 Mutations to various proteins including beta-myosin, alpha-tropomyosin and troponin T  have 
been identified. 
 type of mutation  Frame-shift mutation 
 The estimated prevalence is 1 in 500.

 The estimated prevalence is 1 in 500. 
 Septal hypertrophy causes left ventricular outflow obstruction.  
 It is an important cause of sudden death in apparently healthy individuals. 
 
Features 
 
Symptoms and signs are similar to those of aortic stenosis, except that the character of the 
pulse in HOCM is jerky  
 
 often asymptomatic 
 dyspnea (the most common presenting symptom) 
 angina,  
 syncope

 angina,  
 syncope 
 sudden death (most commonly due to ventricular arrhythmias), arrhythmias, heart failu re 
 jerky pulse,  
 large 'a' waves,  
 double apex beat 
 ejection systolic murmur: increases with Valsalva manoeuvre and decreases on squatting 
 Diastolic decrescendo murmur of aortic regurgitation (10% of patients) 
 
 Wolff-Parkinson White 
Echo - mnemonic - MR SAM ASH 
 mitral regurgitation (MR)

 mitral regurgitation (MR) 
 systolic anterior motion (SAM) of the anterior mitral valve leaflet 
 asymmetric hypertrophy (ASH) 
ECG 
 left ventricular hypertrophy 
 progressive T wave inversion 
 deep Q waves 
 right or left axis deviation  
 PR prolongation  
 atrial fibrillation may occasionally be seen 
 Right bundle branch block  
 the most ECG FINDING which support a diagnosis of HOCM  
 RBBB is correlated with anterior, anteroseptal and mid-septal myocardial fibrosis in

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  122 
  
ECG showing typical changes of HOCM including LVH and T wave inversion 
 
Dagger-like Q waves  
 
This ECG shows the typical pattern of apical HCM : 
 Large precordial voltages. 
584

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  123 
  Giant T wave inversions in the precordial leads 
 Inverted T waves are also seen in the inferior and lateral leads.  
 
Type of 
cardiomyopathy Selected points 
Hypertrophic 
obstructive 
cardiomyopathy  Leading cause of sudden cardiac death in young athletes 
 Usually due to a mutation in the gene encodi ng β-myosin heavy chain

protein 
 Common cause of sudden death 
 Echo findings include: 
  MR,  
 systolic anterior motion (SAM) of the anterior mitral valve 
 asymmetric septal hypertrophy 
Arrhythmogenic right 
ventricular dysplasia  Right ventricular myocardium is replaced by fatty and fibrofatty tissue 
 Around 50% of patients have a mutation of one of the several genes 
which encode components of desmosome  
 ECG abnormalities in V1-3,  
 typically T wave inversion.

 typically T wave inversion.  
 An epsilon wave is found in about 50% of those with ARV - this 
is best described as a terminal notch in the QRS complex 
 Beta-blockers or verapamil for symptoms 
 Cardioverter defibrillator 
 Dual chamber pacemaker 
 Endocarditis prophylaxis 
 
Beta-blockers 
 Generally first-line agents  
 increase diastolic filling and decrease contractility 
 Reduces provocable gradient 
disopyramide

disopyramide  
 If ß-blockers alone are ineffective, disopyramide, may be added (Class IA anti-arrhythmic 
drug)  
 anticholinergic side-effects include dryeyes and mouth, urinary hesitancy or retention, a nd 
constipation. 
 QTc interval should be monitored during dose up-titration and the dose reduced if it exce eds 480 
ms.  
 Disopyramide should be avoided in patients with glaucoma, prostatism, and in patients takin g

other drugs that prolong the QT interval, such as amiodarone and sotalol. 
Verapamil  
 Verapamil (starting dose 40 mg three times daily to maximum 480 mg daily) can be used when 
ß-blockers are contraindicated or ineffective, 
 close monitoring is required in patients with severe obstruction (≥100 mm Hg) or elevated 
pulmonary artery systolic pressures, as it can provoke pulmonary oedema. 
 Verapamil should however be avoided in HOCM patients with coexistent Wolff Parkinson White

as it may precipitate VT or VF. 
 
Implantable cardioverter defibrillators (ICD) implantation  prevention of sudden cardiac death  
 recommended in patients who have survived a cardiac arrest due to VT or VF  or who have 
spontaneous sustained VT causing syncope or haemodynamic compromise 
 
Invasive treatment (myomectomy or alcohol septal ablation) (ESC Guidelines 2014)  
 Left ventricular outflow tract obstruction (LVOTO) is defined as a peak instantaneous Doppler LV

outflow tract gradient of ≥30 mm Hg, but the threshold for invasive treatment is usually 
considered to be ≥50 mm Hg.  
 Septal reduction therapy  is recommended in patients with LVOT gradient of ≥ 50 mm Hg, who 
are in NYHA functional Class III –IV, despite maximum tolerated medical therapy.  585

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  124 
  The most commonly performed surgical procedure used to treat LVOTO is ventricular septal 
myectomy (Morrow procedure). 
 Pre-operative determinants of a good long-term outcome are age < 50 years, left atrial siz e < 46 
mm, absence of atrial fibrillation and male gender. 
 surgery VS septal alcohol ablation (SAA)

 surgery VS septal alcohol ablation (SAA) 
 both procedures improve functional status with a similar procedural mortality. 
 Septal alcohol ablation is associated with a higher risk of AV block, requiring permanent 
pacemaker implantation and larger residual LV outflow tract gradients. 
 In contrast to myectomy, most patients develop right-, rather than left bundle branch  block 
after SAA. 
Drugs to avoid 
 nitrates 
 ACE-inhibitors 
 Inotropes : Digoxin

 Inotropes : Digoxin 
  
Poor prognostic factors , which  are predictive of sudden cardiac death 
 
 syncope 
 family history of sudden death 
 Maximum left ventricular wall thickness greater than 3 cm 
 young age at presentation 
 non-sustained ventricular tachycardia on 24 or 48-hour Holter monitoring 
 Abnormal blood pressure changes on exercise ( Blood pressure drop during peak exercise on 
stress testing ). 
Screening of HOCM

Screening of HOCM   
 Current guidelines suggest that a resting ECG and TTE (transthoracic ECHO) are the most 
effective screening strategies for relatives of patients with HOCM.  
 Genetic testing is not recommended as a first line screening tool given varying rates of 
penetrance. 
Dilated cardiomyopathy (DCM) 
Overview 
 Most common cardiomyopathy  
 Sex: ♂ > ♀ (approx. 3:1)

 Sex: ♂ > ♀ (approx. 3:1)  
 dilated heart leading to systolic (+/- diastolic) dysfunction 
 all 4 chambers affected but LV more so than RV 
Features 
 arrhythmias,  
 emboli  cardio-embolic stroke,   
 mitral regurgitation 
 absence of congenital, valvular or ischaemic heart disease 
Causes  
 Idiopathic (approx. 50%)  
 alcohol: may improve with thiamine 
 postpartum 
 genetic inherited dilated cardiomyopathy:

 genetic inherited dilated cardiomyopathy: 
 around  third of DCM patients  
 the majority  of defects are inherited in an autosomal dominant  fashion although 
other patterns of inheritance are seen 
 infections e.g.  
 Coxsackie B,  
 HIV,  
 diphtheria,  
 parasitic 
 endocrine e.g.  
586

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  125 
  Hyperthyroidism 
 neuromuscular e.g.  
 Duchenne muscular dystrophy 
 nutritional e.g.  
 Kwashiorkor,  
 pellagra,  
 thiamine/selenium deficiency 
 Selenium deficiency is one of the reversible causes of dilated 
cardiomyopathy.  
 drugs e.g.  
 Doxorubicin

 Doxorubicin 
 Infiltrative (may also lead to restrictive cardiomyopathy ) e.g.  
 Haemochromatosis,  
 Sarcoidosis 
 
Diagnosis  Echocardiogram 
 The echo may show: 
 Reduced left ventricular ejection fraction,  
 myocardial dyssynchrony (myocardial segments contract at different points in time),  
 thinning of the left ventricular wall  
 dilated left ventricle.  
 
Type of cardiomyopathy Selected causes/points

Type of cardiomyopathy Selected causes/points 
Dilated cardiomyopathy Classic causes include 
 alcohol 
 Coxsackie B virus 
 wet beri beri 
 doxorubicin 
Restrictive cardiomyopathy Classic causes include 
 post-radiotherapy 
 Loeffler's endocarditis 
 
Becker ’s muscular dystrophy 
 X-linked recessive  disorder resulting from a mutation in the dystrophin gene .  
 The clinical picture is similar to that of Duchenne ’s muscular dystrophy but it is much  milder .

 Patients usually present between the ages of 5 and 15 years, though presentatio n may not be 
until the fourth or fifth decade.  
 Patients may present with heart failure secondary to dilated cardiomyopathy rather than 
the classic proximal muscle weakness.  
 
Restrictive cardiomyopathy 
  
Causes 
 amyloidosis (e.g. secondary to myeloma) - most common cause in UK

 Cardiac involvement is the most common cause of death in patients with amyloidosis 
associated with an immunocyte dyscrasia - typically as restrictive cardiomyopathy 
 Transthyretin gene mutations can lead to restrictive cardiomyopathy from amyloid 
deposition in the heart. 
 Diagnosis is confirmed by myocardial biopsy , which shows amyloid infiltration  when 
stained with Congo Red .  
587

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  126 
  myocardial biopsy, which when stained with Congo Red  will show " apple 
green birefringence " amyloid under polarized light. 
 haemochromatosis 
 Loffler's syndrome 
 scleroderma 
 Systemic sclerosis 
 Carcinoid syndrome. 
 
Pathophysiology:

 Proliferation of connective tissue ĺ Ļ elasticity of myocardium  ĺ Ļ ventricular  compliance ĺ  Ļ 
diastolic filling ĺ atrial congestion ĺ atrial enlargement and severe  diastolic dysfunction  
 Features 
 Physical examination reveals right heart failure with a raised JVP, characteristically showing a 
prominent deep Y descent 
 Heart size is often normal. 
 S 4 heart sound , due to ventricular noncompliance.

 Pericardial effusion is common, but rarely causes tamponade 
 The most characteristic ECG finding of restrictive cardiomyopathy is diffusely diminished 
voltages 
 Echocardiography findings 
 small thick ventricles and a thick interatrial septum due to amyloid deposits, which 
have a 'granular sparkling' appearance  
 Amyloid deposits in the heart produce generalized thickening of the myocardium 
(as opposed to asymmetrical septal hypertrophy commonly seen in hypertrophic

cardiomyopathy) and diastolic dysfunction. 
 impaired relaxation in the diastolic phase. 
 bright speckled appearance. 
 
 constrictive pericarditis 
 Features  are very similar in constrictive pericarditis, but in constrictive pericarditis: 
 the apex is frequently non-palpable due to the thick pericardium 
 chest X-ray may show pericardial calcifications  
 
Features suggesting restrictive cardiomyopathy rather than constrictive pericarditis

 prominent apical pulse 
 absence of pericardial calcification on CXR 
 heart may be enlarged 
 ECG abnormalities e.g. bundle branch block, Q waves 
 
Clinical Features of Constrictive Pericarditis and Restrictive Cardiomyopathy  
Clinical Features Constrictive Pericarditis Restrictive Cardiomyopathy 
History Prior history of pericarditis or 
condition that causes pericardial 
disease History of systemic disease (eg, 
amyloidosis, hemochromatosis) 
Systemic examination

Systemic examination 
- Heart sounds Pericardial knock, high-frequency 
sound Presence of loud diastolic filling sound 
S3, Low-frequency sound 
Murmurs No murmurs Murmurs of mitral and tricuspid 
insufficiency 
 
apical pulse apex is frequently non-palpable due 
to the thick pericardium prominent apical pulse 
 
Prior chest radiograph Pericardial calcification Normal results of prior chest 
radiograph 
 
 Cardiac transplant

 Cardiac transplant  
___________________________________________________ _____________________________ 588

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  127 
 Peripartum cardiomyopathy (PCM) 
 biventricular heart failure during the third trimester.  
 the aetiology: unknown, although both myocarditis and low levels of dietary seleniu m have been 
postulated as causes.  
 similar to the management of heart failure in any other situation with vasodilato rs, diuretics and

beta blockade. ACE inhibition is reserved for the post-partum period.  
 sodium restriction,  
 diuretics to optimise the volume status,  
 digoxin and afterload-reducing agents.  
 Hydralazine  
 For patients presenting with PCM, defined as left ventricular systolic dysfunction 1 month prio r to 
delivery or 5 months postpartum, volume status should first be managed with diuret ics after 
liaison with obstetricians. Beta-blockers should be added once the patient's volume status

is optimised.  
 Anticoagulation  
 Patients with PCM are at risk of thromboembolism due to both hypercoagulable state  of 
pregnancy and stasis of blood in the left ventricle. Therefore, anticoagulation with heparin 
is recommended.  
 
Type of 
Peripartum 
cardiomyopathy  Typical develops between last month of pregnancy and 5 months post-
partum 
 More common in older women, greater parity and multiple gestations 
Takotsubo

Takotsubo 
cardiomyopathy  'Stress'-induced cardiomyopathy e.g. patient just found out family member 
dies then develops chest pain and features of heart failure 
 Transient, apical ballooning of the myocardium 
 Treatment is supportive 
 
Takotsubo cardiomyopathy 
 
Definition:  
 Takotsubo cardiomyopathy is a type of non-ischaemic cardiomyopathy associated with a

transient, apical ballooning of the myocardium.  
 acute, stress-induced, reversible dysfunction of the left ventricle  
Epidemiology:  
 especially postmenopausal women > 60 years 
Pathophysiology:  
 emotional/physical stress ĺ massive catecholamine discharge ĺ cardiotoxicity, multi -vessel 
spasms and dysfunction ĺ myocardial stunning  
Features  
 chest pain 
 features of heart failure 
 ST elevation 
 normal coronary angiogram 
Treatment   
 supportive 
Prognosis :

Treatment   
 spontaneous recovery if stressors are avoided 
 
 589

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  128 
  
Congenital heart disease: types 
 
Congenital heart disease 
 cyanotic: TGA most common at birth, Fallot's most common overall 
 acyanotic: VSD most common cause 
 
Acyanotic  - most common causes

Acyanotic  - most common causes 
 ventricular septal defects (VSD) - most common , accounts for 30% 
 atrial septal defect (ASD)  10%. 
 patent ductus arteriosus (PDA) 
 coarctation of the aorta 
 aortic valve stenosis 
VSDs are more common than ASDs. However, in adult patients ASDs are the more common new  
diagnosis as they generally presents later 
 
Cyanotic  - most common causes 
 tetralogy of Fallot 
 There is a single sound in Fallot's because of an absent P2.

 A Blalock shunt (anastomosis of subclavian artery to pulmonary artery) used to be 
performed for Fallot's tetralogy and leads to a weak left radial pulse. 
 transposition of the great arteries (TGA) 
 Fallot's  is more common than TGA. However, at birth TGA is the more common lesion as 
patients with Fallot's generally presenting at around 1-2 months 
 TGA is usually treated by prostaglandins in order to keep the ductus arteriosus

patent  (from pulmonary artery to the descending aorta ), so some oxygenated blood can  
reach systemic circulation.  
 tricuspid atresia 
 pulmonary valve stenosis 
 Total anomalous pulmonary venous connection (TAPVC)   
 TAPVC consists of an abnormality of blood flow in which all four pulmonary v eins drain 
into systemic veins or the right atrium with or without pulmonary venous obstruction. 
 Systemic and pulmonary venous blood mix in the right atrium. 
 
 Aortic regurgitation may be a feature of osteogenesis imperfecta. 
 Ebstein's anomaly is associated with maternal LiCO 3 use if exposed in the first trimester. 
 The majority of cases of neonates with complete heart block may be caused by a utoimmune 
disease, particularly anti-ro antibodies in the mother. 
 Left ventricle (LV) hypolasia occurs when the left sided chambers fail to develop an d blood

enters the systemic circulation from the right ventricle via the pulmonary artery and a patent 
ductus arteriosus. 
Tetralogy of Fallot (TOF) 
  TOF is the most common cause of cyanotic congenital heart disease*.  
 *however, at birth transposition of the great arteries is the more common lesi on as patients with 
TOF generally present at around 1-2 months

TOF generally present at around 1-2 months  
 It typically presents at around 1-2 months, although may not be picked up un til the baby is 6 
months old 
 TOF is a result of anterior malalignment of the aorticopulmonary septum. The four cha racteristic 
features are: 
1. ventricular septal defect (VSD) 
Congenital heart diseases 590

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  129 
 2. right ventricular hypertrophy 
3. right ventricular outflow tract obstruction, pulmonary stenosis 
 There is a single sound in Fallot's because of an absent P2. 
4. overriding aorta 
 
 The severity of the right ventricular outflow tract obstruction determines the degree of  cyanosis 
and clinical severity 
 
Other features

Other features  
 cyanosis 
 causes a right- to-left shunt 
 ejection systolic murmur due to pulmonary stenosis (the VSD doesn't usually cause a murmu r) 
 a right-sided aortic arch is seen in 25% of patients 
 chest x-ray shows a 'boot-shaped' heart, ECG shows right ventricular hypertrophy 
 surgical repair is often undertaken in two parts 
 cyanotic episodes may be helped by beta-blockers to reduce infundibular spasm

The most common residual lesion in repaired tetralogy of Fallot is pulmonary regurgitation.  
 
Ventricular septal defects (VSD) 
Overview 
 The second most common congenital heart defect  
 bicuspid aortic valve is the most common congenital heart defect  
 They close spontaneously in around 50% of cases. 
  the most common site for a VSD  Perimembranous

 Perimembranous VSDs account for 70-80% of VSDs and are situated between the inl et 
and outlet portions of the septum. 
 Congenital VSDs : associated with: 
 chromosomal disorders (e.g. Down's syndrome, Edward's syndrome, Patau syndrome)  
 Non-congenital causes incl ude: 
 Fetal alcohol syndrome 
591

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  130 
  Intrauterine infection (e.g., TORCH) 
  post myocardial infarction 
Features  
 Pan-systolic murmur  which is: 
  louder in smaller defects 
 usually loudest at the  left lower sternal edge (LSE) 
 Mid-diastolic murmur  over cardiac apex 
 Due to increased flow through the mitral valve 
 systolic thrill

 systolic thrill 
 Loud pulmonic S2 (if pulmonary hypertension develops) 
 Chest x-ray 
 Enhanced pulmonary vascular markings 
 Left atrial and ventricular enlargement 
 ECG 
 The clue to diagnosis in the ECG finding  Biventricular hypertrophy  
 Biventricular hypertrophy is classically described as having biphasic QRS 
complexes in V2 –5 – which is known as the Katz Wachtel phenomenon  and is 
classic for VSD . 
 Doppler echocardiography: confirms diagnosis

 Doppler echocardiography: confirms diagnosis 
 due to a poorly supported right coronary cusp resulting in cusp prolapse 
 Infective endocarditis 
 Eisenmenger's complex 
 Right heart failure 
 pregnancy is contraindicated in women with pulmonary hypertension as it carries a 30-
50% risk of mortality. 
Treatment 
 small to moderate defects often heal spontaneously 
 Symptomatic and large VSDs   Surgical (patch) repair

 Heart-lung transplant or lung transplant with concurrent VSD repair if Eisenmenger's reaction has  
occurred 
 common congenital heart lesion 
 VSD is more common 
Types 
 Ostium secundum   
 70% of ASDs 
 associated with Holt-Oram syndrome (tri-phalangeal thumbs) 
 ECG: RBBB  with RAD  
 Ostium primum 
 present earlier than ostium secundum defects

 present earlier than ostium secundum defects 
 associated with abnormal AV valves 
 the AV node is displaced posteriorly and inferiorly and atrial and/or AV nodal conduction is  
often delayed.  
 ECG: RBBB with LAD, prolonged PR interval 
wide, fixed, split-second sound + right- axis deviation  Ostium secundum  
wide, fixed, split-second sound + left-axis deviation      Ostium primum  
 
Features 
 Symptoms 
 asymptomatic in youth 
 often discovered on routine school health exams

 mild fatigue 
 frequent respiratory infections 
 Larger ones may lead to signs of right ventricular failure, such as shortness of breath and  
a parasternal heave.  592

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  131 
  Physical exam 
 Mid-systolic ejection murmur (over the left second ICS ) 
 Due to  Relative pulmonary stenosis due to an increase in stroke volume  
 Soft mid-diastolic murmur (over the lower left sternal border)  
 arises from increased flow across the tricuspid valve. 
 loud S1 
 wide fixed-split S2

 loud S1 
 wide fixed-split S2   
 The most frequently tested knowledge  
 splitting is fixed (does not vary with respiration) 
 heaving cardiac impulse (LLSB) 
Predisposes patient to 
 CHF 
 2nd/3rd decades of life 
 Eisenmenger's syndrome  
 pulmonary hypertension 
 right ventricular hypertrophy 
 reversal to a right- to-left shunt 
 stroke 
 due to paroxysmal embolus 
Associated condition

Associated condition 
 Tricuspid atresia is the congenital cardiac disorder most commonly associated with an atrial 
 Down syndrome 
 Fetal alchohol syndrome 
 Holt-Oram syndrome 
 Autosomal dominant disorder, which is also called hand-heart syndrome becau se affected 
children present with an ASD, a first degree heart block, and abnormalities of the u pper 
limbs (e.g., absent radial bones). It affects approx. 1 in 100,000 children. 
ECG 
 Right bundle branch block

ECG 
 ostium primum ASD left axis deviation.  
 ostium secundum ASD   right axis deviation. 
 first degree heart block  prolongation of the PR interval  
 due to delayed conduction through the atria or through the AV node  
 The QRS pattern typically is either an rSr' or an rsR' resulting from dilation and hypertroph y of 
the right ventricular outflow tract caused by volume overload of the right heart.

prominent left precordium  in a young patient with an ejection murmur in the second left 
intercostal space indicat  ASD with pulmonary hypertension 
 A prominent left precordium suggests that:  
 the right ventricle was dilated during childhood  
 RV working against a high pressure  
Patent ductus arteriosus 
 
Overview 
 acyanotic congenital heart defect

Overview 
 acyanotic congenital heart defect 
 connection between the pulmonary trunk and descending aorta 593

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  132 
  more common in premature babies, born at high altitude or maternal rubella infection in  the first 
trimester 
Features 
 left subclavicular thrill 
 continuous 'machinery' murmur at the left upper sternal edge with late systolic accentuation  
 large volume, bounding, collapsing pulse 
 heaving apex beat

 heaving apex beat 
 indomethacin closes the connection in the majority of cases 
 if associated with another congenital heart defect amenable to surgery then prostagland in E1 is 
useful to keep the duct open until after surgical repair 
Patent foramen ovale(PFO) 
  PFO is present in around 20% of the population .

 It may allow embolus (e.g. from DVT) to pass from right side of the heart to the left side lea ding 
to a stroke - 'a paradoxical embolus' 
 There also appears to be an association between migraine and PFO.  
 Some studies have reported improvement in migraine symptoms following closure of the 
PFO 
 right heart catheter :  left to right shunting of oxygenated blood at level of the atrium.  
 oxygen saturation data show a step-up in the saturations between the vena cava and  the

right atrium.  
For a right-sided thrombus (e.g. DVT) to cause a left-sided embolism (e.g. stroke) it must obviously 
pass from the right- to-left side of the heart 
 
The following cardiac lesions may cause such events 
 
 patent foramen ovale - present in around 20% of the population 
 atrial septal defect - a much less common cause 
 
Blue toe syndrome

Blue toe syndrome  
 80% of such digital ischaemias have an emboli originating from the heart and so a n urgent 
echocardiogram is crucial to prevent further and more severe events occurring. 
 sudden onset of a cold, painful, and cyanotic big toe. the next steps  Therapeutic 
heparin and urgent echocardiogram  
Eisenmenger's syndrome

Eisenmenger's syndrome 
 Eisenmenger's syndrome describes the reversal of a left- to-right shunt in a congenital heart 
defect due to pulmonary hypertension.  
 This occurs when an uncorrected left- to-right leads to remodeling of the pulmonary 
microvasculature, eventually causing obstruction to pulmonary blood and pulmonary 
 
 ventricular septal defect 
 atrial septal defect 
Features 
 original murmur may disappear

Features 
 original murmur may disappear 
 cyanosis 
 clubbing 
 right ventricular failure 
 haemoptysis, embolism 
 heart-lung transplantation is required 
 
 594

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  133 
Ebstein's anomaly 
 Ebstein's anomaly is a congenital heart defect characterised by low insertion of the tricuspid 
valve resulting in a large atrium and small ventricle. It is sometimes referred to as 'atrialisatio n' of 
the right ventricle.

the right ventricle.   
 The most common findings are: 
  hypoplastic (atrialised) RV,  
 apical displacement of the septal and posterior tricuspid valve leaflets,  
 ASD. 
 Leads to right bundle branch block pattern on ECG. 
 Ebstein's anomaly may be caused by exposure to lithium in-utero 
 
Associations  
 tricuspid incompetence (pan-systolic murmur, giant V waves in JVP) 
 Wolff-Parkinson White syndrome occurs in around 15% of the patients.

The presence of delta waves and short PR interval is indicative of WPW. When correlat ed with  past 
surgical history (repair of atrial septal defect and tricuspid valve abnormalities as a child),  Ebstein ’s 
anomaly is the most likely diagnosis. 
 
Cardiac manifestations of genetic disorders  
 
Peripheral vascular disease  
 is a marker for increased risk of cardiovascular events even when it is asymptomatic.  
 the femoropopliteal artery , the most common site of peripheral arterial disease.  
 paresthesia, intermittent claudication in calf and foot and palpable femoral pulses but 
absent pedal pulses 
 age 
 about 20% of people aged over 60 years have some degree of peripheral arterial disease . 
 male gender  
 Smoking 
 Diabetes 
 hypertension

 Smoking 
 Diabetes 
 coronary artery disease. 
Feature 
 intermittent claudication (leg pain while walking) (The most common initial symptom ). 
 Critical limb ischaemia : ischaemic pain, ulceration, tissue loss and/or gangrene. 
 measuring the ankle brachial pressure index 
 Calculate the index in each leg by dividing the highest ankle pressure by the highest a rm 
pressure. 
Vascular diseases  595

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  134 
  Imaging before considering  revascularization 
 duplex ultrasound  ( first-line imaging ) 
 contrast-enhanced magnetic resonance angiography   (after duplex ultrasound) 
  computed tomography angiography  ( if contrast-enhanced magnetic reso nance 
angiography is contraindicated or not tolerated.) 
Treatment 
Mild symptoms :

Treatment 
Mild symptoms :  
 exercise programme 
 2 hours of supervised exercise a week for a 3 ‑month period 
 encouraging people to exercise to the point of maximal pain.  
 management of cardiovascular risk factors (for example, with aspirin or statins)  
  vasoactive drug treatment (for example, with naftidrofuryl oxalate). 
 Which drug might help improve pain-free walking distance?  
 Naftidrofuryl 
 Indicated only when exercise has not led to satisfactory improvement and th e

person refuse  angioplasty or bypass surgery. 
 discontinue naftidrofuryl oxalate if there has been no symptomatic benefit  after 3 –6 
months.  
 Vasoactive drugs have limited benefit in treating intermittent claudication.  
 There is modest evidence for the use of drugs such as naftidrofuryl and pentoxifylline, but little 
benefit from cinnarizine or inositol nicotinate.  
 Simvastatin may be prescribed for patients with peripheral vascular disease who have eleva ted

cholesterol levels, but there is no data on improvements in walking distance. 
severe symptoms: 
 endovascular treatment (such as angioplasty or stenting), bypass surgery, pain manageme nt 
and/or amputation. 
Venous ulceration 
 venous ulcerations are the most common type of ulcer affecting the lower extremities. 
 The probable underlying cause: venous insufficiency  venous congestion  ulceration

 Treatment of venous ulceration is control of oedema, treating any infection, and compressio n.  
 Compressive dressings or devices should not be applied if the arterial circulation is 
impaired, and ankle-brachial pressure index is needed before application of compression  
 
Monckeberg's calcific medial sclerosis,   
 a benign condition involving muscular arteries of older persons.  
 several prominent calcified vessels seen in the radiograph.  
 Management  Ignore it

 Management  Ignore it  
 
Rheumatic fever: criteria 
 
 Rheumatic fever develops following an immunological reaction to recent (2-6 weeks 
ago) Streptococcus pyogenes  infection. 
 Diagnosis is based on evidence of recent streptococcal infection  accompanied by: 
 
 2 major criteria 
 1 major with 2 minor criteria 
 Evidence of recent streptococcal infection 
 ASOT > 200iu/mL 
 history of scarlet fever 
 positive throat swab 
 increase in DNase B titre 
 
 Major criteria

 Major criteria 
 erythema marginatum 
 Sydenham's chorea Other cardiac diseases  596

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  135 
  polyarthritis 
 carditis (endo-, myo- or peri-) 
 subcutaneous nodules 
 Pea-sized, firm and non-tender.  
 characteristically seen on the extensor surfaces of joints such as knees and elbows 
and also over the spine. 
 Minor criteria 
 raised ESR or CRP 
 pyrexia 
 arthralgia (not if arthritis a major criteria)

 arthralgia (not if arthritis a major criteria) 
 prolonged PR interval 
 
Erythema marginatum is seen in around 10% of children with rheumatic fever. It is rare in  adults 
 
Infective endocarditis ( IE) 
 
597

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  136 
  previous episode of endocarditis  
 The strongest risk factor for developing infective endocarditis.   
 previously normal valves (50%, typically acute presentation) 
 rheumatic valve disease (30%) 
 prosthetic valves 
 congenital heart defects 
 intravenous drug users (IVDUs, e.g. Typically causing tricuspid lesion)

 Hypertrophic cardiomyopathy. 
Frequency  
 In terms of frequency, IE will most likely affect the mitral valve, then aortic valve, then both aortic 
and mitral valves, then tricuspid and finally (and rarely) the pulmonary valve. 
 If the valve is already abnormal, then the likelihood of infection is greater and will be mos t likely 
on the aortic valve.  
 High-pressure systems create more blood turbulence and permit inoculation of the valve.

 Which cardiac lesion is most likely to be prone to infection in patients with known heart 
disease? 
 Aortic regurgitation 
 
Causes 
Streptococcus bovis  endocarditis is associated with colorectal cancer 
 
 Streptococcus viridans  (most common cause - 40-50%).  Technically Streptococcus 
viridans  is a pseudotaxonomic term, referring to viridans streptococci, rather than a particular 
organism. 
 The most common organisms causing subacute bacterial endocarditis (SBE) are the

viridans streptococci.  
  Because viridans streptococci are relatively avirulent pathogens in normal hosts, 
they usually present as SBE. 
 The two most notable viridans streptococci are: 
1. Streptococcus mitis  and  
2. Streptococcus sanguinis .  
 They are both commonly found in the mouth and in particular dental plaque so 
endocarditis caused by these organisms is linked with poor dental hygiene or following a 
dental procedure

dental procedure 
 Staphylococcus epidermidis  (especially prosthetic valves) 
 Staphylococcus aureus  (especially acute presentation, IVDUs) 
 Staphylococcus aureus  endocarditis is an aggressive disease frequently 
associated with valve destruction and abscess formation. 
 Streptococcus bovis  is associated with colorectal cancer  colonoscopy  
 Streptococcus gallolyticus  is a subtype of Streptococcus bovis

 Bacteroides  is the most likely organism following bowel resection , though S. bovis  is also 
seen.  
  Passage of bacteria to the heart occurs via venous drainage, so valve lesions tend to  be 
right-sided. Vegetations may also occur on the left side of the heart. 
 Management in  metronidazole. 
 non-infective:  
 systemic lupus erythematosus (Libman-Sacks), (sterile vegetations) 
 commonly result in mitral regurgitation . 
 malignancy: marantic endocarditis

 malignancy: marantic endocarditis 
 Culture negative causes  
 prior antibiotic therapy 
 Coxiella burnetii  
 is the Q fever agent 
 typically associated with exposure to animals (sheep and cattle). 
 Bartonella  
  from cats 
 Brucella  
 Chlamydia psittaci  
 from birds. 
 HACEK : (Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella ) 
 slow-growing, Gram negative bacteria 598

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  137 
  These are normal flora of the upper respiratory tract  
 constitute 5-10% cases of endocarditis;  
 they require prolonged incubation in enriched media and increased carbon dioxide 
tension. 
 The human bite injury and gram-negative culture make Eikenella 
corrodens  the most likely causative organism.

corrodens  the most likely causative organism. 
 third-generation cephalosporin ( Ceftriaxone ) is effective against enteric gram-
negative rods, including HACEK organisms 
 
Following prosthetic valve surgery Staphylococcus epidermidis  is the most common organism in the 
first 2 months and is usually the result of perioperative contamination. After 2 months th e spectrum of 
organisms which cause endocarditis return to normal, except with a slight increase in Staph. 
aureus  infections

aureus  infections 
 
Infective endocarditis: Modified Duke criteria 
 Infective endocarditis diagnosed if 
 pathological criteria positive, or 
 2 major criteria, or 
 1 major and 3 minor criteria, or 
 5 minor criteria 
 Pathological criteria  
 Positive histology or microbiology of pathological material obtained at autopsy or cardiac 
surgery (valve tissue, vegetations, embolic fragments or intracardiac abscess conten t) 
 Major criteria  
 Positive blood cultures

 Positive blood cultures 
 two positive blood cultures showing typical organisms consistent with infective 
endocarditis, such as Streptococcus viridans  and the HACEK group, or 
 persistent bacteraemia from two blood cultures taken > 12 hours apart or three or 
more positive blood cultures where the pathogen is less specific such as Staph 
aureus  and Staph epidermidis , or 
 positive serology for Coxiella burnetii , Bartonella  species or Chlamydia psittaci , or

 positive molecular assays for specific gene targets 
 Evidence of endocardial involvement 
 positive echocardiogram (oscillating structures, abscess formation, new valvular 
regurgitation or dehiscence of prosthetic valves), or 
 new valvular regurgitation 
Minor criteria  
 predisposing heart condition or intravenous drug use 
 microbiological evidence does not meet major criteria 
 fever > 38  C

 fever > 38  C 
 vascular phenomena: major emboli, splenomegaly, clubbing, splinter haemorrhages, Janeway 
lesions, petechiae or purpura 
 immunological phenomena: glomerulonephritis, Osler's nodes, Roth spots 
Aortic valve endocarditis can cause aortic root abscess which can cause damage to the AV 
node resulting in prolongation of the PR interval on ECG. 
 
Conjunctival petechial haemorrhages are far more common than the classical skin signs of splinte r

haemorrhages, Osler ’s nodes and Janeway lesions. 
 
Most patients with endocarditis have evidence of vasculitis, strongly associated with 
microscopic haematuria.  Other vasculitic features include splinter haemorrhages, Osler ’s nodes 
(finger/toe pulp infarcts) and Janeway lesions (palmar/plantar macules).  
 
 599

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  138 
 Peripheral signs associated with infective endocarditis  
 
Infective endocarditis: management   
Current antibiotic guidelines  (source: British National Formulary) 
Scenario Suggested antibiotic therapy 
Initial blind therapy Native valve 
 amoxicillin , consider adding low-dose gentamicin

If penicillin allergic, MRSA  or severe sepsis  
 vancomycin + low-dose gentamicin 
If prosthetic valve 
 vancomycin + rifampicin + low-dose gentamicin 
Native valve endocarditis caused by 
staphylococci Flucloxacillin 
If penicillin allergic or MRSA 
 vancomycin + rifampicin 
Prosthetic valve endocarditis caused by 
staphylococci Flucloxacillin + rifampicin + low-dose gentamicin 
 vancomycin + rifampicin + low-dose gentamicin

Endocarditis caused by fully-sensitive 
streptococci (e.g. viridans) Benzylpenicillin  
If penicillin allergic 
600

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  139 
 Scenario Suggested antibiotic therapy 
Endocarditis caused by less sensitive 
streptococci  Benzylpenicillin + low-dose gentamicin  
 
IV amoxicillin is the empirical treatment of choice in native valve endocarditis

The most useful laboratory test  used to monitor the treatment of infective endocarditis is 
serial C reactive protein estimation . 
 
 length of treatment: 
 6 weeks of intravenous therapy is generally accepted as the length of treatment neede d. 
 
Indications for surgery 
 
 severe valvular incompetence 
 aortic abscess (often indicated by a lengthening PR interval ) 
 infections resistant to antibiotics/fungal infections 
 cardiac failure  refractory to standard medical treatment

 recurrent emboli after antibiotic therapy 
 organisms that are difficult to eradicate by medical therapy as such fungi , brucella, coxiella, 
pseudomonas aeruginosa, vancomycin-resistant enterococci  
 persistent bacteraemia despite appropriate antibiotic therapy  
 extension of infection to a extravalvular site  
 early prosthetic valve endocarditis (within 2 months)  
 dehiscence or obstruction of a prosthetic valve. 
 
Infective endocarditis related to cardiac devices

 The European Society of Cardiology recommends urgent extraction of the implanted device 
followed by prolonged antibiotic therapy in patients with cardiac device related infective 
endocarditis. 
 Prolonged antibiotic therapy and device removal are recommended 
 Percutaneous extraction is recommended in most patients with cardiac devices even those w ith 
large (>10 mm) vegetations 
 After device extraction, reassessment of the need for re-implantation is recommended , and

 Routine antibiotic prophylaxis is recommended before device implantation. 
 
Candida endocarditis 
 Intravenous drug abuse,  
 immunodeficiency states and  
 indwelling catheters  
 The aortic valve is the most common valve to be involved. 
 Treatment  Valve replacement followed by amphotericin B for 6 weeks  
 
601

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  140 
  
Infective endocarditis: prophylaxis 
 NICE recommends the following procedures do not require prophylaxis : 
 dental procedures 
 upper and lower gastrointestinal tract procedures 
 genitourinary tract; this includes urological, gynaecological and obstetric procedures and 
childbirth

childbirth 
 upper and lower respiratory tract; this includes ear, nose and throat procedures and 
bronchoscopy 
 
 Prophylaxis is only recommended in  those patients who are at highest risk of adverse 
outcomes on the development of endocarditis. These patient groups include: 
 Prosthetic cardiac valve or prosthetic material used for cardiac valve repair 
 Previous endocarditis 
 Unrepaired cyanotic congenital heart disease  including palliative shunts and conduits

 Completely repaired congenital heart defect  with prosthetic material or device, whether 
placed by surgery or by catheter intervention, during the first six months  after the 
procedure 
 Repaired congenital heart disease with residual defects  (persisting leaks or abnormal 
flow) at the site or adjacent to the site of a prosthetic patch or prosthetic device (which 
inhibit endothelialisation) 
 Cardiac transplantation recipients who develop cardiac valve abnormalities.

Infective endocarditis: prognosis  
 
 Staph aureus infection (see below) ( Acute endocarditis )  
 ((Streptococcus viridans )  Subacute bacterial endocarditis has a better 
prognosis.)  
 prosthetic valve (especially 'early', acquired during surgery) 
 culture negative endocarditis 
 low complement levels 
 Infection of the aortic rather than mitral valve 
 Associated rhythm disturbance. 
 Heart failure

 Heart failure 
 Intravenous drug abuse (often left and right sided disease) 
 Old age 
 Insulin dependent diabetes mellitus, and 
 Severe co-morbidities. 
Mortality according to organism 
 staphylococci - 30% 
 bowel organisms - 15% 
 streptococci - 5% 
 
Non-bacterial thrombotic endocarditis (marantic endocarditis)   
 due to platelet-fibrin thrombi that are prone to embolising. 
 This form of non-infective endocarditis can be seen in persons who are very debilitate d or who

have a hypercoagulable state. 
 The deposition of fibrin on valve leaflets causes sterile vegetations that ca n embolise. 
 
602

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  141 
 Myocarditis 
 
The short prodromal illness coupled with the development of biventricular heart failure, 
tachycardia, T-wave inversion and elevated troponin is most consistent with viral 
myocarditis. The features, including the mild flu-like illness, are consistent with Coxsackie B. 
 
Causes 
 viral:

Causes 
 viral:  
 Currently,  the most common  in adults: 
 Parvovirus B19 
 Human herpes virus 6 
 Other Viral Causes  
 Coxsackie B virus 
 most common in children 
 results in dilated cardiomyopathy. 
 Previously, the enteroviruses (including coxsackie virus) were the most 
common identified viruses.  
 Currently, parvovirus B-19 and human herpes virus 6 are considered the 
most common causes of viral myocarditis. 
 Adenovirus 
 HIV  
 Hepatitis C 
 Cytomegalovirus

 HIV  
 Cytomegalovirus 
 Echovirus 
 Influenza virus 
 Epstein-Barr virus 
 
 bacteria: diphtheria, clostridia 
 spirochaetes: Lyme disease    most commonly presents as heart block. 
 protozoa:  
 Chagas' disease,  
 caused by Trypanosoma cruzi,  a common pathogen in South America 
 Chagas disease myocarditis results in  dilated cardiomyopathy. 
 Toxoplasmosis 
 drugs:  
 doxorubicin 
 clozapine. 
Presentation

 usually young patient with acute history 
  history of viral prodrome 2 to 3 weeks prior to the onset 
 fever 
 chest pain,  
 due to involvement of the pericardium. 
 SOB 
 Palpitations 
 typically sinus  tachycardia. 
 Myocarditis can have features similar to cardiomyopathy and the mild valvular disease is quite 
compatible. 
 Markedly raised troponin.

 Markedly raised troponin. 
 Troponin is more sensitive than creatine kinase- MB (CPK- MB) in detecting myocardial 
inflammation. 
 On echocardiography ,   global systolic dysfunction   
Treatment 
 Supportive 
 usually managed similar to heart failure. 
 
 603

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  142 
DVLA: cardiovascular disorders 
 
DVLA advice post MI: 
 if successfully treated by angioplasty  cannot drive for 1 weeks  
 If does not undergo angioplasty  cannot drive for 4 weeks

 For obvious reasons, the rules relating to drivers of heavy goods vehicles tend to be much  
stricter 
 Hypertension: 
 can drive unless treatment causes unacceptable side effects, no need to notify  DVLA.  
 If Group 2 Entitlement the disqualifies from driving if resting BP consistently 180 mmHg 
systolic or more and/or 100 mm Hg diastolic or more

 angioplasty (elective) - 1 week off driving 
 Percutaneous coronary intervention (PCI) – elective angioplasty with or without stent 
 Group 1 car  Must not drive for at least 1 week but need not notify the DVLA 
 Group 2 bus and lorry  He has to stop driving, inform the DVLA and return for an 
exercise tolerance test in 6 weeks after he has stopped his β-blocker for 48 h 
 the DVLA guidelines state that the patient has to complete stage 3 of a Bruce

protocol exercise tolerance test. There should be no residual chest pain or 
significant ECG changes.  
 
 Coronary artery bypass graft (CABG) 
 Group 1 car  4 weeks off driving 
 Group 2 bus and lorry: 
 Must not drive and must notify the DVLA. 
 May be relicensed/licensed after 3 months if: 
1. LV ejection fraction is at least 40% 
2. the requirements for exercise or other functional tests can be met at least 3 
months postoperatively 
3. there is no other disqualifying condition.

3. there is no other disqualifying condition. 
 Acute coronary syndrome:  
 4 weeks off driving ,  
 1 week if successfully treated by angioplasty 
 angina - driving must cease if symptoms occur at rest/at the wheel 
 pacemaker insertion - 1 week off driving 
 implantable cardioverter-defibrillator (ICD):  
 if implanted for sustained ventricular arrhythmia : cease driving for 6 months .  
 If implanted prophylactically then cease driving for 1 month.

 Having an ICD results in a permanent bar for Group 2 drivers  
 successful catheter ablation for an arrhythmia- 2 days off driving 
 aortic aneurysm:  
 aortic aneurysm of 6cm or more: 
 notify DVLA.  
 Licensing will be permitted subject to annual review.  
 aortic diameter of 6.5 cm or more disqualifies patients from driving 
 Heart failure   
 DVLA guidance for Group 2 entitlements (HGVs and buses) is much more strict than 
Group 1 entitlements (cars and vans).

Group 1 entitlements (cars and vans). 
 Symptomatic heart failure will lead to revocation of a Group 2 licence, regardless of 
whether the symptoms lead to incapacity. 
 a left ventricular ejection fraction (LVEF) of < 40% bars him from driving a lorry, 
even if he becomes asymptomatic with treatment  
 If a patient on treatment becomes asymptomatic, then they may be relicensed on ly 
if their LVEF is ≥ 40%.

if their LVEF is ≥ 40%. 
 For Group 1 entitlements, the DVLA does not need to be informed of symptomatic he art 
failure if it does not lead to distracting or incapacitating symptoms. 
 Any form of defibrillator is a bar to a Group 2 entitlement.  
604

Notes & Notes for MRCP                                                                                            By Dr. Yousif Abdallah Hamad  143 
  heart transplant: DVLA do not need to be notified 
Lymphoedema 
 Chronic, progressive swelling of tissue with protein-rich fluid as a consequence of developmental

(primary lymphoedema) or acquired (secondary lymphoedema) disruption of the lymp hatic 
system. 
 Extremities are most commonly affected, followed by genitalia. 
Causes of lymphoedema include: 
 primary: inherited 
 secondary  
 nematode infection ( filariasis )  
 malignancy, or cancer-related treatment. 
 surgery, injury resulting in damage to the lymphatic system 
 radiation, 
Features 
 painless unilateral limb swelling;

Features 
 painless unilateral limb swelling;  
 pitting oedema is present in early disease, whereas non-pitting oedema is a sensitive but  non-
specific finding in advanced disease. 
Diagnosis 
  made on clinical grounds  
 confirmed by lymphoscintigraphy.  
Treatment 
 First-line treatment involves compression , ranging from static garments to complex massage 
and pneumatic compression devices.

and pneumatic compression devices.  
 Surgical procedures are reserved for patients refractory to conservative measures and/or with 
significant morbidity. 
 
605

Pulmonology 
 
Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 1 - 
 
 Notes & Notes
  
By 
  
Respiratory medicine 
 
Updated 
 
2017
 
Contains: 
 
 606

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 2 - 
 Lung development 
 Lamellar bodies in type II pneumocytes that produce surfactant  are seen by 22 
weeks' gestation. 
 These contain 80% phosphatidylcholine. 
 Absence of liquor, which is produced by the fetal kidneys, causes poor lung growth and 
a low phospholipid content. Renal agenesis is therefore a cause of hypoplastic

lungs . 
 Complete alveolisation does not occur until 28 weeks ’ gestation. 
 Complete development of the alveoli and the pores of Kohn only occurs around 
the age of 7 years. 
___________________________________________________ ___________________________ 
Anatomy  
 
 The right lung is divided into three lobes: upper, middle and posterior. These are further 
divided into bronchopulmonary segments as follows: 
 Upper lobe – Three segments: apical, anterior and posterior

 Middle lobe – Two segments: lateral and medial 
 Lower lobe – Five segments: apical, anterior basal, posterior basal, medial basal, 
lateral basal. 
 The left lung has only nine segments. The medial basal is absent in the left lower 
lobe.  Moreover, the middle lobe is replaced by the lingular lobe which has two 
segments called superior and inferior. 
 On the right side the transverse fissure separates the upper lobe from the middle lobe.

 The oblique fissure runs posteriorly to anteriorly. As a result the upper lobe is 
represented anteriorly and the lower lobe is mainly posteriorly. 
 The oblique fissure  runs obliquely at 45 degrees from T4-5 to the anterior costo-
phrenic angle, but is  only seen on the lateral chest radiograph . 
607

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 3 - 
  The horizontal fissure  runs from the hilum anteriorly to anterior chest wall, on the right 
side. The area above the horizontal fissure is the upper lobe, below the horizontal 
fissure is the middle lobe and below the oblique fissure  is the lower lobe. 
 Most of the resistance of the airway is due to the large central airways.

 The Angle of Louis  (also known as the sternal angle or Angle of Ludwig) corresponds 
to T4/T5 vertebral bodies , which is the location at which the  trachea bifurcates to the 
main stem bronchi (carina).  
 
 Azygos lobe of the lung 
 azygos lobe is seen in about 0.5% of routine chest X-rays and is a normal variant.  
 It is seen as a 'reverse comma sign' behind the medial end of the right clavicle.  
  
Phrenic nerve  palsy  
 The diaphragm is innervated by the phrenic nerve (C3,4,5).

 Causes of phrenic nerve palsy:   
 thoracic surgery 
 infection 
 Guillain-Barré   invasion by an adjacent tumour 
 It may also be stretched by an aortic aneurysm. 
 supine FVC is significantly reduced 
 Diagnosis  of unilateral paralysis: 
 In patients with normal lungs unilateral paralysis is usually asymptomatic and 
rarely requires treatment.                                                     
  suggested by  asymmetric elevation of the affected hemidiaphragm on X-ray,

Confirmed by  fluoroscopy  
 confirmed fluoroscopically by observing paradoxical diaphragmatic 
motion on sniff and cough  
 During a forced inspiratory manoeuvre (the 'sniff test),  the unaffected 
hemidiaphragm descends forcefully, increasing intra-abdominal pressure 
and pushing the paralysed hemidiaphragm cephalad (paradoxical 
motion)  
 Fluoroscopy is inaccurate for the diagnosis of bilateral paralysis.  
 
The epithelium of respiratory tract

The epithelium of respiratory tract 
 The epithelium that lines the majority of the conducting portion of the respiratory tract is 
pseudostratified columnar epithelium with cilia and goblet cells. 
 For trachea to primary bronchus to secondary bronchus, the epithelium in all regions is 
pseudostratified.  
 For Secondary bronchus to large bronchiole, the epithelium changes from 
pseudostratified to simple columnar

pseudostratified to simple columnar  
 For large bronchiole to small bronchiole, the epithelium changes from  simple columnar 
to simple cuboidal.  
 For small bronchiole to terminal bronchiole, the epithelium in both these regions is 
simple cuboidal.  608

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 4 - 
  
Lung physiology 
Pulmonary surfactant 
 Surfactant is a mixture of phospholipids, carbohydrates and proteins  
 Released by type 2 pneumocytes 
 The main functioning component  in surfactant is dipalmitoyl phosphatidylcholine

(DPPC) or lecithin. which reduces alveolar surface tension.  
 Lecithin makes up more than 75% of the phospholipids covering the air-liquid 
interface in pulmonary alveoli. 
 The most abundant phospholipid in surfactant is dipalmitoylphosphatidylcholine, 
or lecithin. Lecithin makes up more than 75% of the phospholipids covering the air-liquid 
Basics  
 first detectable around 28 weeks

Basics  
 first detectable around 28 weeks 
 as alveoli decrease in size, surfactant concentration is increased, helping prevent the 
alveoli from collapsing 
 reduces the muscular force needed to expand the lungs (i.e. decreases the work of 
breathing) 
 lowers the elastic recoil at low lung volumes and thus helps to prevent the alveoli from 
collapsing at the end of each expiration 
 Because of surfactant, the pressure difference across the pleura required to inflate the

lungs, is usually no more than about 4 cmH 2O. 
 Resting pulmonary blood flow in an adult is around 5 L/min. 
 The V: Q ratio is higher in the apical than the basal segments. 
 While a single small airway provides more resistance than a single large airway, 
resistance to air flow depends on the number of parallel pathways present. For this 
reason, the large and particularly the medium-sized airways provide greater resistance 
to flow than do the more numerous small airways.

to flow than do the more numerous small airways. 
 Cartilage disappears in the terminal bronchioles. 
Deference between pulmonary vascular system and systemic circulation: 
 The normal pulmonary circulation  is characterised by low pressures, low flow rates,  
high compliance vessels . 
Control of respiration 
 central regulatory centres 
 medullary respiratory centre 
 apneustic centre (lower pons)

 apneustic centre (lower pons) 
 pneumotaxic centre (upper pons) 
 central and peripheral chemoreceptors 
 central: raised [H+] in ECF stimulates respiration 
 peripheral: carotid + aortic bodies, respond to raised pCO2 & [H+], lesser extent 
low pO2 
 pulmonary receptors 
 stretch receptors, lung distension causes slowing of respiratory rate (Hering-
Bruer reflex) 609

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 5 - 
  irritant receptor, leading to bronchoconstriction 
 juxtacapillary receptors, stimulated by stretching of the microvasculature 
 
Peripheral chemoreceptors are known to transmit information via the glossopharyngeal and 
vagus nerves regarding changes of carbon dioxide in the blood. Which will most likely

receive information regarding these changes?  
 Solitary nucleus ( in the medulla oblongata)  
 
September 2015 exam: Which one is the most important stimulator of the central 
chemoreceptors? Decrease in pH  
 
Chloride shift 
 CO2 diffuses into RBCs 
 CO2 + H2O  carbonic anhydrase  HCO3- + H+ 
 H+ combines with Hb 
 HCO3- diffuses out of cell, - Cl- replaces it

 HCO3- diffuses out of cell, - Cl- replaces it 
 Therefore, during exercise , there is increased formation of CO 2 in the peripheral 
tissues that needs to be transported to the lungs. Since exercise increases 
CO 2 production which will enter the venous blood  the values of HHb, HbCO 2, RBC Cl-
 content, and plasma HCO 3- will all increase. 
Bohr Effect 
 Increasing acidity (or pCO2) means O2 binds less well to Hb 
Haldane effect 
 Ĺ pO2 means CO2 binds less well to Hb

 Ĺ pO2 means CO2 binds less well to Hb  
Acclimatisation to life at high altitudes:  
 Acclimatisation results in increased Hb with erythrocytosis. 
 Pulmonary artery pressure increases to oxygenate more blood. 
 2,3-DPG increases. 
 Respiration is normal when subjects are acclimatised to altitude as is cardiac output. 
(Periodic respiration is a feature of non-acclimatisation).

Lung compliance  is defined as change in lung volume per unit change in airway 
pressure 
Causes of Ļ compliance  
 Pulmonary edema 
 Pulmonary fibrosis 
 Pneumonectomy 
 Kyphosis Causes of Ĺ compliance  
 Age 
 Emphysema 
 
 610

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 6 - 
  
Gas exchange  
 
Oxygen Dissociation Curve  
 
611

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 7 - 
  
 Oxygen Dissociation Curve describes the relationship between the percentage of 
saturated hemoglobin and partial pressure of oxygen in the blood. 
 It is not affected by hemoglobin concentration , but affected by its quality (HbF, 
methemoglobin). 
 Each hemoglobin molecule has the capacity to carry four oxygen molecules.

Basics 
 Shifts to right = for given oxygen tension there is Ļ saturation of Hb with oxygen i.e. 
Enhanced oxygen delivery to tissues 
 Shifts to left = for given oxygen tension there is Ĺ saturation of Hb with oxygen i.e. Ļ 
oxygen delivery to tissues 
Shifts to Right = Raised oxygen 
delivery Shifts to Left = Lower oxygen delivery 
 Raised [H+] (acidity) 
 Raised PCO2 
 Raised 2,3-DPG 
 Raised temperature 
  Low [H+] (alkali) 
 Low PCO2 
 Low 2,3-DPG 
 Low temperature

 Low PCO2 
 Low temperature 
 HbF, methemoglobin, 
carboxyhaemoglobin                                         
 Left shift of the curve is a sign of hemoglobin's Ĺ affinity for oxygen (eg. at the lungs).  
 Similarly, right shift shows Ļ affinity, as would appear with an Ĺ in body temperature, 
hydrogen ion, 2,3- diphos phoglycerate (also known as bisphosphoglycerate) or carbon 
dioxide concentration (the Bohr effect)

dioxide concentration (the Bohr effect) 
 Carbon monoxide has a much higher affinity for hemoglobin than oxygen does. In 
carbon monoxide poisoning, oxygen cannot be transported and released to body 
tissues thus resulting in hypoxia. 
 With fetal hemoglobin, the shift facilitates diffusion of oxygen across the placenta. The 
oxygen dissociation curve for myoglobin exists even further to the lef t. 
 A fall in the partial pressure of oxygen (pO2) in the blood leads to vasoconstriction of

the pulmonary arteries. This allows blood to be divered to better aerated areas of the 
lung and improves the efficiency of gaseous exchange. 
 The P 50   
 The P 50 is the oxygen tension at which hemoglobin is 50% saturated.  
 The normal P 50 is 26.7 mm Hg.  
612

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 8 - 
  With increasing oxygen affinity of hemoglobin, P50 is decreased and unloading of 
oxygen to tissues becomes more difficult.  
 
Pulmonary arteries vasoconstrict in the presence of hypoxia  
 
Question 
A 24-year-old woman is evaluated before and 
after practice to assess oxygen delivery to her

after practice to assess oxygen delivery to her 
muscles. The hemoglobin-oxygen dissociation 
curve is shown. 
Curve B is taken before practice. 
Which characteristics will most probably 
describe curve A? 
Answer: 
If curve B is taken before practice, it will be 
used as reference point. Curve A shows shifts 
to the left. 
Increased pH with decreased 2,3-
diphosphoglycerate concentration 
  
___________________________________________________ ___________________________

Pulmonary function tests 
Pulmonary function tests can be used to determine whether a respiratory disease is 
obstructive or restrictive.  
Tidal Volume (TV) 
 Volume inspired or expired with each breath at rest 
 500ml in ♂s, 350ml in ♀s  
Inspiratory Reserve Volume (IRV)  = 2-3 L 
 Maximum volume of air that can be inspired after normal tidal inspiration 
 Inspiratory capacity = TV + IRV 
Expiratory Reserve Volume (ERV)  = 750ml

Expiratory Reserve Volume (ERV)  = 750ml 
 Maximum volume of air that can be expired after normal tidal expiration 
Residual volume (RV)  = 1.2L 
 Volume of air remaining after maximal expiration 
 Ĺ with age  
 Increased in obstructive lung disease due to air trapping 
 RV = FRC – ERV (Functional Residual Capacity - Expiratory Reserve Volume) 
The FEV1/FVC ratio :  
 is < 70% in obstructive lung disease  
 and > 70% in restrictive lung disease. 
Vital Capacity (VC)  = 5L

Vital Capacity (VC)  = 5L 
 Maximum volume of air that can be expired after a maximal inspiration 
 4,500ml in ♂s, 3,500 mls in ♀s  
 Ļ with age 
 VC = IC + ERV 
613

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 9 - 
  In the absence of equipment, having the patient count at a steady rate for one breath 
gives a rough estimate of how much air they can expel. This is a common bedside or 
outpatient procedure that is done with myasthenic patients. 
Forced vital capacity

Forced vital capacity  
  is a measure of the force, volume, and speed with which air can be maximally 
expelled from the lungs. 
 The maneuver would be to take a deep breath, and then blow it out as hard as you 
can for as long as you can to maximally expel air from the lungs.  
 This is commonly done to assess patients with asthma and chronic obstructive 
pulmonary disease. 
Total lung capacity (TLC)  is the sum of the vital capacity + residual volume 
Minute ventilation

Minute ventilation  
 Minute ventilation is equal to tidal volume (volume of air moved in normal breathing) 
multiplied by the respiratory rate.  
 In metabolic alkalosis , one could increase CO 2 content by decreasing the minute 
ventilation (volume of air moved per minute).   
 Reducing either one of these variables ( ↓tidal volume or ↓ respiratory rate)  will 
decrease minute ventilation and lead to increased CO 2 retention . 
 
Pre-operative screen of pulmonary function

Pre-operative screen of pulmonary function  
 What is the best pre-operative screen of pulmonary function for a smoker patient  
evaluated for a coronary artery bypass graft (CABG).? 
 Ratio of the forced expiratory volume in 1 second to the forced vital 
capacity 
 The arterial blood gas measurements reflect acid –base disorders, but they 
do not predict pulmonary complications in the post-operative period. 

Anatomical dead space in the lung 
 The anatomical dead space can be used to calculate alveolar ventilation  by 
subtracting it from the tidal volume and multiplying the result by the respiratory rate. 
 Alveolar ventilation = (tidal volume – anatomical dead space) X respiratory 
rate 
 The normal anatomical dead space is approximately 150 ml .  
 eg: If we take the tidal volume to be about 500 ml and the respiratory rate to be

about 15/min, this gives a normal alveolar ventilation of (500 - 150) X 15 = 5250 
ml/min.  
 The dead space can be increased in diseases that cause an additional physiological 
dead space, where parts of lung do not take part in gas exchange (eg pneumonia ) 
Forced vital capacity (FVC) 
 Respiratory muscle function is best monitored by frequent assessment of the forced 
vital capacity (FVC).

vital capacity (FVC). 
 FVC is also the best way to monitor respiratory function in any neurological 
disorders that can affect the respiratory muscles (e.g. GBS, myasthenia gravis) 
 Diaphragmatic weakness occurs in one-third of patients with Guillain-Barré syndrome 
(GBS) and involvement of the neck muscles, tongue and palate leads to further 
respiratory compromise 614

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 10 - 
  ITU admission  is recommended when FVC is less than 20 mL/kg  and intubation is 
recommended in most cases when FVC is less than 15 mL/kg.  
 
Obstructive vs. Restrictive lung diseases  
 Obstructive Restrictive 
 
Spirometry  FEV1/FVC < 80%

Spirometry  FEV1/FVC < 80% 
(FEV1/FVC <0.7)  
 FEV1/FVC > 80% 
(FEV1/FVC >0.7)  
 
FEV1 - significantly 
reduced (<80% predicted 
normal) FEV1 - reduced (<80% predicted normal) 
 
FVC - reduced or normal 
FEV1% (FEV1/FVC) - 
reduced FVC - significantly reduced (<80% predicted 
normal) 
FEV1% (FEV1/FVC) - normal (>0.7) or 
increased 
Examples  Chronic obstructive 
pulmonary disease 
 chronic bronchitis 
 emphysema 
Asthma 
Bronchiectasis Intrapulmonary

Asthma 
Bronchiectasis Intrapulmonary 
 idiopathic pulmonary fibrosis 
 extrinsic allergic alveolitis 
 coal worker's 
pneumoconiosis/progressive massive 
fibrosis 
 silicosis 
 histiocytosis 
 drug-induced fibrosis: amiodarone, 
bleomycin, methotrexate 
 asbestosis 
Extrapulmonary 
 neuromuscular disease: polio, 
myasthenia gravis 
 obesity 
 scoliosis 
 
Explanation of  high FEV-1/FVC ratio in lung fibrosis:

 In lung fibrosis both (FEV-1) and (FVC) are reduced below predicted values, but 
because of high elastic recoil most forced expiratory volume will be expelled in the 
first second compared to full forced expiration - this leading to a relatively high FEV-
1/FVC ratio. 
Pulmonary function in obesity 
 Obesity could show a significant restrictive defect . 
 It is associated with hypoventilation and thus can cause hypercapnia.  615

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 11 - 
  would not affect the transfer coefficient (Kco)  (ie after correcting for alveolar 
volumes). the gas exchange after correcting for the alveolar volume would in fact be 
high. 
 FVC falls when measured in the supine position due to increased abdominal fat, leading 
to a functional reduction in FVC.

to a functional reduction in FVC. 
Peak expiratory flow rate (PEFR) 
 PEFR readings are an objective measure of airway obstruction and advised for regular  
assessment of lung function.  
 A mid-expiratory flow rate ( between 25% and 75%  of the expired vital capacity) is a 
good measure of airways obstruction . 
 It is more sensitive than the forced expiratory volume in 1 second (FEV-1) for identifying 
early airway obstruction. It is effort-independent.

 In a restrictive pattern the flow-volume loop is reduced in size but looks similar in shape 
to normal. 
 The most accurate correlation of the peak expiratory flow rate (PEFR) is with 
height . 
 It is impaired in bronchiolitis obliterans, smokers , patients with rejection reactions 
following bone-marrow, lung and heart transplants. 

Transfer factor  (DLCO or TLCO (diffusing capacity or transfer factor of the lung for carbon 
monoxide (CO))  
 
 The transfer factor describes the rate at which a gas will diffuse from alveoli into blood. 
 Carbon monoxide is used to test the rate of diffusion.  
 Results may be given as the total gas transfer (TLCO) or that corrected for lung volume 
(transfer coefficient, KCO). 
  Dlco is measured by looking at end-expiratory levels of carbon monoxide after inspiring

a      small amount and breath-holding.  
 Diffusion capacity of carbon monoxide  depends on the thickness of the alveolar wall. 
diffusion will be increased in healthy compared with unhealthy lungs, where the 
thickness is likely to increase and the surface area available for gas exchange to 
decrease.  
Causes of raised and lower TLCO:  
Where alveolar haemorrhage occurs, the TLCO tends to increase due to the enhanced uptake 
of carbon monoxide by intra-alveolar haemoglobin.  
616

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 12 - 
 Causes of a raised TLCO 
 asthma 
 pulmonary haemorrhage (Wegener's, 
Goodpasture's) 
 left-to-right cardiac shunts 
 polycythaemia 
 hyperkinetic states 
 early left heart failure 
 male gender,  
 exercise  
 obesity Causes of a lower TLCO 
 pulmonary fibrosis 
 pulmonary emboli 
 pulmonary oedema

 pulmonary oedema 
 anaemia 
 low cardiac output  
 
 convalescent asthma  (مستقر -ربو في طور النقاهة  ) Ĺtransfer factor - in contrast to acute 
asthma where it is decreased 
 Asthma is most likely  associated with normal Tlco  , but sometimes increased during 
an attack, and the cause of this change is not known.  
 Pulmonary AV malformations cause right- to-left shunts, so reducing Tlco values

and provoking hypoxaemia (↓  Pao2 ), with a normal lung volumes  (eg FEV1 & 
FVC).  
 
Factors interfere with interpretation of the Diffusing capacity (DLCO) test : 
 Smoking on the morning of the test  (within around eight hours of the test ):  
 Carbon monoxide in cigarette smoke ==> raises ↑ carboxyhaemoglobin (COHb) 
(to as high as 10-15% (normal value 1- 2%). ==> ↓ reduces DLCO.  
 Increasing COHb reduces DLCO because:

 Increasing COHb reduces DLCO because:  
 carbon monoxide (CO) is substantially increased, leading to a reduced 
driving pressure for CO across the air-blood barrier.  
 some of the patient's haemoglobin (Hb) will already be tightly bound by 
CO and therefore the overall amount of Hb available for binding by the test 
CO is decreased.  
 Significant amount of Alcohol vapours in the morning of the test (not small amount)  
 Severe kyphosis (not mild)  
 Sever scoliosis (not mild)

 Sever scoliosis (not mild)  
Transfer coefficient  of carbon monoxide (KCO)  
 .KCO is a measure of the efficiency of gas exchange into the blood stream.  
 It is reduced if the lungs are damaged 
 The transfer coefficient will be reduced in patients with interstitial lung 
disease 
 normal KCO may rule out significant restrictive lung disease

 the best test - after CT-  to confirm restrictive lung disease due to a 
parenchymal  disorder 
 sarcoidosis would reduce the transfer coefficient as there is damage to the 
alveolar cells themselves 
 Causes of an increased Kco 
 increased if there is additional blood in the lungs to remove carbon monoxide. 617

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 13 - 
  usually as results from an increase in red blood cells in the lungs due to greater 
blood flow, haemorrhage, or polycythaemia.  
 If the density of pulmonary capillaries per unit alveolar volume is greater than 
normal.  
 This occurs most commonly in patients with extrapulmonary volume

restriction , when the density of pulmonary capillaries is unusually 
high in relation to the (restricted) lung volume  at which the 
measurement is made. 
 increase with age. 
 Causes of an increased KCO with a normal or reduced TLCO   
  (Low Tlco but normal/high Kco (ie the same cardiac output is going through a 
smaller alveolar volume) is characteristic of extra-thoracic restriction : 
 pneumonectomy/lobectomy 
 scoliosis/kyphosis 
 neuromuscular weakness

 neuromuscular weakness 
 ankylosis of costovertebral joints e.g. ankylosing spondylitis  
 Severe thoracic skin thickening, 
 Pleural disease 
  Obesity  
 In intrapulmonary restriction , both (Tlco & Kco) are usually decreased. 
 Isolated decreases in gas transfer are typical of pulmonary vascular diseases such as 
vasculitis and recurrent pulmonary embolism. 
 Relation between  Dlco, VA (alveolar volume) & KCO (transfer coefficient)

 Dlco is simply the product of Va and Kco,  
 TLCO = KCO x Alveolar volume (VA) 
 The transfer coefficient (Kco) represents the uptake of carbon monoxide per litre 
of effective alveolar volume (Va)  
 The Kco tending to be normal after lung resection, when both Tlco and Va are 
reduced to roughly the same degree  
 Dlco is used to monitor disease progression and response to treatment in 
fibrosing lung disease.

fibrosing lung disease.  
 In lung fibrosis the Dlco is low, typically as a product of both low Va and Kco. 
 In lung haemorrhage, Dlco is high as a product of a low Va but a high Kco 
(in contrast to the pattern in pulmonary vasculitis, where there is a low Kco but 
often a normal Va). 
 
Arterial Blood Gas (ABG) 
 
Arterial blood gases should be used for assessing respiratory failure in Critically ill

Patients or those with Shock or Hypotension (Systolic blood pressure  < 90mmHg) 
(British Thoracic Society, 2017) 
 
The best site for sampling  
 The radial artery  is the one most often used in practice in the acute care setting 
because of easy access and the fact that the artery is superficial and easily palpated.  618

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 14 - 
  Prior to any attempt at arterial puncture the practitioner must perform the 
Modified Allen ’s Test  (WHO, 2010) 
 
Contra-Indications of ABG sampling 
 Absent ulnar circulation – as demonstrated by Modified Allen ’s Test. 
 Impaired circulation e.g. Raynaud ’s Disease  
 History of arterial spasms 
 Arteriovenous fistula

 Arteriovenous fistula 
 Distorted anatomy/ trauma/burns to the limb - at or proximal to the 
 attempted arterial puncture site 
 Medium or high dose anticoagulation therapy, or history of clotting disorder 
 Severe coagulopathy 
 Abnormal or infectious skin processes at/or near puncture site 
 
Modified Allen's test 
 
 modified Allen test measures arterial competency, and should be performed before 
taking an arterial sample .  
 Method

 Method 
 Instruct the patient to clench his or her fist; if the patient is unable to do this, 
close the person's hand tightly. 
 Using your fingers, apply occlusive pressure to both the ulnar and radial arteries, 
to obstruct blood flow to the hand. 
 While applying occlusive pressure to both arteries, have the patient relax his or 
her hand, and check whether the palm and fingers have blanched. If this is not

the case, you have not completely occluded the arteries with your fingers. 
 Release the occlusive pressure on the ulnar artery only to determine whether the 
modified Allen test is positive or negative. 
 Interpretation 
 Positive modified Allen test  
 If the hand flushes within 5-15 seconds  it indicates that the ulnar artery 
has good blood flow; this normal flushing of the hand is considered to be a 
positive test . 
 Negative modified Allen test

 Negative modified Allen test   
 If the hand does not flush within 5-15 seconds, it indicates that ulnar 
circulation is inadequate or nonexistent;  
 in this situation, the radial artery supplying  arterial blood to that hand 
should not be punctured.  619

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 15 - 
  
Interpretation of ABG 
 Mixed metabolic and respiratory acidosis 
 pH   below 7.35 
 PCO 2   elevated (> 6 kP a) indicating a respiratory cause for acidosis 
 Bicarbonate  reduced (< 20  mmol/L) which is contributing to the acidosis. 
 
620

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 16 - 
 ____________________________________________________ 
Respiratory acidosis 
 Respiratory acidosis may be caused by a number of conditions: 
 COPD 
 decompensation in other respiratory conditions e.g. life-threatening asthma / 
pulmonary oedema 
 sedative drugs: benzodiazepines, opiate overdose

Signs and symptoms of respiratory acidosis  
Central nervous system 
 Respiratory system  Cardiovascular system  
Cerebral vasodilation 
 Breathlessness Flushing, bounding pulse 
Increased intracranial pressure 
 Cyanosis Cor pulmonale 
Headache, confusion, agitation 
 Pulmonary hypertension Systemic hypotension 
Hallucinations, transient 
pyschosis 
  Arrhythmias    
Myolonic jerks, flapping tremor, 
extensor plantars, depressed 
reflexes  Initially good cardiac output, 
then decreas es

then decreas es 
Papilloedema, constricted pupils 
   
Seizures, coma 
   
 Pathophysiological changes in case of acute acidosis : 
 
 Occurred too quickly for metabolic compensation to occur via renal bicarbonate 
reabsorption, which takes 3-5 days to occur. (bicarbonate will be normal in 
acute respiratory acidosis)  
 The oxygen dissociation curve is shifted to the right in acute acidosis, i.e. 
haemoglobin has a decreased affinity for oxygen.

 High pulmonary pressures would be expected after arrest scenario, as the 
pulmonary arterioles constrict in response to hypoxia . 
 
 Compensated respiratory acidosis ==> normal PH, high CO 2, low O 2 . 
 The fact that the pH is normal means that there must be bicarbonate retention to 
compensate.  
 621

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 17 - 
  In bronchopulmonary dysplasia , there is usually long-term CO 2 retention with 
compensatory increase in bicarbonate leading to a positive base excess and 
normal pH. 
____________________________________________________ 
Respiratory alkalosis 
Common causes

Common causes 
 Anxiety leading to hyperventilation (Hyperventilation will result in carbon dioxide being 
'blown off', causing an alkalosis.) => high PH , low PCO2 , normal PO2.   
 not associated with hypoxia.  
 pulmonary embolism 
 Acute severe asthma  
 associated with hypoxia and normal or rising CO 2  
 salicylate poisoning 
 salicylate overdose leads to a mixed respiratory alkalosis and metabolic acidosis.

 Early stimulation of the respiratory centre  leads to a respiratory 
alkalosis whilst later the direct acid effects of salicylates  (combined 
with acute renal failure) may lead to an acidosis . 
 CNS disorders:  
 stroke,  
 subarachnoid haemorrhage,  
 encephalitis 
 altitude 
 pain 
 Excessive mechanical ventilation.  
 
Differential diagnosis of respiratory alkalosis with type 1 respiratory failure (low  
pO 2 and low pCO 2.):

pO 2 and low pCO 2.): 
 Chronic venous thromboembolism (most likely) . 
 Pulmonary fibrosis (but basal crackles may be expected) . 
 
Acute vascular response to hypoxia  
 acute vascular response to hypoxia is thought to be mediated by nitrous oxide (NO).  
 Systemic reaction to hypoxia is an increase in sympathetic tone, which leads to 
vasoconstriction;

vasoconstriction;  
 however in the vital body organs (such as the brain, heart, kidneys and intestines) local 
mediators cause vasodilation in the vascular bed to maintain sufficient glucose and 
oxygen supply.  
 Within the pulmonary vasculature, hypoxia induces sustained vasoconstriction  
which redirects blood flow to areas of the lungs that are relatively oxygen rich. This 
limits the amount of blood passing through the lungs that is not oxygenated; i.e. it

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 18 - 
  
Which vascular beds vasoconstrict in response to hypoxia? 
 Pulmonary  
 
Chest x- ray 
Cavitating lung lesion 
Differential  
 abscess (Staph aureus, Klebsiella and Pseudomonas ) 
 squamous cell lung cancer 
 tuberculosis

 tuberculosis 
 Wegener's granulomatosis 
 Progressive massive fibrosis: is a complicated coal worker's pneumoconiosis where 
pulmonary nodules coalesce and cavitate. 
 Systemic embolisation: occurs in 20-50% of cases of infective endocarditis, and can 
involve the lungs, central nervous system, coronary arteries, spleen, bowel and 
 aspergillosis, histoplasmosis, coccidioidomycosis

 Actinomycosis: is a chronic granulomatous disorder caused by a Gram-positive 
anaerob e. 
Differential diagnosis of diffuse opacities on chest X-ray 
The fluffy shadows on the chest X-ray could represent: 
 Pulmonary oedema 
 Interstitial lung disease 
 Vasculitic lung disease 
 Pulmonary haemorrhage  
Coin lesions on chest x-ray 
 Coin lesions ( solitary pulmonary nodule ) 
 malignant tumour: lung cancer or metastases 
 benign tumour: hamartoma

 benign tumour: hamartoma 
 infection: pneumonia, abscess, TB, hydatid cyst 
 AV malformation  
 Risk stratification of incidental pulmonary nodules 
  Risk stratification needs to take into account the risk factors for lung cancer or 
metastases, as well as size and character of the nodule.  
 surveillance according to British Thoracic Society Guidelines published in 2005. 
 Nodules < 5 mm require no further surveillance. 
 Nodules 5-6mm require CT at 1 year

 Nodules 5-6mm require CT at 1 year 
 Nodules 6-8 mm require CT at 3 months 
 Nodules > 8 mm require malignancy risk calculation using the Brock model 
and should then have CT or PET according to whether this risk is > 10%. 
 The Brock model takes into account age, gender, family history and 
features of the nodule 623

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 19 - 
 Lobar collapse on chest x-ray 
 Common causes of lobar collapse include: 
 lung cancer (the most common cause in older adults) 
 asthma (due to mucous plugging) 
 Mucous plugging is not uncommon in asthmatic patients and can 
occasionally cause lobar collapse. 
 Treatment  
 adequate hydration and chest physiotherapy.

 adequate hydration and chest physiotherapy. 
 Bronchoscopy with lavage may be required if this is unsuccessful. 
 foreign body 
 The general signs of lobar collapse on a chest x-ray  are as follows: 
 tracheal deviation towards the side of the collapse 
 mediastinal shift towards the side of the collapse 
 elevation of the hemidiaphragm  
  
This patient has a left upper lobe 
collapse . The following can be seen 
on the film to support this: 
 
 hazy opacity projected over the

 hazy opacity projected over the 
left upper zone 
 deviation of the trachea to the left 
 elevation of the left 
hemidiaphragm 
 loss of lung volume in the left 
hemithorax 
 
White lung lesions on chest x-ray 
There are numerous causes of white shadowing in the lungs including: 
 consolidation 
 collapse   pneumonectomy 
 specific lesions e.g. tumours 
 fluid e.g. pulmonary oedema 
 
624

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 20 - 
 If there is a 'white-out' of a hemithorax  it is useful to assess the position of the trachea - is it 
central, pulled or pushed from the side of opacification. 
 
Trachea pulled toward the white-
out Trachea central Trachea pushed away 
from the white- out 
Pneumonectomy  
Complete lung collapse (Atelectasis)

Complete lung collapse (Atelectasis) 
e.g. endobronchial intubation 
Pulmonary hypoplasia  Consolidation  
Pulmonary oedema 
(usually bilateral) 
Mesothelioma  Pleural effusion  
Diaphragmatic hernia 
Large thoracic mass  
 
 In the context of an acute aspiration, the most likely process is atelectasis 
secondary to bronchial obstruction.  
 Obstruction of the mainstem bronchus will prevent gas from entering the affected lung 
and will lead to the collapse of that lung.

and will lead to the collapse of that lung.  
 The collapsed lung will cause complete whiteout of the hemithorax on chest X-ray and 
will cause ipsilateral tension on the mediastinum leading to shifting of the trachea 
toward the affected lung. 
 
Lung collapse  - note how the trachea is pulled towards the side of the white-out 
 
Characteristics of consolidation on chest x-ray:  
 Consolidation in the left lower lobe  obliterates the diaphragm.

 Lingular consolidation  will obliterate the left heart border. The loss of the left heart 
border is a classic sign of left lingual consolidation.  
 Consolidation of the right middle lobe  obscures the right heart border (right atrial 
edge). More extensive consolidation also involves the right and left peri-hilar regions. 
The superior extent is well demarcated, due to the horizontal fissure. 
 Right upper lobe collapse  results in displacement of the horizontal fissure upwards.

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 21 - 
  The classical signs of right upper lobe consolidation  abnormal opacity 
within the right upper lobe abutting the horizontal fissure. 
Atelectasis  (lung collapse) 
 Atelectasis is when part or all of one lung collapses, preventing normal oxygen 
absorption.

absorption.  
 Breath sounds are quietened over areas of atelectasis.  
 During expiration normal breath sounds rapidly fade out, probably due to the decreasing 
airflow rate. 
Causes of atelectasis 
 Obstruction of an air passage by a thick mucus plug from an infection or other disease, 
such as cystic fibrosis 
 Tumours in the air passages 
 Tumours or blood vessels outside the air passages, causing pressure on the airways 
 Inhaled objects, such as peanuts or small toys

 Inhaled objects, such as peanuts or small toys 
 Prologoned chest or abdomincal surgery under general anaesthet ic 
 Atelectasis is a common post-operative complication 
 Chest injury or fractured ribs 
 Penetrating wounds  
 
There is increased opacity in the right upper zone, The lateral / inferior border of the 
shadowing actually represents the horizontal fissure which has been 'dragged' upwards. 
 
626

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 22 - 
 ___________________________________________________ ___________________________
Alveolar-arterial (A-a) oxygen gradient  
 is a measure of the difference between the alveolar concentration ( A) of oxygen and 
the arterial ( a) concentration of oxygen. 
  It is used in diagnosing the source of hypoxemia. For example,

 in high altitude, the arterial oxygen PaO 2 is low but only because the alveolar oxygen 
(PAO 2) is also low.  
 in states of ventilation perfusion mismatch, such as pulmonary embolism or right-
to-left shunt, oxygen is not effectively transferred from the alveoli to the blood which 
results in elevated A-a gradient  
 the normal approximately 0.5-2.0 kPa (< 15 mmHg).  
 Causes of widening A-a gradient  
 Ventilation/perfusion (V/Q) mismatch,  
 diffusion abnormalities and

 diffusion abnormalities and  
 right to-left shunting   
 Hypoventilation causes hypoxaemia with a normal A-a gradient. 
 This means that changes in alveolar-arterial gradient occur with ventilatory disorders 
such as pneumonia and disorders of the vasculature such as a pulmonary embolus.  
 The alveolar arterial (a-a) gradient is calculated using the following equation (where 
PAO2 = alveolar oxygen and the Pao2 and PaCO2 are the arterial O2 and CO2 levels 
respectively):

respectively): 
  A–a gradient = PAO2 − PaO2  
 A–a gradient is approximated: (150 − 5/4(pCO 2)) – PaO2  
Flow volume loop  Assessing compression of the upper airway    
 
A normal flow volume loop is often described as a 'triangle on top of a semi circle'  
Cough (www.brit-thoracic.org.uk)

Cough (www.brit-thoracic.org.uk)  
 Acute cough is defined as one lasting less than 3 weeks 
 Chronic cough is defined as one lasting more than 8 weeks. 
 There is a grey area between 3 to 8 weeks and this includes post-viral coughs.  
 Failure to consider GORD as a cause for cough is a common reason for treatment 
failure.  
 Reflux associated cough may occur in the absence of gastrointestinal symptoms. 
 proton pump inhibitors and alginates should be undertaken for a minimum of 3

months. 
  the cough center of the brain, located in  the nucleus tractus solitarius of the 
medulla  of the brainstem 
 
627

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 23 - 
 ___________________________________________________ ___________________________ 
Dyspnoea  
Medical Research Council dyspnoea scale: 
Grade Degree of breathlessness related to activities 
1 Not troubled by breathlessness except on strenuous exercise 
2 Short of breath when hurrying or walking up a slight hill

3 Walks slower than contemporaries on level ground because of 
breathlessness, or has to stop for breath when walking at own pace 
4 Stops for breath after walking about 100 m or after a few minutes on level 
ground 
5 Too breathless to leave the house, or breathless when dressing or 
undressing 
 
Respiratory failure: 
Type 1  hypoxaemia (P aO2 < 8.0 kPa) without hypercapnoea (P aCO 2 normal or decreased

(<6.0 kPa) 
Causes:  
 Low ambient oxygen (e.g. at high altitude) 
 Ventilation-perfusion mismatch (parts of the lung receive oxygen but not enough blood to 
absorb it, e.g. pulmonary embolism ) 
 Alveolar hypoventilation (decreased minute volume due to reduced respiratory muscle 
activity, e.g. in acute neuromuscular disease); this form can also cause type 2 respiratory 
failure if severe 
 Diffusion problem (oxygen cannot enter the capillaries due to parenchymal disease, e.g.

in pneumonia or ARDS) 
 Shunt (oxygenated blood mixes with non-oxygenated blood from the venous system, 
e.g. right- to-left shunt ) 
 
Type 2  Hypoxemia (PaO2 <8kPa) with hypercapnia (PaCO2 >6.0kPa). 
Causes: 
 Increased airways resistance (COPD, asthma , suffocation) 
 The commonest cause is chronic obstructive airway disease,  
 Reduced breathing effort  hypoventilation : 
  due to drug overdose and brain stem lesion 
 acutely

acutely
 due to: gross obesity, kyphoscoliosis (and similar musculoskeletal 
 chronically 
disorders)  628

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 24 - 
  Hypoventilation, where inadequate alveolar ventilation results in low alveolar 
PO 2, is the only cause of hypoxia that inevitably causes raised PaCO 2. 
 A decrease in the area of the lung available for gas exchange (such as in chronic 
bronchitis)

bronchitis) 
 Neuromuscular problems ( respiratory muscle weakness ) (Guillain-Barre syndrome , 
motor neuron disease)  
 Deformed (kyphoscoliosis), rigid (ankylosing spondylitis), or flial chest.  
Bronchial Asthma 
Basics  
Immunomodulators involved in asthma: 
Inhalation of allergens by individuals with atopic asthma initiates:  
 Immediate response: 
 type I hypersensitivity 
 immunomodulators involved:

 immunomodulators involved: 
 mast cells 
 histamine  prostaglandin D 2 
 Leukotriene C 4 (LTC 4) and D 4. 
 Result in immediate bronchoconstriction reaction 
 Usually subsides within two hours  
 Reversible with bronchodilators.  
 Late phase: 
 type IV hypersensitivity response  
 Eosinophil cationic protein 
(ECP) 
 Major basic protein (MBP)  Platelet activating factor 
(PAF) 
 TH2 lymphocytes

(PAF) 
 TH2 lymphocytes 
 Results in bronchoconstriction, airways inflammation, hyper-responsiveness and 
oedema. 
 This typically occurs three to12 hours after the immediate response  
 Less susceptible to bronchodilators. 
Pathogenesis of asthma :  
 Asthma occurs due to a combination of airway hyper-responsiveness, airflow 
limitation and  airway inflammation  
 The alveolar functional structure is preserved in asthma. 
Genetics of bronchial asthma

Genetics of bronchial asthma 
 autosomal recessive pattern of inheritance is prominent in asthma;  
 parental consanguinity (قرابةصلةand serum intracellular cell adhesion molecule-1  
(ICAM- 1) is significantly associated with asthma 
 There is a contribution from HLA alleles  629

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 25 - 
  There may be genetic linkage of atopic trait to chromosome 11, with association 
between response to antigen and HLA haplotype. 
 IgE concentrations are influenced by genetic factors. 
 
Classification of asthma severity 
 Mild, intermittent asthma  - symptoms occur less than weekly, with normal or near-

normal lung function between episodes 
 Mild persistent asthma  - symptoms occur more than weekly but less than daily, with 
normal or near-normal lung function between episodes 
 Moderate persistent asthma  - symptoms occur daily, with mild to moderate variable 
airflow limitation 
 Severe persistent asthma  - symptoms occur daily and interfere with normal activities; 
there is frequent nocturnal waking and moderate to severe variable airflow limitation

 Severe asthma  - severe distressing symptoms prevent sleep; severe airflow limitation 
responds poorly to inhaled bronchodilators and can be life-threatening 
Near fatal asthma  
 The British Thoracic Society defines near fatal asthma as an attack with raised 
PaCO 2 and/or requiring mechanical ventilation with raised inflation pressures. 
 A raised PaCO 2 is an important sign that intubation may be required if the patient is not 
responding to maximum medical management.

responding to maximum medical management. 
 
Allergic and non-allergic forms of asthma 
 Allergic asthma 
 results from excess immunoglobulin E (IgE) produced in response to 
environmental allergens such as house dust mites, pollen and moulds.  
 Non-allergic asthma 
 can be triggered by factors such as anxiety, stress, exercise, cold air, smoke and 
infection. 
 
Diagnosis of asthma in adults 
 
 If the FEV1/FVC < 0.7 then a trial of treatment is appropriate. Otherwise further

investigations should be performed. 
 If a patient has typical symptoms of asthma, a trial of treatment is recommended.  
 we should classify patients as having either a high, intermediate or low probability of 
asthma based on the presence or absence of certain symptoms. 
 For adults it is recommend that they have a clinical assessment including 
spirometry  (or Peak Expiratory Flow measurement if spirometry is not available).

 The BTS produced a list of features, which are helpful when deciding this: 
 
630

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 26 - 
 Features which make a diagnosis of 
asthma more likely Features which make a diagnosis of 
asthma less likely 
More than one of the following symptoms: 
wheeze, breathlessness, chest tightness 
and cough, particularly if : 
symptoms worse at night and in the early 
morning 
symptoms in response to exercise,

morning 
symptoms in response to exercise, 
allergen exposure and cold air 
symptoms after taking aspirin or beta 
blockers 
History of atopic disorder 
Family history of asthma and/or atopic 
disorder 
Widespread wheeze heard on 
auscultation of the chest 
Otherwise unexplained low FEV1 or PEF 
(historical or serial readings) 
Otherwise unexplained peripheral blood 
eosinophilia Prominent dizziness, li ght-headedness, 
peripheral tingling 
Chronic productive cough in the absence of

Chronic productive cough in the absence of 
wheeze or breathlessness 
Repeatedly normal physical examination of 
chest when symptomatic 
Voice disturbance 
Symptoms with colds only 
Significant smoking history (ie > 20 pack-
years) 
 
Cardiac disease 
Normal PEF or spirometry when symptomatic 
 High probability  of asthma 
 patient has many symptoms which make a diagnosis of asthma more likely  
 BTS recommend that we start a trial of treatment.

 A good response is considered a positive 'test of reversibility'.  
 If a patient has a poor response to treatment then further investigations should be 
 Low probability  of asthma  
 an alternative diagnosis should be sought.  
 Further investigations and referral to a respiratory specialist should be 
 Intermediate probability  of asthma 
 BTS recommend 'to carry out further investigations, including an explicit trial of

treatments for a specified period, before confirming a diagnosis and establishing 
maintenance treatment.  
 Spirometry is the preferred initial test 
 Treatment should be partly guided by the FEV 1/FVC ratio:  
 a ratio of < 0.7 is suggestive of asthma  trial of treatment  
  a ratio of > 0.7   further investigation/consider referral 
 
Spirometer vs peak flow meter 
 Spirometer  measures the total volume of air that can be exhaled or inhaled. It can also

measure the rate at which a certain volume of air is expelled from the lungs.  
 Spirometry is the most accurate breathing test for asthma.  631

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 27 - 
  spirometry may be normal in asymptomatic patients so it may be necessary to 
repeat spirometry or peak flow readings on a number of occasions in patients 
where the diagnosis is not clear. 
 In adults with obstructive spirometry, an improvement in FEV1 of 12% or more

in response to either β2 agonists or corticosteroid treatment trials, together with 
an increase in volume of 200 ml or more , is regarded as a positive test. (British 
guideline on the management of asthma 2016) (this fact was tested in mrcp 
part 1 sep 2017)  
 Peak flow meter , on the other hand, only measures the rate at which air is forced out of 
the lungs. This is known as the peak expiratory flow.  
 It is now advised to interpret peak flow variability with caution due to the poor

sensitivity of the test 
 diurnal variation % = [(Highest - Lowest PEFR) / Highest PEFR] x 100 
 assessment should be made over 2 weeks 
 greater than 20% diurnal variation is considered significant  
 A variation of > 25%  on a peak flow chart ( pre- and post-bronchodilator ) 
would support a diagnosis of asthma.  
 
NICE quality statement : Adults with new onset asthma are assessed for occupational 
causes.  
 Are you better on days away from work?  
 Are you better on holiday?

Are you better on holiday? 
 
Asthma diagnosis (NICE guidelines 2017) 
 
 Patients ≥ 17 years  
 patients should be asked if their symptoms are better on days away from 
work/during holidays. If so, patients should be referred to a specialist as possible 
occupational asthma 
 all patients should have spirometry with a bronchodilator reversibility (BDR) test 
 all patients should have a FeNO test 
 Patients 5-16 years

 Patients 5-16 years 
 a FeNO test should be requested if there is normal spirometry or obstructive 
spirometry with a negative bronchodilator reversibility (BDR) test 
 Patients < 5 years 
 diagnosis should be made on clinical judgement Do not use symptoms alone 
without an objective test to diagnose asthma. 
 
Objective tests for diagnosing asthma: 
 Airway inflammation measures

 Airway inflammation measures 
 Fractional exhaled nitric oxide ( FeNO) test  
 FeNO level of 40 parts per billion (ppb) or more is a positive test. 
 current smoking status can lower FeNO levels 
 
 Lung function tests 632

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 28 - 
  Spirometry 
 (FEV1/FVC) ratio < 70% is a positive test for obstructive airway disease 
(obstructive spirometry). 
 Bronchodilator reversibility (BDR ) 
 Offered for patient with obstructive spirometry (FEV1/FVC ratio < 70%).  
 improvement in FEV1 ≥ 12%, together with an increase in volume ≥  
200 ml is a positive test.

200 ml is a positive test. 
 Peak expiratory flow variability 
 if there is diagnostic uncertainty after initial assessment and a FeNO test + 
either:  
 normal spirometry or  
 (positive BDR) but a FeNO ≤ 39 ppb. 
 if there is diagnostic uncertainty after initial assessment and they have: 
 obstructive spirometry and irreversible airways obstruction (negative 
BDR) and a FeNO level between 25 and 39 ppb. 
 monitoring peak flow variability for 2 to 4 weeks

 value ≥ 20% variability i s a positive test. 
 Airway hyperreactivity measures 
 Direct bronchial challenge test with histamine or methacholine 
 if there is diagnostic uncertainty after a normal spirometry and either a: 
 FeNO ≥ 40 ppb + no variability in peak flow readings or  
 FeNO ≤ 39 ppb + variability in peak flow readings.  
 If there is obstructive spirometry without bronchodilator reversibility and a 
FeNO level between 25 and 39 ppb and no variability in peak flow readings

 PC20 value ≤  8  mg/ml is a positive test. 
Order of tests 
 
Measure FeNO first followed by spirometry in adults with symptoms of asthma · Carry  
out BDR test if spirometry shows an obstruction 
 
If diagnostic uncertainty remains after FeNO, spirometry and BDR, monitor peak flow 
variability for 2 to 4 weeks 
 
If diagnostic uncertainty remains after measuring peak flow variability, refer for a 
histamine or methacholine direct bronchial challenge test

If histamine or methacholine direct bronchial challenge test is unavailable: · suspect 
asthma and review diagnosis after treatment or · refer to a centre with access to 
histamine or methacholine challenge testing 
 
Positive test thresholds: 
 Obstructive spirometry: FEV1/FVC ratio less than 70% (or below the lower limit of 
normal if available)  
 FeNO: 40 ppb or more  
 BDR: improvement in FEV1 of 12% or more and increase in volume of 200 ml or more  633

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 29 - 
  Peak flow variability: variability over 20%  
 Direct bronchial challenge test with histamine or methacholine: PC20 of 8 mg/ml or less 
 
forced expiratory flow 25 –75%  of vital capacity (FEF 25 –75)  
 One of parameters measured in spirometry

 One of parameters measured in spirometry 
 the flow (or speed) of air coming out of the lung during the middle portion of a forced 
expiration.  
 It reflects the status of the small airways 
 It is more sensitive than the forced expiratory volume in 1 second (FEV1) for 
identifying early airway obstruction. 
 This portion of the flow volume curve is the most effort independent  portion. 
 A normal FEF 25-75 was defined as ≥ 60% predicted.  
 
Lab findings  
  sputum

  sputum   
 Curschmann's spirals  
 microscopic finding in the sputum of asthmatics.  
 spiral-shaped mucus plugs from subepithelial mucous gland ducts or 
bronchioles.  
 Charcot –Leyden crystals  
 microscopic crystals found in allergic diseases such as asthma or parasitic 
infections 
  hallmark of eosinophil-associated allergic inflammatory diseases such as 
asthma, allergic rhinitis and also atopic dermatitis.

 formed from the breakdown of eosinophils in sputum and crystallization of 
major basic protein. 
 
Management of asthma (NICE  guidance 2017).  
One of the key changes is in 'step 3' - patients on a SABA + ICS whose asthma is not 
well controlled should be offered a leukotriene receptor antagonist, not a LABA 
 
Step Notes 
1 
 
Newly-diagnosed asthma Short-acting beta agonist (SABA) 
2 
 
Not controlled on previous step 
OR

2 
 
OR 
Newly-diagnosed asthma with symptoms SABA + low-dose inhaled corticosteroid (ICS) 634

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 30 - 
 Step Notes 
>= 3 / week or night-time waking 
3 SABA + low-dose ICS + leukotriene receptor 
antagonist (LTRA) 
4 SABA + low-dose ICS + long-acting beta agonist 
(LABA) 
 
Continue LTRA depending on patient's response 
to LTRA 
5 SABA +/- LTRA 
 
Switch ICS/LABA for a maintenance and reliever

Switch ICS/LABA for a maintenance and reliever 
therapy (MART), that includes a low-dose ICS 
6 SABA +/- LTRA + medium-dose ICS MART 
 
OR consider changing back to a fixed-dose of a 
moderate-dose ICS and a separate LABA 
7 SABA +/- LTRA + one of the following options: 
 increase ICS to high-dose (only as part of 
a fixed-dose regime, not as a MART) 
 a trial of an additional drug (for example, a 
long-acting muscarinic receptor antagonist 
or theophylline)

or theophylline) 
 seeking advice from a healthcare 
professional with expertise in asthma 
 
 Maintenance and reliever therapy (MART)  
 a form of combined ICS and LABA treatment in which a single inhaler, containing 
both ICS and a fast-acting LABA, is used for both daily maintenance therapy and 
the relief of symptoms as required 
 MART is only available for ICS and LABA combinations in which the LABA has a 
fast-acting component (for example, formoterol) 
 635

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 31 - 
  Table showing examples of inhaled corticosteroid doses  
Dose  Example  
low dose ≤ 400  micrograms budesonide or equivalent 
moderate dose 400 micrograms - 800 micrograms budesonide or equivalent 
high dose > 800 micrograms budesonide or equivalent 
 
Β-blockers, including eye drops, are contraindicated in patients with asthma

Steroid inhalation  
 Fluticasone is more lipophilic and has a longer duration of action than beclometasone  
 Hydrofluoroalkane is now replacing chlorofluorocarbon as the propellant of choice.  
 Only half the usually dose is needed with hydrofluoroalkane due to the smaller 
size of the particles  
 Inhaled corticosteroids  ↓↓ skin collagen synthesis  skin fragility  ↑↑ 
tendency for bruising & vascular changes  
Long acting B2-agonists

Long acting B2-agonists   
 acts as bronchodilators but also inhibit mediator release from mast cells. 
 Salmeterol  may cause paradoxical bronchospasm 
 Salmeterol has been reported to produce an acute exacerbation of asthma, 
possibly through an acute hypersensitivity reaction . 
 The  duration of action of salmetrol is around 12 hours, and has gone completely by 36 
hours.  
 
Leukotriene receptor antagonists  
 Action 
 Montelukast, zafirlukast

 Action 
 Montelukast, zafirlukast 
 Cys LT1 antagonist; it blocks the action of leukotriene on  cysteinyl 
leukotriene receptor CysLT1 by binding to it. 
 Zileuton  blocks leukotriene  synthesis  by inhibiting 5-lipoxygenase , 
 inhibits  5-lipoxygenase pathway, blocking the conversion 
of arachidonic acid to leukotrienes.  
 have both anti-inflammatory and bronchodilatory properties 
 Inductions: 
 should be used when patients are poorly controlled on high-dose inhaled

corticosteroids and a long-acting b2-agonist 
 have been shown to be as effective as doubling the dose of inhaled steroid.  
 asthma with allergic rhinitis 
 aspirin-induced asthma   
 exercise-induced asthma  
 associated with the development of Churg-Strauss syndrome 
 
 636

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 32 - 
  
Asthma drugs: leukotriene inhibitor action: 
 Zafirlukast  Inhibitor of LT receptor  
 Zilueton  Antagonist of lipoxygenase 
Omalizumab (NICE guidelines 2013) 
 a monoclonal antibody that binds to IgE . 
 given subcutaneously every 2 or 4 weeks.

 given subcutaneously every 2 or 4 weeks.  
  recommended for treating severe persistent confirmed allergic IgE-mediated asthma  
 Common SE: 
 injection site pain, swelling, erythema and pruritus, and  headaches  
Drugs used in asthma 
Drug Mechanism of 
action Notes 
Salbutamol Beta receptor 
agonist • Short-acting inhaled bronchodilator. Relaxes 
bronchial smooth muscle through effects on beta 2 
receptors 
• Used in asthma and chronic obstructive pulmonary 
disease (COPD).

disease (COPD). 
• Salmeterol has similar effects but is long -acting 
Corticosteroids Anti-inflammatory • Inhaled corticosteroids are used as mainterance 
therapy 
• Oral or intravenous corticosteroids are used 
following an acute exacerbation of asthma or COPD 
Ipratropium Blocks the 
muscarinic 
acetylcholine 
receptors • Short -acting inhaled bronchodilator. Relaxes 
bronchial smooth muscle  
• Used primarily in COPD  
• Tiotropium has similar effects but is long -acting 
Methylxanthines

Methylxanthines 
(e.g. 
theophylline) Non-specific 
inhibitor of 
phosphodiesterase 
resulting in an 
increase in cAMP • Given orally or intravenously 
• Has a narrow therapeutic index  
Monteleukast, 
zafirlukast Blocks leukotriene 
receptors • Usually taken orally  
• Useful in aspirin -induced asthma 
 
 637

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 33 - 
  
NON-PHARMACOLOGICAL MANAGEMENT (British guideline on the management of 
asthma 2016)  
 stop smoking.  
 Weight-loss  interventions (including dietary and exercise-based programmes) can be 
considered for overweight and obese with asthma to improve asthma control.

 Breathing exercise  programmes (including physiotherapist-taught methods) can be 
offered to people with asthma as an adjuvant to pharmacological treatment to improve 
quality of life and reduce symptoms. 
 
Teaching diaphragmatic breathing , (as opposed to thoracic breathing which is practised 
by many asthmatics), may significantly impact on symptoms.   Reducing the likelihood of 
future attendance in the Emergency department 
 
Buteyko technique    associated with improved symptoms.

 The Buteyko technique controls chronic hyperventilation, as such patients perceive less 
symptoms of shortness of breath, and their use of short acting bronchodilators is 
reduced. 
 This does not however have any impact on lung function including FEV1 and FVC. 
 It may be particularly valuable in patients who complain of symptoms of shortness of 
breath significantly in excess of those expected when you review their lung function.

Mepolizumab  may be used for  resistant asthma with high eosinophils 
 Mepolizumab is an anti-IL5 monoclonal antibody  
 IL5 is a cytokine which promotes growth in eosinophil numbers and activity.  
 By blocking IL5 mepolizumab down-regulates eosinophil activity and has been shown to 
significantly improve symptoms in resistant asthma.   
 
Omalizumab  is an anti-IgE monoclonal antibody, it is effective in treating resistant 
asthma with evidence of raised IgE and allergic symptoms.

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 34 - 
  
Acute severe asthma 
Patients with acute severe asthma are stratified into moderate, severe or life-threatening 
Moderate Severe Life-threatening 
 PEFR 50-75% 
best or predicted 
 Speech normal 
 RR < 25 / min 
 Pulse  < 110 bpm  PEFR 33 - 50%

 Pulse  < 110 bpm  PEFR 33 - 50%  
 Can't complete 
sentences 
 RR > 25/min 
 Pulse  > 110 bpm  PEFR < 33% best or predicted 
 Oxygen sats < 92% 
 PaO 2 < 8 kPa 
 Normal PaCO 2 (4.6-6.0 kPa) 
 Silent chest, cyanosis or feeble ( Poor ) 
respiratory effort 
 Bradycardia, dysrhythmia or hypotension 
 Exhaustion, confusion or coma 
 Note that a patient having any one of the life-threatening features should be treated as 
having a life-threatening attack.

having a life-threatening attack. 
 A pH less than 7.35 likely represents carbon dioxide retention in a tiring patient and is 
an ominous sign in acute asthma.   
 A normal or elevated pCO2 in an asthmatic indicates failing respiratory effort,  and 
although oxygen saturation may be not severely depressed, patient is in danger of 
decompensation and - aside from high flow oxygen, nebulised salbutamol and

ipatropium, and steroids - it would be prudent to inform the ICU. Therefore, even though 
it is in the normal range, this is  the most worrying result for life-threatening . 
 A normal PaCO2 in an asthmatic is a warning of impending respiratory failure as 
the patient becomes too tired to ventilate adequately.  
 If PCO2 is just outside the upper limit of normal, the patient will requires urgent 
admission to the Intensive Therapy Unit.  
 
Lung function in an acute asthma attack

Lung function in an acute asthma attack 
 The classic abnormalities are reduced  (FEV-1) & (FVC) & FEV-1/FVC ratio.  
 Because of gas trapping there is an  increase in residual volume  and an increase in 
total lung capacity, but the ratio of residual volume (RV) to total lung capacity (TLC) is 
increased (TLC = vital capacity [VC] + RV).  
 Airway conductance (the reciprocal of airway resistance) is decreased in acute asthma.

 Gas transfer would be difficult to measure in acute asthma but can be elevated in stable 
asthma where there might be chronic hyperinflation giving rise to a greater surface area 
for blood/gas interfacing. 
 asthma is most likely associated with an obstructive spirometry and normal Tlco 
(transfer factor for carbon monoxide)  
 
639

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 35 - 
 In acute severe asthma,  β2-agonists should be administered as soon as possible, 
preferably nebulised driven with high flow  oxygen .  
 salbutamol  administration can rapidly worsen the V/Q mismatch which is the 
cause of hypoxia in asthma. They can therefore cause reduction in arterial

oxygen tension unless supplemental oxygen is given 
Physiologic changes following a nebuliser in acute asthma  : 
initially , poor ventilation  hypoperfusion to certain lung areas  . 
Following a nebuliser and subsequent improved ventilation, there is then a 
ventilation/perfusion mismatch which may lead to  a transient drop in oxygen saturation . 
 
  Nebulised ipratropium bromide should be added for patients with acute severe or life

threatening asthma, or those with a poor initial response. It's addition produces 
significantly greater bronchodilation than a β2 -agonist alone.  
 Oxygen: 
 Targeted oxygen in asthma => SpO2 level of 94 –98%.                      
 Patients with saturations less than 92% on air should have an ABG to exclude 
hypercapnia. However, starting treatment should not be delayed to do the ABG.  
 Initially high-flow oxygen is used, and then weaned to maintain adequate

saturations. Unless you suspect COPD there is no need to be cautious with 
oxygen therapy. 
 Steroids: 
Nice 2013  People aged 5 years or older presenting to a healthcare professional with a 
severe or life-threatening acute exacerbation of asthma receive  oral or intravenous steroids 
within  1 hour  of presentation.  
 
 steroids reduce mortality, relapses, subsequent hospital admission and 
requirement for β2 -agonists1.

requirement for β2 -agonists1.  
 The earlier they are given in the attack, the better the outcome. 
 A dose of 40-50 mg should be given once oxygen and nebuliser therapy has 
been established. This should be continued for five days, and can then be 
stopped abruptly.  
 Magnesium sulphate  recommended as next step for patients who are not responding 
(e.g. 1.2 - 2g IV over 20 mins) . 
 Mechanism: low magnesium levels in bronchial smooth muscle favour 
bronchoconstriction.

bronchoconstriction.  
 reduce rates of admission to intensive therapy units  
 little evidence to support use of IV aminophylline (although still mentioned in 
management plans) 
 if no response consider IV salbutamol 
 Intensive care  is indicated for patients with severe acute or life threatening asthma who 
are failing to respond to therapy.  
 Strongest indicator of a need for intubation and ventilation ?  
 PH 7.31  
 
 640

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 36 - 
Asthma in pregnancy  
 In general, the medicines used for asthma are safe during pregnancy.  
 The British Thoracic Society (BTS) guidelines make it clear that short-acting /long-acting

beta 2-agonists, inhaled and oral corticosteroids should all be used as normal during 
 The BNF advises that 'inhaled drugs, theophylline and prednisolone can be taken as 
normal during pregnancy and breast-feeding'.  
Asthma during labour: 
 Women receiving steroid tablets at a dose exceeding prednisolone 7.5 mg per day for 
more than two weeks prior to delivery should receive parenteral hydrocortisone 100 
mg 6 –8 hourly during labour.:

mg 6 –8 hourly during labour.: 
 prostaglandin F2α  inducing bronchoconstriction 
 
Extra notes 
Pulsus paradoxus: 
 The right heart responds directly to changes in intrathoracic pressure, while the filling of 
the left heart depends on the pulmonary vascular volume.  
 At high respiratory rates, with severe air flow limitation (for example, acute asthma) 
there is an increased and sudden negative intrathoracic pressure on inspiration and this

will enhance the normal fall in blood pressure.  
 
Exercise-induced asthma : 
 The most likely diagnosis  would be with spiromet ry before and after exercise , 
(NOT before and after administration of bronchodilators)  where a typical obstructive 
pattern may be displayed following exercise. 
Cough-variant asthma 
 airway inflammation but minimal bronchoconstriction. 
 Response to steroids is helpful when making the diagnosis of asthma.   
 Bronchodilators often have little effect.

 Bronchodilators often have little effect. 
 No typical asthma history; the cough is typically worse in the mornings, in the cold air 
and after exercise. 
 Treatment is with high-dose inhaled steroids for at least 2 months, or a short course of 
oral steroids.  
 
 641

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 37 - 
  
Difficult asthma  persisting asthma, despite prescription of high-dose asthma 
therapy.  
 Always consider poor adherence to maintenance therapy. 
 Consider monitoring induced sputum eosinophil counts to guide steroid treatment. 
 Dysfunctional breathing should be considered as part of a difficult asthma assessment.

 allergen testing to moulds should be performed .  
 Commonly associated with co-existent psychological 
 differential diagnosis in difficult asthma clinic:  
 Subglottic stenosis  
 defined as a narrowing of the airway below the vocal cords (subglottis) 
and above the trachea. It may be congenital or acquired. 
 can occur from birth, idiopathically and in patients who have been 
intubated . 
 predominance of inspiratory  rather expiratory wheeze

Chronic Obstructive Pulmonary Disease(COPD) 
 COPD is a long-term respiratory condition characterised by airflow obstruction that is 
not fully reversible. 
Subtypes  of COPD 
1. chronic bronchitis  
 defined as chronic cough and sputum production for at least three months of two 
consecutive years in the absence of other disease which could explain these 
symptoms.

symptoms. 
 inflammatory changes leads to ciliary dysfunction and increased goblet cell 
size and number , which leads to the excessive mucus secretion.  
2. Emphysema  
 
 These changes are responsible for decreased airflow, hypersecretion, and chronic 
cough. In both conditions, changes are progressive and usually not reversible.  
 Increased airway resistance  is the physiological definition of COPD.

 Decreased elastic recoil, fibrotic changes in lung parenchyma, and luminal 
obstruction of airways by secretions all contribute to increased airways 
resistance. 
 Progressive hypoxia causes vascular smooth muscle thickening with subsequent 
pulmonary hypertension 
 Which mechanism  is most likely responsible for the increased mean arterial 
pulmonary pressure in COPD ?  
 Hypoxic induced pulmonary vasoconstriction 
Causes 
 Smoking 
 Alpha-1 antitrypsin deficiency 642

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 38 - 
  patients from the developing world present with a COPD-like history from using open 
fires in their homes for cooking or heating (accounting for up to 1 million deaths 
worldwide as a result of COPD without smoking history) 
 Other causes (particularly occupational exposures , such as harmful dust and 
chemicals)

chemicals) 
 cadmium (used in smelting) (recognised cause of emphysema specifically) 
 coal 
 cotton  
 cement 
 grain 
 
Emphysema  
 emphysema is a term that refers to the actual damage to the air sacs in the lung, 
called the alveoli. In other words, emphysema is a pathological term.  
 destruction of alveolar air sacs due to an imbalance between protease and 
anti-protease action.  
 Emphysema is an irreversible degenerative condition;

 loss of elastic recoil, which drives airflow limitation.   
 Although airflow limitation is virtually irreversible, the small inflammatory 
component can respond to high-dose inhaled corticosteroids.  
 Lung recoil decreases in emphysema. 
 the final outcome of the inflammatory responses is elastin breakdown  and 
subsequent loss of alveolar integrity.   
 involves an increase in elastase activity.  
 Types 
 Panlobular (panacinar) pulmonary emphysema  
 Rare

 Rare 
 Associated with  α1-antitrypsin deficiency  
 Characterized by destruction of the entire acinus 
 Usually affects the lower lobe  
 Centrilobular or proximal acinar pulmonary emphysema  
 Common 
 Classically seen in smokers  
 Characterized by destruction of the respiratory bronchiole (central portion 
of the acinus) 
 Usually affects the upper lobe  
 most severe at the apex of the lung. 
 Features

 Features  
 Hyper-expanded lung fields on CXR, reduced transfer factor and an FEV1/FVC < 
70 %.  
 MacLeod syndrome is unilateral emphysema following childhood 
bronchiolitis . 
 Loss of lung recoil causes a reduction of alveolar pressure (elastic recoil pressure 
of lung + pleural pressure) leading to collapse of peripheral airways on expiration. 643

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 39 - 
 Emphysematous patients purse their lips in expiration to increase airway 
pressure to prevent this collapse. 
 CO transfer factor is reduced. 
 Ĺ Residual Volume (RV)  
 Ĺ Total Lung Capacity (TLC)  
 Giving typical obstructive pathology 
 Flattening of diaphragms: Ĺ lung volumes  
 Enlarged left pulmonary artery

 Enlarged left pulmonary artery 
 Attenuation of vessels 
 Diffuse hyperlucency 
 
Types of emphysema 
Type  Centriacinar (centrilobula ) Panacinar  
Prevalence  the most common  type  Less common 
destruction focal destruction mainly 
localized to the proximal 
respiratory bronchioles  destroys the entire alveolus 
uniformly  
Location  upper lung  zones.  lower half of the lungs.  
causes smoking  & dust  alpha 1-antitrypsin (AAT) 
deficiency

deficiency 
 
What is the most important factor in airflow limitation in severe emphysema? 
 Loss of elastic recoil  
 
 extensor plantar response is common in (COPD) due to carbon dioxide retention, 
which results in carbon dioxide narcosis.  
 
644

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 40 - 
  
Investigation and diagnosis 
 
 NICE recommend considering a diagnosis of COPD in patients over 35 years of age 
who are smokers or ex-smokers and have symptoms such as exertional 
breathlessness, chronic cough or regular sputum production. 
 The following investigations are recommended in patients with suspected COPD:

 Post-bronchodilator spirometry to demonstrate airflow obstruction: FEV1/FVC 
ratio less than 70% 
 Chest x-ray: hyperinflation, bullae, flat hemidiaphragm. Also important to exclude 
lung cancer 
 Full blood count: exclude secondary polycythaemia 
 Body mass index (BMI) calculation 
 Measuring peak expiratory flow is of limited value in COPD, as it may underestimate the 
degree of airflow obstruction. 
 A methacholine challenge is useful in differentiating between asthma and chronic

obstructive pulmonary disease (COPD). 
 methacholine utilizes the M3 receptor for bronchoconstriction. 
 In long standing COPD the bicarbonate is likely to be normal, or raised if the patient has 
chronic hypercapnia.  (a low pH, low pO 2, high pCO 2 and a high HCO 3) 
 Peripheral oedema may be present as a dependent oedema, as patients with COPD 
may have limited mobility due to dyspnoea, and therefore does not necessarily indicate 
 
645

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 41 - 
 The severity of COPD  is categorised using the FEV1: 
Post-bronchodilator 
FEV1/FVC FEV1 (of 
predicted) Severity 
< 0.7 > 80% Stage 1 - Mild 
< 0.7 50-79% Stage 2 - Moderate 
< 0.7 30-49% Stage 3 - Severe 
< 0.7 < 30% Stage 4 - Very severe 
 
Nocturnal oxygen desaturation in COPD

Nocturnal oxygen desaturation in COPD   
 COPD patients commonly suffer from nocturnal oxygen desaturation  which is not 
usually caused by sleep apnoea. Sleep-related hypoxaemia  can result in the patient 
reporting morning headaches and daytime somnolence. The diagnosis is made via 
overnight home monitoring with a pulse oximeter  which shows dramatic falls in 
saturation levels that occur during REM sleep. 
 
Acute exacerbations  
Infective exacerbation of COPD

Infective exacerbation of COPD  
 is the most common cause of haemoptysis in UK patients  
COPD: causes of acute exacerbations  
 The most common bacterial organisms that cause infective exacerbations of COPD are: 
 Haemophilus influenzae  (most common cause)  
 The patient should be treated with a course of amoxicillin or a tetracycline 
together with prednisolone. 
 Streptococcus pneumoniae  
 Moraxella catarrhalis

 Moraxella catarrhalis  
 If the patient had pneumonia then Streptococcus pneumoniae  would be the most likely 
causative organism. But if the chest x-ray shows no evidence of consolidation this will 
make a diagnosis of pneumonia unlikely.  
 Respiratory viruses account for around 30% of exacerbations, with the  human 
rhinovirus  being the most important pathogen. 
COPD: management of acute exacerbations : NICE guidelines from 2010 recommend the 
following:

 increase frequency of bronchodilator use and consider giving via a nebuliser 
 Give prednisolone 30 mg daily for 7-14 days. Prolonged courses offer no additional 
benefit  
 It is common practice for all patients with an exacerbation of COPD to receive 
antibiotics. NICE do not support this approach. They recommend giving oral antibiotics 
'if sputum is purulent or there are clinical signs of pneumonia' 

 Doxapram  infusion can be useful in patients as a short-term treatment while other, 
more effective support is instituted or a decision is made not to proceed with mechanical 
support. 646

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 42 - 
  Doxapram is a respiratory stimulant, which can be effective at improving 
ventilation.  
 Its use has been superseded by non-invasive ventilation (NIV), but it might be 
useful in situations where NIV is unavailable. 
 
COPD: stable management 
 
NICE guidance (2010)  
General management 
 smoking cessation advice

 smoking cessation advice 
 annual influenza vaccination 
 one-off pneumococcal vaccination 
Bronchodilator therapy 
 a short-acting beta2-agonist (SABA) or short-acting muscarinic antagonist (SAMA) is 
first-line treatment 
for patients who remain breathless or have exacerbations despite using short-acting 
bronchodilators the next step is determined by the FEV1 
 FEV1 > 50% 
 long-acting beta2-agonist (LABA), for example salmeterol, or:

 long-acting muscarinic antagonist (LAMA), for example tiotropium 
 FEV1 < 50% 
 LABA + inhaled corticosteroid (ICS) in a combination inhaler, or: 
 LAMA 
For patients with persistent exacerbations or breathlessness 
 if taking a LABA then switch to a LABA + ICS combination inhaler 
 otherwise give a LAMA and a LABA + ICS combination inhaler 
Oral theophylline 
 NICE only recommends theophylline after trials of short and long-acting bronchodilators

or to people who cannot used inhaled therapy 
 the dose should be reduced if macrolide or fluoroquinolone antibiotics are co-prescribed 
Mucolytics 
 should be 'considered' in patients with a chronic productive cough and continued if 
symptoms improve 
Cor pulmonale 
647

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 43 - 
  features include peripheral oedema, raised jugular venous pressure, systolic 
parasternal heave, loud P2 
 use a loop diuretic for oedema, consider long-term oxygen therapy 
 ACE-inhibitors, calcium channel blockers and alpha blockers are not recommended by 
NICE 
Factors, which may improve survival in patients with stable COPD

 smoking cessation - the single most important intervention in patients who are 
still smoking 
 long term oxygen therapy  in patients who fit criteria 
 lung volume reduction surgery in selected patients 
LTOT should be offered to patients with a pO2 of < 7.3 kPa or to those with a pO2 of 7.3 - 8 
kPa and one of the following: 
 secondary polycythaemia 
 nocturnal hypoxaemia 
 peripheral oedema 
 pulmonary hypertension

 pulmonary hypertension 
Inhaled steroids  have been shown to improve quality of life and reduce hospitalisation rates 
by reducing the number of exacerbations, but they do not slow the rate of decline of 
FEV 1 (hence do not affect prognosis ). 
 
Roflumilast should be used in COPD for patients who are losing control on triple 
inhaled therapy 
 Roflumilast is a selective long-acting phosphodiesterase-4 inhibitor .

 recommended by NICE for patients who have suffered two or more exacerbations in a 
year, despite triple inhaled therapy, where FEV1 is less than 50% of predicted.  
 It is orally administered. 
 
Management of side effect of steroid inhaler ( oro-pharyngeal and oesophageal 
candidiasis ): 
 the patient should be taught adequate inhaler technique . Advise him to rinse his 
mouth each time he uses his inhaler  use a spacer device  review him in a 
 and and
month .

and and
month . 
 Resistant symptoms can be managed with oral nystatin or a course of fluconazole.  
 
Pulmonary rehabilitation 
 This is a programme of aerobic lower-extremity training combined with education. 
 Patients with very limited exercise tolerances may benefit from pulmonary rehabilitation 
and in the most severely limited patients chair-based exercises can be taught. 
 It leads to improvements in exercise capacity (walking distance should improve

after the rehabilitation programme)   
 Pulmonary rehabilitation does not improve lung function.  
 The improvement in walking distance  would  not be a long-lasting  improvement  
 Decline in exercise tolerance and health status tends to occur 6 –12 months after 
the completion of a course. 648

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 44 - 
  The effect of sustained improvement with ongoing rehabilitation has yet to be 
evaluated. 
 Patients who have completed pulmonary rehabilitation experience no fewer hospital 
admissions because of chest problems , but their  hospital stays are likely to be 
shorter.  
 
Surgery

shorter.  
 
Surgery 
 The National Emphysema Treatment Trial was a prospective, randomised, multi-centre 
trial which compared the results of lung volume reduction surgery  to medical therapy 
which showed that there were 3 groups of patients that tend to benefit : 
 Group 1 : Upper lobe emphysema and low exercise capacity .  
 These patients show improvement in both functional outcomes and 
survival after lung volume reduction surgery compared to medical therapy.

 Group 2 : upper lobe emphysema and high exercise capacity .  
 These patients have improved functional outcomes but no difference 
in survival compared to medical therapy.  
 Group 3 : non-upper lobe emphysema and low exercise capacity .  
 These patients have improved survival after surgery but there is no 
difference in survival compared to medical therapy.  
 The trial also identified patients with emphysema that are unlikely to do well from

lung volume reduction surgery  and have a high risk of death. This includes:  
1. Patients with non-upper lobe emphysema and high exercise capacity . 
2. Patients with extremely poor pulmonary function  (forced expiratory volume in 
1 second (FEV1) 20% or less than predicted) and either homogenous 
distribution of emphysema on computed tomography scan or extremely poor 
carbon monoxide diffusing capacity (20% or less than predicted).  
Lung volume reduction surgery :

Lung volume reduction surgery :  
 Is a palliative treatment which can be used in advanced COPD to remove the least 
functional part of the lungs.  
 Techniques used include median sternotomy, video-assisted thoracoscopy and 
thoracotomy. 
 Indications :  
 CO 2 retention: The upper cut off for referral for lung reduction surgery for 
pCO 2 is 7.3  
 Severe limitation of exercise capacity despite maximal therapy 
 predominant upper lobe emphysema, and persistent symptoms despite a period

of pulmonary rehabilitation. 
 selection criteria : used when assessing suitability for treatment: 
 Age <75 years 
 Emphysema by clinical evaluation 
 Ex-smoker of more than 4 months 
 Clinically stable on no more than 20mg prednisolone daily 
 Significant functional limitation after 6-12 weeks of pulmonary rehabilitation on 
optimal medical therapy 649

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 45 - 
  Demonstrated compliance with medical regimen 
 FEV-1 >20% predicted 
 Post-bronchodilator FEV-1 >45% predicted and >15% if >70 years 
 Hyperinflation demonstrated by TLC >100% predicted and RV >150% predicted 
 Carbon monoxide lung transfer factor greater than 20% predicted 
 Post rehabilitation 6 minute walk distance >140 m

 Low post rehabilitation exercise capacity 
 HRCT demonstrating bilateral severe emphysema, ideally with upper-lobe 
predominance 
 
Symptomatic relief of breathlessness in e nd-stage COPD   
 If the patient has end-stage COPD  and has himself indicated that control of symptoms 
is his priority. As such, consideration of use of opioid or benzodiazepine medications 
for symptomatic relief of breathlessness is appropriate.

 A recent prospective study demonstrated that lower dose opioid use (< 30 mg daily oral 
morphine equivalent) does not increase risk of hospitalisation or increase mortality in 
patients with COPD on long-term oxygen therapy .  
Oxygen therapy  
 When managing patients with COPD, once the pCO2 is known to be normal the target 
oxygen saturations should be 94-98%.

oxygen saturations should be 94-98%.  
 Patients with (COPD) should not in general receive more than 24-28% oxygen without 
arterial blood gas monitoring. 
 In patients who are critically ill (anaphylaxis, shock etc) oxygen should initially be 
given via a reservoir mask at 15 l/min. Hypoxia kills.  
Oxygen saturation targets  
 acutely ill patients: 94- 98% 
 patients at risk of hypercapnia (e.g. COPD patients): 88-92% (see below)

 oxygen should be reduced in stable patients with satisfactory oxygen saturation 
Management of COPD patients  
 prior to availability of blood gases, use a 28% Venturi mask at 4 l/min and aim for an 
oxygen saturation of 88-92% for patients with risk factors for hypercapnia but no prior 
history of respiratory acidosis 
 adjust target range to 94-98% if the pCO2 is normal 
 Oxygen should be given to maintain SaO2 within the patient's individual target range, if

available (COPD patients are being given cards with this information, so always ask) . If 
the individual target is not known, saturations should be maintained at 88-92%.  
 Hudson face masks are less precise than venturi masks, so do not use if hypercapnic or 
type II respiratory failure. Risk of CO 2 accumulation if flow rate <5 L/min due to 
rebreathing of CO 2. 
 Venturi mask  
 often utilized in the COPD patient  
 often employed when the clinician has a concern about carbon

dioxide retention  or when respiratory drive is inconsistent.  
 mixes oxygen with room air, creating high-flow  oxygen  650

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 46 - 
  addition of humidification is not necessary with this device,  
 provides an accurate and constant FiO 2 despite varied respiratory rates 
and tidal volumes.  
 The British Thoracic Society in conjunction with the Intensive Care Society has 
produced oxygen alert cards  that can be downloaded and printed to give to patients.it

include  – in addition to patient's name:  
 that they are at risk of type II respiratory failure (with raised CO 2 levels), 
 the concentration of oxygen to be delivered via venturi mask  
 their target oxygen saturations. 
 advice regarding the use of air and oxygen driven nebuliser machines  
 
 Situations where oxygen therapy should not be used routinely if there is no evidence 
of hypoxia:  
 myocardial infarction and acute coronary syndromes 
 stroke 
 obstetric emergencies

 stroke 
 obstetric emergencies 
 anxiety-related hyperventilation 
 
There are three forms of domiciliary supplemental oxygen therapy: 
1. Long -term controlled oxygen therapy for at least 15 hours per day in patients with 
chronic respiratory failure 
2. Portable oxygen therapy for exercise-related hypoxaemia 
3. Short-burst oxygen therapy, as a palliative treatment for the temporary relief of 
symptoms.  

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 47 - 
 Non-invasive ventilation - key indications 
 COPD with respiratory acidosis pH 7.25-7.35  who have not improved on controlled 
oxygen and standard medical therapy.  
 (NIV) is the treatment of choice for persistent hypercapnic ventilation failure 
despite optimal medical therapy.

despite optimal medical therapy.  
 According to the guidelines, 'maximal medical therapy' is defined as:  
 Controlled oxygen to maintain SaO 2 88-92% 
 Nebulised salbutamol 2.5-5 mg 
 Nebulised ipratropium 500 μg  
 Prednisolone 30 mg 
 Antibiotic agent (when indicated). 
 The evidence surrounding the use of NIV in COPD shows that patients with a pH 
in the range of 7.25-7.35 achieve the most benefit.  
 The guidelines mention that NIV should be considered in patients with COPD

exacerbation in whom a respiratory acidosis persists despite immediate 
maximum standard medical treatment on controlled oxygen for no more 
than one hour.  
 If the pH is < 7.25 then invasive ventilation should be considered if appropriate . 
 pCO 2 >6.0  (fits the criterion for respiratory acidosis)  
 Hypercapnia without profound hypoxia 
 type II respiratory failure secondary to chest wall deformity, neuromuscular disease or 
obstructive sleep apnoea

obstructive sleep apnoea  
 cardiogenic pulmonary oedema unresponsive to CPAP 
 weaning from tracheal intubation 
 
Non-invasive, positive-pressure ventilation (NIPPV) has been shown to reduce intubation 
rates, lower hospital mortality rates and lead to shorter hospital stays. 
 
Recommended initial settings for bi-level pressure support in COPD 
 
 Expiratory Positive Airway Pressure ( EPAP ): 4-5 cm H2O 
 Inspiratory Positive Airway Pressure ( IPAP ): RCP advocate 10 cm H20 whilst BTS

suggest 12-15 cm H2O.   
 back up rate: 15 breaths/min 
 back up inspiration: expiration ratio: 1:3 
 ABGs  
 ABGs should be repeated after 1 hour of NIV therapy, and 1 hour after 
subsequent change in settings or 4 hours in stable patients.  
 If gas exchange is not significantly improved: 
  the IPAP  can be gradually increased at a rate of approximately 5 cms ( 2-5cm ) 
H2O every 10 minutes with a usual target of 20cm H2O or  until a response has

been achieved or patient tolerability has been reached.  
 Increases in EPAP  are not recommended without specialist advice.  
 
How to give nebulisation  during NIV in patient with severe exacerbation of COPD ? 
 take off the mask to administer nebulisers 652

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 48 - 
  Giving nebulised medication into ongoing NIV is not recommended by the BTS as 
the pressures reduce the effective dose reaching the airways. 
 
Important complication of NIV   
 ventilation associated pneumothorax is (most important complication of NIV ==> 
present acutely)

present acutely) 
 Ventilator associated pneumonia ==> present in patients who have been ventilated for 
long period of time and would not present so acutely).  
 
Contraindications  to NIV  include:  
 facial burns/trauma/recent facial or upper airway surgery 
 vomiting 
 fixed upper airway obstruction 
 undrained pneumothorax 
 upper gastrointestinal surgery 
 inability to protect the airway 
 copious respiratory secretions 
 life threatening hypoxaemia

 life threatening hypoxaemia 
 haemodynamically unstable  requiring inotropes/pressors (unless in a critical care unit) 
 severe co-morbidity 
 confusion/agitation 
 bowel obstruction 
 patient declines treatment 
Invasive ventilation: 
 Patients with a pH <7.26 should be managed with a low threshold for intubation.  
 Mechanical ventilation might be necessary if the patient is unconscious or if the pH is

below 7.25. 
 give NIV whilst awaiting for intensive care.  
 in Guillain Barre syndrome with respiratory involvement => the parameter used to 
assess whether a patient needs ventilator support is an FVC <15-20ml/kg.  
 
Decision to ventilate in COPD 
 If the patient had a written advanced directive, properly witnessed, while he was well , 
then it would not be possible to consider intervention if he wished for it not to happen.

 On the other hand , if he has significant hypoxia, he might not be able to give a 
rational decision  with respect to his further treatment.  
 The family should not have the final decision with respect to intubation - the decision on. 
 so if significantly hypoxic patient refused intubation during acute exacerbation =>  
Intubate and act on the best interests of the patient, while informing the relatives   
 
Intermittent positive-pressure ventilation (IPPV)

Effects of increased lung volume 
 Volumes are significantly increased when compared with spontaneous ventilation  
 ↑↑tidal volume  pulmonary vascular resistance, which may lead to   pulmonary 
hypertension  right ventricular compromise . 653

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 49 - 
  over-inflated alveoli  compression of the alveolar blood vessels  ↑↑ right ventricle 
volume ↓↓ left ventricle (LV) filling (ventricular interdependence)  
 Hyperinflation also leads to prostaglandin release which may be a protective 
mechanism against lung injury 
 
Effects of increased intrathoracic pressure

Effects of increased intrathoracic pressure 
 Intrathoracic pressure is increased at all points in the respiratory cycle 
 Inspiration during IPPV  ↑↑ intrathoracic pressure  ↑↑ right atrial pressure   
↓↓ venous return  ↓↓ cardiac output  
 The increased intrathoracic pressure also decreases the gradient across the LV that it 
has to work against, which results in a decreased afterload. Both these effects reduce 
intrathoracic blood volume

intrathoracic blood volume 
Long -term oxygen therapy (LTOT)  
 
COPD - LTOT if 2 measurements of pO2 < 7.3 kPa  
 
Which patients should be assessed for and offered (LTOT)? ( 2010 NICE guidelines ) 
 Assess patients if any of the following:  
 Very severe airflow obstruction (FEV1 < 30% predicted).  
 Assessment should be 'considered' for patients with severe airflow 
obstruction (FEV1 30-49% predicted)  
 cyanosis 
 polycythaemia

 cyanosis 
 polycythaemia 
 peripheral oedema 
 raised jugular venous pressure 
 oxygen saturations less than or equal to 92% on room air 
 
How to assess patient for LTOT? 
 Assessment is done by measuring arterial blood gases  on 2 occasions  at least 3 
weeks apart  in patients with stable COPD  on optimal management. 
 Blood gases should be performed in a stable state , which should be at least four 
weeks after an exacerbation of the disease.

weeks after an exacerbation of the disease.  
 
Indications (British Thoracic Society (BTS) 
 General Indications for LTOT:   
 Chronic obstructive pulmonary disease (COPD) 
 Severe chronic asthma 
 Interstitial lung disease 
 Cystic fibrosis 
 Bronchiectasis 
 Pulmonary vascular disease 
 Primary pulmonary hypertension 
 Pulmonary malignancy 
 Chronic heart failure 654

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 50 - 
  Indications for LTOT in COPD: 
 patients with pO2 of < 7.3 kPa  
 patients with  pO2 of 7.3 - 8 kPa and one of the following:  
 secondary polycythaemia 
 nocturnal hypoxaemia 
 peripheral oedema 
 Borderline results should be repeated in three months (eg PO2 = 7.3 or

slightly above, without additional factors).  
 
 Duration of LTOT: 
 Patients who receive LTOT should breathe supplementary oxygen for at least  15 hours  
a day including at night time.  
 At least 15 hours  of oxygen therapy per day is required to reduce the pulmonary 
hypertension associated with (COPD) and to treat the underlying pathology of 
incipient right heart failure.  
 A reduction in mortality is only seen when oxygen therapy is used for more than 
19 hours a day.

19 hours a day. 
 Improvements in pulmonary artery hypertension  were obtained in patients 
who used oxygen for more than 15 hours  per day,  
 reduction in  mortality was only improved in patients who used oxygen for more 
than 18 hours  per day.  
 Continued cigarette smoking should be a relative contraindication to long-term oxygen 
therapy.  
 
In patients with chronic hypoxaemia, LTOT  should be prescribed after assessment, when the

PaO 2 is consistently at or below 7.3 kPa (55 mm Hg) when breathing air during a period of 
clinical stability. Clinical stability  is defined as the absence of exacerbation of chronic lung 
disease for the previous five weeks.  The level of PaCO 2(which may be normal or elevated) 
does not influence the need for LTOT  prescription.                                                                           
mrcpass.com

mrcpass.com 
 
The only treatment that improves the long-term prognosis in patients with (COPD) is 
LTOT, given for at least 15 hours per da y. 
 
 Effects of  supplementary oxygen therapy:  
 Improvement in survival,  
 Improvement in exercise endurance, associated with a reduction in ventilation at a given 
submaximal work rate, and an improvement in walking distance and in the ability to 
perform daily activities.

perform daily activities. 
 After 6 months of oxygen therapy, 42% of patients showed evidence of an 
improvement in cognitive function , but little change in mood or quality of life. 
 Affect the polycythaemia that occurs in patients with chronic hypoxaemia, by reducing 
both the haematocrit and the red cell mass . 655

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 51 - 
  
Ambulatory oxygen therapy (AOT): 
(New development with light portable cylinders lasting six hours). 
 Offer (AOT) to people already on LTOT who want to use oxygen outside the home, 
following assessment by a specialist.

following assessment by a specialist. 
 Consider it in motivated individuals who have exercise desaturation and PaO 2 less than 
or equal to 7.3 kPa and whose exercise capacity and/or breathlessness improve with 
oxygen. 
The British Thoracic Society (BTS) recommends:  
 AOT should not be routinely offered to patients who are not eligible for LTOT. 
 AOT should not be routinely offered to patients already on LTOT.

 AOT assessment should only be offered to patients already on LTOT if they are mobile 
outdoors. 
 AOT should be offered to patients for use during exercise in a pulmonary rehabilitation 
programme or during an exercise programme following a formal assessment 
demonstrating improvement in exercise endurance. 
Ref: Patient.info

Ref: Patient.info 
 
Clinical variants of COPD  
Pink puffers 
Pink puffers have a good respiratory drive. 
Clinical features: 
 Pursed-lip breathing with intense dyspnoea 
 Often thin and elderly 
 Sparce production of sputum 
 Oedema and overt heart failure (rare complications)  
Investigations:

Investigations: 
 Blood gases are near-normal until pre-terminally there is very severe airways 
obstructi on 
 total lung capacity increased 
 Reduction in transfer factor 
Blue bloaters 
Blue bloaters have a poor respiratory drive. 
Clinical features: *COPD Patients without chronic hypoxaemia (=paO2 ≤ 7.3 kPa on air + Clinical stability 
(=no exacerbation of COPD in last 5 weeks) ) and not on LTOT  perform Walking test with

a trial of oxygen    if they show evidence of exercise oxygen desaturation (a fall of SaO2 of 
at least 4% below 90%) + improvement in exercise capacity with  O2 ambulatory 
oxygen therapy (AOT)  mrcpass.com  656

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 52 - 
  Quite mild dyspnoea 
 Often obese 
 Production of large volumes of sputum 
 Infective exacerbations 
 Often oedematous 
 Can develop cor pulmonale  
 Blood gases show hypercapnia, hypoxaemia, elevated plasma bicarbonate 
 Severe nocturnal hypoxaemia 
 Airways obstruction might only be moderate

 Airways obstruction might only be moderate  
 
Prognosis of COPD 
 Once respiratory failure criteria have been met, the 5-year survival rate is only around 
25%.  
 Prognostic indicators in COPD  
 The strongest predictors of survival in patients with (COPD) are: 
 FEV1  
 Age  
 Fewer than 50% of patients whose FEV-1 has fallen to 30% of predicted are alive 
5 years later. 
 There is a stronger relationship between survival and the post-bronchodilator

FEV-1, rather than the pre-bronchodilator FEV-1. 
 Other unfavourable prognostic factors which become apparent in patients with 
severe disease include: 
 Severe hypoxaemia 
 Raised pulmonary arterial pressure 
 Low carbon monoxide transfer 
 Factors favouring improved survival are: 
 stopping smoking  
 marked bronchodilator response.  
 A reduced FEV-1 is also an important additional risk factor for lung cancer, 
independent of age or cigarette smoking.

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 53 - 
  
 MRC dyspnoea scale:  
 One of the main symptoms of chronic obstructive pulmonary disease (COPD) is 
breathlessness and the MRC dyspnoea scale should be used to quantify this. 
 
1 Not troubled by breathlessness except on strenuous exercise

2 Short of breath when hurrying or walking up a slight hill 
breathlessness, 
 or has to stop for breath when walking at own pace 
4 Stops for breath after walking about 100 metres or after a few minutes on level 
ground 
5 Too breathless to leave the house, or breathless when dressing or undressing 
 
 BODE index , an index of mortality in COPD developed by the Medical Research

Council ( MRC ). This index also incorporates the body mass index, dyspnoea and 
exercise capacity (as 
 evidenced by a 6-minute walk test). The BODE index can also be used to 
estimate the risk of hospitalisation. 
 
Air flight in COPD: 
 Assessment of severity of (COPD) and O 2 sat at sea level should be performed.  
A summary is present in the table below: 
assessment  advice   The additional risk factors  
Sea level SpO 2 > 95% Oxygen not required  1/ hypercapnia  
Sea level SpO 2 92-95%

Sea level SpO 2 92-95% 
and NO additional risk 
factor  Oxygen not required   2/ FEV1 <50% predicted, 
and additional risk 
factor  Perform hypoxic challenge test 
with arterial or capillary 
measurements   3/ restrictive lung disease 
involving the parenchyma 
[fibrosis], chest wall 
[kyphoscoliosis] or 
respiratory muscles  
Sea level SpO 2 < 92%  In-flight oxygen   4/ ventilator support  
Receiving 
supplemental oxygen

Receiving 
supplemental oxygen 
at sea level  Increase the flow while at 
cruising altitude.   5/ within six weeks of 
discharge for an 
exacerbation of chronic lung 
or cardiac disease  
   6/ cerebrovascular or cardiac 658

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 54 - 
 disease  
 
Hypoxic challenge test: (to assess flight fitness if SpO2= 92 – 95% + additional risk factor in 
COPD) 
Give the patient FiO 2 15% for 15 minutes and measures PaO 2. 
 PaO2 > 7.4 kPa (> 55 mmHg) - Oxygen not required. 
 PaO2 6.6-7.4 kPa (50-55 mmHg) - Borderline. A walk test may be helpful.

 PaO2 < 6.6 kPa (< 50 mmHg) - In-flight oxygen (2L/min). 
____________________________________________________  
Pulmonary embolism (PE)  
 
Basic 
 PE can cause ventilation- perfusion mismatches.  
 When blood flow to the lung is decreased to embolism, the perfusion (Q) is diminished, 
but ventilation remains unchanged. This results in increasing physiologic dead space. 
 Decreased perfusion +  normal ventilation 
 
major risk factors  (relative risk 5-20) in the

major risk factors  (relative risk 5-20) in the 
development of VTE minor risk factors  with a relative risk of (2- 4) 
 lower limb problems including a fracture 
or varicose veins  
 postoperative intensive care 
 hospitalisation 
 abdominal/pelvic or advanced 
malignancy 
 previous VTE, and 
 pregnancy.  occult malignancy 
 long distance travel 
 congestive cardiac failure, and 
 thrombotic disorder. 
 use of the oral contraceptive pill 
 
Features

Features  
Sudden shortness of breath, pleuritic chest pain with haemoptysis and tachy pnoea are 
the commonest features. (triad of pleuritic chest pain, dyspnoea and haemoptysis)  
 
 Sudden shortness of breath, tachypnoea  
 Pleuritic chest pain 
  worse on deep breathing 
 haemoptysis  
 PE can present with virtually any cardiorespiratory symptom/sign depending on its 
location and size. 
Which features make pulmonary embolism more  likely?

The relative frequency of common clinical signs is shown below: 
 Tachypnea (respiratory rate >16/min) - 96% 
 Crackles - 58% 659

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 55 - 
  Tachycardia (heart rate >100/min) - 44% 
 Fever (temperature >37.8 C) - 43%.  
 Low-grade pyrexia is common in pulmonary embolism.  
 Atrial flutter, atrial fibrillation and premature beats can also occur  
 
Diagnosis  
 If a patient presents with signs or symptoms of pulmonary embolism (PE)

 performed chest x-ray to exclude other pathology. 
 estimate the clinical probability of PE by two-level PE Wells score   
Clinical feature Points 
Clinical signs and symptoms of DVT (minimum of leg swelling and pain 
with palpation of the deep veins) 3 
An alternative diagnosis is less likely than PE 3 
Heart rate > 100 beats per minute 1.5 
Immobilisation for more than 3 days or surgery in the previous 4 weeks 1.5 
Previous DVT/PE 1.5 
Haemoptysis 1

Haemoptysis 1 
Malignancy (on treatment, treated in the last 6 months, or palliative) 1 
 
Clinical probability simplified scores 
PE likely  More than 4 points 
PE unlikely  4 points or less 
 
 PE likely (> 4 points ): 
 arrange an immediate computed tomography pulmonary angiogram (CTPA). 
 If there is a delay in getting the CTPA then give low-molecular weight 
heparin until the scan is performed.

heparin until the scan is performed. 
 If the patient has an allergy to contrast media or renal impairment a V/Q 
scan should be used instead of a CTPA. 
 ventilation/perfusion single photon emission computed tomography 
(V/Q SPECT) scan 
 if a V/Q SPECT scan is not available  V/Q planar  
 PE unlikely (≤ 4 points):  
 arranged a D-dimer test: 
 If this is positive arrange an immediate (CTPA).  
 If there is a delay in getting the CTPA then give low-molecular weight

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 56 - 
 It is interesting to note that the Well's criteria for diagnosing a PE use tachycardia rather than 
tachypnoea. 
 
Question 
The chest X-ray is normal. However, the patient ’s respiratory rate is high and his 
oxygen saturation is low. What is the most appropriate next step ?  
Answer

Answer  
  assess clinical probability score for pulmonary thromboembolism  
 
Pulmonary embolism - normal CXR  
 
 Chest x-ray   
 Should be performed in all patients with symptoms or signs suggestive of PE   
 to exclude other pathology  
 usually normal in PE  
 Computed tomographic pulmonary angiography  (CTPA ) 
 the first-line investigation  
 Advantages compared to V/Q scans?  
 speed, easier to perform out- of-hours,  
 reduced need for further imaging

 reduced need for further imaging  
 if the CTPA is negative then patients do not need further 
investigations or treatment for PE 
 the possibility of providing an alternative diagnosis if PE is excluded  
 Disadvantages of CTPA 
 peripheral emboli affecting subsegmental arteries may be missed .  
  Low sensitivity for detecting pulmonary emboli in sub-segmental 
pulmonary arteries  
 
 Ventilation-perfusion (V/Q) scans  
 Indication?  
 If CTPA  is contra-indicated

 If CTPA  is contra-indicated  
 renal impairment (as the contrast media used during CTPAs is 
nephrotoxic). 
 allergy to contrast media 
 high risk from irradiation 
 which type of (V/Q SPECT) scan? 
 If CTPA is contra-indicated  ventilation/perfusion single photon emission 
computed tomography ( V/Q SPECT ) scan 
 if a V/Q SPECT scan is not available  V/Q planar   
 Sensitivity & specificity?  
661

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 57 - 
  sensitivity = 98%; specificity = 40%  
 predictive value of  (V/Q) scans? 
 high negative predictive value, i.e. if normal virtually excludes PE 
 other causes of mismatch in V/Q ?  
 old pulmonary embolisms, 
  AV malformations,  
 vasculitis,  
 previous radiotherapy 
 COPD 
 Asthma

 COPD 
 Asthma  
 Increased pulmonary venous pressure, especially secondary to mitral 
valve disease, causes increased flow to the upper lobes.  
 (V/Q) scan in pregnancy  
 Ventilation quotient (VQ) scan is not contraindicated in pregnant women, 
although the perfusion only scan is adequate.  
 Radiation to the fetus is small.  
 Which materials are used in (V/Q) imaging?  
 Xenon  is used for imaging  ventilation , whilst technetium labelled

macroaggregated human serum albumin ( MAA ) is used to image 
perfusion . 
 D-dimers  
 Indication? 
 Measurement of D-dimer should only be performed when the probability of 
PE is low, when a normal value would be taken as reassuring and further 
investigation would not be pursued. 
 high sensitivity ( 95-98%), but poor specificity  
 A negative d-dimer is useful for excluding PE in patients who are clinically

thought to be at low risk, but a 'positive' result does not establish the 
 The predictive value of d-dimer?  
 the negative predictive value is greater than the positive predictive value   
 only 30% of patients with positive d-Dimer have a confirmatory 
diagnosis of PE 
 d-dimers can be positive in: 
 hospitalised patients 
 obstetric patients 
 patients with peripheral vascular disease, cancer and inflammatory 
conditions 
 increasing age

 D-Dimer measurements should not be performed if: 
 an alternative diagnosis is likely, 
 the clinical probability is high or 
 there is a probable massive PE. 
 ECG 
 sinus tachycardia  
 the most common abnormality ; seen in 44% of patients. 662

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 58 - 
  the classic ECG changes   S1Q3T3  (seen in no more than 20% of patients) 
 large S wave in lead I  
 large Q wave in lead III  
 inverted T wave in lead III  
 Right bundle branch block 
 seen in 18% of patients. 
 associated with increased mortality;  
 Right axis deviation (seen in 16% of patients).

 Pulmonary angiography 
 the gold standard 
 significant complication rate compared to other investigations 
 Elevated cardiac troponin levels also occur in patients with pulmonary embolism 
because of right ventricular dilation and myocardial injury 
 
Start  low molecular weight heparin  and request CT pulmonary angiography if the 
symptoms and findings clearly point towards pulmonary embolism (PE).

Fluid resuscitation is the most appropriate immediate measure before further 
investigations confirm the presence of a pulmonary embolism (PE).  
 
 anticoagulant  
 Heparin 
 When should be started? 
 For patients with a high or intermediate probability of a non-massive 
PE  low molecular weight heparin should be given before 
imaging  
663

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 59 - 
  For patient with low probability of non-massive PE  immediately 
after diagnosis.  
 Which type? 
 For non-massive PE  Low molecular weight heparin (LMWH) or 
fondaparinux. 
 For patients with severe renal impairment  
([eGFR] <30 ml/min/1.73 m2) offer either:   
 unfractionated heparin (UFH) with dose adjustments based

on the APTT or  
 LMWH with dose adjustments based on an anti-Xa assay. 
 For patients with an increased risk of bleeding  consider UFH.  
 for massive PE  where  thrombolysis  is being considered ,  
unfractionated heparin  should be used 
 For how long?  
 the LMWH or fondaparinux should be continued for at least 5 days 
or until the international normalised ratio (INR) is 2.0 or above for at 
least 24 hours, whichever is longer, i.e. LMWH or fondaparinux is

given at the same time as warfarin until the INR is in the therapeutic 
range 
 for patients with active cancer NICE recommend using LMWH for 6 
months 
 Benefit of heparin?  
 Heparin reduces risk of further embolism (anticoagulant) and 
reduces pulmonary vasoconstriction.  
 Warfarin  
 a vitamin K antagonist (i.e. warfarin) should be given within 24 hours of the 
diagnosis 
 for how long? 
 warfarin should be continued for at least 3 months.

 NICE advise extending warfarin beyond 3 months for patients 
with unprovoked  PE. This essentially means that if there was no 
obvious cause or provoking factor (surgery, trauma, significant 
immobility) 
 Thrombolysis  
 Thrombolysis is now recommended as the first-line treatment for massive 
PE where there is circulatory failure (e.g. hypotension). 
 Haemodynamic instability may be demonstrated by hypotension,

right ventricular strain on an ECG or signs of right heart failure.  
 Thrombolysis is indicated in the cardiac arrest situation for suspected PEs. 
However, it can take 90 minutes to be effective and therefore must only be 
used if it is appropriate to continue CPR for this duration. 
 Cardiac arrest for suspected PEs   Intravenous thrombolysis 
followed by CPR for 90 minutes  
 Which drug? by which root?  
 Give alteplase 100 mg over 1.5 hours peripherally.  664

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 60 - 
  Thrombolysis administered through a peripheral vein is as effective 
as through a pulmonary artery catheter  
 percutaneous insertion of Inferior vena cava (IVC) filter  
 If anticoagulation is a contraindicated (eg PE following a recent 
haemorrhagic stroke)   
 if anticoagulation alone fails

 if anticoagulation alone fails  
 Benefit of IVC filter? 
 may be as effective as anticoagulation. 
 
PE causing pneumothorax  
 serious rare complication of PE  
 It is important to treat the underlying pneumothorax if severe while still treating the PE 
with anticoagulation.  
 It may be favourable, therefore, to use unfractionated heparin where there is 
increased risk of bleeding from the drain site.  
 Rivaroxaban and other NOACs, such as apixiban, are becoming more favourable

in treating DVTs and PEs, however, the inability to monitor the level 
accurately  poses an increased risk for this patient. 
 
Ref: 
NICE guidelines. published date: June 2012 Last updated: November 2015   
____________________________________________________
Recurrent pulmonary emboli  
 Recurrent pulmonary emboli should always be considered in cases of progressive 
shortness of breath with no obvious cause. 
 Predisposing factors for recurrent pulmonary embolism include:

 Antithrombin III deficiency 
 Protein C deficiency 
 Factor V Leiden mutation 
 Possible clues  include pulmonary hypertension, right ventricular enlargement, hypoxia 
with a low PaCO2 and a low transfer factor. 
 Widening of the alveolar-arterial (A-a) gradient on exercise is likely to be found .  
 Mismatched defects are classic features of pulmonary embolus. 
 Consider inferior vena caval filters for patients with recurrent proximal DVT or PE

despite adequate anticoagulation treatment only after considering alternative treatments 
such as: 
 increasing target INR to 3 –4 for long ‑term high-intensity oral anticoagulant 
therapy or 
 switching treatment to LMWH. 
 
 665

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 61 - 
  
DVT/PE in pregnancy 
In suspected PE in pregnant patients the Royal College of Obstetricians and Gynaecologists 
recommend the following (updated in 2015):  
 Chest x-ray and ECG to look for an alternative diagnosis such as pneumonia and 
pneumothorax.

pneumothorax. 
 If the chest x-ray is normal: 
 In women with suspected PE who also have symptoms and signs of DVT   
consider a compression duplex doppler of both legs to exclude a DVT.  
 this may provide indirect evidence of a pulmonary embolism and negate 
the need for further radiation exposure  
 If this is positive, the patient is treated with full dose low molecular weight 
heparin (LMWH) (warfarin is of course teratogenic).

 In women with suspected PE without symptoms and signs of DVT   
ventilation/perfusion (V/Q) lung scan or a computerised tomography pulmonary 
angiogram (CTPA) should be performed. 
 When the chest X-ray is abnormal  and there is a clinical suspicion of 
PE, CTPA  should be performed in preference to a V/Q scan. [New 2015]  
 Current guidance however favours a perfusion scan as it has lower 
lung radiation doses than a CTPA.  
 Half dose VQ involves a lower dose of radiation and therefore

preferred. 
 If V/Q scan or CTPA is normal but the clinical suspicion of PE remains: 
 Alternative or repeat testing should be carried out 
 Anticoagulant treatment should be continued until PE is definitively excluded. 
Comparing CTPA to V/Q scanning in pregnancy  
CTPA V/Q scanning 
CTPA slightly increases the lifetime risk 
of maternal breast cancer  (increased by 
up to 13.6%, background risk of 1/200 for 
study population). Pregnancy makes breast

study population). Pregnancy makes breast 
tissue particularly sensitive to the effects of 
radiation V/Q scanning carries a slightly increased risk 
of childhood cancer  compared with CTPA 
(1/280,000 versus less than 1/1,000,000) 
 D-dimer is of limited use in the investigation of thromboembolism as it often raised in 
Treatment of PE in pregnancy 
 In clinically suspected DVT or PE, treatment with low-molecular-weight heparin (LMWH)

should be commenced immediately until the diagnosis is excluded by objective testing 
 Obstetric patients who are postoperative and receiving unfractionated heparin should 
have platelet count monitoring performed every 2 –3 days from days 4 to 14 or until 
heparin is stopped. [New 2015] 666

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 62 - 
  Postpartum warfarin should be avoided until at least the fifth day and for longer in 
women at increased risk of postpartum haemorrhage. [New 2015]  
 Intravenous unfractionated heparin is the preferred, initial treatment in massive PE with 
cardiovascular compromise. 
 
Post-thrombotic syndrome (PTS)

Post-thrombotic syndrome (PTS) 
 can develop in nearly half of all patients who experience a DVT 
 symptoms include chronic leg pain, swelling, redness, and ulcers  
 prevention of post-thrombotic syndrome 
 prolonged use of LMWH (more than 12 weeks)  is associated with a 
significantly lower chance of developing post-thrombotic syndrome. [New 2015] 
 Following a DVT, elastic compression stockings should be worn on the affected 
leg to reduce pain and swelling.

leg to reduce pain and swelling.   
 the role of compression stockings in the prevention of post-thrombotic 
syndrome is unclear . [New 2015] 
Fat embolism  
The classic triad of presentation is: 
 Eosinophilia 
 Acute renal failure and 
 Livedo reticularis. 
 
The diagnosis of cholesterol embolism should be considered in any patient with 
atherosclerotic disease presenting with deteriorating renal function, multisystem

disease or distal ischaemia developing after an invasive arterial procedure. 
Overview 
 Unlike emboli that arise from a thrombus, fat emboli are small and multiple producing 
widespread effects.  
 They may occur one to three days following a fracture   
 more common in closed fractures on the long bones or pelvis. 
mechanism : suggested 2 mechanisms: 
 release of lipid globules from damaged bone marrow fat cells.(eg fracture femor). 
 increased mobilisation of fatty acids peripherally.

Features:  depends on what part of the microvasculature is affected by the lipid globules. 
 Pulmonary symptoms  (shortness of breath, hypoxia) are caused by ventilation 
perfusion mismatch. 
 may progress to respiratory failure and ARDS requiring mechanical ventilation. 
 Neurological (confusion and agitation)  
  Cerebral emboli produce neurological signs in up to 86% cases.  667

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 63 - 
  often occur after onset of respiratory symptoms 
 Usually there is an acute confusional state with or without focal signs.  
 Most neurological deficits are transient and reversible. 
 Haematological (thrombocytopenia, anaemia). 
 Dermatological: Petechial rash caused by capillary damage in the skin.

 Multiple petechiae in the distribution of the axilla or upper body is 
characteristic of a fat embolism.   
 The petechial rash is pathognomonic of this syndrome, but occurs in only 30-50% 
of cases 
 Rash is seen in the conjunctiva, mucous membranes, skin folds of upper body 
particularly neck and axilla, appearing within the first 36 hours. 
 Other features: 
 pyrexia 
 tachycardia 
 ECG changes (ST segment depression and right heart strain) 
 fluffy retinal exudates

 fluffy retinal exudates 
 coagulopathy, and 
 renal changes (oliguria, lipiduria, proteinuria or haematuria). 
Treatment 
 Initial resuscitation should involve 
 high flow oxygen   
 intravenous (iv) fluids  to maintain high right ventricular filling pressures.  
 Continuous positive airways pressure ventilation would help in the management of the 
pulmonary oedema and is the next consideration after IV fluids.

 Steroid therapy is normally introduced later in ARDS, used at early stage can worsen 
pulmonary oedema, and evidence is equivocal as to benefit.  
 It should be noted that diuretic treatment would be strongly contraindicated  in this 
case. This is because right ventricular output is dependent on elevated filling pressures. 
Reducing the preload is therefore not a good idea. 
Pneumonia 
Community-acquired pneumonia (CAP)

Pneumonia 
Community-acquired pneumonia (CAP) 
 
Streptococcus pneumoniae  is associated with cold sores  
 
Preceding influenza predisposes to Staphylococcus aureus  pneumonia  
 
 668

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 64 - 
  
Both Klebsiella and Staphylococcus are associated with empyema formation and 
cavitating lung lesions.  
 
Causes of Community acquired pneumonia (CAP) :  
 Streptococcus pneumoniae   
 (accounts for around 80% of cases) the most common cause  of CAP & 
single lobar  pneumonia.

single lobar  pneumonia.  
 Streptococcus pneumoniae commonly causes reactivation of the herpes 
simplex virus resulting in 'cold sores' 
 S. pneumoniae is the most important cause of fulminant sepsis in patients 
with hyposplenism. 
 Streptococcus pneumoniae is the commonest cause of community-
acquired pneumonia in the elderly and young children . 
 Elderly patients may present atypically, complaining less frequently of

respiratory symptoms, headache, and myalgias, and are more likely to 
have absence of fever and altered mental status  on admission. 
 Bacteraemic Streptococcus pneumoniae pneumonia is the number one cause of 
mortality in community- acquired pneumonia, representing up to 70% of all 
deaths. 
 most common cause of a single lobar pneumonia.  
 Characteristic features of pneumococcal pneumonia 
 rapid onset 
 high fever 
 pleuritic chest pain 
 herpes labialis 
 
 Haemophilus influenzae

 Haemophilus influenzae  
 more likely to be associated with exacerbations of COPD 
 Staphylococcus aureus : 
 commonly after the 'flu  . 
  the BNF advises the co-prescription of flucloxacillin. 
  It's an organism often found on the skin. It is therefore commonly associated with 
systemic infections in intravenous drug users  ,this is may  hinted in questions 
by the presence of track marks. 
  It also causes a bibasal pneumonia  as opposed to Streptococcus

pneumoniae  that is the most common cause of a single lobar pneumonia.  
  seen most frequently in the  elderly  and in intravenous drug users  or patients 
with underlying disease .  
 It can result in a cavitating pneumonia.   
 S. aureus is the most common organism responsible for secondary necrotizing 
pneumonia  
 characteristics of necrotizing pneumonia include:  
 preceding influenza infection,  
 rapid onset and progressive symptom worsening,  
 decreased WBC count,  669

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 65 - 
  airway hemorrhages,  
 respiratory failure,  
 necrotic destruction of lung parenchyma,  
 high mortality rate. 
 Carries a high mortality, and therefore if suspected treatment should 
initially be for a severe CAP. 
 Capable of production of Panton-Valentine-Leucocidin toxin , associated with

severe illness and high mortality.   
 Pneumothorax, pleural effusion and empyema are common in staphylococcal 
pneumonia. 
 atypical pneumonias  (e.g. Due to Mycoplasma pneumoniae ) 
 Coxiella burnetii (Q fever)  ==> relation to animal sources (usually sheep) . 
 Chlamydophila psittaci ==> bird contact (eg, poultry or duck workers)   
 Viruses 
 Klebsiella pneumoniae  is classically in alcoholics .   
 Klebsiella pneumonia (Friedlander's pneumonia) typically occurs in middle- aged

alcoholic men.  
 can cause cavitating pneumonia  
 usually affects the upper lobes  
 occurs in immunosuppressed individuals or, classically, alcoholics.  
 Chest x-ray features may include abscess formation in the middle/upper lobes 
and empyema.  
 The mortality approaches 30- 50%. 
 
Organism  Characteristic chest x-ray  
Streptococcus pneumoniae lobar  consolidation 
Legionella bibasal  consolidation 
Staphylococcus aureus  bilateral cavitating  bronchopneumonia, 
 
Mild community acquired pneumonia (CURB 0-1) should be treated with oral penicillin  
therapy alone assuming no allergies and no other complicating factors 
 
 CURB -65 criteria of severe pneumonia 
1) Confusion (abbreviated mental test score <= 8/10) 
2) Urea > 7 mmol/L 
3) Respiratory rate >= 30 / min 
4) BP: systolic <= 90 or diastolic <= 60 mmHg 
5) age ≥ 65 years 
 
 Patients with 3 or more  (out of 5) of the above criteria are regarded as having a 
severe pneumonia

severe pneumonia  
 
 Low or moderate severity CAP :  
 oral amoxicillin.  
 A macrolide should be added for patients admitted to hospital.  670

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 66 - 
  There is a high incidence of Staphylococcus aureus  pneumonia in patients 
following influenza. As a result the BNF advises the co-prescription of 
flucloxacillin in this situation. 
 High severity CAP :  
 intravenous co-amoxiclav + clarithromycin OR cefuroxime + clarithromycin OR 
cefotaxime + clarithromycin

cefotaxime + clarithromycin 
 Intravenous clarithromycin is an extremely irritant drug and it should be 
avoided wherever possible if a patient can take it orally.  
 Where patients require intravenous administration this should be via a 
wide bore cannula and the site checked regularly for signs of 
thrombophlebitis . 
 the current BNF has slightly different recommendations for high severity CAP:  
 intravenous benzylpenicillin + clarithromycin OR benzylpenicillin + 
doxycycline.

doxycycline.  
 For 'life-threatening' infections the BNF recommends the same as the BTS 
guidelines for high-severity CAP 
 
 Follow up 
 NICE have provided guidance on what advice patients should be given in terms 
of response to treatment and recovery , by: 
 week 1: fever should resolve 
 week 4: chest pain and sputum should have significantly reduced 
 week 6: cough and shortness of breath should have significantly 
reduced

reduced 
 month 3: most symptoms should have resolved, except for tiredness 
 month 6: should be returned to normal 
 
 A repeat chest X-ray may be indicated to ensure resolution and that there is no 
underlying pathology, but radiological changes can take up to 6 weeks to 
improve .  
 
 671

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 67 - 
  
A summary table of empirical antibiotics  as suggested by the BTS is shown below.  
Pneumonia 
Severity (based 
on clinical 
judgement and 
CURB score) Treatment Site First line Second line 
Low Severity  
(CURB65 = 0- 1) Home Amoxicillin orally Doxycycline or 
clarithromycin 
orally 
Low Severity

orally 
(CURB65 = 0- 1) Hospital(reason for 
admission other than 
pneumonia severity 
i.e. social reasons) Amoxicillin orally Doxycycline or 
orally 
Moderate severity 
(CURB65 = 2) Hospital Amoxicillin plus 
clarithromycin orally 
(IV if oral 
administration not 
possible) Doxycycline, 
Levofloxacin or 
moxifloxacin orally 
High Severity 
(CURB65 = 3- 5) Hospital Co-amoxiclav plus 
clarithromycin IV Benzylpenicillin 
plus levofloxacin

plus levofloxacin 
or ciprofloxacin IV 
OR 
Cefuroxime plus 
clarithromycin IV  
 
 Adding a fluoroquinolone is an option for those with high severity pneumo nia not 
responding to a b-lactam/ macrolide combination antibiotic regimen  (BTS 2009).  
 The chance of cross reactivity of penicillin allergy with beta-lactams is only 10%. 
A rash is not a contraindication for this.  
 
 Panton-Valentine Leukocidin-producing Staphylococcus aureus (PVL-SA)

 a rare cause of high severity pneumonia , associated with rapid lung cavitation 
(necrotising pneumonia)  and multiorgan failure .  
 empirical antibiotic combination of IV  linezolid  600 mg twice daily, IV 
clindamycin  1.2 g four times a day and IV rifampicin 600 mg twice daily  
 For those patients referred to hospital with suspected life threatening CAP , 
general practitioners should administer I.V Penicillin G 1.2 g or amoxicillin 1 g 
orally.  (BTS 2009).

orally.  (BTS 2009).  
 For high severity the BNF suggest benzylpenicillin with either clarithromycin or 
doxycycline as first line, however if the patient has life-threatening infection, 672

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 68 - 
 gram-negative organisms are suspected, co-morbidities are present or the patient 
is a nursing or residential home resident (probably the vast majority of hospital 
inpatients) then co-amoxiclav and clarithromycin should be used.  
 If Staphylococcus aureus  is identified, treatment should be altered:

 Non- MRSA organisms should be treated with flucloxacillin and/or 
rifampicin; an alternative for penicillin-allergic patients is teicoplanin and 
rifampicin.  
 MRSA  should be treated with vancomycin.  
BNF antibiotic guidelines 
The following is based on current BNF guidelines: Respiratory system  
Condition Recommended treatment 
Exacerbations of 
chronic bronchitis Amoxicillin or tetracycline or clarithromycin 
Uncomplicated 
community-acquired

community-acquired 
pneumonia Amoxicillin (Doxycycline or clarithromycin in 
penicillin allergic, add flucloxacillin if 
staphylococci suspected e.g. In influenza) 
Pneumonia possibly 
caused by atypical 
pathogens Clarithromycin 
Hospital-acquired 
pneumonia Within 5 days of admission: co-amoxiclav or 
cefuroxime 
More than 5 days after admission: piperacillin 
with tazobactam OR a broad-spectrum 
cephalosporin (e.g. ceftazidime) OR a 
quinolone (e.g. ciprofloxacin)

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 69 - 
 Pneumonia: Prognostic factors  
 The British Thoracic Society recommends that patients should be assessed for the 
severity of their pneumonia using several core prognostic features (CURB-65 score). 
 
 The CURB-65 score  is as follows: 
 
Criterion Marker 
C Confusion (abbreviated mental test score ≤ 8/10) 
U Urea >7 mmol/L

U Urea >7 mmol/L 
R Respiration rate >= 30/min 
B Blood pressure: systolic <= 90 mmHg and/or diastolic <= 60 
mmHg 
65 Aged ≥ 65 years 
 Interpretation 
 CURB -65 score of 0: 
 should be managed in the community. 
 CURB -65 score of 1: 
 should have their SaO 2 assessed which should be > 92% to be 
safely managed in the community and a CXR performed.  
 If the CXR shows bilateral/multi-lobar shadowing hospital admission 
is advised.  
 CURB -65 score of 2 or more:

 CURB -65 score of 2 or more:  
 should be managed in hospital as this represents a severe 
community acquired pneumonia.  
 CURB -65 score of 4: 
 CURB -65 score correlates with an increased risk of mortality at 30 
days with patients with a CURB-65 score of 4 approaching a  30% 
mortality rate at 30 days . 
 Factors associated with a poor prognosis include: 
 ↑ CURB -65 score  
 Co-morbidity such as renal disease 
 hypoxaemia (pO2 < 8 kPa) independent of FiO2

 hypoxaemia (pO2 < 8 kPa) independent of FiO2 
 White cell count less than 4 ×109/L or greater than 20 ×109/L 
 Multi-lobar involvement on CXR  
 Temperature less than 35°C or more than 40°C. 
 Thrombocytosis  is associated with increased mortality compared to 
thrombocytopaenia or normal platelet levels. 
 
 How to define mental confusion in the CURB65 severity score? 
Abbreviated Mental Test 
 The Abbreviated Mental Test  (each question scores 1 mark, total 10 marks) 674

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 70 - 
 1. Age 
2. Date of birth 
3. Time (to nearest hour) 
4. Year 
5. Hospital name 
6. Recognition of two persons (eg, doctor, nurse) 
7. Recall address (eg, 42 West Street) 
8. Date of First World War 
9. Name of monarchs 
10. Count backwards 20 R 1 
 Score of 8 or less has been used to define mental confusion in the

CURB65 severity score. (2009 BTS guideline  for CAP),  
 
 The risk of death at 30 days increases as the score increases : 
Score Risk of death at 30 days 
0 0.7% 
1 3.2% 
2 13.0% 
3 17.0% 
4 41.5% 
5 57.0% 
 
 Similarly, with any infection the risk of mortality increases as the CURB score 
increases  
0 to 1 <5% mortality 
2 to 3 < 10% mortality 
4 to 5 15-30% mortality 
 
 Factors help guide the decision to admit  
 age,  
 co-morbidities,

 age,  
 co-morbidities,  
 social factors  
 CURB score  675

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 71 - 
  hypoxia  
 bilateral chest consolidation which can also indicate a more severe pneumonia.  
 
Score Management 
0-1 Treat as an outpatient 
>2 Treat as an inpatient 
 
 Indicators of poor prognosis in pneumonia  include: 
 Age more than 65 
 Co-existing morbidity including diabetes mellitus , congestive cardiac failure,

coronary artery disease, stroke, chronic lung disease 
 Respiratory rate more than 30 
 Low systolic ( <90mmHg) or diastolic ( <60mmHg) blood pressure 
 Bilateral involvement or involvement of more than two lobes on chest radiograph 
 Altered mental state. 
 Biochemical/haematological markers include: 
 White count less than 4 or more than 20 
 Hypoxaemiaia or patients requiring FiO2 greater than 60% to maintain 
saturations 
 Positive blood culture 
 Blood urea more than 7.

 Blood urea more than 7. 
 CRP test 
 NICE also mention point- of-care CRP test.  
 This is currently not widely available but they make the following 
recommendation with reference to the use of antibiotic therapy : 
 CRP < 20 mg/L - do not routinely offer antibiotic therapy 
 CRP 20 - 100 mg/L - consider a delayed antibiotic prescription 
 CRP > 100 mg/L - offer antibiotic therapy 
 
Discharge criteria and advice post-discharge

Discharge criteria and advice post-discharge  
 NICE recommend that patients are not routinely discharged if in the past 24 hours 
they have had 2 or more of the following findings:  
 temperature higher than 37.5°C 
 respiratory rate 24 breaths per minute or more 
 heart rate over 100 beats per minute 
 systolic blood pressure 90 mmHg or less 
 oxygen saturation under 90% on room air 
 abnormal mental status 
 inability to eat without assistance.

 inability to eat without assistance. 
 They also recommend delaying discharge if the temperature is higher than 37.5°C. 
 
How quickly their symptoms should resolve? 676

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 72 - 
  NICE recommend that the following information is given to patients with pneumonia in 
terms of how quickly their symptoms should resolve: 
 
Time Progress 
1 week Fever should have resolved 
4 weeks Chest pain and sputum production should have substantially reduced

6 weeks Cough and breathlessness should have substantially reduced 
3 months Most symptoms should have resolved but fatigue may still be present 
6 months Most people will feel back to normal. 
 
Follow up 
 What review policy should be adopted in patients managed in the community? 
 Review is recommended after 48 h or earlier if clinically indicated for disease 
severity assessment 
 Those who fail to improve after 48 h of treatment should be considered for

hospital admission or chest radiography. 
 C-reactive protein should be re-measured and a chest radiograph repeated in 
patients who are not progressing satisfactorily after 3 days of treatment. 
 Chest x ray in six weeks  to ensure complete resolution .  
 This is to exclude any underlying cause especially malignancy.  
 those who have persistent shadowing on the lung need referral to a respiratory 
physician . 
 What arrangements should be made for follow-up after hospital discharge?

 Clinical review should be arranged for all patients at around 6 weeks. 
 
Complications of pneumonia 
 Acute complications :  
 might be obvious at presentation or might appear after an interval (empyema, 
abscess, fistula and organising pneumonia).  
 Chronic complication:  
 Bronchiectasis  
 only diagnosed after the illness because temporary or reversible bronchial 
dilatation is sometimes seen during the acute illness. 
Prevention and vaccination

Prevention and vaccination 
 All patients aged 65 years or at risk of invasive pneumococcal disease who are 
admitted with CAP and who have not previously received pneumococcal vaccine should 
receive 23-valent pneumococcal polysaccharide vaccine (23-PPV) 
 
Ref:  
 NICE 2014 Pneumonia in adults: diagnosis and management  
 The British Thoracic Society published guidelines in 2009 
 
 677

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 73 - 
 ____________________________________________________ _______________ 
Klebsiella  
 
Overview  
 Klebsiella  is a Gram-negative rod  that is part of the normal gut flora .  
 It can cause many infections in humans including:  
  pneumonia (typically following aspiration) and  
 urinary tract infections.

 urinary tract infections.  
Pathophysiological mechanism  
 colonization of the oropharynx followed by microaspiration of upper airway secretions in 
the setting of decreased consciousness (due to heavy drinking). 
Features  of Klebsiella  pneumonia  
 more common in alcoholic and diabetics 
 may occur following aspiration 
 'red-currant jelly' sputum 
 Cavitating lesions, often affects upper lobes . 
Treatment:

Treatment: 
 Third-generation cephalosporins or quinolones are used as standard therapy 
Prognosis  
 commonly causes lung abscess formation and empyema 
 mortality is 30- 50% 
Legionella pneumonia  
Legionella pneumophilia is best diagnosed by the urinary antigen test  
  
Epidemiology: 
 Cause 2-5% of community-acquired pneumonia admitted to hospital.

 Most patients require hospital admission within 5-7 days of the start of symptoms.  
 Incubation period  2-10 days, 
 Males are two to three times more frequently affected than females.  
 Highest incidence in the 40- to 70-year-old age group.   
 
features  which strongly suggest Legionella:  
 recent foreign travel 
 flu-like symptoms 
 hyponatraemia 
Etiology  
 Legionella  are gram-negative rod  bacteria

 Legionella  are gram-negative rod  bacteria 
 Legionnaire's disease is caused by the intracellular  bacterium Legionella 
pneumophilia .  
Source infections  
678

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 74 - 
  It is typically colonizes water tanks  and hence questions may hint at air-conditioning 
systems or foreign holidays.  
 Factors that encourage colonisation and multiplication are:  
  temperature (20-45 °C) and  
 stagnation.  
 The most common sources in buildings in which Legionella organisms have been 
found  are:

found  are: 
 Hot-water calorifiers 
 Storage tanks 
 Piped water, especially hot water from the calorifiers in large buildings and 
industrial complexes with long runs of pipework 
 
 Other well-recognised sources  include: 
 Recirculating water in air-conditioning and cooling systems 
 Whirlpool spas and other warm-water baths 
 Decorative fountains 
 Nebulisers and humidifier reservoirs of hospital ventilation machines if topped up 
with contaminated tap water 
 
Transmission

Transmission   
 Dissemination of infection is by inhalation of contaminated water droplets (aerosol) 
aerosolised bacteria 
 To cause infection the droplets must be of a size that can reach the alveoli of the 
lungs (less than 5 mm in diameter).  
 Taps and shower-heads produce very localised aerosols, whereas the water 
droplets (drift) contained in the airstream released from a cooling tower can be

carried a considerable distance and expose a greater number of people to risk. 
 rarely, micro-aspiration of contaminated drinking water.  
 Person- to-person transmission is not seen 
 
Features  
 flu-like symptoms including fever ( present in > 95% of patients ) 
 dry cough 
 relative bradycardia 
 may represent toxic encephalopathy.  
 lymphopaenia 
 A marked neutrophil  leukocytosis  may be associated with concomitant 
lymphopenia . 
 hyponatraemia

 Hyponatraemia secondary to  syndrome of inappropriate antidiuretic hormone 
secretion (SIADH)  is more common in Legionella  infection than other pathogens.   
 Hyponatraemia occurs more commonly than with other pneumonias. 
 deranged liver function tests 
 pleural effusion:  
 seen in around 30% of ptients 
 may be accompanied by pleuritic chest pain  679

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 75 - 
  Typically, starts with high fever, shivers, severe headache and muscle pains.  
 may start abruptly with a brief prodrome of malaise, myalgia and headache. High 
fever and non-productive cough are common and may be accompanied by 
pleuritic chest pain. 
 dyspnoea is common  
 diarrhea  
 renal

 diarrhea  
 renal  
 Up to 40% of patients may also have proteinuria.  
 microscopic haematur ia 
 Amnesia on recovery is common. 
 
Two classic signs  of Legionnaires' disease are fever that does not coincide with  
tachycardia and a prominent headache .  
 
Diagnosis  
 urinary antigen ( the most useful diagnostic test ) 
 Sensitivity 80%; specificity >99%. 
 a negative urinary antigen does not exclude the diagnosis of Legionella  infection,

because it only identifies serogroup 1  (which is the most common serogroup).  
 Test may remain positive for weeks or months and it is, therefore, not a test for 
cure. 
 It is important to remember that the organism does not show up on Gram-staining.  
 Cultures 
 on buffered charcoal yeast extract (BCYE) agar.   
 Sensitivity 20% to 95%; specificity 100% 
 Legionnaires' disease is treated with antibiotics that achieve high intracellular 
concentration, particularly:

concentration, particularly: 
 First line  
 macrolides  
 erythromycin (500-1000 mg every 6 hours) or clarithromycin (500 
mg twice daily for clarithromycin) 
 if patient allergic or intolerant  to macrolides  ciprofloxacin 
 fluoroquinolones (such as levofloxacin).  
 favoured when the illness is severe enough to warrant 
admission.   
 Second line  
 tetracyclines 
doxycycline open_in_new: 200 mg orally/intravenously as a loading dose,

followed by 100 mg every 12 hours for 14-21 days 
 OR 
 tetracycline open_in_new: 500 mg orally every 6 hours for 14-21 days  
 For severe infections  
 quinolone-macrolide combinations  680

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 76 - 
  Ciprofloxacin is also a useful drug in combination with 
clarithromycin .  
 this combination has significant potential toxicity, such as 
prolongation of the QT interval and possible torsades de pointes 
arrhythmia 
 Both doxycycline and ciprofloxacin are reasonable second line choices for the treatment 
of Legionella .

of Legionella .  
 Rifampicin is often recommended as additional therapy to erythromycin, in a dose of 
600 mg once or twice daily in patients with severe infection or who are deteriorating.  
 Legionella  resistance to rifampicin is noted, therefore this is not a first line option.  
 A small recent study also noted increased liver function abnormalities in patients 
with legionnaire's exposed to rifampicin.  

 The most important  principle to follow is to avoid holding water at temperatures 
between 20 °C and 45 °C, which is the range in which Legionella multiplication occurs.   
Prognosis  
 The mortality rate may approach 100% in patients with underlying disease.  
 In untreated patients, the mortality rate may be as high as 80%. 
 
 Pontiac fever  
 Non-pneumonic Legionella  infection is known as Pontiac fever.

 It causes a mild upper respiratory infection that resembles acute influenza.  
 unlike Legionnaires' disease Pontiac fever  does not cause pneumonia. 
 
Mycoplasma pneumoniae  
Mycoplasma  pneumonia presents with systemic upset , dry cough  and fever . Myalgia and 
arthralgia  are common. The WBC  is often within the normal  range. 
 
 Mycoplasma pneumoniae  is a cause of atypical pneumonia which often affects younger 
patients

patients  
 most commonly causes disease in individuals aged 15-30 years. 
 accounts for about 7% of all community-acquired pneumonias.   
 it occurs in epidemics every 4 years  , more commonly among close-knit 
populations like those in schools and colleges.  
 It is important to recognise atypical pneumonias as they may not respond to 
penicillins  or cephalosporins due to it lacking a peptidoglycan cell wall ., 
Features

Features  
The longer duration of symptoms and unusual features of abdominal pain , dry cough  and 
hyponatraemia  should alert you to an atypical organism of which Mycoplasma 
pneumoniae  is one of the commonest.  
 the disease typically has a prolonged and gradual onset 
 flu-like symptoms classically precede a dry cough 
 It is characterised by Headaches, malaise and cough.  
 bilateral consolidation on x-ray 681

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 77 - 
  complications may occur as below 
Extra-pulmonary manifestations occur in ~10% of cases:  
 Rash 
 erythema multiforme 
 erythema nodosum 
 urticarial 
 Neurological syndromes  
 aseptic meningitis 
 encephalitis,  
 neuropathies 
 Guillain-Barré syndrome 
 transverse myelitis 
 cardiac: 
 Myocarditis 
 Pericarditis

 cardiac: 
 Pericarditis 
 Hepatitis  
 Pancreatitis (rarely). 
 Arthritis 
 Cold agglutinins 
 Haemolytic anaemia .  
 found in up to 50% of cases .  
 Presence of spherocytes or fragmented red blood cells on the film is 
suggestive of haemolytic anaemia . 
  In mycoplasma infection spherocytes are a result of cold agglutinin damage to 
the red cell membrane.  
 Nucleated red cells may also be seen.

 Nucleated red cells may also be seen. 
 Haemolysis is associated with the presence of IgM antibodies (cold agglutinins) 
directed against the I antigen of the erythrocyte membrane.  
 Haemolysis would be confirmed on a blood film and a direct Coombs' test. 
 Reticulocyte counts are increased   
 bilirubin is predominantly unconjugated.  
 Lactate dehydrogenase (LDH) is increased and haptoglobins are reduced.  
 Urinary urobilinogen is increased and haemosiderinuria may be seen.

 cold agglutins (IgM) may cause an haemolytic anaemia, thrombocytopenia 
 erythema multiforme, erythema nodosum 
 meningoencephalitis, Guillain-Barre syndrome 
 bullous myringitis: painful vesicles on the tympanic membrane 
 pericarditis/myocarditis 
 gastrointestinal: hepatitis, pancreatitis , Vomiting  , Diarrhoea  
 renal: acute glomerulonephritis 
 682

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 78 - 
  
Mycoplasma? - Serology is diagnostic  
 
 diagnosis is generally by Mycoplasma serology 
 positive cold agglutination test ( cold agglutinins occur in only half of patients ) 
 The chest X-ray findings might not correlate with the patient's condition.theX-ray

appearances are usually much worse than would be suggested by the clinical 
examination of the respiratory system. 
 The white blood count can be normal  
Mycoplasma pneumonia if allergic/intolerant to macrolides – 
doxycycline 
 First line  erythromycin/clarithromycin 
 alternative  tetracyclines such as doxycycline. 
 The pathogen does not have a cell wall and so is not susceptible to penicillin,

cephalosporins or other antibiotics that are active against the bacterial cell wall 
 
Prognosis 
 Most cases resolve  spontaneously within a few weeks.  
 
The golden notes  
Mycoplasma pneumoniae 
 more closely related to gram positive bacteria .  
 Basic 
 The absence of cell wall structure  
 Distinguish them from other bacteria 
 makes them insensitive to beta-lactam anti-microbial 
 prevents them from staining by gram's stain  
 responsible for their polymorphism

 responsible for their polymorphism 
 dry cough (preceded by flu-like symptoms)  and fever  
 systemic upset (arthralgia, haemolytic anaemia, erythema multiforme, 
Neurological, pericarditis/myocarditis, GIT, renal)  
 the most common non-pulmonary manifestation  neurological  
 occurs in epidemics every 4 years , commonly in close-knit populations (eg: 
schools and colleges) 
 Haemolysis: 
 Caused by IgM antibodies (cold agglutinins) directed against the I

antigen of the erythrocyte membrane.  
 confirmed by blood film and a direct Coombs' test  
 Hyponatraemia 
 Normal WBC 
 the cause of spherocytes in In mycoplasma?  683

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 79 - 
 
 cold agglutinin damage to the red cell membrane 
 CXR:  might not correlate with the patient's condition  much worse than would 
be suggested by the clinical examination   
 bilateral consolidation on x-ray 
 the commonest chest x-ray abnormality is interstitial infiltrate (90%)

  the commonest chest CT  abnormality is bronchial wall thickening. 
 M. pneumoniae  attaches to cilia via P1 protein and multiplies in the 
respiratory epithelial layer. 
 Attachment to epithelial cilia is responsible for bronchial wall 
thickenings. 
 the diagnostic test  serology is the "gold standard" 
 Enzyme immunoassays (EIAs) are the most widely used and reliable 
commercial Mycoplasma serology tests. 
  92% sensitivity and 95% specificity

  92% sensitivity and 95% specificity   
 It allows IgG and IgM titration  
 more sensitive than culture for detecting acute infection 
 positive cold agglutination test 
 PCR 
 sensitivity is very high  
 Faster than serology 
  Unlike serology, it requires only one specimen. 
 does not require viable organisms only. It can amplify the dead bacilli also.   
 Causes of Positive PCR but negative serology tests 
 asymptomatic carriage of M. pneumoniae (after disease, or during

incubation period). 
 immuno compromised patients,  no diagnostic antibody response. 
 Early successful antibiotics therapy. 
 Culture  
 rarely used for routine diagnosis   
 sensitivity may be no more than 60% , But when positive, its specificity is 
100%, 
 First line  erythromycin/clarithromycin 
 alternative  tetracyclines such as doxycycline. 
 
Aspiration pneumonia

Aspiration pneumonia 
 The typical patient with aspiration pneumonia has gingival crevice disease combined 
with a predisposition for aspiration that is usually due to a suppressed level of 
consciousness or dysphagia.  
 Chest X-rays usually show infection in a dependent segment (usually the superior 
segments of the lower lobes or posterior segments of the upper lobes as these are 
dependent in the recumbent position),  684

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 80 - 
  Aspiration pneumonia  => typically affects in right  lower lobe  in persons with impaired 
swallowing. 
Psittacosis (Chlamydia psittaci pneumonia) 
 
Exposure to an ill bird and a rash (Horder ’s spots) are pathognomonic

 Chlamydia psittaci infection (psittacosis) is characterised by malaise, fever, myalgia and 
  Exposure to an ill bird and a rash (Horder's spots) are pathognomonic.  
 Pet owners, vets and zoo keepers are most at risk. It is rare in children. 
 Person to person transmission occurs especially in a hospital environment. 
 Sputum Gram stain reveals a few leucocytes and no predominant bacteria. There are 
few signs and few laboratory/x ray findings.

few signs and few laboratory/x ray findings. 
 The chest X-ray can show segmental or diffuse consolidation. 
 Relative bradycardia with non-specific chest signs, coupled with diffuse chest x ray 
changes, a low white count and abnormal LFTs are consistent with the disease.  
Abnormal LFTs in up to 50%.  
 Positive serology is with complement-fixing antibodies. 
 Diagnosis is confirmed by enzyme immunoassay  
 Erythromycin or tetracyclines are the drugs of choice.

____________________________________________________ _______________ 
Pseudomonas pneumonia 
 bronchiectasis  
 cystic fibrosis. 
 hospital-acquired infections,  
 particularly in intensive care units or after surgery.  
 Nosocomial or hospital-acquired infections should be suspected in patients 
with an onset of symptoms at least 48 hours after admission to the hospital.  
Treatment 
  anti-pseudomonal penicillin, ceftazidime, meropenem or ciprofloxacin.

Hospital-acquired pneumonia 
 The third most common hospital-acquired infection after urinary tract infections and 
wound infections.  
Causes 
 Gram-negative organisms  are far more common, owing to: 
 Colonisation of the oropharynx by Gram-negative bacilli, which is very common in 
hospitalised patients, who have often been on broad-spectrum antibiotics already

 Increased risk of micro-aspiration of nasopharyngeal secretions 
 Increased likelihood of immunodepression 685

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 81 - 
 Treatment 
 most commonly as combination therapy. A third generation cephalosporin with an 
aminoglycoside is the current British Thoracic Society (BTS) recommendation. 
Mendelson syndrome 

 acute pneumonia caused by regurgitation of stomach contents and aspiration of 
chemical material, usually gastric juices.  
 Often follows anaesthesia, when the gag reflex is depressed. 
Features  
 Symptoms  develops rapidly, and within hours the patient can become tachypnoeic, 
hypoxic and febrile.  
 It can cause severe bronchospasm .  
 There is minimal sputum. 
_____________________________________ ______________________________

Chest auscultation signs 
 Whispering pectoriloquy  is a sign of consolidation. It can occur because of the tumour 
and the locally trapped secretions. 
 Polyphonic wheeze  can indicate obstructive lung disease, 
 inspiratory crackles  can be associated with: 
 pulmonary fibrosis  
 consolidation. 
Lung abscess  
 dental disease,

 dental disease,  
  impaired consciousness , for example, alcohol, post-anaesthesia , 
  bronchial carcinoma  
 immunosuppression.  
 An air-fluid level is characteristic of a lung abscess.  
 A contrast-enhanced computerised tomography (CT) scan would show the abscess 
more clearly. 
Radiation pneumonitis 
 Occur in 10-30% of patients following radiotherapy for lung cancer. 
Symptoms

Symptoms   
 cough (which can be severe and can produce thick sputum),  
 breathlessness  
 fever. 
On examination   
 tachypnoea,  
 cyanosis in severe disease,  
 local crepitations.  686

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 82 - 
  Telangiectases, the result of cutaneous radiation damage, are often observed in the 
overlying skin. 
Radiographic changes :  
 X-ray  
 The most characteristic X-ray feature is an area of hazy consolidation  
demarcated by a sharp margin (crossing anatomical pulmonary planes) that

corresponds to the limits of the irradiation field, though additional effects are 
usually detectable beyond these boundaries. 
 CT provides the best means of early identification,  
 ground-glass attenuation and inter-alveolar septal thickening being the early 
characteristic features.  
 Dense local fibrosis can develop up to 1-2 years after radiation,  
 (MRI) might be required to differentiate this from tumour recurrence. 

 If symptoms are slight, no specific treatment is needed.  
 In more severe disease, corticosteroids produce symptomatic relief  
 Corticosteroids at high dose (prednisolone at least 60 mg/day) are the 
initial therapy of choice.  
 Response to corticosteroids occurs within 3-4 days, with clinical and radiographic 
improvement,  
 treatment should be continued for 3-4 weeks before tapering and stopping.

 Corticosteroids do not, however, influence the extent of subsequent pulmonary 
fibrosis. 
 Symptomatic relief of cough and hypoxaemia by an opioid antitussive and oxygen 
supplementation may also be needed. 
 In those who cannot tolerate corticosteroids, azathioprine is a reasonable alternative. 
HIV: Pneumocystis jiroveci  pneumonia 
 
Pneumocystis jiroveci pneumonia - pneumothorax is a common complication  
 
Overview

Overview 
 Whilst the organism Pneumocystis carinii  is now referred to as Pneumocystis jiroveci , 
the term Pneumocystis carinii  pneumonia (PCP) is still in common use. 
 Pneumocystis jiroveci  is an unicellular eukaryote, generally classified as a fungus  but 
some authorities consider it a protozoa. 
Association  
 PCP is the most common opportunistic infection in AIDS 
 Pneumocystis jirovecii pneumonia is unlikely in a patient who has had a

CD4 count above 200 cells/mm3  in the preceding 2 months in the absence of 
other HIV-associated symptoms. 
 immunosuppressed patients, particularly after organ transplantation 
 The organism is confined to the alveolar space  of the lung and produces debris and 
cysts in the alveolar space with interstitial infiltration of lymphocytes and plasma cells.  687

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 83 - 
 As a result, it can cause profound disturbance of oxygen exchange  and fatal 
hypoxaemia if left untreated. 
 The morphological appearance of Pneumocystis jirovecii  infection in the lung => 
An interstitial pneumonitis with foamy intra-alveolar exudate  
Features 
 dyspnoea 
 dry cough 
 fever 
 very few chest signs

 dry cough 
 fever 
 very few chest signs 
 Auscultation of the lungs usually reveals no abnormality 
 Pneumothorax is a common complication of PCP.  
 Extra-pulmonary manifestations are rare (1-2% of cases), may cause 
 hepatosplenomegaly 
 lymphadenopathy 
 choroid lesions  can result in  
 pancytopenia, retinal cotton wool spots and thyroid masses. 
 The lungs are commonly clear on auscultation   
 
Pneumocystis carinii  pneumonia  Definitive diagnosis is by bronchial alveolar lavage 
with silver staining  
 CXR:  
 typically shows bilateral interstitial pulmonary infiltrates  (usually diffuse 
ground-glass opacities )  
 can present with other x-ray findings e.g. lobar consolidation.  
 May be normal 
 exercise-induced desaturation 
 bronchoalveolar lavage (BAL)  often needed to demonstrate PCP ( silver stain shows 
characteristic cysts ).

characteristic cysts ).  
 The organism may be identified on microscopy after :  
 methenamine silver staining  for the cyst phase of the organism  
 giemsa staining that demonstrates the small, punctate nuclei of the 
trophozoites and intracystic  sporozoites, or  
 fluorescence-tagged monoclonal antibody.  
 sputum often fails to show PCP, 
 Lactate dehydrogenase  
 raised in 90% of patients with PCP (but this can occur with other pulmonary 
diseases).

diseases). 
 lymphopenia is very suggestive of PCP with AIDS  (and therefore low CD4 
lymphocyte count),  
 although patients may have low lymphocyte counts with other acute viral 
infections  
 indeed may be normal in HIV/AIDS due to a compensatory increase in the CD8 
lymphocyte subset. 
 
Management 688

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 84 - 
  co-trimoxazole  (120 mg/kg daily in divided doses) for 3 weeks  ( should be given for 21 
days in HIV, but can be shorter in other causes of immunosuppression ) 
 IV pentamidine in severe cases (or  In patients who are intolerant of co-trimoxazole  ) 
 allergic to co-trimoxazole alternative therapy would be IV pentamidine or

clindamycin with primaquine. 
 Steroids have been shown to reduce mortality and prevent lung damage in people with 
moderate- to-severe PCP. (The severity is determined on the basis of arterial blood gas 
results). 
 severe PCP is defined by a room air arterial oxygen pressure (pO2) of less 
than 9 kPa  (70 mmHg) or an arterial-alveolar O2 gradient that exceeds 4.5 kPa 
(35 mmHg). 
 if pO2 < 9.3kPa then steroids reduce risk of respiratory failure by 50% and death 
by a third

by a third 
 While it is true that long term steroid use is immunosuppressive a 21 day  
tapering course has been shown to be safe and effective. 
 co-trimoxazole is the preferred initial therapy during pregnancy according to 
consensus guidelines.  
 The BNF states tha t there is a teratogenic risk in the first trimester  (as 
trimethoprim is a folate antagonist), and neonatal haemolysis and 
methaemoglobinaemia in the third trimester. However, there is also considerable

risk of harm to the foetus if the mother is unwell. The benefits in this situation 
therefore outweigh the risks , and it should be used.  
 Glucose 6-phosphate dehydrogenase deficiency (G6PD) levels should be checked prior 
to TMP-SMX, dapsone or primaquine use  
 If allergic to co-trimoxazole, IV pentamidine or clindamycin are appropriate.   
 For the treatment of infections that are resistant to TMP-SMX, the combination of

clindamycin and primaquine is likely to be more effective than intravenous pentamidine.  
Prophylaxis 
 all patients with a CD4 count < 200/mm should receive PCP prophylaxis (Co-
trimoxazole is the preferred agent. Dapsone and inhaled pentamidine are also used.) 
 Discontinuing Primary Prophylaxis 
 Primary Pneumocystis  prophylaxis should be discontinued if the patient 
responded to ART with an increas e in CD4 counts ≥200 cells/mm3 for ≥3 months.  
 
January 2016 exam :

January 2016 exam :  
HIV positive but poorly compliant with his antiretroviral therapy (ART). CD4 :  180 
cells/ml. oxygen saturations 97%  on room air with a temperature of 38.1ºC. He has 
coarse crackles on the right side of his chest. A chest x-ray shows consolidation of 
the right mid zone . What is the most likely causative organism? Streptococcus 
pneumoniae  (Whilst Pneumocystis jirovecii  is of course associated with HIV, patients who

are immunocompromised are more likely to develop infections due to the common 
pathogens which affect immunocompetent individuals. Streptococcus pneumoniae  is 
therefore the most likely cause of community-acquired pneumonia in this patient. 
Pneumocystis jirovecii  tends to present with very few chest signs and bilateral interstitial 
pulmonary infiltrates on chest x-ray)   689

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 85 - 
Allergic bronchopulmonary aspergillosis (ABPA) 
 
In the exam questions often give a history of bronchiectasis and eosinophilia.  
 
 ABPA results from an allergy to Aspergillus spores  (Type I hypersensitivity  to 
Aspergillus fumigatus ).

Aspergillus fumigatus ).  
 asthma,  
 cystic fibrosis  
 bronchiectasis.  
 
Features  
 bronchoconstriction: wheeze, cough, dyspnoea 
 Clinical deterioration in asthma symptoms  
 bronchiectasis ( proximal ) 
 serum eosinophilia  
 Raised IgE 
 helpful test, but in isolation is not specific  enough to establish the diagnosis. 
 Aspergillus skin-prick test (the most specific investigation)  
 Positive radioallergosorbent (RAST) test to Aspergillus.

 Immediate (type I) reactions occur in virtually all patients with ABPA following 
intradermal injections of Aspergillus fumigatus  extracts, with only 16% developing 
delayed (type IV) reactions.   
 An early positive skin-prick test for Aspergillus fumigatus is the 
 most 
to (ABPA) .  
 specific 
 Positive skin-prick tests reflect antigen-specific IgE. 
 Positive IgG precipitins  (not as positive as in aspergilloma)  in 70% of patients.

 Precipitins (IgG) are more usual with an aspergilloma , but may be positive in 
ABPA or in up to 10% of patients with asthma. 
 Pulmonary infiltrates on CXR. Lobar collapse can also occur, due to mucus plugging. 
 
 First line  steroids 
 Second line  add itraconazole   
 
Aspergilloma 
 
the clue can be a lack of improvement with broad spectrum intravenous antibiotics ,

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 86 - 
  An aspergilloma is a mycetoma ( mass-like fungus ball ) which often colonises an 
existing lung cavity (e.g. secondary to tuberculosis, lung cancer, cystic fibrosis or 
emphysema) 
Feature :  
 often asymptomatic  
 cough 
 haemoptysis in up to three quarters of patients  (may be severe and fatal )

 Systemic symptoms of weight loss, lethargy and fever are less common. 
 chest x-ray containing a rounded opacity  within a cavity often associated with a rim of 
air.  
 These features are seen more clearly on CT.  
 high titres Aspergillus precipitins ( IgG antibodies ) 
 present in 95% of cases. 
 Up to 10% of aspergillomas resolve spontaneously but, if treatment is required, 
possibilities are: 
  surgical excision or

  surgical excision or  
 long-term treatment with oral itraconazole. 
 Surgery should be considered as a first-line  option where erosion into a major 
vessel and massive haemoptysis is a possibility  
 In case of massive haemoptysis the next appropriate management – after 
transfusion and resuscitation- is  Angiography and embolisation, after that  
lobar resection as the intervention of next resort

Invasive aspergillosis  
 Risk factors of fungal infections:   
 patients undergoing chemotherapy ,  
 stem cell transplant,  
 It is a leading cause of death in acute leukaemia and haemopoietic stem cell 
transplantation.  
 patients on immunosuppressive medications for autoimmune conditions  
 HIV positive.  
Features: 
691

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 87 - 
  Symptoms of active infection & haemoptysis. 
 include cough, haemoptysis, chest wall pain, fever and shock. 
Investigations :  
 the classical signs on CT scanning the ' halo sign ' air crescent sign  
 Silver staining shows  hyphae.  
 Haematoxylin and eosin (H&E) stain  does not stain most of the fungi, except

the Aspergillus  species. 
 galactomannan test: 
 Galactomannan is a component of the cell wall of the  Aspergillus  and is released 
during growth.  
 Detection of galactomannan in blood by ELISA is used to diagnose 
invasive aspergillosis  
 The first line treatment is voriconazole  
 should be started intravenously before oral dosing is considered. This is due to 
oral voriconazole taking at least 10 days to get to therapeutic levels.

 If voriconazole is not tolerated, then lipsomal  amphotericin  B should be used. 
Prognosis 
 Mortality for invasive aspergillosis vary from 40-90% in the literature. As such it is 
important to identify it and treat quickly.  
 
 Typical morphology of Aspergillus fumigatus . 
 
Alpha-1 antitrypsin (A1AT) deficiency  
 
Alpha-1 antitrypsin deficiency - autosomal recessive / co-dominant

 Alpha-1 antitrypsin (A1AT) deficiency is a common inherited condition 
 Caused by a lack of a protease inhibitor (Pi)  normally produced by the liver. 
  the main role of alpha-1 antitrypsin in the body  Protease inhibitor  
 The role of A1AT is to protect cells from enzymes such as neutrophil elastase.  
692

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 88 - 
  AAT neutralises neutrophil elastase, thereby preventing lung destruction. 
 
Genetics  
 located on   the long arm of  chromosome 14  
 inherited in an autosomal recessive / co-dominant fashion  
 the likely mode of inheritance   Autosomal codominant  
 caused by a mutation in the SERPINA-1 gene  on chromosome 14 (14q32),

 alleles classified by their electrophoretic mobility - M for normal, S for slow, and Z for 
very slow 
The serum levels of some of the common genotypes are: 
 PiMM: 100% (normal) 
 PiMS: 80% of normal serum level of A1AT 
 PiSS: 60% of normal serum level of A1AT 
 PiMZ: 60% of normal serum level of A1AT 
 PiSZ: 40% of normal serum level of A1AT 
 PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency). 
 
Features 
 patients who manifest disease usually have PiZZ  genotype 
 lungs:

 lungs:  
 panacinar emphysema , most marked in lower lobes  (2% of cases of 
 75% of patients develop chest pathology 
 Which form of lung disease develops typically in people with α1 -
antitrypsin deficiency? 
 Emphysema 
 results from an imbalance between proteases and 
antiproteases within the lung. 
 The elastase and α1 -antitrypsin balance  clearly illustrates 
the processes involved in the development of emphysema

 the interplay between the environmental and genetic 
factors  determine its onset. 
 Patients usually present with increasing dyspnoea and weight 
loss, with cor pulmonale and polycythaemia occurring late in 
the course of the disease.  
 Chest X-rays typically show bilateral basal emphysema  with 
paucity  and pruning of the basal pulmonary vessels. 
 liver:  
 cirrhosis and hepatocellular carcinoma in adults,  
 (15% of patients have associated cirrhosis) 
 cholestasis in children .

 cholestasis in children . 
 A1AT concentrations 
 All patients under the age of 35 years presenting with COPD should have their α1 - 
antitrypsin tested. 693

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 89 - 
 no smoking 
 smoking is harmful to those with A1AT deficiency and can accelerate the 
progression of emphysema by 10 years. 
 supportive:  
 bronchodilators,  
 physiotherapy 
 intravenous alpha1-antitrypsin protein concentrates 
 surgery:  
 volume reduction surgery, lung transplantation

Associated conditions:  
 malignancies including: 
  hepatocellular cancer,  
 lung cancer,  
 bladder cancer and  
 lymphoma. 
 Cirrhosis 
 Pancreatitis 
 Gall stones 
 COPD 
 Bronchiectasis 
 Primary sclerosing cholangitis 
 Wegener's granulomatosis and 
 Pelvic prolapse. 
Acute respiratory distress syndrome (ARDS) 
Basics 
 Pathophysiology

Basics 
 Ĺ permeability of alveolar capillaries Ĺfluid accumulation in alveoli i.e. non-
cardiogenic pulmonary oedema 
 deficiency in surfactant which reduces lung compliance and predisposes to 
collapse  (especially in dependent zones)  
 there tends to be a type 1 respiratory failure, rather than type 2.  
 ARDS is characterised by diffuse injury to the pulmonary capillary endothelium and

alveolar epithelium that ultimately leads to alveolar collapse and impaired pulmonary 
gas exchange. 
 
Diagnostic Criteria  (American-European Consensus Conference) 
1. Acute onset 
2. Bilateral infiltrates (on chest x ray or CT scan) 
3. PaO 2:FiO 2 ratio < 26.7 kPa (200 mmHg) 
4. Lack of evidence of left atrial hypertension  694

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 90 - 
  (pulmonary artery wedge pressure (PAWP) <18 mmHg if available). 
 Patients with acute respiratory distress syndrome have normal pulmonary 
capillary wedge pressure.  
 
Deferential diagnosis 
 The following are helpful in differentiating ARDS from other conditions, such as LVF: 
 normal heart size 
 absent septal lines

 absent septal lines 
 air bronchograms, and 
 a peripheral distribution. 
 
Causes 
 infection: sepsis, pneumonia 
 the most common CAUSE is systemic inflammation. 
 trauma 
 smoke inhalation 
 pancreatitis  
 cardio-pulmonary bypass 
Direct and indirect causes: 
 Direct  pulmonary causes include: 
 Inhalation of gastric contents (pH <2) 
 Infective (pneumonia, tuberculosis) 
 Pulmonary trauma 
 Near drowning

 Near drowning 
 Toxic gas inhalation and 
 Oxygen toxicity. 
 Indirect  causes include: 
 Sepsis 
 Non-thoracic trauma 
 Uraemia 
 Bowel infraction 
 Anaphylaxis and 
 Burns. 
 
ARDS causes restrictive lung disease. 
 The CXR classically shows bilateral peripheral interstitial and alveolar infiltrates  
that become progressively more confluent but spare the costophrenic angles .

 A lecithin: sphingomyelin ratio  of less than 1.5  is predictive of infant respiratory 
distress syndrome. 
 ARDS is associated with increased elastic recoil. 
 ARDS is associated with low pulmonary artery wedge pressure . 695

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 91 - 
  ARDS is associated with low compliance .  
 Treatment: 
 Which therapies has been shown to most likely decrease overall mortality of 
ARDS? 
 Implementing a low tidal volume ventilation protocol 
 ARDS with respiratory acidosis is best managed with invasive ventilation

using low tidal volumes (6 mL/kg based upon ideal body weight).  
 mechanical ventilation itself can injure the damaged lungs causing 
ventilation-induced lung injury.  
 The main goal of treatment is to minimise any additional damage while 
maintaining adequate gas exchange. This has been effectively done by 
maintaining low tidal volume ventilation. 
 low tidal volume ventilation reduces the absolute mortality by about 7-9% 
as compared to using higher tidal volumes.

as compared to using higher tidal volumes.  
 Mechanical ventilation  
 if the patient ’s blood gases reflect hypoxaemia and a slight respiratory 
alkalosis, (despite high FiO 2 settings and sufficient ventilation, his arterial 
oxygenation remains inadequate ): 
 the best next step is  adding positive end-expiratory pressure 
(PEEP) 
 The ventilator strategy should employ a relatively high level of 
positive end-expiratory pressure (PEEP)

positive end-expiratory pressure (PEEP)  
 Generally speaking, oxygenation may be improved by further 
increasing the FiO 2 or by adding positive end-expiratory pressure 
(PEEP). 
 High FiO 2 is contraindicated due to the risk of pulmonary oxygen 
toxicity. Thus, the goal in managing mechanically ventilated patients 
should be to keep the FiO 2 below 40% at all times.  
 The patients FiO 2 may need to be reduced soon- if more than 40% -

in order to avoid pulmonary oxygen toxicity, but this should be 
accomplished by first increasing oxygenation by another 
means, such as by increasing PEEP.  
 Adding PEEP is the next best step here. 
 PEEP prevents alveolar collapse, directly counteracting the means 
by which ARDS causes hypoxaemia. It may also reopen some 
alveoli that have already collapsed. 
 
 Extracorporeal membrane oxygenation (ECMO): 
 If the patient is on maximal ventilatory therapy but is still hypoxic &

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 92 - 
  trial demonstrated a significant increase in survival without significant disability  
 ECMO involves connecting a patient's circulation to an external oxygenator and 
pump, via a catheter placed in the right side of the heart.  
 It requires the continuous infusion of anticoagulant, and as such bleeding is the

most commonly associated complication.  
 Infection and haemolysis are also a risk. 
 Since the infiltrate of ARDS is primarily inflammatory, diuretics  are NOT  particularly 
effective. Over-diuresis also runs the risk of hemodynamic compromise, further 
decreasing the patient's already insufficient oxygen delivery to tissues. 
 glucocorticoids   have NOT  been shown to help patients in the acute phase of ARDS.

 There is some evidence that they may help in the fibroproliferative stage but not 
acutely.   
 
Acute Respiratory Distress Syndrome (ARDS) & Acute Lung Injury (ALI): 
 ARDS is a severe form of Acute Lung Injury (ALI)  
 ARDS has the same definition except that the PaO 2/FiO 2 ratio is less than 200.  
 ALI has a specific definition:  
 PaO 2/FiO 2 ratio of less than 300 
 Bilateral infiltrates on a chest radiograph 
 Pulmonary capillary wedge pressure of less than 18 mmHg

Prognosis: 
 ARDS mortality is generally high (40%), but is determined by the cause with aspiration 
pneumonia having a mortality rate of almost 80% when associated with ARDS. 
 
Acetazolamide  can be used to prevent acute mountain sickness . It causes a primary 
metabolic acidosis and compensatory respiratory alkalosis which increases respiratory 
rate and improves oxygenation

rate and improves oxygenation 
 
 There are three main types of altitude related disorders:  
1. acute mountain sickness (AMS),  which may progress to  
2. high altitude pulmonary edema  (HAPE) or  
3. high altitude cerebral edema  (HACE).  
 All three conditions are due to the chronic hypobaric hypoxia which develops at high 
altitudes 
Acute mountain sickness  
 Acute mountain sickness is generally a self-limiting condition.  697

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 93 - 
  Features of AMS start to occur above 2,500 - 3,000m, developing gradually over 6- 12 
hours and potentially last a number of days: 
 headache 
 nausea 
 fatigue 
 Altitude sickness is characterized by no change in the A-a gradient.  
 Prevention and treatment of AMS

 Prevention and treatment of AMS 
 the risk of AMS may actually be positively correlated to physical fitness 
 gain altitude at no more than 500 m per day 
 acetazolamide (a carbonic anhydrase inhibitor) is widely used to prevent AMS 
and has a supporting evidence base 
 treatment: descent 
 
High altitude pulmonary oedema (HAPE) or high altitude cerebral oedema (HACE) 
 A minority of people above 4,000m go onto develop high altitude pulmonary oedema

(HAPE) or high altitude cerebral oedema (HACE), potentially fatal conditions 
 HAPE presents with classical pulmonary oedema features 
 HACE presents with headache, ataxia, papilloedema 
Management of HACE 
 descent 
 dexamethasone 
Management of HAPE 
 descent 
 High concentration O 2  
  oxygen should be initiated first  
 Is the next most appropriate intervention  
 nifedipine, dexamethasone, acetazolamide, phosphodiesterase type V inhibitors*

 If high-flow oxygen is not available, then nifedipine can be used as second line.   
 * All seem to work by reducing systolic pulmonary artery pressure   
 
Other features of Altitude sickness: 
 acid-base abnormality  respiratory alkalosis as an. 
 hematological manifestation  Increase in erythropoietin. 
Bronchiectasis  
Bronchiectasis should be suspected in a patient with chronic cough producing large

amounts of sputum 
 permanent dilatation of the airways secondary to chronic infection or inflammation.  
Causes  
 Post-infective: (i.e., bacterial, viral, fungal) 
 tuberculosis, measles, pertussis, pneumonia 
 A history of previous whooping cough suggests bronchiectasis.  
 Disorders of secretion clearance or mucous plugging 
 Cystic fibrosis   698

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 94 - 
  Primary ciliary dyskinesia  
 Kartagener's syndrome (situs inversus and sinusitis associated with non-
motile cilia), 
 Young's syndrome (a combination of bronchiectasis, rhinosinusitis and 
infertility) 
 Allergic bronchopulmonary aspergillosis (ABPA) 
 proximal bronchiectasis (centrally dilated thickened airways with ‘signet

rings ’) 
 raised IgE is most useful for confirming the diagnosis 
 Bronchial obstruction e.g. 
  lung cancer/foreign body 
 Patients with longstanding chronic obstructive pulmonary disease (COPD)  
 Patients with longstanding COPD often develop localised areas of 
bronchiectasis because of progressive damage to the lung tissue 
 HRCT is the most useful investigation in establishing the  
 Immune deficiency  
 selective IgA,  
 hypogammaglobulinaemia

 hypogammaglobulinaemia 
 Hypogammaglobulinaemia in ataxia telangiectasia 
 common variable immunodeficiency, 
 HIV 
 Chronic inflammatory diseases  
 Inflammatory bowel disease  
 Rheumatoid arthritis  (3-4% of RA developed bronchiectasis ). 
 yellow nail syndrome 
 
Features:  The most common findings on examination are crackles (75%) and wheeze (22%). 
Clubbing is only found in 2%.

Clubbing is only found in 2%.  
 chronic productive cough, with copious amounts of sputum  (expectorating phlegm on 
most days)  
 Dyspnea  
 frequent chest infections  
 Post nasal drip - common (chronic sinusitis in around 30%)  
 tiredness - many patients find this more troublesome than the productive cough  
 Low Ventilation perfusion ratio leading to hypercapnia  Respiratory acidosis, and 
the body  compensate by increasing heart rate and vasodilatation.

Diagnosis 
 Chest X-ray 
 the best initial  test 
 can be normal in 50% of patients  
 Bronchiectasis cannot be ruled out with a chest x-ray 699

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 95 - 
  the findings: 
 thickened and dilated bronchi, which produce tramline opacities  and ring 
shadows . 
 “tram track ” lines  
 Due to Inflammation and fibrosis of bronchial walls 
 Retained mucus might be seen as tubular opacities,  
 volume loss of the affected lobe.

 volume loss of the affected lobe.   
 Thin-walled cysts (i.e., dilated bronchi forming sacs), possibly with air-fluid 
levels 
 Late-stage bronchiectasis: honeycombing 
 High-resolution computed tomography scan of the lungs (HRCT)   is the gold 
standard for the diagnosis of bronchiectasis. 
  
 The diagnostic criteria for bronchiectasis on HRCT  depend on finding both 
dilatation and thickening of the affected bronchi. 
  tram track lines and honeycombing  
 'signet ring' sign

 'signet ring' sign  
 The classic appearance of a cross-section of a thick-walled dilated  
bronchus next to the accompanying pulmonary artery. 
 Bronchial dilatation   
 Dilatation being present if the internal diameter of the bronchus is 
greater than the diameter of its accompanying pulmonary artery.  
 increased broncho-arterial ratio  (bronchus larger than 
neighboring pulmonary artery) 
 Carcinoma of the lung:

 Carcinoma of the lung:  
 Lung cancer can present with non-resolving respiratory infection with productive 
cough due to endobronchial obstruction by tumour, but there would be a much 
shorter duration of symptoms . Without treatment most patients would be 
dead  within a year of the onset of lung cancer .  
 
Chest x-ray showing tramlines, most prominent in the left lower zone 
700

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 96 - 
  
CT chest showing widespread tram-track and signet ring sign S 
 
Symptom control in non-CF bronchiectasis  inspiratory muscle training + postural 
drainage  
 
The mainstay of therapy for bronchiectasis is antibiotics and chest physiotherapy.

After assessing for treatable causes (e.g. immune deficiency) management is as follows: 
 physical training (e.g. inspiratory muscle training) - has a good evidence base for 
patients with non-cystic fibrosis bronchiectasis 
 postural drainage 
 antibiotics for exacerbations + long-term rotating antibiotics in severe cases 
 bronchodilators in selected cases 
 Immunisations : Influenza and pneumococcal vaccinations are strongly recommended.

 surgery in selected cases (e.g. Localised disease that fails to resolve after I.V antibiotic 
) 
Most common organisms isolated from patients with bronchiectasis: 
Bronchiectasis: most common organism  Haemophilus influenzae  
 
 Haemophilus influenzae  (most common ) 
 Pseudomonas aeruginosa  
 Klebsiella spp. 
 Streptococcus pneumoniae  
 
 Primary prevention:  
 antibiotic control of bronchial and pulmonary infections in predisposed individuals 
 Secondary prevention:

 Secondary prevention:  
 long-term low-dose macrolide treatment (e.g., azithromycin) in patients with two 
or more bronchiectasis exacerbations within one year. 
701

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 97 - 
 Cystic fibrosis 
Genetics  
 autosomal recessive 
 Due to mutation of CFTR gene on chromosome 7.  
 The most common mutations is delta-F508. 
 If both parents are carriers  of the CF gene: 
 The chance of another child being affected (homozygote) is 1 in 4 (25%).

 The chance of their child being free from the CF gene is also 1 in 4 (25%)  
 And the chance of a child being a carrier (heterozygote) is 1 in 2 (50%). 
 the sibling of an  affected person has a 3 in 4 chance of being a CF carrier or having the 
disease.  if one sibling is not affected , the chance of being a carrier for the CF gene is 
           2 in 3.  
  Occurs in 1 in 2500 live births.  
 The carrier frequency in white populations is 1 in 25.

 the most common genetically inherited diseases in Caucasian individuals.  
 Rare in patients of Afro-Caribbean and Asian origin.  
 10% of people with cystic fibrosis are not diagnosed until adult life. 
 
The most common features 
 failure to thrive and delayed puberty (100%) 
 infertility   
 male infertility  occurs in 98%  due to failure of development of the vas 
deferens  
 Female subfertility  secondary to viscid cervical secretions.  (only a 20% will be 
infertile)

infertile)  
 Pancreatic insufficiency  (the most common , 85% ) 
 almost always present in adult patients 
 diabetes mellitus : occurs in > 65% of patients by age 25  
 main manifestations => weight loss, repeated respiratory infections and decline   
in lung function. 
 treatment of choice is subcutaneous insulin  
 Calorie intake should not be restricted in CF patients, who are prone to 
malnutrition due to their pancreatic insufficiency. 
 Recurrent chest infections (40%)

 Recurrent chest infections (40%) 
 malabsorption (30%): steatorrhoea, It is associated with pancreatic insufficiency, 
which is almost always present in adult patients  
Constipation is common 
 hepatobiliary dysfunction (cholestasis) 
 due to Defective cystic fibrosis transmembrane regulator (CFTR) protein on 
bile duct epithelial cells 
 neonatal period (around 20%): meconium ileus, less commonly prolonged jaundice 
 other features (10%): liver disease  
 702

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 98 - 
 Other features of cystic fibrosis 
 short stature 
 rectal prolapse (due to bulky stools) 
 nasal polyps 
 While nasal polyps occur in adults secondary to recurrent episodes of rhinitis,  
nasal polyps in children should always raise the suspicion for cystic 
fibrosis.

fibrosis.   
 Depletion of sodium, chloride and potassium due to excessive sweating, and secondary 
renal chloride retention, can result in presentation with dehydration and heat exhaustion 
in an otherwise apparently completely fit adult.   
 Pneumothorax is seen in up to 5% of patients over 10 years of age and approximately 
50% recur.  
 Allergic bronchopulmonary aspergillosis (ABPA)   is a recognised complication, 
occurring in 15% of adult CF patients

occurring in 15% of adult CF patients  
 Affect 1 in 6 adult CF patients .  
 Manifestations => asthma symptoms, flitting opacities on chest X-ray, 
ĹĹeosinophil count, hyper -reactivity to skin prick test and ĹĹ plasma IgE.  
 Main treatment => high-dose corticosteroids initially, with a smaller maintenance 
dose.  Antifungal agents may be used to allow a reduction in corticosteroid dose. 
 Distal intestinal obstruction syndrome :

 Distal intestinal obstruction syndrome :  
 Occurs in 10-20% of patients with cystic fibrosis and incidence increases with 
age. About 80% of cases present for the first time in adults.  
 The pathogenesis  is partially due to loss of CFTR function in the intestine which 
results in deregulation of chloride secretion from the crypts, bicarbonate secretion 
from Brunner's glands and sodium transport. This leads to the accumulation of

viscous mucus and faecal material in the terminal ileum, caecum and ascending 
colon.  
Diagnosis 
 Sweat test 
 patient's with CF have abnormally high sweat chloride 
 normal value < 40 mEq/l, CF indicated by > 60 mEq/l  
 99% of children with CF have sweat chloride  > 70 and sodium levels > 60. 
 In normal children, sweat sodium is higher than chloride. The reversed ratio is 
another pointer to CF.  
 Two sweat tests should be performed spontaneously on both arms with

pilocarpine iontophoresis.  
 A negative sweat test is sufficient evidence to exclude cystic fibrosis.  
 If the sweat chloride test is abnormal, the patient should undergo CFTR gene 
mutation testing.  
 Method of sweat test  
 sweat test is conducted using pilocarpine  iontophoresis.( a direct acting 
muscarinic agonist)  
 A 3 mA current carries pilocarpine into the skin of the forearm stimulating local 
sweating. 703

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 99 - 
  The arm is washed with distilled water and sweat collected on a filter paper or 
gauze.  
 The duration of collection is usually 30-60 minutes.  
 The filter paper is removed, weighed and eluted in distilled water. 
 At least 50 mg and preferably 100 mg of sweat should be collected for reliable

results. It may not be possible to collect this amount in young infants. 
 More than 60 mmol/L of chloride is diagnostic of CF when one or more other 
criteria are present.  
 
 Causes of false  negative  sweat test  
 nephrotic syndromes.  
 
 Causes of false positive sweat test 
 malnutrition 
 adrenal insufficiency 
 glycogen storage diseases 
 nephrogenic diabetes insipidus 
 hypothyroidism, hypoparathyroidism 
 G6PD 
 ectodermal dysplasia 

 G6PD 
Management of cystic fibrosis involves a multidisciplinary approach 
 
Key points  
 chest physiotherapy and postural drainage  
 regular (at least twice daily).  
 Parents are usually taught to do this.  
 Deep breathing exercises are also useful 
 high calorie  diet, including high fat  intake, 
 Patients with cystic fibrosis suffer significant difficulties in maintaining their 
weight.

weight.  
 Weight loss in cystic fibrosis is closely allied to both risk of exacerbations of the 
disease and an increase in overall mortality.  
 For this reasons: 
 it's important to maintain a high calorie diet 
 the best way to manage diabetes in CF is insulin and high calorie  
diet to allow them to convert those calories into stored energy. 
 vitamin supplementation 
 pancreatic enzyme supplements taken with meals 
 antibiotics 
 heart and lung transplant

 heart and lung transplant 
 
Chest infections in cystic fibrosis: 704

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 100 - 
  The culture plate shows a growth 
of Pseudomonas aeruginosa , 
characterised by the green 
colouration of the colonies due to 
production of the pigment 
pyocyanin. 
 
 bronchiectasis associated with 
CF frequently results in 
recurrent infections 
with Pseudomonas . 
 
 Mechanism:

 Mechanism: 
 In cystic fibrosis  defective chloride secretion and increased sodium resorption 
 thick mucus  airways  obstruction bacterial colonisation early in life. 
 Organisms: 
  infants and young children become colonised by Staphylococcus aureus and 
then Haemophilus influenzae . 
 (70 –80% of children aged 6 –18 years with CF have chronic S. aureus 
infection). 
  In teenagers, Pseudomonas aeruginosa  colonisation occurs.

 Pseudomonas aeruginosa is the commonest colonising organism in 
patients with cystic fibrosis  after the age of 10 years, with a reported 
prevalence of 40-80%. 
 (70% of adults with CF have chronic P. aeruginosa infection) 
 Aspergillus    
 One Australian study suggested that colonisation rates for Aspergillus  in 
patients with cystic fibrosis approach 19%.  (CF is most likely to be 
associated with Aspergillus  colonisation) 
 Burkhold eria cepacia

 Burkhold eria cepacia  
  Gram-negative,  aerobic, rod bacteria, part of Proteobacteria l 
genus   (previously part of Pseudomonas ) 
 occurs in 5 –10% of patients,  
 associated with the worst prognosis  
 Burkholderia cepacia is seen in severe lung disease and is often 
associated with a rapid deterioration. 
 Burkholderia and Pseudomonas are two pathogens which are very difficult 
to eradicate. Of those, Burkholderia has the worst prognosis. 
 Other organisms 
705

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 101 - 
  pneumoniae,  
 Mycobacterium tuberculosis , other mycobacteria, Aspergillus fumigatus 
and viruses. 
 Treatment: 
 Indications of antibiotics: In the UK, antibiotics are usually given when: 
 the sputum becomes purulent,  
 pulmonary function deteriorates,  
 or the patient is unwell (e.g. weight loss). 
 Drugs

 Drugs 
 Anti- Pseudomonal 
 In teenagers groups, Pseudomonal cover is needed and a 
combination of intravenous antibiotics is used to reduce the 
risk of resistance developing. The usual combination is  
ceftazidime and tobramycin , for a period of two weeks. 
 The combination of ceftazidime and tobramycin  is the antibiotic 
regimen of choice  for the treatment of cystic fibrosis exacerbations 
in patients with Pseudomonas aeruginosa .   
 Treatment should be continued for 10-14 days.

 Treatment should be continued for 10-14 days.  
 ceftazidime  is a third-generation cephalosporin ,  and 
works by interfering with bacterial cell wall.  
 Tobramycin  is an aminoglycoside antibiotic , works by 
binding to a site on the bacterial 30S and 50S ribosome , 
preventing formation of the 70S complex.  As a 
result, mRNA cannot be translated into protein  cell death   
 SE:  
 Nephrotoxicity  
 ototoxicity (generally irreversible).

ototoxicity (generally irreversible). 
 Most colonising types of P. aeruginosa are sensitive to antibiotics at 
first, but over the years and in association with antibiotic treatment, 
multiple resistance to most antibiotics (except colistin) develops.  
 
 The combination of piperacillin and tazobactam  (Tazocin®) is 
indicated for the treatment of cystic fibrosis exacerbations.   
 Tazobactam is not an antibiotic rather a beta-lactamase inhibitor, so

Tazocin, which is a mixture of piperacillin (an antibiotic) and 
tazobactam (a drug which prevents bacteria from inactivating 
piperacillin) does not count as combination antibiotic therapy.   
 Tazocin® is active against Pseudomonas aeruginosa . However, a 
combination of antibiotics is preferable to minimise the risk of 
antibiotic resistance which is why  the correct choice here is 
ceftazidime and tobramycin.  
 SE: Rash and fever  are more common  in patients with cystic

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 102 - 
  Nebulised tobramycin for Pseudomonas  colonisation of the lower 
respiratory tract 
 Nebulised tobramycin or gentamicin may be given when airway 
pathogens are resistant to oral antibiotics, or where infection is 
difficult to control at home. 
 Gentamicin can be used in place of tobramycin, but has poorer

pseudomonal cover and is associated with significant side effects 
(nephrotoxicity and ototoxicity). 
 Nebulised treatments  such as aminoglycosides and colistin can be 
used for prevention of a flare-up of a patient colonised with 
Pseudomonas aeroginosa and their use as prophylactic therapy  
has been shown to imporove lung funtion in patients with cystic 
fibrosis, but this not adequate as a treatment of acute infection . 
 Lung transplantation in cystic fibrosis

 Lung transplantation in cystic fibrosis 
 Heart-lung transplantation is offered to patients who exhibit a rapid decline in lung 
function despite optimal treatment, and to patients with respiratory failure. 
 Age under 60 years 
 Life expectancy of less than 18 months 
 No underlying cancer or serious systemic disease 
 severe reduction in BMI is a relative  contraindication to transplantation because

it is associated with reduced survival but it is not an absolute contraindication. 
 Donor characteristics 
 The donor is matched for ABO grouping. 
 Rhesus blood group compatibility is not essential. 
 The donor should have had good cardiac and lung function 
 The donor should have been under the age of 40. 
 The chest of the donor should be slightly smaller than that of the recipient. 
 A double lung transplant is usually performed because of the risk of

chronic infection in the remaining lung. 
Prognosis  
 The median survival is now predicted to be at least 40 years for children born in the 
1990s. 
 Median survival has increased significantly over the past 10 years, and is now around 
37 years.  
Occupational lung diseases  
Occupational asthma 
 
707

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 103 - 
  Occupational asthma occurs more frequently in atopic persons  and smokers.  
Causes:  Exposure to the following chemicals is associated with occupational asthma: 
 Isocyanates - the most common cause . Example occupations include spray painting 
and foam moulding using adhesives ( used in the manufacture of foams/plastics )

 platinum salts 
 other metals: Aluminium, Chrome, Manganese, Nickel, Zinc 
 soldering flux resin 
 glutaraldehyde (and other disinfectant and preservatives: Chlorhexidine , 
Formaldehyde) 
 flour 
 epoxy resins 
 proteolytic enzymes 
Diagnosis 
 Patients may either present with concerns that chemicals at work are worsening their 
asthma or you may notice in the history that symptoms seem better at weekends / 
when away from work.

when away from work.  
 Serial PEFR measurement is the diagnositic test of choice   
 Serial measurements of peak expiratory flow are recommended at work and 
away from work.   
 Recordings should be performed two hourly for four weeks or if this is not 
possible methacholine/histamine challenges can be undertaken after days at 
work and away from work.  
 bronchial provocation tests and specific IgE radioallergosorbent tests (RAST) are

required to identify the specific agent at work causing the asthma.  
 Referral should be made to a respiratory specialist for patients with suspected 
occupational asthma. 
 Reduction of further exposure to the allergen.     
 Affected individuals who continue to work in the occupation responsible for their disease 
can often reduce their exposure substantially by changing the pattern of their

particular duties . An alternative is to use  industrial respirators , which filter out 98-
99% of respirable dust from the ambient air. 
 Corticosteroid 
 
Extrinsic allergic alveolitis (EAA)  
 
708

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 104 - 
  Extrinsic allergic alveolitis (EAA, also known as hypersensitivity pneumonitis) is a 
condition caused by hypersensitivity induced lung damage due to a variety of inhaled 
organic particles.  
 It is thought to be largely caused by immune-complex mediated tissue damage (type III

hypersensitivity) although delayed hypersensitivity (type IV) is also thought to play a role 
in EAA, especially in the chronic phase.   
 Despite its name, EAA is not allergic and therefore features associated with allergy and 
type I reactions do not tend to occur in EAA (ie wheeze, immediate symptoms, raised 
IgE, positive skin-prick test, eosinophilia of blood or sputum). 
 Extrinsic allergic alveolitis is characterised histologically  by:

 alveolar destruction  and interstitial inflammation .  
 Non-caseating granulomas  are also present  
 asteroid bodies may be found in or adjacent to the granulomas. 
Examples  
 bird fanciers' lung : avian proteins 
 farmer's lung : spores of Saccharopolyspora rectivirgula  (formerly Micropolyspora faeni ) 
 the commonest occupational hypersensitivity pneumonitis 
 Contaminated hay is the most common source of Saccharopolyspora 
rectivirgula

rectivirgula    
 caused by dust from mouldy hay contaminated with 
thermophilic Actinomyces  bacteria  
 Basal crackles are the  typical  feature.  
 Serum precipitating antibodies  to Saccharopolyspora rectivirgula  is the 
most useful diagnostic test 
 precipitins to Saccharopolyspora rectivirgula  or Thermoactinomyces vulgaris  are 
found in 75-100% of cases during an acute episode. 
 malt workers' lung : Aspergillus clavatus  
 mushroom workers' lung: thermophilic actinomycetes

 maple bark stripper's lung  : caused by Cryptostroma corticale 
 Penicillium  species are responsible for respiratory disease in cheese and cork workers 
and are due to fungal contaminants of materials.  
 acute: occur 4-8 hrs after exposure, SOB, dry cough, fever 
 chronic: exertional shortness of breath and pulmonary fibrosis (typically upper-lobe).  
 Chest x-ray: upper/mid-zone fibrosis.  nodular shadowing or ground glass appearances.

Classically show diffuse air-space consolidation  
 Broncho alveolar lavage: lymphocytosis , eosinophilia 
 Blood:  Circulating IgG precipitins. NO eosinophilia 
 confirmed by demonstration of precipitating antibodies (precipitins) in the patient's 
serum to the causal antigen. 
 Prednisolone  
 Symptoms may settle within 12 hours of removal of the antigen.  
 Optimal management is removal of exposure to the antigen,  change of job plan 
 709

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 105 - 
 A 65-year-old farmer  presents with SOB and wheeze progressively worsening over the past 6 
months. He is a  smoker , and has two daughters with asthma . There was obvious wheeze 
and coarse end-inspiratory crackles on examination of the chest. A chest X- ray shows diffuse 
non-specific changes consistent with lung disease.

Which would be the next most appropriate  investigation?  
 Spirometry and reversibility  
 This man either has asthma, chronic obstructive pulmonary disease or 
farmer ’s lung 
 Spirometry and reversibility would be the investigation of choice. 
 A restrictive defect  would support a diagnosis of farmer ’s lung ;  
 an obstructive defect with reversibility  would support a diagnosis 
of asthma ,  
 respiratory obstruction without reversibility  would support a 
diagnosis of COPD .

diagnosis of COPD . 
 
Byssinosis 
 Rare in UK, occurs in areas of cotton  production, such as India. 
 Characteristic symptoms : shortness of breath, cough and chest tightness that begin on 
the first day of the working week and ease during the remainder of the working week.  
 It is thought to be due to endotoxin released by bacteria that are found in cotton dust.  
 Usually no chest X-ray changes.

 Usually no chest X-ray changes. 
 The more severe changes noted in some patients might be related to associated 
asthma or cigarette smoking.   
 
Pneumoconioses 
 
 A group of chronic lung diseases caused by exposure to a mineral dust or a metal.  
Type  
 The major pneumoconioses include: 
 asbestosis,  
 silicosis,  
 coal workers' pneumoconiosis (black lung disease), and  
 chronic beryllium disease.

 chronic beryllium disease. 
Risk factor 
 In silicosis  and coal workers' pneumoconiosis, exposure should be (at least 10 and 
usually 20 or more years prior to radiographic changes). 
 The best predictor for the development of silicosis or coal workers' 
pneumoconiosis is the total amount of silica or coal inhaled (the cumulative 
dose  inhaled).  
 Beryllium  is immunologically mediated with a strong genetic component , so that the

typical dose response demonstrated with the other pneumoconioses is not seen. 
 NO need for cumulative dose 
Features 710

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 106 - 
  dyspnoea on exertion 
 Typically the first sign of pneumoconiosis 
 Dry, non-productive cough  
 productive cough if developed COPD as a complication 
 Chest auscultation will be normal early in these diseases. 
Diagnosis   
 usually by typical chest x-ray appearance.

 usually by typical chest x-ray appearance.  
 The presence of non-calcified, multiple (in the hundreds), rounded opacities  in 
the upper zones  is highly suggestive of silicosis or coal workers'  
pneumoconiosis.  
 high-resolution CT (HRCT) scan chest 
 more sensitive than CXR in identifying interstitial fibrosis. 
 Individuals with silicosis should be tested for TB. 
Treatment 
 smoking cessation + removal of occupational exposure 
 advice regarding compensation

 advice regarding compensation 
 Patients with end-stage respiratory failure (PaO2 <60 mmHg despite oxygen therapy)  
 Referral for lung transplant  
 Absolute contraindications include: 
 other incurable advanced disease,  
 addictions including tobacco,  
 lack of social support,  
 untreatable psychiatric condition, or  
 documented non-adherence to medical therapy.  
 Relative contraindications include: 
 age >65 and  
 obesity.  
 Major complications include:

 obesity.  
 Major complications include: 
 graft failure and  
 development of bronchiolitis obliterans.  
 Ĺ risk of hypertension, diabetes, dyslipidaemia, renal dysfunction, and 
infection from the immunosuppressive medication. 
Asbestos and the lung 
Risk of asbestos exposure  
 Ship building ,  
 car manufacture,  
 boiler making and  
 plumbing industries

 plumbing industries  
Asbestos can cause a variety of lung disease from benign pleural plaques to  mesothelioma.  
 
Pleural plaques  
 the most common form of asbestos related lung disease  
 occur after a latent period of 20-40 years. 
 rarely cause symptoms  
 benign and do not undergo malignant change. 711

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 107 - 
   CXR may shows  calcification on both hemidiaphragms  which are most likely to be 
pleural plaques from previous asbestos exposure. 
 Do not require long term follow up  
Pleural thickening  
 Asbestos exposure may cause diffuse pleural thickening in a similar pattern to that seen 
following an empyema or haemothorax.

following an empyema or haemothorax.  
Asbestosis  (asbestos-related pulmonary fibrosis) 
 Asbestosis, defined as diffuse interstitial fibrosis  secondary to asbestos 
inhalation  
 Overview 
 The latent period is typically 15-30 years. 
 The condition is slowly progressive  
 The severity of asbestosis is related to the length of exposure.  
 This is in contrast to mesothelioma where even very limited exposure can 
cause disease. 
 Feature

 Feature 
 Asbestosis typically causes lower lobe fibrosis.  
 As with other forms of lung fibrosis the most common symptoms are shortness-
of-breath and reduced exercise tolerance.   
 Clubbing occurs in 43% of people with asbestosis.  
 Biopsy is not mandatory as the diagnosis can be made on clinical and 
radiological grounds. 
 In an alveolar sputum sample obtained by bronchoalveolar 
lavage, asbestos bodies are visualized using Prussian blue stain.

 avoid further exposure to asbestos  
 stop smoking. 
 resistant to treatment with immunosuppressive therapy. 
 The risk of lung cancer is raised more than 50-fold in smokers with asbestos. 
 
Mesothelioma  
 Mesothelioma is a malignant disease of the pleura.  
 Loss of material from chromosome 22 is commonly seen in mesothelioma 
cell lines 
 Risk factor

cell lines 
 Risk factor  
 asbestos  is the primary risk factor associated with the development of 
mesothelioma.  
 Crocidolite (blue) asbestos is the most dangerous form.  
 it takes 40 years for the disease to begin 
  Smoking is not a risk factor for mesothelioma.  
 Features  
 progressive shortness- of-breath 712

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 108 - 
  chest pain 
 pleural effusion (exudative and hemorrhagic) 
 pleural thickening 
 made with patient's  history, imaging (chest x-  ray or computed tomography), and 
is confirmed with biopsy. 
 The appearance on CT is of nodular thickening which spreads along the pleural 
surfaces.

surfaces. 
 Psammoma bodies  are seen on histology in mesotheliomas. 
 Cytokeratin  and calretinin are two markers that are positive in almost all 
mesotheliomas. 
 palliative chemotherapy  
 there is also a limited role for surgery and radiotherapy.  
 Surgical cure is usually not possible , although pleurectomy or 
pneumonectomy can provide symptomatic relief. 
 Drainage of pleural effusion may cause tumour seeding along the track. 

 Prognosis   
 very poor, with a median survival from diagnosis of 8-14 months. 
 
  CT scan showing mesothelioma 
 There is a large rind of soft tissue related to 
the left chest wall. 
 This is a malignant process as there is 
destruction of the associated rib. 
 
Lung cancer  
 Asbestos exposure is a risk factor for lung cancer and also has a synergistic effect with 
cigarette smoke. 
 Bronchogenic carcinoma  is the most common malignant pulmonary tumor in patients

with asbestosis  
 Bronchogenic carcinoma is more common than mesothelioma 
 The lack of smoking history along with previous asbestos exposure and 
signs of a pleural effusion make malignant mesothelioma more likely than 
bronchial carcinoma. 
 
713

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 109 - 
  
Disease Agent Effects 
Aluminosis Alum, and al. oxide Fibrosis, bullae, pneumothorax 
Asbestosis Asbestos Pleural plaques, lung cancer, 
mesothelioma 
Byssinosis Cotton, flax, hemp Airway obstruction, loss of elasticity 
Metal fume fever Cadmium, cobalt, nickel, zinc 
and others Chemical pneumonitis 
Occupational

Occupational 
asthma Western Red SCedar and 
others Reversible airway obstruction 
Siderosis Iron oxide Dust deposits 
Silicosis Silica Dust deposits and fibrosis 
Talcosis Talc, hydrated Mg. silicates Perivascular fibrosis 
 
Silicosis 
Overview  
 Is a form of occupational lung disease caused by inhalation of crystalline silica dust, 
usually in the form of quartz.

usually in the form of quartz. 
 It is a type of pneumoconiosis  
 affects upper lobes  
 Risky jobs:   
 Silicosis can affect anyone involved in quarrying(المحاجرcarving, mining (تعدين ,)
tunneling (حgrinding(طحنor sand-blasting(نسفif the dust generated 
contains quartz.  
 manufacture of toilet bowls, sinks(مغاسلand ceramics; 
  hydraulic fracking while drilling for gas and oil. 
Pathology 
 macrophages activated by silica (quartz) 
 release fibrogenic cytokines

 release fibrogenic cytokines 
 It causes inflammation and scarring in the form of nodular lesions in the upper 
lobes of the lungs.  
 Silicosis features pathologic changes of both restrictive and obstructive lung 
disease  
Classifications 
 Acute silicosis :  
 The most severe form 714

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 110 - 
  develops a few weeks to 5 years after exposure 
 acquired after very heavy exposure over just a few months, patients become 
intensely breathless and die within months.  
 The X-ray shows appearances resembling pulmonary oedema. 
 Accelerated silicosis:   
 develops 5 –10 years after first exposure

 develops 5 –10 years after first exposure  
 Less heavy exposure causes progressively less dramatic symptoms, a 
progressive upper lobe fibrosis with slowly increasing exertional dyspnoea over 
several years 
 Simple nodular silicosis:   
 the most common type 
 resulting from long-term exposure (10 years or more) to relatively low 
concentrations of silica dust  
 Usually appearing 10 –30 years after first exposure

 radiographic nodular changes similar to coal-worker's pneumoconiosis ,  
 usually associated with exposure to dust containing 10-30% silica over a 
prolonged period. 
 In early disease no signs or symptoms , but abnormalities may be detected by x-
ray. Chronic cough and exertional dyspnoea are common findings 
 Radiographically, chronic simple silicosis reveals a profusion of small (<10 mm in 
diameter) opacities, typically rounded, and predominating in the upper lung 
zones.

zones. 
 Differential diagnosis  
 Simple nodular silicosis differs from coal-worker's pneumoconiosis 
in that  : 
 the lesions tend to be larger (3-5 mm)  
 and it is progressive even after dust exposure ceases 
Features  
 fibrosing lung disease 
 pulmonary function usually reveal mixed obstructive / restrictive picture 
 'egg-shell' calcification of the hilar lymph nodes is pathognomonic for  silicosis; 
 biopsy shows silica particles (birefringent) surrounded by collagen 
Sequelae

Sequelae 
 may impair macrophage function  
 ↑ susceptibility to TB  
 Patients with silicosis should be considered for treatment of latent TB if 
their tuberculin skin test result is 10 mm or greater, or if the blood assay 
for M tuberculosis  interferon gamma-release assay (IGRA) result is 
positive.  
 silica is toxic to macrophages  
 Ĺ incidence of primary lung cancer  
 Ĺ risk of connective -tissue disease, vasculitides, (COPD), and chronic renal failure. 
 715

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 111 - 
  
The chest radiograph shows "eggshell" calcification  of the hilar lymph nodes, as seen with 
silicosis. 
 
Treatment  
 acute secondary alveolar proteinosis (acute silicosis) 
 occur within weeks to months of extremely high exposure. 
 Symptoms same as chronic silicosis, but develop at a faster rate.

 1st line  whole lung lavage.  
Berylliosis   
 aerospace or nuclear industry workers 
 Pathology 
 noncaseating granulomas , nodular infiltrates, and enlarged lymph nodes 
 resembles sarcoidosis 
 Risk factor 
 manufacture of electronics, manufacture of heat-resistant ceramics, dental 
prostheses, and metal products 
 The presence of glutamic acid at position 69 of the HLA-DP1 beta chain is

strongly associated with chronic beryllium disease. 
 Features 
 acute form of berylliosis may present as pneumonitis, with acute wheezing, chest 
tightness, and shortness of breath. 
716

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 112 - 
  the usual radiographic changes with chronic beryllium disease are linear  
opacities.  
 silicosis and coal workers' are  rounded opacities 
 beryllium lymphocyte proliferation test (BeLPT) 
 Essential component of the diagnosis of chronic beryllium disease.

 Sensitive test that identifies individuals sensitised to beryllium. 
 if sensitised to beryllium: positive response 
 performed on a blood sample first, and confirmed with a repeat test. 
 Bronchoscopic lavage fluid may be positive when the blood test is 
negative. 
 The occurrence of a positive BeLPT without granulomas on histology  
is an indication of sensitisation to beryllium and absence of chronic 
beryllium disease.  
 Bronchoscopic biopsy 
 granulomas present 
 
 Sequelae

 Sequelae 
 Ĺ risk for primary lung cancer   
 Acute and chronic berylliosis  Oral corticosteroid therapy.  
Coal workers' pneumoconiosis (CWP) 
 affects upper lobes  (high ventilation) 
 macrophages phagocytose particles ("dust cells") 
 Types 
 simple CWP 
 like smoking, can produce centrilobular emphysema 
 1 cm fibrotic centers

 1 cm fibrotic centers 
 Simple coal-worker's pneumoconiosis causes no symptoms or physical 
signs, but it predisposes to progressive massive fibrosis  
 complicated CWP 
 1-2 cm fibrotic centers 
 Sequelae 
 Ĺ risk of connective -tissue disease and COPD 
 NO association with lung cancer or TB 
 
Categories: depends on chest x-ray appearance 
 Category 1 disease 
 the least severe, with fewer opacities and normal lung markings clearly visible.

 progression to massive fibrosis  never 
 Category 2 pneumoconiosis  
 less severe, with a number of opacities but normal lung markings still visible; 
 progression to massive fibrosis  7% 
 Category 3 pneumoconiosis 717

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 113 - 
  chest X-ray reveals a large number of small round opacities within the lung fields, 
with almost complete obscuration of normal lung markings.  
 progression to massive fibrosis  30% 
__________________________________________________________
Progressive massive fibrosis (PMF)  
Causes

Causes  
 exposure to dust of high silicon content  and hence PMF is more likely with higher 
silicon exposure than in simple coal worker's lung. 
  Coal worker's pneumoconiosis  
 The rate of progression of category 3 pneumoconiosis is much higher, at around 
30%. 
 Category 2 pneumoconiosis progresses to PMF in around 7% of cases.  
Feature 
 There is usually a history of dust inhalation (eg coal dust).

 An unusual, but pathognomonic symptom  is melanoptysis  -the expectoration of the 
black contents of a cavitated lesion. 
 There are also emphysematous changes.  
 there is a mixed obstructive and restrictive lung defect with reduced transfer factor.  
 Rheumatoid factor and antinuclear antibody are often positive. 
 PMF can progress rapidly, even in the absence of further dust exposure, leading to 
respiratory failure and eventually death.  
Diagnosis 
 Is diagnosed by chest x ray :

Diagnosis 
 Is diagnosed by chest x ray : 
  as round masses, several centimetres in diameter, sometimes up to 10 cm   
 usually in the upper lobes.  
 They may have necrotic centres.  
 In silicosis a more accurate term is 'conglomerate nodules' 
 CT 
 Mass-like areas of lung opacification associated with radiating strands are seen; 
the "sausage-shaped" mass is characteristic. 
 MRI 
 can be helpful for distinguishing between progressive massive fibrosis and lung 
cancer.

cancer. 
  lung cancer  typically appears as T2- bright ,  
 whereas progressive massive fibrosis appears as T2- dark (compared to 
skeletal muscle) 
Caplan's syndrome   
 Is the combination of rheumatoid arthritis with pneumoconiosis related to coal dust.  
 There is a rapid development of basal peripheral nodules, which can progress to severe 
pulmonary fibrosis. 
 
 718

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 114 - 
Other occupational risks and cancer 
 Exposure to isocyanates  most likely associated with squamous-cell carcinoma of 
the bronchus. 
 Aromatic amines are associated with bladder carcinoma,  
 exposure to vinyl chloride is associated with angiosarcoma of the liver.

hard metal lung disease (Cobalt exposure) 
 Persons working in the hard metal industry  are prone to develop a condition called 
hard metal lung disease. 
 A worker in the hard metal industry, comes with progressive dyspnea. Chest X-ray 
shows diffuse interstitial fibrosis bilaterally. what is the typical cellular component 
found in a bronchoalveolar lavage (BAL) of this patient?  
 Giant cells

Giant cells 
 Pathological findings in lung biopsy include bronchiolitis and bizarre 
multinucleated giant cells in the alveoli. The pathological diagnosis is giant cell 
interstitial pneumonia (GIP).  
Churg-Strauss syndrome 
 Churg-Strauss syndrome is an ANCA associated small-medium vessel vasculitis. 
 also known as Eosinophilic granulomatosis with polyangiitis 
 
Features  
 asthma 
 paranasal sinusitis 
 mononeuritis multiplex

 mononeuritis multiplex 
 blood eosinophilia (e.g. > 10%) 
 Serum IgE is very commonly elevated and correlates with disease severity. 
 pANCA positive in 60% 
 Commonly associated with antimyeloperoxidase antibodies.  
 Non-fixed pulmonary infiltrates visible on chest radiographs  
 Rarely, it can cause ischaemic optic neuropathy, which presents with visual loss.  
 
Leukotriene receptor antagonists may precipitate the disease 
 
Diagnosis

Diagnosis 
 It is diagnosed clinically , although a biopsy should be sought for pathological 
confirmation. 
 Skin biopsy  reveals small-vessel arteriopathy with granuloma  formation and is the 
diagnostic investigation of choice. 
 Blood vessels with extravascular eosinophils  on biopsy. 
 719

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 115 - 
 Treatment : 
 High-dose methylprednisolone, with or without cyclophosphamide is the treatment of 
choice 
 Without treatment, the 5-year survival rate for Churg-Strauss syndrome is around 25%; 
with appropriate therapy this rises to over 60%. 

Primary ciliary dyskinesia (PCD)  
 autosomal recessive disorder  
 deficiency of dynein  arms of cilia causing slow and poorly co-ordinated ciliary beating 
throughout the body. 
 characterised by abnormal ciliary motion and impaired mucociliary clearance.  
 incidence  1:15 000 in the Caucasian population 
 Features 
  Recurrent or persistent respiratory infections (which may lead to bronchiectasis) ,  
 sinusitis,  
 otitis media,  
 male infertility.

 male infertility.  
 ↑ risk of ectopic pregnancy due to defective movement of the cilia in the fallopian 
tube 
 In 50% of the patients, PCD is associated with situs inversus ( Kartagener's 
syndrome).  
 Differential diagnoses  
 cystic fibrosis  
 The diagnosis of CF is based on typical pulmonary and/or gastrointestinal 
tract manifestations and positive results on sweat test (pilocarpine 
iontophoresis).

iontophoresis).  
 A negative sweat test is sufficient evidence to exclude CF as a diagnostic 
possibility. 
Diagnosis 
 Nasal nitric oxide (NNO) levels,  
 the most sensitive and specific screening test for PCD 
 Sensitivity of 97% and specificity of 90% for PCD. 
 A low NNO (<100 parts per billion) should be followed up with confirmatory 
testing ( nasal or bronchial brush biopsy for ciliary examination) because other 
conditions such as cystic fibrosis may present with low NNO.

 A high NNO virtually excludes PCD 
 Ciliary function tests:  
 This would confirm a diagnosis of primary ciliary dyskinesia.  
 Ciliary function is commonly tested by the use of saccharin.  
 Saccharin is placed 1cm behind the inferior turbinate and the test is positive if the 
patient does not taste sweetness within 20min.  
 This is because if cilia work normally they will sweep the sweet saccharin 
inwards, allowing the patient to taste it.  720

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 116 - 
  light microscopy of biopsies for ciliary beat pattern and frequency  
 electron microscopic examination of dynein arms. 
 Genetic test is difficult due to multiple phenotypes  
Kartagener's syndrome 
 PCD + situs inversus  Kartagener's syndrome

PCD + situs inversus  Kartagener's syndrome 
 most frequently occurs in examinations due to its association with dextrocardia (e.g. 
'quiet heart sounds', 'small volume complexes in lateral leads') 
 autosomal recessive mutation. 
 dynein  arm defect results in immotile cilia  
 dynein  is a protein found in Cilia and flagella of microtubule  
Features 
 Kartagener syndrome: triad 
of  
1. situs inversus,  
2. chronic sinusitis, and  
3. bronchiectasis.

3. bronchiectasis. 
 
 Dextrocardia or complete situs inversus 
 Situs inversus occurs in about half of people with Kartagener syndrome 
 bronchiectasis 
 recurrent sinusitis 
 male infertility and female subfertility (secondary to diminished sperm motility and 
defective ciliary action in the fallopian tubes) 
 Deafness 
 Hydrocephalus. 
 
 H/O recurrent chest infections , situs inversus, and  sperm sample shows nonmotile

spermatozoa. The cause of this condition is most likely a mutation in the genes for 
which protein?   Dynein  
 
Lung cancer 
 Smoking 
 increases risk of lung ca by a factor of 10  
 Smoking and asbestos are synergistic , i.e. a smoker with asbestos exposure 
has a 10 X 5 = 50 times increased risk  
 Whilst many chemicals have been implicated in the development of lung cancer

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 117 - 
  Up to 15% of lung cancers in patients who do not smoke are thought to be 
caused by passive smoking  
 
 Other factors:  (coal dust is not a risk factor)  
 asbestos - increases risk of lung ca by a factor of 5 
 Isocyanates  are a recognised risk factor for the development of non-small-
cell lung cancer.

cell lung cancer. 
 Exposure to isocyanate fumes occurs in chemical workers, particularly 
those who work in the rubber industry,  
 most likely to be associated with squamous-cell carcinoma  of the 
bronchus. 
 arsenic 
 radon 
 nickel 
 chromate 
 aromatic hydrocarbon 
 cryptogenic fibrosing alveolitis 
 TTF-1 (thyroid transcription factor 1) is a protein which regulates the transcription 
of genes specific for the thyroid and lung.

of genes specific for the thyroid and lung.  
 Lung adenocarcinomas and small cell carcinomas are usually TTF- 1 
positive.  
 Factors that are NOT related 
 coal dust  
Lung cancer: types 
 The most common type of lung cancer  
 In the UK  squamous cell cancer  
 in the USA  Adenocarcinoma  
 squamous: c. 35% 
 adenocarcinoma: c. 30% 
 small (oat) cell: c. 15% 
 large cell: c. 10% 
 other c. 5% 
Other tumours

Other tumours 
 alveolar cell carcinoma:  
 not related to smoking,  
 ++ sputum ( production of large amounts of sputum ( bronchorrhoea ).  
 account for up to 1% of all bronchial carcinomas. 
 alveoli are often filled with mucin. 
 bronchial adenoma: mostly carcinoid 
 
 722

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 118 - 
  
What is the most common malignant tumour found in the lung? 
 Metastatic carcinoma  
 Solitary metastasis represents some 10% of round lesions in general, but 
some 70% of round lesions in patients with a known malignancy.  
 Colorectal cancer  is the most common tumour of origin .

 Lymphangitis carcinomatosa  is most commonly due to breast and 
primary lung tumours (usually adenocarcinomas).  
 Patients can be asymptomatic when the disease is first suspected 
on the basis of an X-ray showing diffusely increased interstitial 
markings accompanied by Kerley B lines, hilar lymphadenopathy or 
pleural effusion. 
Lung cancer: non-small cell 
 There are three main subtypes of non-small cell lung cancer:

1. Squamous cell cancer: 
2. Adenocarcinoma: 
3. Large cell lung carcinoma: 
Squamous cell cancer  
 Typically central (Squamous = Sentral ) 
 associated with: 
 parathyroid hormone- related protein (PTHrP) secretion ĺ hypercalcaemia  
 strongly associated with finger clubbing  
 hypertrophic pulmonary osteoarthropathy ( HPOA ) 
 The presence of clubbing and tender wrists without synovitis makes 
pulmonary osteoarthropathy the most likely diagnosis.

 It is usually associated with underlying carcinoma of the lung.  
 associated with bronchogenic carcinoma in 90% of cases .  
 The most sensitive diagnostic investigation is isotope bone scan :  
 increase in the uptake in long bones, around periarticular surfaces, 
and also mandible and scapulae. 
 Regression of the pain has been reported with successful resection 
of the tumour and after vagotomy . 
 Hyperthyroidism due to ectopic TSH 
 Cavitate (In 10% of cases)

 Cavitate (In 10% of cases) 
 Most squamous-cell carcinomas present as obstructive lesions, which can manifest as 
 Life threatening haemoptysis  is a medical emergency that requires prompt action.  
 Pulmonary angiography  will identify the blood supply to the tumour and 
embolisation of this vessel(s)  will immediately stem the bleeding. 
 Histology will show clusters of lightly stained cells, often associated with groups of

partially keratinized , acidophilic cell clusters. 
 Pleomorphic cells in cluster with keratin  pearls and intercellular bridges 
 723

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 119 - 
 Adenocarcinoma 
 
 most common type of lung cancer in non-smokers, although the majority of patients who 
develop lung adenocarcinoma are smokers 
 Typically located on the lung periphery  Normal bronchoscopy.  
 May associate with Gynaecomastia.

 May associate with Gynaecomastia. 
 PET/CT scan offers the best imaging modality to determine  LN involvement in bronchial 
adenocarcinoma 
 Histology will show: 
  malignant cells more often arranged in small clusters with an  obvious lumen 
and duct-like structures.  
 Mucin-containing tumor cells with glandular differentiation 
 
Bronchioloalveolar cell carcinoma  
 It is an adenocarcinoma. 
 accounts for around 5% of all primary lung carcinomas. 
 1% of all bronchial carcinomas.

 1% of all bronchial carcinomas.  
 Its name arises from its pattern of growth along the alveolar walls without actually 
destroying them. 
 The classic massive clear frothy sputum (bronchorrhoea) can be up to one litr e a 
day.  
 Other symptoms are dyspnoea, weight loss and chest pain. 
 Almost a half of patients are diagnosed on routine CXR, usually demonstrating a 
peripheral lesi on. 
 The tumour spreads using the alveolar walls as a frame and the alveoli are often filled

with mucin. 
 In those whose tumour is not resectable, prognosis is poor. 
 
Management of non-small cell lung cancer 
 
Surgery  
 only 20% suitable for surgery 
 Stage I (cT1N0 and cT2N0) and stage II (cT1N1, cT2N1 and cT3N0) tumours 
should be considered operable.   
  Stage IIIA (cT3N1 and cT1-3N2) tumours have a low chance of being cured by 
surgery alone, but it can be used in combination with chemotherapy .  
 Stage IIIB and IV tumours considered inoperable.  
724

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 120 - 
  mediastinoscopy performed prior to surgery as CT does not always show mediastinal 
lymph node involvement 
 The functional criteria for pneumonectomy are:  
 Forced expiratory volume in 1 second (FEV-1) of >1.5 litres 
 FEV-1 > 50% of the observed forced vital capacity,  and

 Normal partial pressure of arterial CO2 (Paco2) with the patient at rest 
 Prognosis after surgery is about 50-67% at 5 years with stage 1disease  
Absolute contraindications for surgery include:  
 Patient refusal 
 FEV1 < 1.5 litres  is considered a general cut-off point  
 If the tumour necessitates a pneumonectomy, the post-bronchodilator FEV 
should be more than 2 litres.  
 Reduction  in the gas transfer  test of more than 50%  is a contraindication to surgery. 
 Metastases.

 Metastases. 
 stage IIIb or IV (i.e. metastases present) 
 tumour near hilum 
 vocal cord paralysis (implies extracapsular spread to mediastinal L.N) 
 SVC obstruction 
 malignant pleural effusion (not just 'pleural effusion' (which may be 
reactive)) 
 Most pleural effusions associated with lung carcinoma are due to the 
tumour (and results in classification as a T4 tumour).  
 Spread to involve the C8, T1 and T2 nerve roots  occurs by rib erosion by

tumour to involve the lower roots of the brachial plexus and is known as 
a Pancoast tumour . 
 This causes severe pain in the shoulder and down the inner aspect of the 
arm on the affected side and is a contraindication to surgery. 
Relative contraindications include: 
 Cell type: small cell carcinoma are usually inoperable 
 Poor respiratory reserve - FEV1 > 1.2l is necessary for lobectomy, and > 1.8l for 
pneumonectomy 
 Raised PaCO2 is a contraindication for surgery

 Raised PaCO2 is a contraindication for surgery 
 Other disease - especially myocardial 
 surgery should be delayed until 6 weeks following myocardial infarct if possible. 
 Mediastinal involvement 
 Age - in patients over 70, surgery is usually inadvisable because the benefits are 
outweighed by operative morbidity and mortality. 
 Age over 80 alone is not a contraindication to lobectomy or wedge resection for 
stage I disease, but may be a contraindication to pneumonectomy.

Radiotherapy  Curative or palliative  
 Radical radiotherapy is indicated for patients with stage I, II or III NSCLC who have 
good performance status (WHO 0, 1)  
 Sequential chemo-radiotherapy should be offered to patients with stage III NSCLC 
who are not suitable for surgery but are eligible for radical radiotherapy . 
 Chemotherapy and radical radiotherapy is the first choice treatment in eligible 
patients with stage IIIa non-small cell lung cancer (NSCLC).  725

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 121 - 
  
Radical radiotherapy  
 Definition =>That is, radiotherapy with intention to cure using doses of at least 60 Gy. 
 Indication =>Patients with potentially operable tumours that are either too unfit for 
surgery or refuse surgery may be suitable for radical radiotherapy,

 Benefit => using continuous hyperfractionated accelerated radiotherapy (CHART) can 
improve two year survival significantly from 20% to 29% compared with conventional 
radiotherapy. 
 Contraindications =>  
 tumours larger than 4 cm  
 and poor pulmonary function (generally taken as FEV1 less than 50% predicted). 
 Malignant pleural effusion 
Chemotherapy  poor response  
 
Prognosis 
Overall lung cancer survival is less than 15% at five years

___________________________________________________________________
Performance status   
 Assessing a patient's performance status is important when evaluating the most 
appropriate treatment options.  
 It is commonly used by cancer MDTs, but has a role in assessing patients with chronic 
illnesses including COPD. 
WHO (Zubrod) Scale Description 
0 Asymptomatic 
1 Symptomatic but ambulatory (can carry out light work) 
2 In bed less than 50% of the day. Unable to work but can live at

home with some assistance 
3 In bed more than 50% of the day (unable to care for self) 
4 Bedridden 
As taken from NICE guidance on Lung cancer (CG121).  
Staging lung carcinoma  
 It is important to remember the criteria for staging carcinoma of the lung. TNM staging 
takes into account; 
 The size and position of the tumour (T) 
 Whether the cancer cells have spread into the lymph nodes (N) 726

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 122 - 
  Whether the tumour has spread anywhere else in the body - secondary cancer or 
metastases (M) 
 Computed tomographic (CT) scanning is recommended as a staging procedure . Where 
available, PET scanning may be superior, but there are a limited number of scanners in 
the UK.

the UK. 
 CT can be performed with or without contrast enhancement, but Contrast enhancement 
makes it easier for inexperienced observers to interpret the CT. 
 Overall, preoperative CT staging has been shown to overstage or understage when 
compared with operative findings in 40% of patients. So biopsy is also needed. 
 
Chest computed tomography is the best method for staging squamous-cell carcinoma 
of the lung.  
 
SEVENTH EDITION OF THE TNM  SYSTEM

SEVENTH EDITION OF THE TNM  SYSTEM    
The International Association for the Study of Lung Cancer (IASLC) developed a   SEVENTH 
EDITION OF THE TNM SYSTEM  in 2010 replaced earlier editions: as fellow  
Primary tumor  — (T)  
 T0 – No evidence of primary tumor. 
 Tis – Carcinoma in situ. 
 T1 – Tumor that is ≤ 3 cm  
 T1a: Tumor is ≤2 cm  
 T1b: Tumor is >2 cm, but ≤3 cm  
 T2 – Tumor that is >3 cm but ≤7 cm   
 T2a: Tumor is >3 cm, but ≤5 cm  
 T2b: Tumor is >5 cm, but ≤7 cm

 T2b: Tumor is >5 cm, but ≤7 cm  
 T3 – Tumor that is  >7 cm ; invades the chest wall (including superior sulcus tumors), 
diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium 
 T4 – Tumor of any size that invades the mediastinum, heart, great vessels, trachea, 
recurrent laryngeal nerve, esophagus, vertebral body, or carina; or separate tumor 
nodule(s) located in a different lobe of the ipsilateral lung. 
Regional lymph nodes  — (N)

Regional lymph nodes  — (N) 
 N0 – No regional lymph node involvement. 
 N1 – Involvement of ipsilateral intrapulmonary, peribronchial, or hilar lymph 
nodes.  
 N2 – Involvement of ipsilateral mediastinal or subcarinal lymph nodes. 
 N3 – Involvement of contralateral mediastinal or hilar lymph nodes.  
Metastasis  — (M) 
 M0 – No distant metastasis  
 M1a – Malignant pleural effusion, pericardial effusion, pleural nodules, or metastatic 
nodules in the contralateral lung

nodules in the contralateral lung 
 M1b – Distant (extra-thoracic) metastasis 
 Carcinoid lung cancer: 
 The vast majority of bronchial adenomas are carcinoid tumours, arising from the amine 
precursor uptake and decarboxylation (APUD) system, like small cell tumours.  727

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 123 - 
  The term bronchial adenoma is being phased out.  
 
Carcinoid tumour as general (see gastroenterology section) 
 neuroendocrine tumours of predominantly enterochromaffin cell origin.  
 can occur in the small intestine, bronchi, rectum appendix or stomach.

 in the lung are most often located in the main bronchi, and occur most frequency in the 
right middle lobe.  
 
Carcinoid lung  
Overview  
 Carcinoid tumours (so called argentafinomas as they take up silver) are neuroendocrine 
cells 
 originate from Kulchitsky (K) cells in the lung   
 slow growing 
 smoking is NOT  a risk factor 
Incidence: Lung carcinoid accounts  
  1% of lung tumours  
  10% of carcinoid tumours.  
 typical age = 40-50 years

 typical age = 40-50 years 
 The incidence is equal between men and women. 
Feature 
Recurrent haemoptysis with segmental collapse on x-ray is a typical presentation  of 
bronchial carcinoid. 
 
 Often asymptomatic  
 long history of cough,  
 Recurrent haemoptysis 
 Recurrent infections  
 carcinoid tumours  (80-90%) develops in a bronchus  bronchial obstruction 
 lower respiratory tract infection. 
 Carcinoid syndrome (rare)

 Carcinoid syndrome (rare)  
 Associated conditions with carcinoid tumour in the lung  
 carcinoid syndrome ( rare) 
 depends on associated  liver metastases 
 occurs in less than 10% of patients with carcinoid tumours, but occurs 
most commonly in GIT tumours.  
 can secrete a number of vasoactive compounds (including serotonin and 
bradykinin), which result in: 
 bronchospasm 
 diarrhoea,  
 skin flushing and  
 right-sided valvular heart lesions.

 right-sided valvular heart lesions.  
 ACTH secretion and subsequent Cushing's syndrome. 
 ectopic growth hormone-releasing hormone [GHRH] and subsequent acromegaly 728

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 124 - 
  multiple endocrine neoplasia (MEN) type 1 where pancreatic neuroendocrine 
tumours predominate. 
 
The 'cherry-red' lesion is a typical finding of lung 
carcinoid. 
 CXR  
 often centrally  located and not seen on CXR.   
 Usually occur in the major bronchi, 85% can be seen bronchoscopically.

 most often located in the main bronchi, and occur most frequency in the right 
middle lobe.  
 A carcinoid tumour in the left lower lobe bronchus could cause distal collapse of 
the left lower lobe.  
 Bronchoscopy:  
 identifies up to 80% of carcinoid tumours in the main bronchi .  
 seen as a highly vascular 'cherry-like' tumour  ('cherry red ball' ) 
  Biopsy is usually followed with brisk bleeding and should be done via rigid 
bronchoscopy .

bronchoscopy . 
 The histological picture of granular eosinophilic staining of the cytoplasm , is 
highly suggestive of a carcinoid tumour. 
 Histologically, these tumors consist of compact nests of epithelial cells 
surrounded by neat, delicate connective tissue capsules.  
 histology might not be necessary prior to surgery if the clinical picture is 
typical . 
 Plasma chromograffin A  is an effective screening test  for carcinoid as it is very 
sensitive , but it is not specific.

sensitive , but it is not specific. 
  24 hour urinary excretion of 5-hydroxyindoleacetic acid  is more specific  for the 
diagnosis , but false positives and negatives are present. 
 Scintigraphic imaging with labelled somatostatin increases the ability to diagnose a 
carcinoid tumour, but biopsy is required to confirm. 
 
 surgical resection 
 A person with an isolated pulmonary carcinoid should be referred for 
tumour resection,

tumour resection, 
typical . 
Prognosis 
 if no metastases then 90% survival at 5 years 
 
 729

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 125 - 
  
Small cell lung cancer 
The presence of hyponatraemia strongly points towards a diagnosis of small cell lung 
cancer. 
 Also known as "oat-cell carcinoma" 
 usually central 
 arise from APUD* cells 
 *an acronym for  
 Amine - high amine content

 Amine - high amine content 
 Precursor Uptake - high uptake of amine precursors 
 Decarboxylase - high content of the enzyme decarboxylase 
 Most aggressive cancer which typically presents with a short history and 80 –90% will 
have metastases at the time of presentation. 
 Features  
 ectopic ADH ĺ hyponatraemia  (SIADH) 
  SIADH occurs in 5 –10% of cases. 
 ectopic ACTH ĺ Cushing's syndrome

 ectopic ACTH ĺ Cushing's syndrome  
 Due to the short natural history of this type of cancer, Cushing syndrome in small-
cell carcinoma does not manifest classically  by buffalo hump, striae or central 
obesity.  
 Its presence is suspected by arterial hypertension, hyperglycaemia, 
hypokalaemia, alkalosis and muscle weakness.  
 ACTH secretion can cause bilateral adrenal hyperplasia,  
 the high levels of cortisol can lead to hypokalaemic alkalosis

 in case of chronic heavy smoker with chest infection + hyperglycaemia + Ļ K + Ĺ 
HCO3 ? 
 Suspect SCLC with ectopic ACTH secretion.  
 But if with ĻNa and ĹK  think of Adrenal metastasis  MRI adrenals 
 Lambert-Eaton syndrome: antibodies to voltage gated calcium channels causing 
myasthenic like syndrome 
 Neuron-specific enolase (NSE)  is a tumor marker indicative of small cell carcinoma  
 associated with L-myc amplification.

 associated with L-myc amplification.  
 Histologically, Small cell carcinoma has clusters of small, basophilic cells  and 
surrounding areas of tissue necrosis. 
 
H/O Rapid progression (cough, lung mass and weight loss within 2 months)  + 
paraneoplastic peripheral neuropathy. What is the most likely diagnosis ?  
 small-cell carcinoma.  
 Squamous cell carcinoma and adenocarcinoma are usually very slow 
growing. 
 
 730

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 126 - 
 Stage Treatment 
Early stage (T1-2a,N0,M0) Surgery 
Early stage (T1-2a,N0,M0)-
Limited disease (T1-4,N0-3,M0) 4-6 cycles cisplatin  based chemotherapy, carboplatin if poor 
renal function/poor performance status +/- radiotherapy 
Extensive disease (T1-4, N0-3, 
M1a/b) 6 cycles platinum based combination chemotherapy + thoracic

radiotherapy if good response 
 
 Surgery   
 patients with very early stage disease (T1-2a, N0, M0) are now considered for 
surgery.  
 usually metastatic disease by time of diagnosis . Surgery is therefore not 
recommended as first-line treatment in the UK.  
 Chemotherapy and radiotherapy   
 most patients with limited disease receive a combination of chemotherapy and 
radiotherapy.  they are  very sensitive to combination chemo-radiation . It is t he 
standard treatment in the UK.

standard treatment in the UK.  
 Because of the frequent presence of occult metastatic disease , chemotherapy is 
the cornerstone of treatment for patients with limited-stage small cell lung 
cancer .  
 Cytotoxic chemotherapy with a platinum-based regimen  would be the 
treatment of choice. 
 The chemotherapy should be initiated immediately , whilst the radiotherapy 
is being planned , 
 radiotherapy should be started during either the first or second cycle of 
chemotherapy.

chemotherapy.  
 Current programmes yield overall objective response rates of 65% to 90% and 
complete response rates of 45% to 75%.  
 Patients who are not fit enough for concurrent chemoradiotherapy should be 
offered sequential chemo-radiation: 4 to 6 cycles of platinum-etoposide 
chemotherapy with consolidative radiotherapy for those who respond to 
chemotherapy. 
 patients with more extensive disease are offered palliative chemotherapy 
Prognosis

Prognosis  
 very poor and survival beyond two 2 years is exceptional 
 median survival is 6 –12 months. 
 Adverse prognostic factors in small cell lung cancer :  
 Serum Na < 132 mmol/l  
 Weight loss > 10%  
 WHO performance status > 2  
 Alkaline phosphatase > 1.5 times upper limit of normal  
 LDH > 1.5 times upper limit of normal  731

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 127 - 
  Extensive disease (occurring outside one hemi-thorax and ipsilateral 
supraclavicular fossa nodes). 
Bronchial Carcinoma  
 20-30% of cases with bronchial carcinoma are of small (oat) cell type from endocrine K- 
cells (Kulchitsky) cells.

cells (Kulchitsky) cells.  
 Primary bronchial cancer  the tumour edge may have a fluffy or spiked 
appearance . 
 Paraneoplastic manifestations:  
  SIADH (5 - 10%)  
 ACTH (5 %)  
 ANP 
 The most appropriate tool to confirm the diagnosis of bronchial carcinoma is  
Bronchoscopy ± Trans bronchial biopsy (NOT CT-guided FNA biopsy). 
 CT-guided FNA would be useful; however, there is a high risk of pneumothorax  
in patients with FEV1 < 1.

in patients with FEV1 < 1. 
Superior vena cava obstruction (SVCO) 
 (SVCO) an oncological emergency caused by compression of the SVC.  
 most commonly associated with lung cancer. 
 Up to 4% of patients with lung cancer will develop SVCO at some point during their 
disease.  
 SVCO is much more likely to be associated with right sided lung lesion  4 times 
than with left sided lesions 
Features  
 dyspnoea is the most common symptom

Features  
 dyspnoea is the most common symptom 
 swelling of the face, neck and arms - conjunctival and periorbital oedema may be seen 
 headache 
 pulseless jugular venous distension 
 may be associated with voice hoarseness  
 CXR is abnormal in around 85% of cases, mediastinal widening is common.  
Causes 
 the most common cause   Non-small cell lung cancer 
 common malignancies: small cell lung cancer, lymphoma

 other malignancies: metastatic seminoma, Kaposi's sarcoma, breast cancer 
 aortic aneurysm 
 mediastinal fibrosis 
 Mediastinal  goitre 
 SVC thrombosis 
 
 732

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 128 - 
  
Below are the rates of SVC obstruction with different malignancies (UpToDate,2016)  
Malignancy Percent 
Non-small cell lung cancer 50% 
Small cell lung cancer 25% 
Non-Hodgkin lymphoma 10% 
Other malignancies 15% 
 
Association: 
 Recurrent laryngeal nerve palsy (voice hoarseness):  usually occurs with malignant

tumour but can occur with aneurysm of aortic arch.  
 Horner's syndrome due to involvement of sympathetic chain. 
 elevated non-pulsatile jugular venous pressure (JVP)  
 Compression of vital structures can result in stridor and dysphagia.  
 general: dexamethasone, balloon venoplasty, stenting 
 Corticosteroids are most useful where the cause of compression is an underlying 
haematological malignancy . 
 SVCO: immediate management  Dexamethasone IV + LMWH. 
 Stenting

 Stenting   
 In 2004 NICE recommended considering stenting in the majority of cases 
of SVCO. This is a minimally invasive procedure which relieves 
symptoms quicker than chemotherapy or radiotherapy.   
 Stenting is better than radiotherapy in terms of relief of symptoms.  
 Radiotherapy  
 may be an option  later . If radiotherapy is used initially then stenting 
becomes significantly more difficult due to local fibrosis.

 Mediastinal radiotherapy leads to symptomatic relief in 80% of patients, 
 
 small cell: chemotherapy + radiotherapy 
 Chemotherapy may be a first-line option in cases of histologically proven small-
cell cancer. 
 non-small cell: radiotherapy 
Prognosis:   
 Median survival of lung cancer presenting with SVCO, even with treatment is five 
months.  
 Lymphoma has a better prognosis and will require specific chemotherapy ± 
radiotherapy.  
 
 733

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 129 - 
  
Lung cancer: paraneoplastic features   
Paraneoplastic features of lung cancer   
 Squamous cell: PTHrp, TSH, Clubbing, HPOA   
 Adenocarcinoma: Gynaecomastia  
 Small cell: ADH, ACTH, Lambert-Eaton syndrome  
 Bronchial carcinoma: SIADH, ACTH, ANP

 Bronchial carcinoma: SIADH, ACTH, ANP  
 
 Paraneoplastic syndromes are a result of antibody generation from or against malignant 
cells attacking normal tissue.  
 Both non-small cell and small cell lung cancers are associated with Paraneoplastic 
syndromes, although they are more common with the small cell due to its 
neuroendocrine cell origin.  
 
Squamous cell 
 Parathyroid hormone-related protein (PTH-rp)  secretion causing hypercalcaemia 
 occurs in about 15%

 occurs in about 15%  
 best treated with intravenous fluids and bisphosphonates  
 clubbing 
 hypertrophic pulmonary osteoarthropathy (HPOA)  
 (HPOA) is a proliferative peri-ostisis typically involves the long bones.  
 It is often painful. 
 hyperthyroidism due to ectopic TSH 
Adenocarcinoma 
 Gynaecomastia 
 Bronchial carcinoma can presents with ataxia and bilateral Gynaecomastia  
. 
 It can be painful and may be associated with testicular atrophy.

 Ataxia  can occur as a result of a paraneoplastic cerebellar degeneration associated 
with the malignancy.  
 
Small cell 
 ADH 
 Symptomatic hyponatraemia due to SIADH is treated with demeclocycline which 
induces nephrogenic diabetes insipidus leading to excretion of excess water. 
 ACTH  
 not typical, hypertension, hyperglycaemia, hypokalaemia, alkalosis and muscle 
weakness are more common than buffalo hump etc.

weakness are more common than buffalo hump etc. 
  May manifest by Cushingoid facies and hyperpigmentation of the skin  
 Lambert-Eaton syndrome 
 70% occur in small cell carcinoma  
  
 is a pre-synaptic disorder of auto-antibody IgG directed against the pre-synaptic 
voltage gated calcium channel (VGCC) leading to impaired acetylcholine release.  734

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 130 - 
  characterised by:  
 Proximal muscle weakness (the cranial nerves and respiratory muscles are 
usually spared) 
 Depressed or absent tendon reflexes and 
 Autonomic features (for example, dry mouth, impotence, etc). 
 Weakness and fatiguability can be improved with guanidine hydrochloride

 Unlike myasthenia gravis exercise is associated with increasing muscle strength 
and there is a negative response to Tensilon.  
 Electromyography is useful in confirming the diagnosis where repeated nerve 
stimulations cause a progressive increase in the size of the muscle action 
potential. 
 Cerebellar ataxia :  
 Paraneoplastic syndromes are a result of antibody generation from or against 
malignant cells attacking normal tissue.

malignant cells attacking normal tissue. 
 Examples include antineuronal antibodies (anti-Hu, anti-Yo, anti-Ri ) directed 
against the Purkinje cells of the cerebellum leading to the cerebellar syndrome 
(truncal ataxia ).  
 To diagnose this  Anti-Purkinje cell antibody levels. 
Lung cancer: referral  
Consider immediate referral for patients with:

Consider immediate referral for patients with:  
 signs of superior vena caval obstruction (swelling of the face/neck with fixed elevation of 
jugular venous pressure) 
 stridor 
Refer urgently (for an appointment within 2 weeks)   patients with: 
 persistent haemoptysis (in smokers or ex-smokers aged 40 years and older) 
 a chest X-ray suggestive of lung cancer (including pleural effusion and slowly resolving 
consolidation)

consolidation) 
 a normal chest X-ray where there is a high suspicion of lung cancer 
 a history of asbestos exposure and recent onset of chest pain, shortness of breath or 
unexplained systemic symptoms where a chest x-ray indicates pleural effusion, pleural 
mass or any suspicious lung pathology 
Refer urgently for chest x-ray for patients with  any of the following: 
 haemoptysis 
 unexplained or persistent (longer than 3 weeks): chest and/or shoulder pain, dyspnoea,

weight loss, chest signs, hoarseness, finger clubbing, cervical or supraclavicular 
lymphadenopathy, cough, features suggestive of metastasis from a lung cancer (for 
example, secondaries in the brain, bone, liver, skin) 
 underlying chronic respiratory problems with unexplained changes in existing symptoms 
 Under NICE guidelines a hoarse voice for three weeks or more is an indication for 
investigation to exclude malignancy.   
 735

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 131 - 
  
Lung cancer: stepwise investigations 
1. x-ray  :NICE guidelines recommend urgent chest radiograph in patients with 
haemoptysis or unexplained, persistent (>3 weeks) cough, chest or shoulder pain, 
dyspnoea, weight loss, chest signs, hoarseness, finger clubbing, cervical or

supraclavicular lymphadenopathy. If this suggests lung carcinoma, patients should be 
referred urgently to the lung cancer multidisciplinary team (MDT). 
2. CT: Patients should then be offered a contrast-enhanced CT chest (including the 
liver and adrenals). before bronchoscopy or any other biopsy procedure.  
3. Biopsy: If the CT demonstrates a peripheral lung lesion, CT or ultrasound-guided 
transthoracic needle biopsy should be offered.

transthoracic needle biopsy should be offered. 
  Endobronchial ultrasound guided biopsy is recommended for paratracheal and 
peri-bronchial intra-parenchymal lung lesions. 
 Enlarged mediastinal lymph nodes (>10 mm maximum short axis on CT) or other 
lesions should be biopsied in preference to the primary lesion if determination of 
stage affects treatment. 
4. Sputum cytology  is rarely indicated and should be reserved for the investigation of

patients who have centrally placed masses and are unable to tolerate, or unwilling to 
undergo, bronchoscopy or other invasive tests. 
 
Radiographical features of pulmonary tumours 
 No initial examination is complete without a lateral film . 
 normal X-ray of the chest does not exclude bronchial carcinoma  as patients 
presenting with haemoptysis and a normal chest X-ray are sometimes found to have a 
central tumour on bronchoscopy.

central tumour on bronchoscopy. 
 The common appearance  of a tumour arising from the main central airways (70% of all 
cases) is enlargement of one or other hilum .  
 Consolidation and collapse distal to the tumour might have occurred. 
 Collapse of the left lower lobe is often hard to identify, as is a tumour situated behind 
the heart. 
 Apically located masses or superior sulcus tumours (Pancoast tumours) can be

misdiagnosed as pleural caps, and patients often have a long history of pain in the 
distribution of the brachial nerve roots.  
 Loss of the head of the first, second or third rib is not unusual. 
 The mediastinum might be widened by enlarged nodes. 
 Involvement of the phrenic nerve can lead to paralysis and elevation of the 
hemidiaphragm, which then moves paradoxically on sniffing. 
 Spread of tumour from mediastinal nodes peripherally along the lymphatics gives the

characteristic appearance of lymphangitis carcinomatosa - bilateral hilar enlargement 
with streaky shadows fanning out into the lung fields on either side. 
  Pleural effusion: either by Tumour spread to the pleura or secondary to infection 
beyond obstruction caused by a central tumour. 736

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 132 - 
  Rarely, localised obstructive emphysema is observed. 
 
PET in lung cancer assessment 
 Positron-emission tomography (PET) would determine whether there are distant 
metastases and is performed after the CT. 
 Routine imaging to screen for distant metastases is not required for every case of

suspected NSCLC. Imaging for metastatic disease should be symptom-focused or CT-
directed 
 For example in a patient with operable non-small-cell lung cancer, if CT has shown 
enlarged mediastinal nodes , he needs further assessment of his mediastinal nodes 
prior to surgery, because CT is not particularly good for assessing whether enlarged 
nodes are inflammatory or malignant.  and this can be done with mediastinoscopy or a 
positron-emission tomography (PET) scan.

positron-emission tomography (PET) scan. 
 What is the usual tracer used for PET imaging in lung cancer? 
 Fluorodeoxyglucose 
 In a PET scan radiolabeled glucose is injected peripherally and is taken up by 
metabolically active tissues, such as the brain and any cancer. It would show 
metastases from the primary cancer. 
Radiological signs: 
 
 An endobronchial lesion commonly leads to partial or complete  atelectasis  and this is 
the commonest sign of bronchogenic carcinoma.

the commonest sign of bronchogenic carcinoma.  
 Bronchial stenosis and post-stenotic changes are commonly seen because most non-
small-cell carcinomas demonstrate intraluminal growth. Narrowing of the main bronchi 
or a complete cut-off can be identified on chest Xrays. 
 Complete endobronchial obstruction can sometimes produce distal mucoid impaction, 
which can be visible on plain chest X-rays as a tubular or branching opacity.

 The opacity can contain air bronchograms and air alveolograms. This presentation is 
often seen with adenocarcinoma and bronchoalveolar carcinoma. 
Mediastinal masses  
 anterior/superior  mediastinum may relate to the thymus, thyroid. 
 Inferior  or middle mediastinal masses relate to the aorta, lungs, hilar lymph nodes, 
oesophagus and heart. 
737

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 133 - 
  Posterior mediastinal masses may relate to the nerves and vertebrae. 
Lung metastases 
 Metastatic carcinoma is the most common malignant tumour found in the lu ng 
 Malignant metastases to the lung can present as a solitary enlarging nodule, as multiple 
nodules or with diffuse lymphatic involvement. 
 Solitary metastases

 Solitary metastases 
 represents some 10% of round lesions in general, but some 70% of round lesions 
in patients with a known malignancy.  
 Colorectal cancer is reported to be the commonest tumour of origin.  
 A diagnosis can usually be secured by percutaneous computed tomography- 
(CT-) guided biopsy. 
  Multiple metastases 
 Range in size and number, from cannon balls to miliary shadowing, and can be 
accompanied by hilar lymphadenopathy or pleural effusion.

 Breast, colon, renal and lung primaries are the commonest underlying tumours.  
 A diagnosis might be made on the basis of cytology or histology (from pleura, 
lung or  sputum) .  
 Solitary or multiple Kaposi's sarcoma : 
 Is a feature of AIDS, and can involve the bronchi and pleura as well as lung 
tissue. 
 Lymphangitis carcinomatosa:  
 Most commonly due to breast and primary lung tumours (usually 
adenocarcinomas).

adenocarcinomas).  
 Patients can be asymptomatic when the disease is first suspected on the basis of 
an X-ray showing diffusely increased interstitial markings accompanied by Kerley 
B lines, hilar lymphadenopathy or pleural effusion.  
 Although the diagnosis can be established by cytology from sputum or pleural 
fluid, it often requires a bronchoscopic or transbronchial lung biopsy.  
 Later, progressive and severe breathlessness with hypoxaemia often develops,

and patients require vigorous palliative relief with opiates and oxygen. 
 Bronchial metastases 
 Not visible on a plain chest X-ray - diagnosis requires bronchoscopy.  
 Present with haemoptysis, effectively controlled by radiotherapy. 
 Renal carcinoma and malignant melanoma are recorded cause 
Pancoast tumour  
 a neoplasm of the apex of the lung that typically invades the chest wall and brachial

plexus and is causing a Horner's syndrome (ptosis and constriction of the pupil). 
 compresses the sympathetic fibres (from T1 and T2) as they travel upwards to 
superior cervical ganglion and then to the dilator pupillae as  the long ciliary 
nerve . 
 The tumour causes pain in the C8 and T1 distribution  and Horner's syndrome . 
 pain in the shoulder and the medial surface of the arm.  
 Patients may initially present to rheumatologists or orthopaedic surgeons.

 It may cause small muscle wasting of the hands  and erosion of the first rib . 738

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 134 - 
   the investigation of choice  CT of chest 
 CT is essential to locate the tumour and the extent of rib, vertebral and muscle 
 Chest x-ray may be normal 
 Tumours are most commonly squamous cell and are usually inoperable on 
presentation. 
Lung fibrosis

Lung fibrosis  
Fibrosis predominately affecting the upper zones  
 coal worker's pneumoconiosis/progressive massive fibrosis 
 silicosis   (Silica is found in coal dust)  
 ankylosing spondylitis (rare) 
 histiocytosis: 
 (Pentalaminar X bodies (Birbeck granules) found on bronchoalveolar lavage 
(BAL) are diagnostic ) 
 Allergic bronchopulmonary aspergillosis and farmers lung  
 Radiation

 Radiation 
Fibrosis predominately affecting the lower zones  
 cryptogenic fibrosing alveolitis (the more common cause) 
 most connective tissue disorders (except ankylosing spondylitis) 
 drug-induced: amiodarone, bleomycin, methotrexate 
 asbestosis  
 
CT scan showing advanced pulmonary fibrosis including 'honeycombi ng' 
 
739

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 135 - 
  
___________________________________________________________________  
Idiopathic pulmonary fibrosis (IPF)   (previously termed cryptogenic fibrosing 
alveolitis)  
 
 progressive fibrosis of the interstitium of the lungs, when no underlying cause exists . 

 IPF is typically seen in patients aged 50-70 years  
 twice as common in men. 
 Transforming growth factor-beta  is a cytokine released from injured pneumocytes, 
inducing fibrosis  in patients with IPF. 
 
Features  
 progressive exertional dyspnoea : 
 bibasal  crackles on auscultation 
 dry cough 
 Clubbing occurs in two-thirds of cases.  
 Bilateral lower-zone  reticulonodular shadows are seen on chest X-ray.  
Diagnosis 
 spirometry:

Diagnosis 
 spirometry:  
 classically a restrictive picture (FEV1 normal/decreased, FVC decreased, 
FEV1/FVC increased) 
 impaired gas exchange: reduced transfer factor (TLCO) 
 imaging:  
 bilateral interstitial shadowing (typically small, irregular, peripheral opacities - 
'ground-glass' - later progressing to 'honeycombing') may be seen on a chest x-
ray but high-resolution CT scanning is the investigation of choice  and 
required to make a diagnosis of IPF.

required to make a diagnosis of IPF. 
 The first chest x-ray findings develops small, peripheral opacities in the 
lower zones  (The classic finding => reticular opacities predominantly in the 
bases) 
 The late chest x-ray findings develops  Honeycombing 
 ANA positive in 30%, rheumatoid factor positive in 10% but this does not necessarily 
mean that the fibrosis is secondary to a connective tissue disease. Titres are usually 
low.

low. 
 Arterial oxygen desaturation on exercise is an early feature and this is reflected in 
widening of the alveolar-arterial (a-a) gradient on exercise.  
 IPF lungs are stiff, ie poorly compliant, and therefore if compliance is low then  elastic 
recoil will be high as the two are inversely related. 
 pulmonary rehabilitation 
 pirfenidone  
 (anti-fibrotic agent) may be useful in selected patients .  740

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 136 - 
  Pirfenidone reduces risk of disease progression by 30 % and has been approved 
by NICE for use in mild-moderate disease (FVC 50-80 % predicted).  
 mechanism of action includes anti-fibrotic, anti-inflammatory and antioxidant 
effects.  
 many patients will require supplementary oxygen  and eventually a lung transplant

 Treatment of idiopathic pulmonary fibrosis with immunosuppression have been shown 
by meta-analysis to have no benefit.  
 N-acetyl cysteine, Nintedanib and Co-trimoxazole have all shown possible benefit in 
preliminary trials with further investigation on-going. 
 only 20% of patients may be steroid responsive ( 1 in 5  ) 
Prognosis 
 poor, average life expectancy is around 3-4 years  
 increased risk of developing lung cancer (by 7- to 14-fold).

Chest X-ray shows sub-pleural reticular opacities that increase from the apex to the 
bases of the lungs  
 
741

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 137 - 
  
   CT scan showing advanced pulmonary fibrosis including 'honeycombing' 
 
Idiopathic interstitial pneumonitis (IIP) 
IIP is further subdivided into: 
 Usual interstitial pneumonia and 
 Non-usual interstitial pneumonitis. 
Usual interstitial pneumonia  (UIP)

Usual interstitial pneumonia  (UIP) 
 ((previously known as idiopathic pulmonary fibrosis, or cryptogenic fibrosing  
alveolitis ) 
 causes 70% of IIP  
 typically found in an older population 
 characterised by a gradual onset with acute exacerbations. 
 It is worse in smokers. 
 Diagnosis : typical HRCT findings =>Reticular abnormalities, honeycombing and 
traction bronchiectasis.  
 Treatment : UIP have a poor response to steroids and immunosuppressants.

 Prognosis : the median survival is 2 - 3  years post-diagnosis. 
Non-usual interstitial pneumonitis  (non-UIP): 
 Contains :  
 Non-specific interstitial pneumonia (NSIP):  is the most common non-UIP 
 Cryptogenic organising pneumonia (COP) :is subacute and tends to cause 
patchy consolidation and/or nodules on CT scan. 
742

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 138 - 
   Desquamative interstitial pneumonia (DIP) ;is a form of severe RB-ILD. 
  Respiratory bronchiolitis - interstitial lung disease (RB-ILD 
 On CT there is typically ground glass appearance and there is better steroid 
responsiveness when compared to UIP, with an improved survival.

Respiratory manifestations of rheumatoid arthritis 
A variety of respiratory problems may be seen in patients with rheumatoid arthritis:  
 found in up to 60% of patients with rheumatoid arthritis, but chest X-ray changes 
are seen in only 5%.  
 Interstitial fibrosis - occurs in up to 20% of patients with rheumatoid arthritis  
 pulmonary nodules

 pulmonary nodules 
 bronchiolitis obliterans  (spirometry reveals an obstructive picture ) 
 complications of drug therapy e.g. methotrexate pneumonitis  (Acute interstitial 
pneumonitis is associated with methotrexate). 
 Methotrexate is a recognised cause of pulmonary fibrosis. However, it is 
sometimes used in the treatment of idiopathic pulmonary fibrosis as a steroid 
sparing agent.  
 Methotrexate-induced pneumonitis  usually occurs within 4 months of starting

the drug  a CT scan would show pulmonary infiltrates. 
 pleurisy 
 Caplan's syndrome - massive fibrotic nodules with occupational coal dust exposure 
 infection (possibly atypical) secondary to immunosuppression  
 Organising pneumonia: can occur in rheumatoid arthritis, with fever, dyspnoea 
and multifocal consolidation . This responds dramatically to steroids. 
Rheumatoid respiratory nodules:   
 Commonly associated with the disease.

 Commonly associated with the disease.  
  Associated with increased risk of respiratory tract infection.  
 CXR - Nodular changes 
 If the appearance on chest X- ray has not changed over long times (from previous 
CXR) , no intervention is required , only observation  
 They are typically benign but can lead to pleural effusion, pneumothorax, haemoptysis, 
secondary infection, and bronchopulmonary fistula. 

Bronchiolitis obliterans (BO) 
 'Bronchiolitis obliterans' is the term used to describe fibrous scarring of the smal l 
airways , characterized by fixed airway obstruction. 
Mechanism  
 inflammation that results in scar tissue formation. 
 submucosal and peribronchiolar inflammation and fibrosis without any intraluminal 
granulation tissue  743

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 139 - 
  BO should not be confused with bronchiolitis obliterans organising pneumonia (BOOP),  
a completely different disease.  
Causes 
 Inhalation of toxic fumes 
 Exposure to mineral dust 
 Respiratory infections: Viral, Mycoplasma, Legionella  
 post-transplantation: Bone marrow, heart-lung or lung transplantation

 BO seen as early as 3 months post-transplant, and responsible for over 50% of 
deaths after the first year.  
 Connective tissue disorder: Rheumatoid arthritis  or SLE 
 rheumatoid arthritis considered the commonest connective tissue disease to be 
associated with obliterative bronchiolitis 
 Penicillamine treatment 
 inflammatory bowel disease 
 Idiopathic obliterative bronchiolitis disorder is rare  
Feature 
 dry cough and dyspnoea.  
 wheeze might be audible. 

 HRCT  
 there are often sharply defined, areas of decreased lung attenuation associated 
with vessels of decreased calibre. These changes represent a combination of air 
trapping and oligaemia. This combination can give a mosaic attenuation pattern.  
 air trapping  
 thickening in the airway and haziness in the lungs.  
 spirometry   
 a mixed obstructive/restrictive picture would be seen.

 Inflammation in the small distal airways leads to obstructive spirometry .    
 Air trapping can occur, which leads to increased lung volumes.  
 The chest X-ray findings can vary from normal to a reticular or reticulonodular pattern.  
 transfer factor may be low but the transfer coefficient (Kco) is often normal.  
 Rheumatoid serology often worsens with the onset of bronchiolitis obliterans.  
 lung biopsy  
 The diagnosis can be confirmed by lung biopsy.

 The diagnosis can be confirmed by lung biopsy. 
  Histologically there is a mural concentric narrowing of the lumina of the 
 Transthoracic lung biopsies are preferable for diagnosis of constrictive BO 
compared to transbronchial biopsies 
Differential Diagnosis 
 Bronchiolitis obliterans is often misdiagnosed as asthma, chronic bronchitis, 
emphysema or pneumonia. 
Treatment 
 Patients rarely respond to steroids and the prognosis is poor.

 This disease is irreversible and severe cases often require a lung transplant 
 
 744

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 140 - 
 __________________________________________________________
Drugs causing lung fibrosis 
Causes 
 Cardiac drugs: amiodarone, hydralazine , tocainide 
 cytotoxic agents: busulphan, bleomycin  , cyclophosphamide, carmustine ,  leflunomide 
 anti-rheumatoid drugs: methotrexate, sulfasalazine, gold 
 antibiotics: nitrofurantoin

 antibiotics: nitrofurantoin 
 ergot-derived dopamine receptor agonists (bromocriptine, cabergoline, pergolide). 
  Opiates: e.g. heroin abuse 
Sulphasalazine pulmonary toxicity  
  Is rare, but is increasingly recognised. 
  Typically presents with new-onset dyspnoea and pulmonary infiltrates visible on 
chest radiograph.  
 There may be peripheral blood eosinophilia. 
  Histology most commonly demonstrates an eosinophilic pneumonia with 
interstitial inflammation and fibrosis.

interstitial inflammation and fibrosis.  
 Drug withdrawal is standard treatment, with or without the addition of 
corticosteroids.  
Penicillamine   
 is associated with pulmonary toxicity in the form of diffuse alveolar damage, 
hypersensitivity pneumonitis and obliterative bronchitis. 
  It does not cause pulmonary fibrosis however, and D-penicillamine has actually 
been shown to stabilse pulmonary fibrosis in the setting of systemic sclerosis.  
Cyclophosphamide-induced lung fibrosis:

Cyclophosphamide-induced lung fibrosis: 
 is rare  
 most likely occur in patients who have had concomitant pulmonary radiation therapy 
or have taken other drugs associated with pulmonary toxicity.  
 The disorder usually occurs in patients who have been taking low doses for relatively 
prolonged periods (over six months) and presents several years after cessation of the 
drug and 
 hence the deterioration of symptoms with time.

 hence the deterioration of symptoms with time. 
 The diagnosis is clinical. Chest X-ray reveals reticulonodular shadowing of the  upper 
zones . Lung function tests demonstrate a restrictive lung defect. Lung biopsy is not 
helpful. 
 Cyclophosphamide per se is not toxic to the lungs; however, it is metabolized in the 
liver to toxic metabolites such as hydroxycyclophosphamide, acrolein and 
phosphoramide mustard, which are responsible for pulmonary damage.

 Genetic factors may play a role in determining which individuals develop pulmonary 
fibrosis after exposure to the drug. 745

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 141 - 
  Cyclophosphamide therapy can also result in an acute pneumonitis during treatment 
with the drug that causes cough, dyspnoea, hypoxia and bilateral nodular opacities in 
the upper zones  of the lung.  
 Acute cyclophosphamideinduced pneumonitis responds to cessation of the drug and

corticosteroid therapy.                                                         
Pulmonary disorder associated with inflammatory bowel disease  
 Alveolitis : 
 Restrictive defect. 
 A clinical picture similar to cryptogenic fibrosing alveolitis,  
 responsive to steroids ,  
 Seen more often in patients with Crohn's , rather than ulcerative colitis. 
 Bronchiectasis : lower zone signs would be more prevalent.

 Bronchiolitis obliterans :  mixed obstructive/restrictive picture would be seen. 
Lung disease in systemic sclerosis => Fibrosing alveolitis 
History 
 Lung disease is sometimes the first manifestation of systemic sclerosis,  
 dyspnoea occurs in around 55% of patients.  
 Cough is a less frequently reported symptom, but when it occurs it is dry and non 
productive.  
 There is often a history of Raynaud's phenomenon.

Clinical findings 
 Digital clubbing is rare because of the poor vasculature of the digits. 
  Fine crackles are heard at the bases and are of a 'Velcro' character. 
  Lung fibrosis occurs more commonly in patients with the Scl 70, anti-DNA 
topoisomerase autoantibody.  
 Chest X-ray series have identified diffuse lung disease in up to 67% of patients. 
 Oesophageal dilatation may be seen on chest X-ray and is almost universally present 
on high-resolution computed tomography.

on high-resolution computed tomography. 
Stridor  
 Stridor is an abnormal sound produced by turbulent airflow through a partially 
obstructed airway at the level of the supraglottis, glottis, subglottis, or trachea.  
 It can be inspiratory, expiratory or biphasic, although it is usually heard during 
inspiration.  
 Inspiratory stridor  
 often occurs in children with croup.

 often occurs in children with croup.  
 It may be indicative of serious airway obstruction from severe conditions such as 
epiglottitis, a foreign body lodged in the airway, or a laryngeal tumor.  
 Expiratory stridor  
 implies tracheobronchial obstruction.  
 Causes 
 can be congenital  
 tracheomalacia,  746

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 142 - 
  previous surgery,  
 reflux (particularly in paediatric cases). 
Cricoarytenoid arthritis and stridor 
 This is seen in up to 75% of patients with rheumatoid  arthritis.  
 It can cause  sore throat, hoarse voice and stridor , but is often asymptomatic.

 symptoms can rapidly worsen in the postoperative period .  
 The flow-volume loop  can be abnormal, as can direct laryngoscopy and high-resolution 
CT of the larynx.  
 Patients can need urgent tracheostomy and steroids, both orally and via joint injection.  
___________________________________________________________________________  
Post-extubation stridor (PES) 
 PES is a frequent complication of intubation, occurring in 2-16% of cases.

 It is caused by laryngeal oedema that results from damage to the mucosa of the larynx.  
 Mucosal damage is caused by pressure and ischaemia resulting in an 
inflammatory response.  
 Laryngeal oedema, in severe cases, can lead to acute respiratory compromise 
necessitating emergency reintubation. 
 Risk factors  
 Female gender 
 Female gender is a risk factor for both laryngeal oedema and PES .  
 due to the female mucous membrane being less resistant to trauma and

thinner than that in men. 
 Intubation >36 hours 
 Excessive cuff pressure 
 Large tube size, and 
 Tracheal infection. 
Obstructive sleep apnoea (OSA) 
 
Sleep apnoea causes include obesity and 
macroglossia  
Overview  
 Cessation of breathing during sleep because of upper airway obstruction. 
 Apnea: respiratory arrests of ≥ 10 seconds

 Apnea: respiratory arrests of ≥ 10 seconds  
 Hypopnea: reduction of airflow by ≥ 50% for ≥ 10 seconds in combination with reduction 
of blood oxygenation by ≥ 3%  
 Sex: ♂ > ♀ (2:1)  
 Prevalence: ∼ 20–30% in men and 10 –15% in women  747

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 143 - 
 Pathophysiology 
 Obstruction of the upper airways ĺ apnea ĺ Ļ (PaO2), Ĺ (PaCO2, hypercapnia)  
 ĺ Ĺ Hypoxic pulmonary vasoconstriction ĺ Ĺ pulmonary hypertension ĺ  
 ĺ Ĺ Sympathetic activity ĺ secondary hypertension 
 ĺ Respiratory acidosis ĺ renal compensation  ĺ increased HCO3 retention and

decreased chloride reabsorption 
 
Associations and Predisposing factors 
 Obesity 
 the most important risk factor 
 macroglossia:  
 acromegaly, hypothyroidism, amyloidosis 
 large tonsils 
 Marfan's syndrome   
 Small pharyngeal opening  
 Coexisting COPD  
 Myxedema 
 micrognathia/ retrognathia.  
 Sedatives such as  alcohol.  
 small or set-back mandible  
 Collar size greater than (17 inches) 43 cm is strongly associated .

 Neck size  is the best predictor of obstructive sleep apnoea (OSA).  
Features 
 Excessive daytime somnolence as a result of repeated arousals. 
 The dominant symptom is hypersomnolence (sleepiness). 
 Repetative apnoeas (cessation of airflow for more than 10 seconds) and hypopnoeas 
(50% reduction in airflow for greater than 10 seconds) 
 Loud snoring,  
 Other more common symptoms include: 
 Apparent personality changes ,  
 True nocturnal polyuria, irritability 

 less common  
 Reduced libido and erectile dysfunction 
 erectile dysfunction 
 Possibly related to hypoxaemia.  
 May respond to continuous positive airway pressure (CPAP) treatment. 
 
 Sleep apnoea is an independent risk factor for stroke  , Sudden death   (and death 
from all causes),  
 hypertension,  
 Pulmonary hypertension and cor pulmonale  748

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 144 - 
  Hypoxia-induced cardiac arrhythmia  
 hyperglycaemia  
 obesity  insulin resistance   impaired glucose tolerance (IGT)  ↑ risk of type 
2 diabetes.  
 Risk of accidents (e.g., car crashes, occupational accidents)  due to microsleep 
 Increased risk of developing vascular dementia

 Increased risk of developing vascular dementia 
 Poor sleep leads to increased appetite and obesity. 
 
Assessment of sleepiness to diagnose ( excessive daytime sleepiness ) 
 Epworth Sleepiness Scale  - questionnaire completed by patient +/- partner 
 The Epworth sleepiness score can be between 0 and 24 (the higher the score, 
the more sleepy the patient is) and 6/24 is low.  
 A score of 11 or more is suggestive of OSA.

 A score of 11 or more is suggestive of OSA. 
 Multiple Sleep Latency Test (MSLT) - measures the time to fall asleep in a dark room 
(using EEG criteria) 
Diagnostic tests 
 Sleep studies 
 Polysomnography: first-line method 
 The gold standard diagnostic test is overnight polysomnography. 
 Classic findings 
 Apnea and hypopnea events 
 Diagnose OSA  if the Apnoea-Hypopnoea Index (AHI):  
 ≥15 episodes/hour. 
 ≥ 5 episodes/hour + additional symptoms  (eg:

 ≥ 5 episodes/hour + additional symptoms  (eg: 
excessive daytime sleepiness, insomnia, mood 
disorder, or cognitive dysfunction) or comorbidities  
(eg: HTN, IHD, stroke) 
 To assess severity of obstructive sleep apnoea  Apnoea-
Hypopnoea Index (AHI): 
 mild  4-14 episodes,  
 moderate  15-30 episodes, 
 severe  >30 episodes, 
 Oxygen desaturation 
 Arousal events on EEG 
 Bradycardia 
 Fragmentation of sleep  
 Weight loss.   
 the definitive  management

 the definitive  management  
 takes time 
 CPAP  (continuous positive pressure airways ventilation),  
 the most appropriate  initial  and quickest management  which acts as a splint 
to keep the airway open, leading to a normal night's sleep. 
 the treatment of choice  for severe sleep apnoea.   
 In patients who do not want CPAP or who do not tolerate CPAP, Oral appliance or 
Upper airway surgery would be the next best option.   749

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 145 - 
  Intra-oral devices (e.g. mandibular advancement)  
 may be used if CPAP is not tolerated  
 for patients with mild OSA where there is no daytime sleepiness. 
 pharmacological agents   
 limited evidence to support use of pharmacological agents

 Modafanil  is a drug that is licensed for excessive daytime sleepiness in people 
with OSA treated with CPAP, as well as for narcolepsy. 
 BiPAP (bilevel positive airways pressure ventilation)  
 is used if people are in respiratory failure: although this is rare with OSA alone, it 
can occur if they have an associated problem, such as obesity hypoventilation or 
COPD. 
  avoid sedatives drugs/excess alco hol  
 
Ref:  
 bestpractice.bmj.com 2018 
 www.amboss.com  2018

 www.amboss.com  2018 
Obesity hypoventilation syndrome (OHS)  (Pickwick syndrome)  
 
Obesity + feature of OSA + abnormal ABG (↑ PCO2)   (OHS)  
 
 Only affects morbidly obese individuals ;  
 frequently accompanied by OSA, 
 characterized by diurnal hypercapnia  
 Pathophysiology :  
 Ĺ production  of CO 2  + sleep disordered breathing (e.g., OSA) + failure of 
ventilatory compensatory mechanisms ĺ  alveolar hypoventilation

 Clinical features  Same symptoms as those of OSA 
 Diagnostic criteria  
 BMI ≥ 30 kg/m2 
 Arterial blood gasses showing diurnal hypercapnia (PaCO 2 > 45 mm Hg) that 
cannot not be explained by another condition 
 Polysomnography shows hypoventilation during sleep with or without 
obstructive apnea  events. 
 Weight loss 
 Nasal intermittent positive pressure ventilation 

Pneumothorax  (British Thoracic Society (BTS) guidelines 2010) 
 
 primary  pneumothorax : if there is no underlying lung disease,  
 secondary  pneumothorax : if there is.  
Clinical features include: 
 Sudden onset of chest pain, sometimes radiating to the shoulder 750

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 146 - 
  Dyspnoea (may not be a dominant feature) 
 Dry cough. 
 Left-sided pneumothoraces may be associated with a clicking sound  synchronous 
with the heart-beat and may occasionally be audible to the patient.  
 Hamman's sign  (or 'crunch') is a crunching systolic sound heard over the sternal

edge in mediastinal emphysema or left apical pneumothoraces . 
 It appears to be commoner in patients with small left-sided pneumothoraces. 
 Young adult males,  often tall and slim , are frequently affected by spontaneous 
pneumothorax.  
 Patients with Marfan  syndrome are prone to recurrent pneumothoraces . 
 
If the history and examination are suggestive of a pneumothorax and the patient

being relatively stable, not in extremis ( tension pneumothorax not suggested ), the 
most appropriate first step would be  confirmation with chest x ray.  
 
 Questions sometimes discuss the size of the pneumothorax in percentage terms rather 
than giving the interpleural distance.  
 A 50% pneumothorax is likely to have a rim of > 3cm. 
 A pneumothorax of 20% is therefore within the 2 cm limit  
 As a very general rule of thumb:

 As a very general rule of thumb:  
Average interpleural distance Approximate size of pneumothorax 
0.5 cm 10% 
1 cm 15 % 
2 cm 30% 
3 cm 45% 
4 cm 60% 
 
 The next investigation to investigate the underlying cause of recurrent 
pneumothorax: 
 A CT scan is non-invasive and would therefore be a logical next step in 
elucidating any abnormality which may predispose to pneumothorax. 
 If CT not help in pointing to a structural abnormality, and a further episode was to

occur, then video assisted thoracoscopy  would be considered. 
 Ultrasound scanning is mainly used in the diagnosis and management of 
pneumothorax in the trauma setting. 
 
Primary pneumothorax 
 Definition:  Spontaneous primary pneumothorax is defined as: 
 age less than 50-years-old 751

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 147 - 
  no significant smoking history,  
 minimal smoking history would be considered a primary pneumothorax 
 no evidence of underlying lung disease. 
 Caused by the rupture of apical pleural blebs . 
 if the rim of air is < 2cm and the patient is not short of breath then discharge 
should be considered

should be considered 
 otherwise aspiration should be attempted 
 If size is > 2 cm or the patient is breathless  chest aspiration 
 if this fails (defined as > 2 cm or still short of breath) then a chest drain  should 
be inserted 
 patients should be advised to avoid smoking to reduce the risk of further 
episodes - the lifetime risk of developing a pneumothorax in healthy smoking men 
is around 10% compared with around 0.1% in non-smoking men

 if following aspiration  the rim of air is < 2cm and the breathing has improved 
then discharge should be considered with outpatient review. 
 If a patient with a pneumothorax requires oxygen, this should be given at 10 
L/min. 
 
Asthmatics should be treated as a secondary pneumothorax 
 
Secondary pneumothorax:  Recommendations include:  
 if the patient is > 50 years  old and the rim of air is > 2cm and/or  the patient is short of

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 148 - 
  Insert a small bore chest drain (8-14 FG) and attach to an underwater seal 
drain  
 otherwise aspiration should be attempted if the rim of air is between 1-2cm. If aspiration 
fails (i.e. pneumothorax is still greater than 1cm) a chest drain should be inserted.  
 All patients should be admitted for at least 24 hours

 High flow oxygen should be given in all cases of pneumothorax, as it facilitates re-
absorption of the pleural air, which is predominantly composed of nitrogen.  
 if the pneumothorax is less than 1cm then the BTS guidelines suggest giving oxygen 
and admitting for 24 hours.  Supplemental oxygen accelerates reabsorption of air by a 
factor of four  
 if the patient is very dyspneoic  a drain should be inserted even though the 
pneumothorax is small (< 2cm).

pneumothorax is small (< 2cm). 
 All patients should be advised to avoid smoking to reduce the risk of further episodes 
 
Chest x ray reveals a 3.2 cm rim of air around the lung. 
 
Iatrogenic pneumothorax : 
 less likelihood of recurrence than spontaneous pneumothorax 
 majority will resolve with observation, if treatment is required then aspiration should be 
used 
 ventilated patients need chest drains, as may some patients with COPD 
Tension pneumothorax 
753

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 149 - 
  should be suspected in people on mechanical ventilators or nasal non-invasive 
ventilation who suddenly deteriorate or develop EMD arrest, and is frequently missed in 
the intensive care unit setting. 
 needle thoracocentesis  
 Advanced Trauma Life Support (ATLS) guidelines recommend the use of a

3-6-cm-long cannula to perform needle thoracocentesis.  
 However, in 57% of patients with tension pneumothorax the thickness of 
the chest wall has been found to be greater than 3 cm.  
 It is therefore recommended that a cannula length of at least 4.5 cm should 
be used. 
 The cannula should be left in place until bubbling is confirmed in the 
underwater-seal system to confirm proper function of the intercostal tube. 
 
Chest drains for pneumothor ax

Chest drains for pneumothor ax 
 Insertion of a small bore chest drain using a Seldinger technique in the mid-
axillary line  
 The most appropriate point for chest drain insertion is in the 'safe triangle', in the 
mid-axillary line.  
 Scarring from insertion is less obvious than in the second intercostal space and 
mid-clavicular line, particularly important in women. 
 insert 14F drain immediately above a rib margin

 When the patient coughs, nothing happens. When he breathes in and out, the 
fluid in the tube moves up and down that means   Air is no longer draining from 
the pleural space, but the drain is still working.  
 The fluid level rising and falling in the drain (swinging) shows that it is still in 
contact with the pleural space and the fluid level is moving with respiration. 
 Air is not bubbling out of the drain when the patient coughs because the air has stopped

draining from the pleural space and the lung has re-inflated. 
 If a drain does not bubble or swing, then it is blocked or kinked and is not 
working . 
 With a simple pneumothorax, there would be minimal fluid drainage from the chest.  
 Suction  is necessary  if the drain is still bubbling but the lung has not fully re-
inflated on the chest X-ray.  
 After chest drain  if pneumothorax fails to re-expand or if there is a persistent air

leak (bubbling present) after 48 hours , then you should    refer the patient to a 
respiratory specialist because negative suction  might be required.  
 The normal intrapleural pressure is -3.4 cm H2O during expiration, rising to - 8 
cmH2O during inspiration . Negative suction should be started at -10 to - 20 
cmH2O (-1 to -2 kPa = -7.5 to -15 mmHg) using a high-volume/low-pressure 
suction system . 
 If high-volume/high-pressure suction is used, then high-airflow suction

might be generated, which can lead to air stealing, hypoxaemia and/or the 
persistence of air leaks. 
 If appropriate suction fails to result in adequate re-expansion by 5-7 days in patients 
without pre-existing lung disease (earlier if there is lung disease), then   referral to a 
thoracic surgeon is indicated. 754

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 150 - 
  If a repeat chest X-ray reveals a persistent pneumothorax despite low-pressure, 
large-volume suction, you confirm on examination that the chest drain appears to 
have remained in position and is bubbling  Cardiothoracic surgical referral  
 This patient appears to have developed a bronchopleural fistula , as evidenced

by failure of the lung to re-inflate despite the drain remaining in place for 48 h and 
low-pressure suction being deployed.  
 
Video assisted thoracoscopic surgery  is indicated in:  
 Second ipsilateral pneumothorax 
 The management of choice for a second unilateral pneumothorax in a fit 
individual is referral for bullectomy and pleurectomy.  known as video assisted 
thoracoscopic surgery (VATS). 
 Bilateral spontaneous pneumothorax 
 Spontaneous haemothorax

 Spontaneous haemothorax 
 Persistent air leak (more than five to seven days of drainage) 
 Certain occupations, for example, pilots or divers. 
Chemical pleurodesis  through the chest drain:  
 used in older  patients or frail individuals with recurrent pneumothorax, where surgery 
would be high risk.  
 Failure rates can be 10-20%. 
 
Open pneumothorax (stab wound to the chest)  
 the most appropriate next best step  in management  Partially occlusive dressing

(gauze taped on three sides over the wound)  
 dressings taped at 3 out of 4 sides of the lesion 
 is temporary treatment to prevent further expansion of the pneumothorax until the 
diagnosis has been confirmed and definitive treatment (i.e., tube thoracostomy, 
surgery) is available.  
 The dressing works by occluding the wound during inspiration (e.g., “plugging ” 
the wound). The open side allows air to pass out of the wound on expiration. 
 
 Fitness to fly

Fitness to fly   
 Air travel is acceptable once the pneumothorax has fully resolved. 
 Pneumothorax is an absolute contraindication,  
 CAA suggest patients may travel 2 weeks after successful drainage if there is no 
residual air.  
 The British Thoracic Society now recommend 1 week post check x-ray . 
 However, the British Thoracic Society emphasises that the recurrence risk only 
significantly falls after 1 year, and therefore in the absence of a definitive surgical

procedure patients might wish to defer travel until then. 
Diving 755

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 151 - 
  The British Thoracic Society (BTS) guidelines state: 'Diving should be permanently 
avoided unless the patient has undergone bilateral surgical pleurectomy and has 
normal lung function and chest CT scan postoperatively.'  
_________________________________________________________ __________

Pleural effusion  (British Thoracic Society (BTS) produced guidelines in 2010)  
 
Exudate (> 30g/L protein)  Transudate (< 30g/L protein) 
 infection: pneumonia, TB, sub-phrenic 
abscess 
 connective tissue disease: RA, SLE 
 neoplasia: lung cancer, mesothelioma, 
metastases 
 pancreatitis 
 Dressler's syndrome 
 yellow nail syndrome  heart failure 
 hypoalbuminaemia 
 liver disease,  
 nephrotic syndrome,  
 malabsorption 
 Meigs' syndrome

 Meigs' syndrome 
 
Imaging  
 Posterior-anterior (PA) chest x-rays should be performed in all patients 
 Ultrasound is recommended: it increases the likelihood of successful pleural aspiration 
and is sensitive for detecting pleural fluid septations 
 Ultrasound thorax is the next most appropriate step after chest x-ray 
 Ultrasound, followed by drainage of any large pockets of fluid, is much more

effective, and will yield fluid samples for culture, pH, glucose and lactate 
dehydrogenase (LDH) testing. 
 Ultrasound is better for pleural imaging than CT. 
Patients with cytology negative exudative effusions  
 Local anaesthetic thoracoscopy has a high yield and is now the investigation of 
choice in patients with cytology negative exudative effusions. 
Pleural aspiration 
 ultrasound is recommended to reduce the complication rate 
 a 21G needle and 50ml syringe should be used

 a 21G needle and 50ml syringe should be used 
 fluid should be sent for pH, protein, lactate dehydrogenase (LDH), cytology and 
microbiology 
 
Light's criteria   
 developed to distinguish between a transudate and an exudate.  
 The BTS recommend using the criteria for borderline cases: 
 exudates have a protein level of >30 g/L, transudates have a protein level of <30 
g/L 
 if the protein level is between 25-35 g/L, Light's criteria should be applied.

 An exudate is likely if at least one of the following criteria are met: 
 pleural  fluid protein  divided by serum  protein >0.5 756

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 152 - 
  pleural  fluid LDH divided by serum  LDH >0.6 
 pleural  fluid LDH more than two-thirds the upper limits of normal serum LDH 
Pleural infection 
 all patients with a pleural effusion in association with sepsis or a pneumonic illness 
require diagnostic pleural fluid sampling

require diagnostic pleural fluid sampling 
 if the fluid is purulent or turbid/cloudy a chest tube  should be placed to allow drainage 
 if the fluid is clear but the pH is less than 7.2 in patients with suspected pleural infection 
a test tube  should be placed 
 
Rheumatoid pleural effusion  
 Around 5% of patients with RA develop pleural effusions.  
 mainly occur in older male patients who have subcutaneous nodules.  
 About a quarter of patients experience bilateral effusions.

 Characterized by:  
 Low glucose (< 1.6 mmol/l)  
 High lactate dehydrogenase (> 700 IU/l) 
 Low pH (< 7.2) 
 high rheumatoid factor titre (> 1:320) 
 High cholesterol levels 
 The majority of these effusions resolve spontaneously within 3 months and 
require no intervention.  
 Management is with treatment of RA in general.  
 Occasionally they persist and massive pleural thickening develops. These 
patients might need decortication if they are symptomatic.

Other characteristic pleural fluid findings: 
 Low glucose (less than 3.3 mmol/L ) :  
 rheumatoid arthritis,  
 The lowest levels are found in rheumatoid effusions and empyema  
with pleural glucose in rheumatoid effusions rarely being above 1.6 
mmol/L. 
 empyema   
 tuberculosis, 
 malignancy.  
 Oesophageal rupture 
 Lupus  
 raised amylase:  
 pancreatitis,  
 oesophageal perforation 
 Heavy blood-staining:  
 mesothelioma,  
 pulmonary embolism,  
 tuberculosis , or

 tuberculosis , or  
 Rheumatoid effusion is unlikely when peripheral joint disease is so well controlled.  757

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 153 - 
  Pleural fluid eosinophilia (> 10%) makes malignancy and TB less likely, and 
suggests air in the pleural cavity. 
 The presence of antinuclear factor is virtually diagnostic of systemic lupus 
erythematosus (SLE).  
 
 Video-assisted thoracoscopic surgery (VATS)  :

Video-assisted thoracoscopic surgery (VATS)  : 
 An underlying pleural pathology should be strongly suspected in the case of thickened 
pleura, restrictive lung function and non-specific constitutional symptoms.  
 VATS is appropriate to differentiate pleural thickening between organised empyema or 
mesothelioma, and also to obtain tissue to differentiate mesothelioma from other 
primary or metastatic cancers.  
 VATS is optimally performed with a small amount of pleural fluid in situ.

 It should be considered after other non-invasive tests have proven negative. 
 Advantages of VATS   
 Ensure adequate pleural biopsies are obtained 
 Drain pleural fluid 
 Allow pleurodesis to prevent recurrence. 
 pleural procedures should not take place out- of-hours  except in an emergency due to 
increased risk  
 
Indications for chest tube insertion in patients with an infected pleural 
effusion  are: 
 Presence of organisms on a Gram stain of the pleural fluid

 Frankly purulent pleural fluid 
 Pleural pH < 7.2  in the setting of an infected pleural effusion 
 Loculated pleural effusions 
 Poor clinical progress despite antibiotic treatment 
 
Management of recurrent pleural effusion 
 Options for managing patients with recurrent pleural effusions include: 
 recurrent aspiration 
 pleurodesis 
 indwelling pleural catheter 
 drug management to alleviate symptoms e.g. opioids to relieve dyspnoea 
 
Complications of plural fluid drainage

Complications of plural fluid drainage  
 Re-expansion pulmonary oedema 
 This is a potentially life-threatening condition which can occur when a large 
volume of fluid or air is rapidly drained , 
  It is suggested by sudden onset of shortness of breath, cough and hypoxaemia 
following chest drain insertion. 
 758

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 154 - 
  
Meigs syndrome 
 Characterised by the presence of a benign ovarian fibroma, associated with 
ascites and a right-sided pleural effusion. 
 The average age at presentation is 48 years.  
 Meigs syndrome is associated in 0.004% of ovarian tumours.

 The aetiology of the pleural effusion is thought to be related to the size of fibroma, 
leading to accumulated peritoneal ascites that flows into the pleural cavity via the 
lymphatics or via abdominal-pleural communications (via the foramen of Bochdalek).  
 Removal of the ovarian mass is associated with resolution of the ascites and pleural 
effusion and patients have an excellent prognosis. 
Pleural effusion in rheumatoid arthritis

Pleural effusion in rheumatoid arthritis 
 Around 5% of patients with rheumatoid arthritis develop pleural effusions. These mainly 
occur in older male patients 
 who have subcutaneous nodules. About a quarter of patients experience bilateral 
effusions. 
 These effusions are characterised by some or all of the following: 
 Low glucose (< 1.6 mmol/l) 
 High lactate dehydrogenase (> 700 IU/I) 
 Low pH (< 7.2) 
 A high rheumatoid factor titre (> 1:320) 
 High cholesterol levels

 High cholesterol levels 
 The majority of these effusions resolve spontaneously within 3 months. Occasionally 
they persist and massive pleural 
 thickening develops. These patients might need decortication if they are symptomatic. 
Contraindications for Thoracentesis 
absolute contraindications: 
 uncooperative patient  
 coagulation disorders that cannot be corrected  
Relative contraindications:

Relative contraindications: 
 cases in which the site of insertion has known bullous disease (e.g. emphysema),  
 use of positive end-expiratory pressure (PEEP, in mechanical ventilation)  
 only one functioning lung (due to diminished reserve).  
The aspiration should not exceed 1L as there is a risk of development of pulmonary 
edema. 
Chylothorax 
 A chylothorax occurs when lymph fluid from the thoracic duct or its tributaries

accumulates in the pleural space. Chylous ascitic fluid can also flow into the pleural 
space.  759

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 155 - 
  The etiologies of chylothorax can be categorized as nontraumatic or traumatic 
.Malignancy is the leading cause of nontraumatic chylothorax.  
 Chyle (lymphatic fluid of intestinal origin) has a high content of triglycerides in the form 
of chylomicrons, which produce the milky, opalescent appearance of lymphatic fluid.

 The diagnosis of chylothorax is based on the pleural fluid triglyceride level .A triglyceride 
concentration greater than 110 mg/dL (1.24 mmol/L) strongly supports the diagnosis.  
 lymphatic imaging typically performed when the diagnosis of thoracic duct tear is 
uncertain after pleural fluid analysis and chest computed tomography, when a 
chylothorax recurs after thoracic duct ligation, or when anomalous thoracic duct 
anatomy is suspected.

anatomy is suspected.  
 
 It is differentiated from empyema because the latter yields a clear supernatant on 
centrifugation.  
 Pseudochyle  is differentiated from chylothorax by : 
  high cholesterol pleural effusion,  ( cholesterol greater than 
200 mg/dL (5.18 mmol/L) and a triglyceride  below 110 mg/dL (1.24 mmol/L). 
 Cholesterol crystals are diagnostic if present. chylomicrons, which are associated 
with chylothoraces, are absent.

with chylothoraces, are absent. 
  and is typically seen in patients with tuberculosis. 
Causes of chylothorax   
 Trauma (eg surgery) 
 Malignancy, usually a lymphoma (metastatic lung deposits can cause chylothorax, but 
less commonly) 
Less common causes: 
 congenital :absence of thoracic ducts , Down syndrome, Noonan syndrome) 
 filariasis 
 tuberculous mediastinal lymphadenitis 
 lymphangioleiomyomatosis (occurring much more commonly in

 females of child bearing age) 
 CVD :left subclavian venous thrombosis , thoracic aortic aneurysm, , venous 
thrombosis, mitral stenosis, heart failure, 
 others : pleuritis, cirrhosis , lupus, tuberculosis, sarcoidosis, amyloidosis,  nephrosis, 
thyroid goiter, tuberous sclerosis, 
Haemothorax 
 A bleeding into the pleural space,

 A bleeding into the pleural space,  
 Diagnosed  on the basis of having a haematocrit that is more than half that of peripheral 
blood. This distinguishes it from a blood-stained effusion. 
 The treatment of choice is to insert a large intercostal drain (28-32 F)  
 If this reveals continued bleeding, a thoracotomy might be required.  
 Surgery is not indicated simply to remove any residual blood clots because there

is spontaneous lysis with no residual damage in the majority of patients. 
 760

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 156 - 
Pleural calcification  
Unilateral pleural calcification 
 most commonly occurs as a chronic change secondary to: 
 pleural infection (particularly tuberculous empyema),  
 pyogenic empyema, or  
 haemothorax.  
Bilateral  pleural calcification   
 Common

 Common 
 calcified pleural plaques are usually considered asbestos-related. 
 Other rarer causes  
 radiation exposure,  
 hyperparathyroidism,  
 pulmonary infarction, and  
 pancreatitis. 
Mesothelioma 
Basics 
 Malignancy of mesothelial cells of pleura 
 Metastases to contralateral lung and peritoneum 
 Right lung affected more often than left 
Risk factors and pathophysiology

Risk factors and pathophysiology 
  Exposure to asbestos is the primary risk factor   
 The role of cigarette smoking has not been proved 
  Loss of material from chromosome 22 is an abnormality commonly seen in 
mesothelioma , and may contain code for tumour suppressor genes  
 
Features 
 Dyspnoea, weight loss, chest wall pain 
 Clubbing 
 30% present as painless pleural effusion 
 Only 20% have pre-existing asbestosis

 Only 20% have pre-existing asbestosis 
 History of asbestos exposure in 85-90%, latent period of 30-40 years 
 
Investigation/diagnosis 
 suspicion is normally raised by a chest x-ray showing either a pleural effusion or pleural 
thickening  
 (Be aware that only 20% of mesothelioma patients present with radiographic 
changes consistent with asbestosis, although the majority present with pleural 
abnormalities ). 
 the next step is normally a pleural CT .

 the next step is normally a pleural CT . 
 if a pleural effusion is present fluid should be sent for MC&S, biochemistry and cytology 
(but cytology is only helpful in 20-30% of cases ) 
 Thoracoscopy  761

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 157 - 
  local anaesthetic thoracoscopy is increasingly used to investigate cytology 
negative exudative effusions as it has a high diagnostic yield (around 95%).    
 Tissue can be obtained from thoracoscopy with biopsy  from abnormal looking 
areas  
 the most appropriate investigation to deliver the diagnosis.

 if an area of pleural nodularity is seen on CT then an image-guided pleural biopsy 
may be used 
 CT might show pleural thickening and nodularity, which would be 
amenable to either CT-guided biopsy or thoracoscopy.  
 CT pleural biopsy has been shown to have a diagnostic advantage over a 
blind Abrams' biopsy in cytologically negative malignant pleural effusions 
with pleural thickening, with a sensitivity of 87% vs 47%. 
 
 Industrial compensation

 Industrial compensation 
 Chemotherapy  
 Patients with good performance status could be considered for palliative 
chemotherapy, which can result in tumour shrinkage. 
 Radiotherapy   
 Radiotherapy to the thoracoscopy tract site is effective for preventing tumour 
seeding and growth and is recommended after pleural procedures. This is routine 
practice, along with providing symptomatic treatment. 
 Palliative radiotherapy

 Palliative radiotherapy 
 can be useful to reduce chest pain, shortness of breath and to relieve 
superior vena cava obstruction.  
 There is no evidence of benefit for radiology at the surgical port sites and 
surgical resection remains controversial. 
 Surgery if operable 
 Chest drains are usually reserved for recurrent pleural effusions and those that fail talc 
pleurodesis.   
 
Prognosis 
 poor  
 The median survival after diagnosis is 2 years

Pulmonary eosinophilia   
The defining characteristics of pulmonary eosinophilia  include: 
 peripheral blood eosinophilia  
 radiographic evidence of pulmonary parenchymal disease; 
 histopathologic evidence of lung tissue eosinophilia in a transbronchial or open lung 
biopsy specimen;  
 increased eosinophils in bronchoalveolar lavage fluid (eg, >10 %). As peripheral blood

eosinophils are not always increased in eosinophilic lung diseases, the other methods 762

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 158 - 
 (bronchoalveolar lavage [BAL], biopsy) are sometimes needed to document lung 
eosinophilia. 
  
Causes of pulmonary eosinophilia 
 Churg-Strauss syndrome 
 allergic bronchopulmonary aspergillosis (ABPA) 
 eosinophilic pneumonia 
 hypereosinophilic syndrome 
 tropical pulmonary eosinophilia

 tropical pulmonary eosinophilia 
 drugs: nitrofurantoin, sulphonamides 
 less common: Wegener's granulomatosis 
Cryptogenic pulmonary eosinophilia  
 In this condition pulmonary eosinophilia occurs with no identifiable cause  
 patients usually non-atopic (but 10% have had previous asthma) 
 When the disease is self-limiting and lasts less than 1 month it is known as 
Loeffler syndrome.  
Feature

Feature 
 Systemic features : Malaise, fever, weight loss 
 asthma (in around 50%) 
 widespread, mainly peripheral pulmonary infiltrates 
 blood eosinophilia 
 Raised ESR 
Treatment 
 The disease responds to steroid treatment, which needs to be continued for about 1 
year. 
(CEP) eosinophilic pneumonia Chronic 

 CEP is an idiopathic disorder characterized by an abnormal accumulation of eosinophils 
in the interstitial and alveolar spaces 
Feature 
  dyspnea, cough, fever, and wheezing over three weeks to several months. 
Diagnosis  
 Chest imaging  
 showing predominantly peripheral or pleural-based opacities described as the 
"photographic negative" of pulmonary edema, are virtually pathognomonic for 
CEP

CEP 
 Peripheral alveolar filling infiltrate predominantly in the upper lobes  on a chest 
radiograph is typical of chronic eosinophilic pneumonia.  
 
 Bronchoalveolar lavage (BAL) :   763

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 159 - 
  To look for eosinophilia   cell count showing eosinophilia (≥25 %).   
 To exclude infection. 
Treatment : prednisolone  
Tropical pulmonary eosinophilia  
 associated with Wuchereria bancrofti  infection (a condition associated with 
microfilaria).

microfilaria). 
 seen in the Asian subcontinent 
 Presents with cough, wheeze, fever, lassitude and weight loss. 
 The treatment of choice is a 10- 14-day course of diethylcarbamazine to eradicate the 
Loffler's syndrome  
 transient CXR shadowing and blood eosinophilia 
 thought to be due to parasites such as Ascaris lumbricoides  causing an alveolar 
reaction

reaction 
 presents with a fever, cough and night sweats which often last for less than 2 weeks. 
 generally a self-limiting disease 
Organising pneumonia 
 Organising pneumonia (formerly called bronchiolitis obliterans organizing pneumonia or 
BOOP), classified in to : 
1- Cryptogenic organizing pneumonia (COP): idiopathic 
2- secondary organizing pneumonia: can be seen in association with connective

tissue diseases, a variety of drugs, malignancy, and other interstitial pneumonias  
 
 is a type of diffuse interstitial lung disease that affects the distal bronchioles, respiratory 
bronchioles, alveolar ducts, and alveolar walls.  
 The primary area of injury is within the alveolar wall. 
 Onset is typically in the fifth or sixth decades of life,  
 men and women affected equally 
Causes of organizing pneumonia

Causes of organizing pneumonia 
 Cryptogenic organizing pneumonia (previously called bronchiolitis obliterans organizing 
pneumonia) 
 Organizing diffuse alveolar damage 
 Diffuse alveolar hemorrhage 
 Drugs 
 Amiodarone 
 Cocaine 
 Infections (organizing) 
 Mycoplasma 
 Viral 
 Pneumocystis jirovecii (carinii) 
 Bacterial 
 Connective tissue diseases 764

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 160 - 
  Hypersensitivity pneumonitis 
 Idiopathic pulmonary fibrosis (minor scattered foci) 
 Aspiration 
Feature 
 Persistent nonproductive cough (72%) 
 Dyspnea (66 %) 
 Fever (51 %) 
 Malaise (48 %) 
 Weight loss of greater than 10 pounds (57%) 
 Hemoptysis is rarely reported as a presenting manifestation of COP

Cryptogenic organising pneumonia (COP) 
 
 non-specific inflammatory pulmonary process, with buds of granulation tissue forming 
in the distal air spaces . 
 Organising pneumonia can have a number of causes, including connective tissue 
disease, infection and drugs, but if there is no obvious cause it is called 
'cryptogenic'.   
Feature 
 dry cough

Feature 
 dry cough  
 non-specific symptoms of fever, malaise, anorexia and weight loss.  
 ↑WBC and C-reactive protein (CRP) levels. 
 chest X-ray  
 can show consolidation, nodules or thickened septal lines.  
 The consolidation typically occurs in different places at different times.  
 The most common chest imaging features are multiple ground-glass or 
consolidative opacities.

consolidative opacities.  
  Pulmonary function tests  usually show a restrictive  pattern with an associated gas 
transfer defect. 
  CT findings are characteristic, with multiple patchy alveolar opacities, which often 
spontaneously migrate.  
  Reversed halo sign , better known as  an atoll sign . 
 a region of ground-glass opacity surrounded by crescentic or annular 
denser tissue . 
 Cryptogenic organising pneumonia is the most common condition

described in immunocompetent patients with this sign (found in  20% of the 
cases of COP) 
 
Diagnosis 
 The diagnosis might be made on the basis of CT alone, or on transbronchial or open 
lung biopsy.  
 Histopathologic characteristic lesions  include excessive proliferation or “plugs ” of 
granulation tissue within alveolar ducts and alveoli, associated with chronic 
inflammation in the surrounding alveoli.

inflammation in the surrounding alveoli. 
 The diagnosis requires histopathologic identification of a predominant pattern of 
organizing pneumonia and the exclusion of any possible cause 765

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 161 - 
  Differential diagnosis 
 Recurrent lobar bacterial infection is unusual in an immunocompetent adult. 
 Eosinophilic pneumonia leads to flitting peripheral chest X-ray shadows. 
 Lymphangioleiomyomatosis 
 rare idiopathic disease, affecting women of reproductive years.

 characterised by infiltration of immature muscle cells into the bronchiolar and 
alveolar walls. This results in destruction of the airways, cyst formation an d 
progressive decline in lung function.  
 Typical radiological findings are of interstitial lung disease, 
 recurrent pneumothoraces and chylous effusions.  
 If this occurs in men then tuberous sclerosis  
 CT shows multiple small cysts. 
 Treatment is lung transplantation.

 Treatment is lung transplantation.  
 Patients are asked to avoid taking the oral contraceptive pill, pregnancy and long-
haul flights.  
 Conservative management includes progesterone supplements but the response 
is variable.  
 Pulmonary alveolar proteinosis 
 a rare defect in which the alveoli become filled with proteinaceous material that 
cannot be cleared. CT shows air-space shadowing. 
 
Treatment  
 Mild stable disease:

Treatment  
 Mild stable disease:  
 monitor without therapy & reassessed at 8 to 12 week intervals 
 For symptomatic patients with moderate or severe disease:  
 oral prednisolone 
 COP usually responds to corticosteroid. 
 Initial doses of 0.75 –1 mg/kg, weaning over 6 –12 months, are reasonable. 
 Persistent or gradually worsening disease: 
  methylprednisolone 500 to 1000 mg intravenously each day for three to five days 
rather than a lower oral dose

rather than a lower oral dose  
 Failure to respond to systemic glucocorticoids:  
 cyclophosphamide or azathioprine 
Prognosis 
 Relapse is common  
Bronchiolitis obliterans organizing pneumonia  (BOOP) 
 
 BOOP is differentiated from organizing pneumonia, which is defined by the presence of 
granulation tissue in the distal air spaces; but when associated with granulation

tissue in the bronchiolar lumen , organizing pneumonia is qualified by the term 
bronchiolitis obliterans (BO). Hence the term ‘bronchiolitis obliterans organizing 
pneumonia ’ is used. 
 BOOP is characterized by the presence of granulation tissue  in the  bronchiolar  
lumen, alveolar  ducts  and some alveoli , associated with a variable degree of 
interstitial and airspace infiltration by mononuclear cells and foamy macrophages. 766

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 162 - 
 Feature 
 Approximately 50% of patients present with influenza-like illness followed by a short 
illness of few months′ duration characterized by a persistent nonproductive cough, effort 
dyspnea, low-grade pyrexia, malaise and weight loss. 
 Less common symptoms include pleuritic chest pain and hemoptysis.

 fine, dry lung crepitations is common. 
Causes 
 most cases are idiopathic. 
 Association 
 Associated collagen vascular disorder is found in 16%  
 inhalation exposure to toxins in 17% 
 organ transplantation, especially with bone marrow transplant 
 post infection: bacterial , viral, CMV pneumonia 
 Radiotherapy 
 Drugs: phenytoin , carbamazepine 
 chest radiographs revealed that bilateral patchy infiltrates and reticulonodular opacities 
 HRCT

 HRCT  
 Patchy ground-glass opacities in a subpleural and/or peribronchovascular 
distribution (80%). 
 Bilateral basal airspace consolidation (70%) 
 Bronchial wall thickening and cylindrical bronchial dilatation in areas of air 
bronchogram (70%) 
 the consolidation in BOOP commonly involves the lower zones 
 Cytological profile of bronchoalveolar lavage   
 reveals a mixed cell pattern with an increase in lymphocytes (20-40%),

 ↑lymphocytes differentiate the condition from parenchymal pulmonary disease.  
 Neutrophils (10%), eosinophils (5%), mast cells, foamy macrophages and 
occasional plasma cells increase in patients with  Idiopathic pulmonary 
fibrosis  (IPF).  
 Lung biopsy is the preferred method for establishing the diagnosis.  
 Most patients with BOOP require open-lung biopsy for diagnosis.  
 ESR is usually elevated, 
 pulmonary function tests show a restrictive  pattern. 
 Treatment

Treatment 
 BOOP responds well to corticosteroid therapy, while Usual interstitial 
pneumonia  (UIP) and  IPF usually does not. 
 The dosage is generally 0.75 mg/kg/day for 1 to 3 months, then 0.50 mg/kg 
mg/day for 3 months, then 10 to 20 mg/day or every other day for a total of 1 
year.    
 Approximately 30% of the patients experience relapse upon withdrawal of treatment. 
 
 767

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 163 - 
 
 sustained elevation in mean pulmonary arterial pressure of greater than 25 mmHg 
at rest or 30 mmHg after exercise .  
 pulmonary artery wedge pressure ≤15 mmHg and pulmonary vascular resistance > 3 
Wood units.

Wood units.  
 Endothelin-1 is a potent pulmonary vasoconstrictor produced in increased amounts 
in pulmonary hypertension, which also induces the proliferation of pulmonary vascular 
smooth muscle. 
 Bosentan is used to treat pulmonary hypertension by competitively 
antagonizing endothelin, thereby decreasing pulmonary vascular resistance. 
WHO Classification 
 Group 1: Pulmonary arterial hypertension (PAH) 
 Idiopathic

 Idiopathic 
 previously termed primary pulmonary hypertension (PPH) 
 familial 
 account for 15-20% of cases, 
 due to an inherited mutation in the BMPR2 gene  which codes for a 
receptor in the TGF beta family. 
 The gene BMPR2  normally inhibits vascular smooth muscle proliferation, 
and a mutation in this gene can lead to increased proliferation of smooth 
muscle.  
 The gene for primary pulmonary hypertension has now been mapped to 
chromosome 2, 
 
 associated conditions:

 associated conditions:  
 HIV ,  
 appetite suppressants  
 amphetamines 
 cocaine 
 sickle cell disease 
 persistent pulmonary hypertension of the newborn 
 
 Group 2: Pulmonary hypertension with left heart disease 
 left-sided atrial, ventricular or valvular disease such as left ventricular systolic and

diastolic dysfunction, mitral stenosis and mitral regurgitation 
 Group 3: Pulmonary hypertension secondary to lung disease/hypoxia 
 COPD 
 interstitial lung disease 
 sleep apnoea 
 high altitude 768

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 164 - 
  Group 4: Pulmonary hypertension due to thromboembolic disease 
 Group 5: Miscellaneous conditions 
 lymphangiomatosis e.g. secondary to carcinomatosis or sarcoidosis 
 
Features  
 exertional dyspnoea is the most frequent symptom 
 chest pain and syncope may also occur 
 physical signs:

 physical signs: 
 left parasternal heave, (due to right ventricular hypertrophy) 
 loud second pulmonary sound (P2) ,  
 pansystolic murmur of tricuspid regurgitation  
 early diastolic murmur of pulmonary insufficiency.  
 
Mechanisms and causes: 
 Pulmonary venous hypertension  
  Increased left atrial pressure: most commonly caused by left ventricular 
dysfunction as in congestive cardiac failure, which causes an elevation in PA

pressure by increased back-pressure through the lungs. 
 mitral stenosis or insufficient, 
  fibrosing mediastinitis  
 veno-occulsive disease. 
 mechanical obstruction of the pulmonary arteries 
 Acute or chronic thromboembolism. 
   hypoxia leads to constriction of the pulmonary arteries 
 Interstitial lung disease (ILD) 
 Chronic obstructive airways disease (COAD) 
 Acute respiratory distress syndrome (ARDS )  
 
 Pulmonary hypertension in pregnancy:

Pulmonary hypertension in pregnancy:  
 
 Pregnant with pulmonary hypertension have a high mortality of at least 30%  - 
some authors put it at 50% - seemingly highest immediately after delivery . 
 Gold standard for diagnosis is right-heart catheterisation , but echocardiogram can 
also give useful information.  
 The mainstay of treatment is with pulmonary vasodilators, but use in pregnancy needs 
to be discussed with the cardiology and obstetric team, and a decision made regarding

early delivery of the baby.  
 Drugs :  
 anorectic (fenfluramine, dexfenfluramine), 
 amphetamine  
 Cocaine (but not heroin). 
 
 Right heart catheterization is the best investigation for diagnosing pulmonary 
hypertension,  769

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 165 - 
  Pulmonary angiography is the definitive diagnostic test . It shows:  
 narrowed segmental pulmonary arteries,  
 sometimes accompanied by post-stenotic dilatation, 
  irregularity of the intima,  
 luminal narrowing of the central arteries   
 oddly shaped vessels.

 oddly shaped vessels. 
 Pulmonary fibreoptic angioscopy is useful to define surgical accessibility. 
 Ventilation/perfusion lung scans typically show: 
  one or more mismatched segmental or larger perfusion defects,  
 most patients have several bilateral mismatched perfusion defects. 
 
 First step: Treat any underlying conditions, for example with anticoagulants or oxygen.  
 Second step: perform  acute vasodilator testing   to decide on the appropriate

management strategy.  
 Acute vasodilator testing aims to decide which patients show a significant fall in 
pulmonary arterial pressure following the administration of vasodilators such as 
intravenous epoprostenol or inhaled nitric oxide  
 If there is a positive response to acute vasodilator testing:  
 oral calcium channel blockers 
 If there is a negative response to acute vasodilator testing:  
 endothelin receptor antagonists: bosentan 
 phosphodiesterase inhibitors: sildenafil

 phosphodiesterase inhibitors: sildenafil 
 prostacyclin analogues: treprostinil, iloprost 
 Sequence of treatment: 
 10-15% of patients benefit from calcium channel antagonists. 
 If symptoms going on the ideal next step would be an endothelin A receptor 
antagonist,  such as Bosentan.  
 following Bosentan, another oral therapy such as Sildenafil could be a logical 
next step, 
 followed by Prostacyclin. 
 Prostacyclin is currently delivered by infusion, oral prostaglandin receptor

agonists are currently under development. 
 
 Cor pulmonale (right ventricular failure) ,  
 presenting as jugular venous distension and hepatomegaly. 
 
 Several studies report a mean survival of only 2.5 years from diagnosis, 
 Patients with mean pulmonary artery pressures over 30 mmHg have a 5-year survival 
rate of 30%, but this rate falls to 10% if the mean pulmonary artery pressure is over 50 
mmHg. 
 
 770

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 166 - 
Respiratory tract infections: NICE guidelines  (2008) 
 
No antibiotic prescribing or delayed antibiotic prescribing approach  
 recommended for patients with: 
 acute otitis media,  
 acute sore throat/acute pharyngitis/acute tonsillitis,  
 common cold,

 common cold,  
 acute rhinosinusitis   
 acute cough/acute bronchitis. 
Immediate antibiotic prescribing approach 
 may be considered for: 
 children younger than 2 years with bilateral acute otitis media 
 children with otorrhoea who have acute otitis media 
 patients with acute sore throat/acute pharyngitis/acute tonsillitis when 3 or more 
Centor criteria are present 
 The Centor criteria are as follows: 
1. presence of tonsillar exudate

1. presence of tonsillar exudate 
2. tender anterior cervical lymphadenopathy or lymphadenitis 
3. history of fever 
4. absence of cough 
 if 3 or more of the criteria are present there is a 40-60% chance the sore 
throat is caused by Group A beta-haemolytic Streptococcus 
 If the patient is at risk of developing complications: 
 systemically very unwell patient 
 symptoms and signs suggestive of serious illness and/or complications

(particularly pneumonia, mastoiditis, peritonsillar abscess, peri-tonsillar 
cellulitis, intra-orbital or intracranial complications) 
 pre-existing comorbidity 
 significant heart, lung, renal, liver or neuromuscular disease,  
 immunosuppression,  
 cystic fibrosis,  
 young children who were born prematurely 
 older than 65 years with acute cough and two or more of the following, or 
older than 80 years with acute cough and one or more of the following:

1) hospitalisation in previous year 
2) type 1 or type 2 diabetes 
3) history of congestive heart failure 
4) current use of oral glucocorticoids 
 
How long respiratory tract infections may last? 
 acute otitis media: 4 days 
 acute sore throat/acute pharyngitis/acute tonsillitis: 1 week 
 common cold: 1 1/2 weeks 
 acute rhinosinusitis: 2 1/2 weeks 771

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 167 - 
  acute cough/acute bronchitis: 3 weeks 
Sarcoidosis 
 
 Sarcoidosis is a multisystem disorder of unknown aetiology characterised by non-
caseating granulomas. 
 More common in black people (African descent)  and subjects of Caribbean origin

 in Europe, sarcoid is commonest amongst Caucasians and has a significantly 
higher incidence in the Irish . 
 most common in black women   
 More common in young adults.  
 Has a bimodal age distribution with 2 peaks in the third and fifth decades. 
Pathology  
 noncaseating granulomas  in the organ involved.   
 the characteristic pathological feature of sarcoidosis. 
 may occur anywhere 
 The centre of the granuloma includes macrophages and giant cells, which are of

the Langerhans  type and can contain over ten nuclei . This core of cells is 
surrounded by two rings of lymphocytes:  
 the larger, inner component of CD4 helper cells and  
 the outer ring, which can comprise CD8 suppressor cells. 
 The central area of the granuloma will occasionally contain a Schaumann body , 
formed of crystallised material ( calcium phosphate ). 
 These granulomas have the capacity to produce 1,25 vitamin D explaining the 
associated hypercalcaemia.   

 initially presents with one or more of the following Abnormalities:  
 Bilateral hilar lymphadenopathy 
 Pulmonary reticular opacities 
 Lungs and lymph nodes affected in >90% of patients. 
 Skin, joint and/or eye lesions 
Features : 
 Dry cough 
 Dyspnoea (Pulmonary fibrosis) 
 Arthralgia 
 Inflammatory arthritis in sarcoidosis typically targets the ankle joint . 
 Uveitis (25% of cases) 
772

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 168 - 
   Skin lesions:  
 Erythema nodosum (10% of cases) 
 lupus pernio 
 Systemic symptoms: 
 Fever 
  weight loss  
 
 There is no one diagnostic test for sarcoidosis and hence diagnosis is still largely 
clinical.   
 Chest x ray  
 Chest x ray is abnormal in 85% of lung sarcoid, but 30-60% are asymptomatic

(that is, incidental chest x ray finding). 
 All patients should have a chest x-ray, which may show bilateral hilar 
lymphadenopathy.  
 The differential of bilateral hilar lymphadenopathy includes:  
 Sarcoidosis. A positive tuberculin test in a patient with chronic 
sarcoidosis is suggestive of active tuberculosis  
 Tuberculosis 
 Malignancy including lymphoma 
 Cystic fibrosis 
 Churg Strauss disease 
 HIV 
 Extrinsic allergic alveolitis 
 Phenytoin

 Phenytoin 
 Pneumoconiosis, especially berylliosis.   
 (Exposure to beryllium is seen in the nuclear power, 
telecommunications, semi-conductor and electronics 
industries ). 
 
Stage Finding Likehood of spontaneous 
resolution 
0 Normal chest radiograph >90% 
I Bilateral hilar lymphadenopathy 
(BHL) 60-90% 
II BHL plus pulmonary infiltrates 40-60% 
III Pulmonary infiltrates (no BHL) 10-20% 
IV Pulmonary fibrosis (+/- bullae) <20% 
 773

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 169 - 
 Other investigations 
 CT scan:   
 It can demonstrate the degree of fibrosis, micronodules in a subpleural or 
bronchoalveolar distribution, fissural nodularity and bronchial distortion.   
 Irregular linear opacities and ground-glass shadowing may also be seen.

 If the CT scan is diagnostic, then mediastinoscopy, bronchoscopy or biopsies can 
often be avoided.  
 Tissue biopsy : non-caseating granulomas  
 If the history and radiology is typical, the diagnosis of sarcoidosis can be 
confidently made and there may not be a need to proceed to tissue biopsy. 
 The presentation of erythema nodosum, arthropathy, bilateral hilar 
lymphadenopathy is so characteristic that histological diagnosis is not necessary.

 If there were atypical features and tissue biopsy was required, either 
transbronchial or open lung biopsy is preferable. 
 With less characteristic presentations, positive biopsies are needed.   
 Mediastinoscopy is the method of choice for anterior mediastinal nodes. 
 If you are asked to specify the investigation most likely to confirm the 
diagnosis , only transbronchial biopsy will determine whether non-
caseating granulomas are present or not.

caseating granulomas are present or not. 
 Transbronchial lung biopsy  will provide positive histology in about 80% 
of patients, is safe and can be done under sedation with local anaesthesia 
and is therefore the diagnostic investigation of choice.  
 Skin biopsy   
 
 ACE levels   
 It is elevated in about 70% of patients with active sarcoidosis.  
 have a sensitivity of 60% and specificity of 70% and are therefore not reliable in

the diagnosis of sarcoidosis although they may have a role in monitoring 
disease activity .  
 hypercalcaemia (seen in 10% if patients)  
 Hypercalcaemia , a potentially important complication of sarcoidosis, occurs in 
fewer than 10% of patients and is thought to be owing to elevated levels of 1,25-
dihydroxyvitamin D (calcitriol), which is produced by macrophages within the 
granulomas. 
 hypercalciuria (up to 50%) are well recognised in sarcoidosis.

 The pattern resembles hypervitaminosis D, with: 
 Elevated serum calcium 
 Normal serum phosphate and 
 Normal/slightly raised alkaline phosphotase. 
 Calculation of corrected calcium: 
 Add 0.1 mmol/L of calcium for every 4 g/dL that the albumin level is 
below 40 g/dL. 
 Example: (if Total protein = 55 g/L.  Globulin= 31 g/L ) 
 
 774

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 170 - 
  
Albumin + globulin = Total protein  
Albumin = Total protein  −  globulin 
  = 55 − 31 
  = 24 
Corrected calcium = 2.6 + (((40-24)/4) × 0.1) 
  = 2.6 + ((16/4) × 0.1) 
  = 2.6 + (4 × 0.1) 
  = 2.6 + 0.4 
  = 3.0 mmol/L 
 
 Raised ESR.   
 Hypergammaglobulinaemia (Ĺ Immunoglobulins) in 30 -80%.

 Leukopenia in 5-10% of patients 
 Spirometry usually shows a restrictive defect (Decreased gas-transfer factor 
(Tlco) with decreased gas-transfer coefficient (Kco) 
 Broncho-alveolar lavage typically shows a lymphocytosis  
 TB should be excluded by sending sputum or BAL washings for AFB 
 tuberculin test is negative in approximately 80-90 % of sarcoidosis cases 
 gallium-67 scan - not used routinely 
 the Kveim test  (where part of the spleen from a patient with known sarcoidosis is

injected under the skin) is no longer performed due to concerns about cross-infection 
 A positive tuberculin test in a patient with chronic sarcoidosis is suggestive of 
active tuberculosis 
 tuberculin test is usually negative in chronic sarcoidosis,  
 most patients with sarcoidosis who develop tuberculosis become tuberculin-
positive.  
 775

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 171 - 
  
776

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 172 - 
 Chest x-ray and CT scan showing stage 2 sarcoidosis with both bilateral hilar lymphadenopathy + 
interstitial infiltrates. The reticulonodular opacities are particularly noted in the upper zones. 
Remember that pulmonary fibrosis (which this case has not yet progressed to) may be divi ded into

conditions which predominately affect the upper zones and those which predominately affe ct the 
lower zones - sarcoidosis is one of the former. The CT of the chest demonstrates diffu se areas of 
nodularity predominantly in a peribronchial distribution with patchy areas of consolidation  
particularly in the upper lobes. There is some surrounding ground glass opacities. No gross 
reticular changes to suggest fibrosis. 
 
The majority of patients with sarcoidosis get better without treatment  
 
 the fate of acute sarcoidosis 
 Spontaneous remission  occurs in two-thirds of patients 
 progress to chronic course  in 10-30%. 
 Spontaneous remissions occur in 55% to 90% of patients with stage I, 40% to 
70% of patients with stage II, and about 20% of patients with stage III disease, 
but no remissions are expected in stage IV. 
 Duration of remission

 Duration of remission 
 Remissions often occur within the first 6 months  after diagnosis. 
 50% of patients with stage 2 sarcoidosis  (ie hilar lymphadenopathy and 
parenchymal infiltrate) recover spontaneously in 2 years . 
 Treated with topical corticosteroids for mild local cutaneous disease.  
 Systemic corticosteroids are the mainstay of treatment for severe disease. 
 Prednisolone is the mainstay of initial treatment for sarcoidosis , continued for 12

months or more in those patients who respond, but tapered to the minimal effective 
dose to stop within 2 years maximum. 
 Methotrexate and hydroxychloroquine may be added as steroid sparing agents. 
 
Indications for steroids  
 patients with chest x-ray stage 2 or 3 disease who have moderate to severe or 
progressive symptoms. Patients with asymptomatic and stable stage 2 or 3 disease who 
have only mildly abnormal lung function do not require treatment 
 hypercalcaemia (10% of cases)

 hypercalcaemia (10% of cases)  
 eye, heart or neuro involvement 
 
Prognosis  
Erythema nodosum is associated with a good prognosis in 
sarcoidosis.  
 
 Sarcoidosis remits without treatment in approximately two-thirds of people 
 The prognosis is excellent with less than 10% having persistent disease.  
 Mortality in the UK from sarcoidosis is less than 5%. 
 Factors associated with a good prognosis include 
 HLA B8  777

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 173 - 
  Lofgren's syndrome (bilateral hilar lymphadenopathy, erythema nodosum, polyarthritis 
and fever).  
Factors associated with poor prognosis  
 insidious onset, symptoms > 6 months (chronic pulmonary involvement) 
 absence of erythema nodosum 
 extrapulmonary manifestations: e.g.  
 lupus pernio

 lupus pernio  
 Lupus pernio: is a chronic raised indurated (hardened) lesion of the skin, 
often purplish in colour, and is associated with sarcoid.  
 splenomegaly 
 Cardiac involvement  
 Cardiac sarcoidosis is rare but can manifest as a prolonged PR interval. 
 Chronic hypercalcaemia 
 Nasal mucosal involvement 
 Neurosarcoidosis 
 CXR: stage III-IV features 
 black people ( Afro-Caribbean or Afro-American race ) 
 Age of onset >40 years 
 
Lofgren's syndrome

Lofgren's syndrome 
 
 Lofgren's syndrome is an acute form sarcoidosis characterised by: 
  bilateral hilar lymphadenopathy (BHL) 
 erythema nodosum,  
 fever  
 and polyarthralgia.  
 it typically occurs in young females and carries an excellent prognosis. 
 It is typically more common in Scandanavian patients and less common in Afro-
Caribbean patients and typically has amuch better prognosis.  
 Treatment:   
778

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 174 - 
  For less symptomatic patients then supportive measures and NSAIDs for 
arthralgia are the preferred treatment options.  
 For patients who are not responsive to steroids or steroid intolerant then 
immunosuppressant agents such as methotreaxtae can be tried.

Loffler's syndrome  is a cause of pulmonary eosinophilia thought to be caused by parasites 
such as Ascaris lumbricoides 
 
Mikulicz syndrome :  
 It is a chronic condition associated with sarcoidosis  
 characterized by the abnormal enlargement of parotids, lacrimal, salivary glands,  
tonsils and other glands in the soft tissue of the face and neck.  
 
Heerfordt's syndrome   
 is an acute presentation of sarcoidosis, which presents with fever , uveitis  (red, painful

eyes), bilateral swelling of the parotid  and other salivary and lacrimal glands. Facial 
nerve palsy (LMNL) may be a feature, and other features of sarcoidosis may co-exist 
(e.g. skin lesions, pulmonary involvement).   
 As it represents a form of neuro-sarcoidosis, other neurological features may be present 
(e.g. meningism, ophthalmoplegia and pupillary reflex dysfunction).   
 
Cough

Cough 
 Acute cough is defined as one lasting less than three weeks.  
 Chronic cough is defined as one lasting over eight weeks .  
 There is a grey area between three to eight weeks and this includes post-viral coughs .  
 drugs that can cause cough  
 The most common drugs: 
 Angiotensin converting enzyme inhibitors  
 (occurs in up to 15% of patients )  
 smoking.  
 Other drugs that can cause cough are: 
 statins,  
 amiodarone,  
 angiotensin II receptor blockers

 angiotensin II receptor blockers 
 interferon alpha and beta. 
 The British Thoracic Society recommend the following for the initial evaluation of 
chronic cough:  
 History (including occupational) and physical examination 
 Chest x-ray and spirometry are mandatory 
 Bronchial provocation if no obvious aetiology and normal spirometry 
 Bronchoscopy if inhalation of a foreign body is suspected 
 High resolution CT scan if all targeted investigations are normal 
 779

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 175 - 
Pulmonary side effects of drugs 
Cardiac drugs 
 Aspirin   nasal polyps, asthma 
 Atenolol   bronchoconstriction 
 Lisinopril   cough 
 Amiodarone  pulmonary fibrosis 
 Furosemide  bronchoconstriction (very rarely)

Pulmonary complications of cytotoxic and immunosuppressive drugs 
 Methotrexate(disease-modifying anti-rheumatoid drug (DMARD)  may cause 
Pulmonary pneumonitis (inflammation of the lung). 
 Penicillamine ( DMARD)may cause bronchiolitis obliterans. 
 
Other drugs: 
 Non-steroidal anti-inflammatory drugs can cause asthma or pulmonary eosinophili a. 
 Phenytoin characteristically causes pulmonary eosinophilia. 

Idiopathic pulmonary haemosiderosis 
 Idiopathic pulmonary haemosiderosis tends to occur in younger people 
 characterised by pallor, weakness, lethargy, dry cough and occasional haemoptysis 
 There are no extrapulmonary features.  
 There are no abnormal immunological features, which differentiates it from 
Goodpasture syndrome and wegener ’s  
 Gas transfer is elevated as blood is already in the alveolar space. 
Finger clubbing

Finger clubbing 
 Loss of the natural angle between the nail and the nail bed. 
 increased curvature  of the nail 
Causes 
 Suppurative diseases: 
 long-standing bronchiectasis 
 acute  lung abscesses 
 empyema 
 Malignant disease - especially carcinoma of the bronchus and pleural malignancy 
 Fibrosing alveolitis 
 Asbestosis 
 hypertrophic pulmonary osteoarthropathy,  
 painful osteitis of the distal ends of the long bones of the lower arms and legs.

 Malignancy is associated in 95% of these cases. 
Finger clubbing is not seen in uncomplicated bronchitis.  
 780

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 176 - 
Hyper-eosinophilic syndrome : 
 peripheral blood eosinophil count of >1.5 for more than 6 months.  
Features  
 fatigue, myalgia,  
 fever, night sweats,  
 diarrhoea  
 pruritus.  
 Other symptoms depend on the organ involved:

 Other symptoms depend on the organ involved:  
 cardiac disease causes chest pain and dyspnoea,  
 respiratory disease presents with a dry cough.  
Cyanosis without hypoxia 
 Persistent cyanosis without hypoxia (a normal Pao2) suggests a diagnosis of 
methaemoglobinaemia  or sulfhaemoglobinaemia. 
 In a cyanosed patient the amount of reduced haemoglobin in the blood is at least 5 g/dl

 The blue colour of the skin and mucous membranes is due to hypoxia and not 
hypercapnia. Hypoxia should be corrected by oxygen therapy 
 What is the possible cause of Desaturation on SaO 2 (using an oximeter)  in spite 
of normal PaO 2? 
 Methaemoglobinaemia  
 accumulation of reversibly oxidised methaemoglobin causing reduced 
oxygen affinity of the Hb molecule with consequent cyanosis.  
 It can occur due to:  
 an inherited condition or

 an inherited condition or  
 as a consequence of drugs such as nitrites . 
Yellow nail syndrome 
 It is an abnormality of lymphatic drainage . 
 the nails are yellow, thickened, curved, stop growing and may become detached from 
the nail bed. 
 
 congenital lymphoedema 
 pleural effusions 
 bronchiectasis (40%) 
 chronic sinus infections 
 Yellow discolouration of the nails. 781

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 177 - 
  
Hepatopulmonary syndrome: 
 oxygenation defect induced by pulmonary vascular dilatation  in patients with liver 
cirrhosis or portal hypertension,  (wide alveolar-arterial gradient ( >15mmHg)) .  
Mechanism

Mechanism 
 The vascular dilatation is thought to be induced by increased pulmonary levels of nitric 
oxide.  
 It is seen in 15-30% of patients with cirrhosis.  
Features: 
 Dyspnoea  
 dyspnoea with an insidious onset. 
 Dyspnoea whilst standing (platypnoea) and hypoxaemia exacerbated by being 
upright (orthodeoxia) are characteristic, and are thought to be due to the

predominance of vascular dilatation in the lung bases . Blood flow to these areas 
is increased in the upright position. 
 'orthodeoxia': 
 Hepatic disease  intrapulmonary vasodilatation mainly in the lower Lobes 
 right- to-left shunting (similar to pulmonary arteriovenous malformations 
(PAVMs)  increased blood flow through the lower lobes when the patient 
moves from the supine to the erect position  blood from the lower lobes, 
782

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 178 - 
 which is more poorly oxygenated, entering the left side of the heart,  
oxygen desaturation in the erect position.  
 Desaturation during sleep 
 clubbing  
 cyanosis. 
 Contrast-enhanced transthoracic echocardiography is the best test to

demonstrate intrapulmonary vascular dilatation . It can also exclude intracardiac 
shunting which may result in similar signs and symptoms to hepatopulmonary 
syndrome . 
 Method 
 performed by injecting agitated saline intravenously during transthoracic 
echocardiography.  
 In a normal subject microbubbles are visualised in the right ventricle within 
seconds, which are then absorbed in the alveoli.

 Immediate visualization in the left ventricle (within three cardiac cycles) 
indicates intracardiac shunting .  
 Delayed visualisation in the left ventricle (3-6 cardiac cycles) is diagnostic 
of intrapulmonary shunting . 
 Radionuclide lung perfusion scanning can also be used.  
 Chest radiographs can be normal or show non-specific interstitial changes.  
 ABGs should be taken in the sitting position to grade the severity of the condition based 
on the degree of hypoxaemia. 

 Liver transplantation is the only proven beneficial available treatment, with 85% of 
patients showing resolution or significant improvement in gas exchange postoperatively. 
Prognosis 
 It is a poor prognostic indicator. 
Inhalation of hot smoke  
 Inhalation of hot smoke can burn the upper airways and contributes significantly to 
deaths due to fires.

deaths due to fires.  
 Timing of obstruction development: 
 Upper airway obstruction due to heat injury and mucosal swelling usually 
develops within 24 hours of exposure,  
 stenosis due to scarring can develop later.  
 Factors suggesting  significant upper airway damage  
 hoarse voice, stridor, severe conjunctivitis, burnt nasal hairs and falling peak flow 
values. 783

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 179 - 
  The definitive investigation in assessing this condition:  
 Bronchoscopy is the best tool to establish whether there is significant 
oedema or mucosal ulceration obstructing the airways.  
 
Pulmonary alveolar microlithiasis (PAM)  

 rare autosomal recessive disease in which calcium phosphate   accumulate in the 
alveoli causes widespread damage to the alveoli and surrounding lung tissue  
 SLC34A2  gene mutations  Ļ activity of the type IIb sodium -phosphate cotransporter 
(which located mainly in alveolar type II cells)   accumulation of phosphate in the 
alveoli  formation of microliths  
 SLC34A2  gene  is responsible for the uptake of phosphate released from phospholipids

in outdated surfactant. 
Feature 
 usually diagnosed before age 40.  
 Commonly asymptomatic, Often discovered, when medical imaging is done for other 
reasons. worsens slowly over many years.  
 Often patients may have no symptoms despite striking radiological abnormalities.  
 persistent cough 
 dyspnea, especially during physical exertion.  
 PFT shows restrictive pattern  
 chest pain that worsens when coughing, sneezing, or taking deep breaths.

 People with pulmonary alveolar microlithiasis can also develop calcium phosphate 
deposits in kidneys, gallbladder, testes, and aortic valve.  
Diagnosis 
 the best diagnostic schedule for PAM is the association of BAL and chest HRCT ,  
 as the BAL can document the diagnosis while the HRCT provides further information 
about the degree of inflammation and/or fibrosis or calcification of the interstitium. 
 A 'sandstorm-appearing' chest radiograph is a typical diagnostic finding .

  In the initial stages, the radiological finding may mimic miliary tuberculosis.  
 Calcified nodules are found in later stages. 
 An interesting radiological sign in PAM is a black pleura sign . Here, the 
calcification of alveoli and the adjacent rib make the pleura resemble a black line 
in between two white signals.  
 BAL and biopsy show the characteristic calciospherocitis (microliths) in the 
alveoli   (deposition of calcium and phosphate crystals).

 Biopsy also shows variable degrees of fibrosis in the lung interstitium 
 
Treatment 
 lung transplantation is the only effective therapy.  
 No medical intervention has proved successful 
 Bronchial lavage is not useful, unlike in pulmonary alveolar proteinosis. 
 
 784

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 180 - 
 ___________________________________________________________________________  
Pulmonary Alveolar Proteinosis (PAP)   
 It is a rare diffuse lung disease in which the alveolar sacs become filled with proteins 
that characteristically stain for  periodic acid-Schiff (PAS) , a protein derived from 
surfactant  .

surfactant  . 
  prevalence of 1 case per 100,000   
 Common in males (M: F = 4:1)  
 It usually affects people aged between 20-60 years who have no previous lung disease,  
Causes 
 primarily  
 pneumocystis Jirovecii or 
  atypical mycobacteria,  
 Secondary 
 immunosuppressants, HIV 
 organic dusts  
 haematological malignancy  . 
Feature 
 Pulmonary symptoms: Persistent dry cough , progressive dyspnea  and pleuritic chest 
pain

pain 
 General symptoms: Fatigue, malaise, weight loss and low-grade fever  
 Clubbing (25%) 
Diagnosis 
 Flexible bronchoscopy with broncho-alveolar lavage (BAL)  
 The standard diagnostic test 
 PAS-positive stains  
 increased presence of surfactant proteins A and D  . 
 HRCT chest  
 shows a classical picture of dense infiltrates, often referred to as ‘crazy paving ’ 
Pattern.   
 Spirometry 
  shows a restrictive pattern with reduced lung capacity and reduced CO diffusion  .

 Autoantibodies   
 Ĺ autoantibody against GM -CSF (immunoglobulin G [IgG] isotype) in serum and 
BAL fluid  
Treatment 
 Most patients do not require treatment unless their SOB is disabling  . 
 washing the alveoli out with salt solution.  785

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 181 - 
  This can be done with bronchoscopy or under general anaesthesia through the 
trachea.  
 If both lungs need washing then they are done about 5 days apart.  
 The number of washing depends on symptoms  . 
 Prognosis  is good. 
Parotitis

Parotitis 
 Bacterial parotitis  
 Commonly unilateral 
 more common in older patients.  
 The risk is increased by agents that have an atropine-like action, including 
medications prescribed to reduce excess respiratory secretions.  
 A ductal stone, with consequent pooling of infected secretions, should be 
excluded, and ultrasound is an appropriate investigation to perform for this.  
 Antibiotics should be selected that cover typical mouth flora. 
 Viral parotitis

 Viral parotitis 
 Mumps parotitis is usually bilateral 
 ________________________________________________________________  
Carbon monoxide poisoning 
Confusion, pyrexia and pink mucosae are typical features of carbon monoxide poisoning  
 
 Epidemiology 
 Carbon monoxide is the  commonest  cause of poisoning-associated death in the United 
Kingdom 
 There are approximately 50 per year deaths from accidental carbon monoxide 
poisoning in the UK.

poisoning in the UK. 
 Patients with pre-existing vascular disease are at an increased risk of morbidity and 
mortality from carbon monoxide poisoning 
Causes 
 Fumes from cleaning fluids and paint removers that contain methylene chloride 
(dichloromethane) can also cause carbon monoxide poisoning. When breathed in, 
methylene chloride is converted into CO gas. 
 Carbon monoxide binds with haemoglobin with a greater affinity than oxygen displacing

it from the blood causing tissue hypoxia.  
 carbon monoxide shifts the oxygen dissociation curve to the left reducing tissue delivery 
even more. 
 the fetal haemoglobin of t he unborn child in pregnant women preferentially bound to th e 
poisonous carbon monoxide gas which may survived her. 
 
786

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 182 - 
 Questions may hint at badly maintained housing e.g. student houses  
 
Features of carbon monoxide toxicity   
 headache: 90% of cases 
 nausea and vomiting: 50% 
 vertigo: 50% 
 confusion: 30% 
 subjective weakness: 20% 
 hypertension, tachycardia and flushing. 
 severe toxicity: (carboxyhaemoglobin levels more than 50%)

 'pink' skin and mucosae,  
 hyperpyrexia,  
 arrhythmias,  
 extrapyramidal features,  convulsions, coma, death 
 Cerebellar signs are the most reliable indicator of significant neurological toxicity 
Typical carboxyhaemoglobin levels 
 < 3% non-smokers 
 < 10% smokers 
 10 - 30% symptomatic: headache, vomiting 
 > 30% severe toxicity 
Diagnosis 
 Arterial blood-gas analysis  
 Direct spectrophotometric measurement of HbCO in a blood-gas analyser 
is the gold standard.

is the gold standard.  
 Pulse oximeters cannot distinguish between COHb and HbO2, hence it is 
essential to take arterial blood gases  and – to make the specific diagnosis – 
measure the level of CO. 
 Pulse oximetry appears normal because carboxyhaemoglobin has similar 
absorption spectra to oxyhaemoglobin. 
 100% oxygen (Give high-flow oxygen (12 l/min) via a tight-fitting mask without a re-
breathing circuit) 
 hyperbaric oxygen

 hyperbaric oxygen 
 In severe cases intubation and mechanical ventilation may be required  
Indications for hyperbaric oxygen 
 loss of consciousness at any point 
 neurological signs other than headache 
 carboxyhaemoglobin concentrations over 40% at any time 
 myocardial ischaemia or arrhythmia 
 
 787

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 183 - 
 _____________________________________ ______________________________ 
 
Action of smoking 
 Nicotine is a stimulant and releases dopamine in the brain that leads to addictive effects 
of smoking.  
 Its effects can be replaced in other ways using nicotine replacement therapy and this

reduces the addiction to cigarette smoking. 
Management of smoking cessation  - General points (NICE guidance 2008) 
 patients should be offered nicotine replacement therapy (NRT), varenicline or bupropion 
- NICE state that clinicians should not favour one medication over another 
 NRT, varenicline or bupropion should normally be prescribed as part of a commitment 
to stop smoking on or before a particular date (target stop date)

 prescription of NRT, varenicline or bupropion should be sufficient to last only until 2 
weeks after the target stop date. Normally, this will be after 2 weeks of NRT therapy, 
and 3-4 weeks for varenicline and bupropion, to allow for the different methods of 
administration and mode of action. Further prescriptions should be given only to people 
who have demonstrated that their quit attempt is continuing

 if unsuccessful using NRT, varenicline or bupropion, do not offer a repeat prescription 
within 6 months unless special circumstances have intervened 
 do not offer NRT, varenicline or bupropion in any combination 
 
788

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 184 - 
  
NRT Varenicline  Bupropion  
Nicotine replacement 
therapy  Nicotinic receptor partial 
agonist  Norepinephrine and 
dopamine reuptake 
inhibitor, and nicotinic 
antagonist  
 Adverse effects: nausea & 
vomiting, headaches and 
flu-like symptoms 
 Nice recommend offering 
a combination of nicotine 
patches and another form

patches and another form 
of NRT (such as gum, 
inhalator, lozenge or nasal 
spray) to people who 
show a high level of 
dependence on nicotine or 
who have found single 
forms of NRT inadequate 
in the past  Should be started 1 week 
before the patient target 
date to stop 
 The recommended course 
is 12 weeks (but patients 
should be monitored 
regularly and treatment 
only continued if not 
smoking) 
 more effective than 
bupropion 
Adverse effect:  
 the most common SE  is 
Nausea.

Nausea.  
 Other SE : headache, 
insomnia, abnormal 
dreams 
used with caution in   
 patients with a history of 
depression or self-harm  
↑risk of suicidal behaviour 
Contraindicated in   
 pregnancy and breast 
feeding  Should be started 1 to 2 
weeks before target date. 
 Small risk of seizures (1: 
1,000) 
Contraindicated in:   
 epilepsy 
 other conditions that lower 
the seizure threshold, 
such as alcohol or 
benzodiazepine 
withdrawal, anorexia

withdrawal, anorexia 
nervosa, bulimia, or active 
brain tumors. 
  patients taking 
corticosteroids , 
antimalarials, tramadol 
and antidepressants, as 
these lower seizure 
 individuals who are also 
taking MAOIs. When 
switching from MAOIs to 
bupropion, it is important 
to include a washout 
period of 2 weeks.  
 pregnancy and 
breastfeeding. 
relative contraindication 
 eating disorder 
Pregnant women

Pregnant women  
 NICE recommended in 2010 that all pregnant women should be tested for smoking 
using carbon monoxide detectors, partly because 'some women find it difficult to say 
that they smoke because the pressure not to smoke during pregnancy is so intense.'  
 All women who smoke, or have stopped smoking within the last 2 weeks, or those with 
a CO reading of 7 ppm or above should be referred to NHS Stop Smoking Services. 
Adverse effects of smoking in pregnancy

Adverse effects of smoking in pregnancy  
  Reduces birth weight   
 (the reduction in birth weight is related to the number of cigarettes smoked per 
day). 
 increases risk of miscarriage and still birth.  789

Notes  & Notes for MRCP                                                                                       By  Dr. Yousif Abdallah Hamad  - 185 - 
  The infant has a greater risk of sudden infant death syndrome. 
 affect ovarian function in female children. 
 increases lung maturity , possibily by enhancing the production or secretion of cortisol. 
This makes neonates less likely to develop respiratory distress syndrome, but as lung

maturation is often abnormal babies may have reduced lung function and increased 
rates of other respiratory illnesses.  
Interventions  in pregnant smoker: 
 the first-line interventions in pregnancy should be cognitive behaviour therapy, 
motivational interviewing or structured self-help and support from NHS Stop Smoking 
Services 
 if the above measures failed  NRT is often used.  
 There is no evidence that it affects the child's birthweight.

 Pregnant women should remove the patches before going to bed 
 varenicline and bupropion are contraindicated 
 790

Gastroenterology 
 
Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    1 
  
By
 
Gastroenterology
 
Updated 
 
2017
 
Contains: 
2/ On examination 201 7  
 
791

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    2 
  
Basic GIT 
Anatomy 
Relations to peritoneum  
 Primary retroperitoneal organs include: (from the start of their development) 
 adrenal gland, kidneys, ureter,  
 aorta, IVC,  
 esophagus and rectum. 
 Secondary retroperitoneal 
 Pancreas (except the tail which is intraperitoneal)

 Duodenum (except the 1st part) 
 Ascending colon 
 Descending colon  
 Intraperitoneal organs include:  
 stomach, duodenum, liver, spleen, appendix, cecum and transverse colon. 
___________________________________________________________
Gastrointestinal physiology 
Acid secretion 
Principle mediators of acid secretion are 3: 
1. Gastrin 
 presence of breakdown products of protein (small peptides and amino acids)  
stimulate gastric G cells to secrete gastrin

stimulate gastric G cells to secrete gastrin  
 phenylalanine and tryptophan are most potent stimuli for gastric secretion 
2. Vagal stimulation 
 direct pathway 
 vagus nerve innervates gastric parietal cells 
 smelling, tasting of food and distension of stomach  vagal stimulation 
 at synapse, acetylcholine  (Ach) is released and binds muscarinic M3 
receptors  coupled to Gq proteins 
 Ĺ ACh ĺ (+) M3 receptors ĺ (+) Gq proteins ĺ (+) Phospholipase C ( PLC)  ĺ Ĺ

diacyl glycerol ( DAG ) and inositol 1,4,5-trisphosphate ( IP3) 
 IP3 releases Ca2+ from intracellular stores 
 DAG and Ca2+ ĺ (+) protein kinase C ( PKC )  ĺ (+) H+ -K+ ATPase ĺ Ĺ HCl 
secretion via gastric parietal cells 
 indirect pathway 
 vagus nerve innervates gastric G cells 
 at synapse, gastrin-releasing peptide (GRP) is released 
 GRP ĺ Ĺ gastrin secretion via gastric G cells  
3. histamine 
 the primary  modulator of acid secretion

 the primary  modulator of acid secretion  
 Released from: enterochromaffin-like (ECL) cells in gastric mucosa 
 diffused to nearby gastric parietal cells (paracrine mechanism of delivery) 
 action 
 histamine binds H2 receptors coupled to Gs proteins on gastric parietal cells 
 histamine ĺ (+) H2 receptors ĺ (+) Gs proteins ĺ (+) adenylyl cyclase ĺ Ĺ 
cAMP ĺ (+)  protein kinase A (PKA) ĺ (+) H+ -K+ ATPase ĺ Ĺ HCl secretion via 
gastric parietal cells 
Factors increasing acid secretion

Factors increasing acid secretion 
 gastrinoma 
 small bowel resection (removal of inhibition) 
 systemic mastocytosis (elevated histamine levels) 
 basophilia 
Factors decreasing acid secretion 
 drugs: H2-antagonists, PPIs 
 hormones: secretin, VIP, GIP, CCK,  glucagon  
 Prostaglandins . 
 atropine 792

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    3 
  a cholinergic muscarinic antagonist 
 blocks muscarinic M3 receptors on gastric parietal cells 
 blocks ACh-mediated, direct pathway of HCl secretion 
 but does not block GRP-mediated, indirect pathway of HCl secretion 
 so atropine does not inhibit HCl secretion via gastric parietal cells 
completely

completely 
__________________________________________________________  
Gastrointestinal Hormones 
 
 Source  Regulation  Actions  
 
Gastrin  G cells in 
antrum of the 
stomach ↑ by  
 Stomach Distension 
 vagal 
stimulation   
↓ by: 
 low antral pH 
 somatostatin  Ĺ HCL,  Ĺacidity, pepsinogen and  IF 
secretion,  
 Ĺ gastric motility,  
 Ĺ gastric  mucosa breakdown (trophic effect) 
 
CCK  I cells  in 
upper small 
intestine 
(duodenum, 
jejunum)  ↑ by  
Partially digested

Partially digested 
Proteins and 
Triglycerides  Ĺ secretion of enzyme -rich fluid from 
pancreas, contraction of gallbladder  and 
relaxation of sphincter of Oddi, Ļ  gastric 
emptying, trophic effect on pancreatic 
acinar cells, induces satiety 
 
Secretin  S cells in 
intestine 
(duodenum)  ↑ by  
Acidic chyme, 
fatty acids 
↓ by: 
somatostatin  ↑ secretion of bicarbonate -rich fluid from 
pancreas and hepatic duct cells, 
 Ĺ bile flow,

 Ĺ bile flow, 
 Ļ gastric  acid secretion 
 
VIP Small 
intestine 
pancreas Neural  ↑lipolysis, glycolysis  
 ↑ intestinal water and electrolyte secretion 
 ↑ relaxation of intestinal smooth muscle 
and sphincters 
 ↓acid and pepsinogen secretion.  
 vasodilator  
 
Somatostatin  D cells in the 
pancreas & 
Fat, bile salts and 
glucose in the 
intestinal lumen  Ļ acid and pepsin secretion, Ļ  gastrin

secretion, Ļ pancreatic enzyme secretion,  Ļ 
insulin and glucagon secretion 
 inhibits trophic effects of gastrin, stimulates 
gastric mucous production 
 
Brunner's glands which secrete alkaline mucus are found in the duodenum 
 
Clinical relations 
 Gastrin ĹĹ in  Zollinger-Ellison syndrome 
 A patient with cholelithiasis ( gallstones ) experiences worsened pain after fatty food 
ingestion  due to Ĺ release of CCK   contraction of gallbladder

 Secretin   Ĺ pancreatic HCO 3- secretion   neutralizes gastric H+ in duodenum, essential for 
fat digestion (pancreatic lipases have pH optimums between 6 and 8) 
 Somatostatin  
 Inhibitory hormone 
 Antigrowth hormone effects (digestion and absorption of substances needed for grow th) 
 Somatostatin is treatment for  VIPoma  and carcinoid tumors  
 VIPoma is a non- α, non -β islet cell pancreatic tumor that secretes VIP and causes copious 
diarrhea 
 793

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    4 
 January 2015 exam: Which hormone is most responsible for the secretion of bicarbonate in the upper 
gastrointestinal tract?  Secretin  
 
Intrinsic factor  
 Intrinsic factor is a glucoprotein secreted from the parietal cells  which are found in the 
fundus of the stomach  in response to gastrin, food or histamine.

 intrinsic factor transport vitamin B12 across the mucosal wall. 
 When the vitamin B12 bound to intrinsic factor reaches the terminal ileum , it binds to 
receptors on the surface of the mucosal cells and is able to cross the membrane and ente r the 
cytoplasm. The intrinsic factor is then replaced by transcobalamin II which transports 
the B12 out of the cell and into the bloodstream.  
 
 Secreted from  parietal cells of the stomach

 Secreted from  parietal cells of the stomach 
 Function  transport vitamin B12 across the mucosal wall of terminal ileum 
 The intrinsic factor is then replaced by transcobalamin II which transports the B12 out of 
the cell and into the bloodstream. 
B12 : 
 Transported in to the cells by  intrinsic factor 
 Transported out of the cells (into bloodstream) by  transcobalamin II 
Gastrin

Gastrin   
 Produced from the G cells of the gastric antrum into systemic circulation 
 not released into pyloric ducts that empty into lumen of stomach 
 delivered back to stomach via systemic circulation 
 endocrine mechanism of delivery 
 Action   
 stimulates the parietal cells to produce hydrochloric acid 
 stimulates gastric motility 
 Promotes release of secretin 
 Gastrin  promotes the synthesis of intrinsic factor and pepsinogen

 stimulates exocrine pancreatic secretions. 
 Promotes mucosal growth 
 Stimulates increased blood flow to stomach. 
 gastrin stimulates HCl secretion via gastric parietal cells by 2 mechanisms 
 gastrin binds CCK B receptors coupled to Gq proteins on gastric parietal cells 
 gastrin ĺ (+) CCKB receptors ĺ (+) Gq proteins ĺ (+)Phospholipase C ( PLC) 
ĺ Ĺ diacyl glycerol (DAG) and  Inositol trisphosphate receptor (IP3) 
 IP3 releases Ca2+ from intracellular stores

 DAG and Ca2+ ĺ (+) Protein kinase C (PKC) ĺ (+) H+ -K+ ATPase ĺ Ĺ HCl  
 gastrin binds CCK B receptors on enterochromaffin-like (ECL) cells 
 gastrin ĺ (+) CCK B receptors ĺ Ĺ histamine secretion ĺ Ĺ HCl secretion via 
 gastrin stimulates HCl secretion primarily by acting on (ECL)  cells   
 its production is stimulated by :

 its production is stimulated by : 
 neural reflex pathways (parasympathetic nerves) (Vagal stimulation due to the sme ll 
and taste of food) 
 direct effect of digested peptides on the G cells (presence of amino acids  in the 
stomach) 
 High gastric pH 
 Hypercalcaemia 
 Caffeine, alcohol, hypoglycaemia, calcium 
 Inhibited by: 
 acid in stomach 
 somatostatin.  
 Gastrinoma 
 Gastrin levels above 1,000 are strongly indicative of a gastrinoma.  794

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    5 
  Secretin stimulation test is the first choice , and a rise of greater than 200 is a pointer 
towards a gastrinoma  
 localised disease  Surgical resection is the treatment of choice 
 possibility of cure is up to 25% of patients.  
  less advanced, smaller tumours  Whipple's procedure

 A Whipple's procedure offers the best chance of effecting cure but 
excellent long term survival in those with less extensive procedures 
means that these may be considered for less advanced, smaller tumours. 
 metastatic disease  Chemotherapy 
Enzymes 
 
 Amylase is present in saliva and pancreatic secretions.  
 It breaks starch down into sugar

 It breaks starch down into sugar 
 The following brush border enzymes are involved in the breakdown of carbohydrates: 
 maltase: cleaves disaccharide maltose to glucose + glucose 
 sucrase: cleaves sucrose to fructose and glucose 
 lactase: cleaves disaccharide lactose to glucose + galactose 
Biochemical abnormalities in persistent vomiting  
 persistent vomiting  ĻĻ gastric hydrochloric acid  hypochloraemia and metabolic

Alkalosis   
 In the early stages the urine has low chloride and high bicarbonate levels in order to  
compensate for the loss of gastric hydrochloric acid and is appropriately alkaline.  
 With the continued dehydration, sodium is preferentially reabsorbed over the pota ssium and 
hydrogen ions which are excreted by the kidneys.  
 The urine becomes paradoxically acidic, hypokalaemia develops, and alkalosis leads to lower 
circulating levels of ionised calcium.

circulating levels of ionised calcium. 
 
To quickly remember the PH changes associated with GI losses, think :  
 With vomiting, both the PH and food come up. 
 With diarrhoea, both the PH and food go down. 
Clupping in GIT diseases  
 Coeliac disease 
 Crohn's disease 
 Ulcerative colitis 
 Whipple's disease 
 
Ilio-caecal TB  no clupping 
 
Oesophageal diseases 
Achalasia 
 
795

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    6 
  Failure of oesophageal peristalsis and of relaxation of lower oesophageal sphincter (L OS) due 
to degenerative loss of ganglia from Auerbach's plexus i.e. LOS contracted, oesopha gus 
above dilated.  
 prevalence of around 10.8/100,000 persons.  
 typically presents in middle-age

 typically presents in middle-age 
 equally common in men and women.   
Features  
 Symptoms usually develop years before the patient presents 
 dysphagia of BOTH liquids and solids (but dysphagia to solids is most common than 
liquids)  
 typically variation in severity of symptoms 
 heartburn 
 regurgitation of food - may lead to cough, aspiration pneumonia etc 
 Vague chest discomfort is common and results from oesophagal spasm.

 nocturnal cough (30%)  due to aspiration of oesophageal contents.  
 Increased risk of esophageal cancer. 
 
 barium swallow 
 initial investigation  
 will show: 
 dilated oesophagus  
 fluid level,  
 'bird's beak' appearance 
 manometry:  
 considered most important diagnostic test  
 indicated to establish the diagnosis ( confirmatory  test of choice ), irrespective of the 
initial imaging findings.

initial imaging findings. 
 can detect achalasia in the early stage  before oesophagal dilatation has occurred. 
 Will show: 
 excessive LOS tone which doesn't relax on swallowing  
 Lack of peristalsis in the lower two-thirds of the esophagus 
 Upper endoscopy 
 to rule out pseudoachalsia 
 Usually normal 
 May show retained food in esophagus or increased resistance of LES during passag e 
with endoscope 
 CXR:  
 wide mediastinum,

 CXR:  
 wide mediastinum,  
 Widened mediastinum is where the mediastinum has a width greater than 
6 cm  on an upright PA chest X-ray or 8 cm  on supine AP chest film. 
 fluid level 
 
The most appropriate initial investigation  of a high dysphagia  is a barium swallow , 
which identifies the site of pathology and forewarns of pitfalls such as a pharyngeal pouch, 
which if unidentified can increase the risk of perforation at endoscopy.  
 
Treatment

Treatment 
 Heller cardiomyotomy (Laparoscopic myotomy)  
 The best initial treatment for most patients with achalasia.  
 balloon dilation (Pneumatic dilatation)   
 the most cost-effective alternative  
 long-term efficacy is less than that of surgical myotomy .  
 the preferred option for older unfit patients  
 Pneumatic dilation is currently the most effective nonsurgical option for treatment of 
achalasia 
796

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    7 
  Current guidelines recommend obtaining gastrograffin study  followed by barium 
esophagram in all patients after pneumatic dilation to exclude esophageal 
perforation  
 25% of patients treated with pneumatic dilation required re-dilation. 
 intra-sphincteric injection of botulinum toxin

 Botulinum toxin injected into the lower oesophageal sphincter reduces the pressure and 
provides symptomatic relief  better than other drug therapy   
 However, the effects are temporary and patients need to undergo repeat injections 
every six to twelve months. 
 
 Endoscopic botulinum toxin injection can be considered when other forms of treatmen t 
are contraindicated.  reserved for the elderly and who cannot tolerate dilatation 
or surgery.

or surgery.  
 drug therapy has a role but is limited by side-effects 
 Short-term improvement in clinical symptoms may occur with isosorbide mononitrate, a 
long-acting nitrate or with nifedipine, a calcium-channel blocker.  
 Promotility agents like metoclopramide  increase the lower oesophageal sphincter pressure 
and so are contraindicated in achalasia. 
 
This film demonstrates the classical 'bird's beak' appearance of the lower oesophagus t hat is seen in

achalasia. An air-fluid level is also seen due to a lack of peristalsis 
 
797

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    8 
  
Mediastinal widening secondary to achalasia. An air-fluid level can sometimes be seen on CXR b ut it 
is not visible on this film 
 
Barium swallow - grossly dilated filled oesophagus with a tight stricture at the gastroeso phageal

junction resulting in a 'bird's beak' appearance. Tertiary contractions give rise to a corkscrew 
appearance of the oesophagus 
Dysphagia 
 
The table below gives characteristic exam question features for conditions causing dysphagia: 
 
Oesophageal 
cancer Dysphagia may be associated with weight loss, anorexia or vomiting during eating 
Past history may include Barrett's oesophagus, GORD, excessive smoking or 
alcohol use

alcohol use 
Oesophagitis  May be history of heartburn 
Odynophagia but no weight loss and systemically well 
candidiasis  There may be a history of HIV or other risk factors such as steroid inhaler use 
Achalasia  Dysphagia of both liquids and solids from the start 
Heartburn 
Regurgitation of food - may lead to cough, aspiration pneumonia etc 
Pharyngeal 
pouch  More common in older men 
Represents a posteromedial herniation between thyropharyngeus and cricopharyngeus 
muscles

muscles 
Usually not seen but if large then a midline lump in the neck that gurgles on palpation 
798

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    9 
 Oesophageal 
Typical symptoms are dysphagia, regurgitation, aspiration and chronic cough. Halitosis 
may occasionally be seen 
Systemic

Systemic 
sclerosis  Other features of CREST syndrome may be present, namely Calcinosis, Raynaud's 
phenomenon, oEsophageal dysmotility, Sclerodactyly, Telangiectasia 
 
As well as oesophageal dysmotility the lower oesophageal sphincter (LES) pressure is 
decreased. This contrasts to achalasia where the LES pressure is increased 
Myasthenia 
gravis  Other symptoms may include extraocular muscle weakness or ptosis 
Dysphagia with liquids as well as solids 
Globus

Globus 
hystericus  May be history of anxiety 
Symptoms are often intermittent and relieved by swallowing 
Usually painless - the presence of pain should warrant further investigation for organic 
causes 
 
Oesophageal disorders  
The table below lists a small group of oesophageal disorders that are not covered elsewhe re in the 
notes. 
Plummer-Vinson 
syndrome Triad of:

syndrome Triad of: 
 dysphagia (secondary to oesophageal webs) 
 glossitis 
 iron-deficiency anaemia 
Treatment includes iron supplementation and dilation of the webs 
Mallory-Weiss 
syndrome Severe vomiting ĺ painful mucousal  lacerations at the gastroesophageal junction 
resulting in haematemesis. Common in alcoholics 
Boerhaave 
syndrome Severe vomiting ĺ oesophageal rupture  
 
Diffuse oesophageal spasm

Diffuse oesophageal spasm 
Features 
Diagnosis 
 barium swallow demonstrates a 'corkscrew appearance' 
 Manometry reveals: 
 prolonged, repetitive and high amplitude contractions .  
 The lower oesophageal sphincter pressure is increased and there is incomplete 
relaxation of the sphincter. 
 
 Differential diagnosis manometry findings: 
 absence  of peristalsis in the body of the oesophagus +  high lower oesophageal sphincter  
Achalasia

Achalasia  
 normal  contractions in the body of the oesophagus + high lower oesophageal sphincter 
pressure  hypertensive lower oesophageal sphincter 
 high amplitude contractions in the body of the oesophagus + high lower oesophageal 
sphincter pressure   Diffuse oesophageal spasm  799

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    10 
  
Gastro-oesophageal reflux disease (GORD) 
In a patient aged below 55 years the symptoms of heartburn which is exacerbated by fa tty foods and 
the recumbent position in the absence of alarm features such as vomiting, bleeding, ana emia,

unexplained weight loss, abdominal mass, or dysphagia makes the diagnosis of gastr o-oesophageal 
reflux disease (GORD) the most likely. 
 
 decreased tone of the lower esophageal sphincter.  
 the most important physiological mechanism that prevents reflux  
Parasympathetic stimulation of the lower circular smooth-muscle fibres of the 
oesophagus  
Cause 
 Transient lower esophageal sphincter relaxation is the most common cause  
 Other causes include 
 pregnancy

 decreased motility secondary to progesterone 
 gastric acidity 
 gastric outlet obstruction 
 decreased esophageal motility 
 hiatal hernia 
 ≥ 90%  of patients with severe  GORD 
 Obesity 
 Transient relaxations of the lower esophageal sphincter (TRLES) have been 
observed to be more common in patients with obesity.  
 The main stimulus for TRLES is gastric distension, particularly in the fundus. 
 Associated with:

 Associated with:  
 Lifestyle habits such as smoking, caffeine and alcohol consumption   
 Scleroderma 
 Angle of His enlargement (> 60°) 
 
Features 
 heartburn and regurgitation when lying down.  
 (GORD) is the most common non-cardiac cause of chest pain .  
 may occur in a supine position, after meals, and along with a sour, acidic taste in the 
mouth. 
 Chronic GORD can present with chronic cough, new adult-onset of asthma, hoarsen ess, 
regurgitation, and dysphagia.

regurgitation, and dysphagia.  
 The three most common causes of a persistent cough are postnasal drip,  asthma, and 
GORD.  
 Acid reflux in chronic GORD can lead to damage of the enamel layer of teeth. 
 May present  with over-the-counter antacids side effects  which may include magnesium 
hydroxide.  
 Magnesium hydroxide  can act as an osmotic laxative , resulting in the adverse effect 
of diarrhea . 
 Symptoms do not correlate with mucosal status at endoscopy appearance

 endoscopy  
 Indications for upper GI endoscopy: 
 age > 55 years 
 symptoms > 4 weeks or persistent symptoms despite treatment 
 dysphagia 
 relapsing symptoms 
 weight loss 
 The most common endoscopic finding associated with esophageal mucosal injury is 
reflux esophagitis.  
 If endoscopy is negative consider 24-hr oesophageal pH monitoring (the gold 
standard test for diagnosis)  
Treatment 800

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    11 
  lifestyle changes  
 Small portions;  
 avoid eating (< 3 hours) before bedtime. 
 Avoid foods with high fat content 
 Avoid : nicotine, alcohol, coffee[12][7],  and certain drugs (e.g., calcium channel 
blockers, diazepam) 
 Proton pump inhibition

 Proton pump inhibition  
 if lifestyle changes are ineffective, one month course of a proton pump inhibitor 
(PPI)  
 full dose (PPI) for one month  will typically result in healing in 76%,  continuation for a 
further month increases this by a further 14%.  
 In those failing to respond to two months of full dose therapy  doubling the dose 
of proton pump inhibitor for one month increases response rate.  
 increase the dose to (twice daily therapy)

 increase the dose to (twice daily therapy) 
 In those failing to respond to a double dose of proton pump inhibition an H2 receptor  
antagonist may be added or substituted  in treatment or a prokinetic agent added  to 
 Offer H 2RA therapy if there is an inadequate response to a PPI. 
 Simply extending the duration of proton pump inhibitor therapy beyond two 
months without any additional change is not recommended.

 A regular maintenance  low dose  of most PPIs will prevent recurrent GORD 
symptoms in 70-80% of patients and should be used in preference to the hig her healing 
dose.  
 People who have had dilatation of an oesophageal stricture  should remain on  long-
term full-dose PPI therapy 
 Offer a full-dose PPI  long-term as maintenance  treatment for people with severe 
oesophagitis  
  Laparoscopic fundoplication

  Laparoscopic fundoplication  
 the treatment of choice for patients with GORD refractory to or intolerant of 
proton pump inhibitor therapy. 
 The patient should have had an endoscopy within the six months prior to surgery  to 
exclude any unsuspected pathology such as Barrett's oesophagus or adenocarcino ma. 
 the most useful in assessing the role of surgery  Oesophageal motility and pH 
study 
 
GORD management 
 1st line  - lifestyle changes

 1st line  - lifestyle changes 
 don't lie down after eating 
 avoid spicy foods 
 eat small servings 
 2nd line  proton pump inhibitors (omeprazole, lansoprazole)  
 3rd line  H2 receptor antagonists(cimetidine, ranitidine) or  
 4th line  Surgical Nissen fundoplication or hiatal hernia repair  
 
Treatment of choice: Standard-dose of PPI for at least 8 weeks (once daily therapy) 
 No response:  further diagnostic evaluation

 No response:  further diagnostic evaluation 
 Partial response:  increase the dose to (twice daily therapy)  
 Good response:  discontinue PPI after 8 weeks 
 if symptoms recur after discontinuation of PPIs   Maintenance therapy  
 After 8 weeks of initial treatment, reduce PPI to lowest effective dose 
 metaplasia of the lower esophagus, which is the first stage of Barrett esoph agus.  
 Esophageal strictures  occur in 10%  
 Two types of rings  (Schatzki rings ):

 Two types of rings  (Schatzki rings ): 
 muscular ring, or A ring: 
 located approximately 2 cm above the gastroesophageal junction.  
 rare 
 mucosal ring, or B ring, 
 most common  
 located at the squamo-columnar junction. 
 mechanical cause of dysphagia 801

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    12 
  characterized by progressive symptoms . Patients often first notice difficulty 
swallowing solid foods, and this then progresses to softer foods, and then fluids. 
 most patients respond well to dilatation therapy.  
 adenocarcinoma of the lower esophagus. 

Barrett's oesophagus 
  metaplasia of the lower oesophageal mucosa (squamous epithelium replaced by  columnar 
epithelium).  
 The physiological transformation zone ("Z-line") between squamous and columnar epith elium 
is shifted upwards 
 long duration or frequency of GORD symptoms,  
 previous oesophagitis,  
 previous hiatus hernia,  
 oesophageal stricture or ulcer  
 male gender 
Histological features

Histological features 
 the columnar epithelium may resemble that of either the cardiac region of the stomach or th at 
of the small intestine (e.g. with goblet cells, brush border) 
 
Barrett's oesophagus  
 endoscopic surveillance with biopsies 
 the merits of surveillance need to be assessed on a patient to patient basis: 
 NO dysplasia and <3 cm  segment of Barrett's 
 endoscopy every three to five years with biopsies

 NO dysplasia and segment Barrett's >3 cm  
 Endoscopy every two to three  years 
 Start a proton pump inhibitor and repeat the endoscopy and 
biopsy in two years  
 Low grade dysplasia 
 six monthly biopsy  
 high grade dysplasia  
 needs therapy; oesophagectomy, photodynamic therapy, ablative therapy. 
 high-dose proton pump inhibitor : 
  the best next line of management 
 whilst this is commonly used in patients with Barrett's the evidence base that this

reduces the change of progression to dysplasia or induces regression of the lesion is 
limited 
 moderate to severe grade dysplasia or recurrent disease 
 Endoscopic ablation therapy 
802

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    13 
  Endoscopic mucosal resection 
 Lower esophageal resection 
Prognosis 
 ĹĹ risk of oesophageal adenocarcinoma (50 -100 fold). 
 The risks of adenocarcinoma are relatively high but absolute risk is low 1% per year 
develop adeno-carcinoma. 
Oesophagitis

Oesophagitis  
 
 esophagitis in the immunocompromised that presents with punched-out ulcers   Herpes 
simplex virus-1   
 esophagitis in the immunocompromised that presents with a white pseudomembrane    
Candida spp.   
 esophagitis in the immunocompromised that presents with linear ulcers   Cytomegalovirus  
 
Candida  oesophagitis  
Although oropharyngeal candidiasis may be treated with topical antifun gal agents (such as

nystatin, clotrimazole, and amphotericin B oral suspension/lozenges ) Candida  oesophagitis 
requires oral or IV therapy (usually with fluconazole or itraconazole for at least 14- 21 
days).  
 
Eosinophilic oesophagitis (EOE)  
Causes  
 unknown,  
 allergies   
 At least 50% of children with EoE have allergies , including food allergies, allergic 
rhinitis (hay fever) and asthma.  
Features  
 episodic oesophageal spasm and intermittent dysphagia  
Diagnosis

Diagnosis  
 by endoscopy and biopsy   presence of eosinophils   
Treatment  
 Responds to “swallowed ” steroid  
Oesophageal cancer 
 
 Sex: ♂ > ♀ (3:1)  
 Adenocarcinoma is now the most common type  of oesophageal cancer and is more likely 
to develop in patients with a history of gastro-oesophageal reflux disease (GORD) or Barrett's.  
 The majority of tumours are in the middle third  of the oesophagus .

Types  
 Adenocarcinoma 
 the most common form of esophageal cancer in the United States,  
 affects primarily white men. 
 begins in the cells of mucus-secreting glands in the esophagus.  
 develops in the glandular cells of the submucosa . 
 occurs most often in the  lower  portion of the esophagus.  
 Most cancers in the lower oesophagus, including the junction where the 
oesophagus joins the stomach, are adenocarcinomas.

 45% of oesophageal carcinomas occur in the lower third and are usually 
adenocarcinomas. 
 Squamous cell carcinoma 
803

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    14 
  the most prevalent esophageal cancer worldwide. 
 develops in the thin, flat cells  of the mucosa  , which line the oesophagus. 
 occurs most often in the upper and middle portions (upper two-thirds) of the 
esophagus.  
 Cancers in the upper oesophagus are nearly always squamous cell cancers.

 Most cancers in the middle of the oesophagus are squamous cell cancers.  
 40% of oesophageal carcinomas occur in the middle third of the oesophag us and 
are usually squamous-cell carcinomas. 
 
Risk factors (emedicine.medscape.com 2017) 
 Risk factors for SCC 
 Smoking and alcohol use 
 No associations were found between alcohol consumption and esophageal 
adenocarcinoma. 
 Diet 
 Red meat consumption 
 Low selenium levels 
 selenium supplementation reduces the risk

 selenium supplementation reduces the risk 
 Zinc deficiency 
 mediates carcinogenesis by 
 enhancing the carcinogenic effects of nitrosamines and  
 also leads to overexpression of cyclooxygenase (COX)- 2. 
 Low dietary folate intake 
 low intake of fruits and vegetables  
 Foods products containing N-nitroso compounds  
 Toxin-producing fungi (eg, aflatoxin) induce carcinogenesis by reducing nitrates 
to nitroso compounds. 
 hot liquids  
 Certain infections 
 Tylosis

 Tylosis 
 Caustic stricture 
 Achalasia cardia 
 Prior gastrectomy  
 Use of oral bisphosphonates  
 Drinking scalding-hot liquids 
 Poor oral hygiene 
 Plummer-Vinson syndrome 
 Risk factors for adenocarcinoma 
 GORD  
 (the most common predisposing factor) 
 Barrett's oesophagus 
 Obesity and metabolic syndrome 
 rare: coeliac disease, scleroderma 
Risk factors for oesophageal cancer:  
Squamous Adenocarcinoma 
Alcohol - 
Smoking Smoking

Alcohol - 
Smoking Smoking 
Achalasia  Barrett's oesophagus  
Plummer vinson  GORD 
 
Although the mechanism of action is unclear population studies have shown a lower 
incidence of oesophageal cancer in patients infected with H. pylori . 
 
Features 
 Dysphagia is a  late symptom.  
 Presented with progressive dysphagia, initially worse on solids and then later to 
include liquids and weight loss  804

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    15 
  dermatological conditions associated with oesophageal carcinoma  Tylosis   
 
Diagnosis 
 Upper GI endoscopy is the first line test 
 Esophagogastroduodenoscopy  (best initial and confirmatory test) 
 Staging  
 CT 
 initially undertaken with CT scanning of the chest, abdomen and pelvis.

 If overt metastatic disease is identified using this modality then further complex 
imaging is unnecessary 
 If CT does not show metastatic disease, then local stage may be more accurately 
assessed by use of endoscopic ultrasound . 
 Staging laparoscopy  is performed to detect occult peritoneal disease.  
 PET CT  is performed in those with negative laparoscopy.  
Treatment 
 Most oesophageal cancers are not resectable at presentation

 Most patients present with stage 3 disease (late stage) and survival at 5 years is only 
9%.   
 Operable disease is best managed by surgical resection . 
 chemoradiotherapy then surgery is preferred to surgery alone.  
 A study of 1085 patients who underwent oesophagectomy surgery showed a 4 % 
operative mortality rate and a 23% survival rate. For patients who had 
preoperative chemoradiotherapy , the prognosis improved to 48%

 The most standard procedure is an Ivor- Lewis type oesophagectomy .  
 This procedure involves the mobilisation of the stomach and division of the 
oesophageal hiatus.  
 The abdomen is closed and a right sided thoracotomy performed.  
 The stomach is brought into the chest and the oesophagus mobilised further.  
 An intrathoracic oesophagogastric anastomosis is constructed.  
 Alternative surgical strategies include a transhiatal resection (for distal lesions),

 left thoraco-abdominal resection (difficult access due to thoracic aorta)  
 total oesophagectomy (McKeown) with a cervical oesophagogastric anastomosis. 
 
 The biggest surgical challenge is that of anastomotic leak, with an intrathoracic anastomosis 
this will result in mediastinitis. With high mortality. The McKeown technique has an intrinsi cally 
lower systemic insult in the event of anastomotic leakage.

 In addition to surgical resection many patients will be treated with adjuvant chemotherapy. 
 Nifedipine helps relieve painful oesophageal spasm and tenesmus associated with 
gastrointestinal tumours and could be used to relieve his odynophagia. 
 
What is the most common type of Oesophageal cancer? 
 patient.info ( https://patient.info/health/oesophageal-cancer-leaflet )  (04 Dec 2017)  
 Adenocarcinoma  of the oesophagus occurs in about 6 out of 10  cases in the UK.

 Squamous cell carcinoma  of the oesophagus occurs in about 4 out of 10  cases in the 
UK.  
 mayoclinic.org ( https://www.mayoclinic.org/diseases-conditions/esophageal-cancer/symptoms-
causes/syc-20356084 ) 
 Squamous cell carcinoma is the most prevalent esophageal cancer worldwide. 
 Adenocarcinoma is the most common form of esophageal cancer in the United State s 
 emedicine.medscape.com ( https://emedicine.medscape.com/article/277930-overview#a6 ) ( 
Updated: Jun 20, 2017 )

Updated: Jun 20, 2017 ) 
 esophageal adenocarcinoma is the most common  in the United States. 
 Unlike in the United States, squamous cell carcinoma is responsible for 95% of all 
esophageal cancers worldwide. 
Pharyngeal pouch  (or Zenker ’s diverticulum).  
 A pharyngeal pouch is a posteromedial diverticulum through Killian's dehiscence .

 Killian's dehiscence is a triangular area in the wall of the pharynx between the 
thyropharyngeus and cricopharyngeus muscles.  805

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    16 
  Upper esophageal diverticulum   (Common site) 
 Most common type of esophageal diverticula 
 more common in older patients  
 5 times more common in  men  
 they may be related to poor relaxation of the upper oesophageal sphincter.

 association with gastro-oesophageal reflux disease has been noted. 
 
Features 
 regurgitation 
 aspiration 
 neck swelling which gurgles on palpation (Boyce ’s sign). 
 halitosis  (a bad breath)  
Diagnosis 
 by barium studies  
 detected best by using lateral X-ray  shows a contrast-filled pouch protruding dorsally  
from the hypopharynx  at the level of C5/C6   
 Upper gastrointestinal endoscopy is risky, since the pouches are thin-walled and easy

to perforate; this is the reason why a barium swallow may be the preferable first-line 
investigation in elderly patients with dysphagia.   
Treatment  
 surgical, with either an open or endoscopic approach. 
 Diverticula of the middle and distal  esophagus (traction diverticula and epiphrenic diverticula) 
usually do not require treatment 
 
Acute upper gastrointestinal bleeding (UGIB) (NICE 2012)  

 bleeding derived from a source proximal to the ligament of Treitz.  
 
Causes : Most commonly due to either:  
 peptic ulcer disease or  
 oesophageal varices. 
Risk assessment  
 use the Blatchford score at first assessment, and 
 the full Rockall score after endoscopy 
Blatchford score 
 The Blatchford score  is based on clinical parameters alone: 
 Elevated blood urea nitrogen 
 Reduced haemoglobin 
 A drop in systolic blood pressure 
 Raised pulse rate

 Raised pulse rate 
 The presence of melaena or syncope, and 
 Evidence of hepatic or cardiac disease. 
 
Admission risk marker Score 
Urea (mmol/l) 6.5 - 8 = 2 
8 - 10 = 3 
10 - 25 = 4 
> 25 = 6 
Haemoglobin (g/l) Men 
 12 - 13 = 1 
 10 - 12 = 3 
 < 10 = 6 
Women 806

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    17 
 Admission risk marker Score 
 10 - 12 = 1 
 < 10 = 6 
Systolic blood pressure (mmHg) 100 - 109 = 1 
90 - 99 = 2 
< 90 = 3 
Other markers Pulse >=100/min = 1 
Presentation with melaena = 1 
Presentation with syncope = 2 
Hepatic disease = 2 
Cardiac failure = 2

Cardiac failure = 2 
 
Patients with a Blatchford score of 0 may be considered for early discharge 
 
Rockall score   
 Used to: 
  determine the prognosis of upper GIT bleeds.  
 assess severity of GIT bleeds and / or to triage patients for emergency endoscopy . 
 Consists of 5 categories: 
1. age 
2. shock 
3. co-morbidity e.g. ischaemic heart disease (IHD)  
4. diagnosis and 
5. evidence of bleeding (the latter two can only be categorised after endoscopy).

 Each category is scored between 0 and 2 points, with the exception of co-morbidities which 
has a maximum score of 3.   
 Renal failure , liver failure and metastatic cancer carry the highest points, and 
thus confer the highest risk of death , of any of the other parameters included in the 
scoring system. 
 The full Rockall scoring system is shown in the table below: 
  Score 0 Score 1 Score 2 Score 3  
Age <60 60-79 >80 - 
Shock No shock Pulse >100 Systolic blood 
pressure <100 
mmHg -

mmHg - 
Co-morbidity Nil major   CCF, IHD, major 
morbidity Renal or liver failure, 
metastatic cancer  
Diagnosis Mallory-
Weiss tear All other 
diagnoses GI malignancy - 
Evidence of 
bleeding None - Blood, adherent clot, 
spurting vessel - 
 Interpretation: 
 Increasing scores are strongly correlated with increasing risk of mortality ,  
 The total score predicts mortality as follows:  
 Score 0,   0.2%;  
 score 2,  5%;  
 score 4,  24%;  807

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    18 
  score 6,  49%.   
 correlation with risk of re-bleeding  is also present but not as strong. 
 
 Grades of hypovolaemic shock  
The table below outlines the signs and symptoms of the different grades of hy povolaemic shock: 
Grade 
1  Up to about 15% loss  of effective blood volume ( ~750ml  in an average adult

who is assumed to have a blood volume of 5 litres).  
 This leads to a mild resting tachycardia  and can be well tolerated in 
otherwise healthy individuals.  
 In the elderly or those with underlying conditions such as ischaemic heart 
disease the additional myocardial oxygen demands may not be tolerated so 
well. 
Grade 
2  Between  15-30% loss of blood volume ( 750-1500ml )  
 will provoke a moderate tachycardia and begin to narrow the pulse 
pressure .

pressure .  
 The capillary refill time will be extended . 
Grade 
3  At 30 - 40% loss  of effective blood volume ( 1500 - 2000 ml )  
 the compensatory mechanisms begin to fail  and hypotension , tachycardia 
and low urine output  (<0.5ml/kg/hr in adults) are seen. 
Grade 
4  At 40-50% loss  of blood volume ( 2000-2500 ml )  
 profound hypotension  will develop and if prolonged will cause end-organ 
damage and death . 
  
Blood test evidence of upper gastrointestinal haemorrhage

 Reactive thrombocytosis  
 Urea elevated in excess of creatinine  
 
Treatment 
 Resuscitation  
 ABC, wide-bore intravenous access  
 platelet transfusion if actively bleeding platelet count of less than 50  x 10*9/litre 
 fresh frozen plasma to patients who have either a fibrinogen level of less than 1 g/litre , 
or a prothrombin time (international normalised ratio) or activated partial thromboplastin 
time greater than 1.5 times normal

time greater than 1.5 times normal 
 prothrombin complex concentrate to patients who are taking warfarin and actively 
bleeding 
 Endoscopy  
 should be offered immediately after resuscitation in patients with a severe ble ed 
 all patients should have endoscopy within 24 hours 
808

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    19 
  Recent NICE guidelines do not recommend proton pump inhibition (PPIs)  before 
endoscopy.  
 He may have alcohol dependency and therefore should be prescribed Pabrinex  
whilst waiting for endoscopy.  
 Management of non-variceal bleeding  
 NICE do not recommend the use of proton pump inhibitors (PPIs) before endoscopy  to

patients with suspected non-variceal upper gastrointestinal bleeding although PPIs 
should be given to patients with non-variceal  upper gastrointestinal bleeding and 
stigmata of recent haemorrhage shown at endoscopy  
 The best evidence for pharmacological intervention post-stabilisation of bleeding peptic 
ulcer disease is for proton pump inhibitors.  
 the most appropriate intervention to prevent further bleeding  IV 
omeprazole 
 reduction in risk of recurrent bleeding of over 50%,

 reduction in need for surgical intervention of approximately 40%.  
 if further bleeding then options include repeat endoscopy, interventional radiology an d 
surgery 
 Management of variceal bleeding  
 terlipressin  and prophylactic antibiotics should be given to patients at presentation (i.e. 
before endoscopy) 
 band ligation should be used for oesophageal varices and injections of N-butyl-2-
cyanoacrylate for patients with gastric varices

cyanoacrylate for patients with gastric varices 
 transjugular intrahepatic portosystemic shunts (TIPS) should be offered if bleeding from 
varices is not controlled with the above measures 
Oesophageal varices 
 
Oesophageal varices drain into azygous vein  and thence into superior vena cava 
 
 Esophageal varices are the most common cause of death in cirrhosis.  
 
Acute treatment of variceal haemorrhage

Acute treatment of variceal haemorrhage 
 
 ABC: patients should ideally be resuscitated prior to endoscopy 
 correct clotting: FFP, vitamin K 
 vasoactive agents:  
 terlipressin is currently the only licensed vasoactive agent  and is supported by 
NICE guidelines.  
 powerful splanchnic vasoconstrictor  
 It has been shown to be of benefit in initial haemostasis  and preventing 
rebleeding .  
   the most appropriate treatment whilst awaiting urgent endoscopy

 As a vasoconstrictor its administration is contraindicated in those with a 
history of ischaemic heart disease as it may precipitate myocardial ischaemia. 
 Octreotide may also be used although there is some evidence that terlipressin has a 
greater effect on reducing mortality 
 prophylactic antibiotics  
 have been shown in multiple meta-analyses to reduce mortality in patients with liver 
cirrhosis.  
 Quinolones are typically used. 
 endoscopy:

 endoscopy:  
 endoscopic variceal band ligation is superior to endoscopic sclerotherapy. NICE 
recommend band ligation 
809

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    20 
  Sengstaken-Blakemore tube if uncontrolled haemorrhage 
 Balloon tamponade (for example, using a Sengstaken-Blakemore tube) may be use d as 
a holding measure in situations where, for whatever reason, a definitive procedure 
cannot be performed to control bleeding  (for example, endoscopy or transjugular

intrahepatic portosystemic shunting).  
 It is generally very effective in achieving control of variceal bleeding. 
 Transjugular Intrahepatic Portosystemic Shunt (TIPSS) if above measures fail 
Prophylaxis of variceal haemorrhage 
 propranolol:  
 reduced rebleeding and mortality compared to placebo 
 endoscopic variceal band ligation (EVL)  
 is superior to endoscopic sclerotherapy.  
 It should be performed at two-weekly intervals until all varices have been era dicated.

 Proton pump inhibitor cover is given to prevent EVL-induced ulceration 
 
Esophageal Rupture  
 Causes   
 Iatrogenic esophageal perforation:  
 most common cause of esophageal perforation 
 Generally injury during upper endoscopy 
 Symptoms usually within 24 hours of endoscopy 
 Foreign body ingestion 
 Trauma 
 Malignancy 
 Boerhaave syndrome 
 Severe vomiting/increased intrathoracic pressure ĺ rupture of all layers of the 
esophageal wall

esophageal wall 
 In > 90% of cases, the rupture occurs in the distal third  of the esophagus on the 
left dorsolateral wall surface. 
 Sex: ♂ > ♀ (3:1)  
 Associations 
 Excessive intake of alcohol or food in the recent past 
 Repeated episodes of vomiting 
 Childbirth 
 Seizures 
 Prolonged coughing 
 Weightlifting 
  
 Feature:  
 Mackler's triad (vomiting, chest pain and surgical emphysema) is classical but absent in 
almost half the cases. 
 surgical emphysema

 surgical emphysema  
 Subcutaneous emphysema ĺ crepitus in the suprasternal notch  
 mediastinal emphysema ĺ  "crunching" or "crackling" sound on chest 
auscultation ( Hamman's sign )  
 The most relevant finding on examination is the crepitus over 
the chest 
 Dyspnea, cyanosis 
 investigations :  
 Gastrografin swallow  will confirm the site of perforation in approximately 65-75% of 
cases, and is the recommended first line investigation.   
 chest x ray

 chest x ray   
 useful in the initial diagnosis  
 The most common finding is a unilateral effusion , usually on the left.   
 Because the most perforations occur in the left posterior aspect of the 
esophagus. 
 Other findings may include 
 pneumothorax, hydropneumothorax, pneumomediastinum,  
 surgical emphysema. 
 mediastinal widening.  
 Lateral neck x rays   810

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    21 
  may be useful in the early stages where the diagnosis is uncertain and surgical 
emphysema is not seen on a plain CXR. 
 CT scan :  
 indicated in unstable/uncooperative patients, pneumoperitoneum on x-ray, or ifx-
rays and contrast esophagram are inconclusive  
 Barium  swallow

 Barium  swallow  
 more sensitive at 90% for detecting small perforations but carries the risk of a 
severe inflammatory response ( mediastinaitis ). 
 A reported mortality estimate is approximately 35%, making it the most lethal 
perforation of the GI tract.  
 If intervention is delayed longer than 24 hours, the mortality rate (even with surgical 
intervention) rises to higher than 50% and to nearly 90% after 48 hours. Left untreate d, 
the mortality rate is close to 100%.

the mortality rate is close to 100%. 
Hiccup   
 caused by frequent or rhythmic clonic contraction of the diaphragm. 
 When prolonged, other causes should be considered including: 
 CNS disease - posterior fossa tumour, brain injury, encephalitis 
 Phrenic nerve or diaphragm irritation - tumour, pleurisy, pneumonia, intrathoracic 
adenopathy, pericarditis, gastro-oesophageal reflux, oesophagitis

 Systemic causes include alcohol intoxication and uraemia. 
 Other causes include foreign body or insect in the ear. 
 In infants it may be associated with apnoea or hyperventilation. 
 Folk remedies include aerophagia, breath holding, pharyngeal stimulation, distraction. 
 Haloperidol, metaclopramide and several anaesthetic agents are also said to work. 
 
Gastric conditions 
Helicobacter pylori

Helicobacter pylori  
 
 Helicobacter pylori  is a Gram negative bacteria  associated with a variety of gastrointestinal 
problems, principally peptic ulcer disease  
 peptic ulcer disease (95% of duodenal ulcers, 75% of gastric ulcers) 
 gastric cancer 
 B cell lymphoma of MALT tissue (eradication of H pylori results causes regression in 80% of 
patients) 
 atrophic gastritis 
NOT associated with GORD

NOT associated with GORD 
 The role of H pylori in Gastro-oesophageal reflux disease (GORD) is unclear - there is 
currently no role in GORD for the eradication of H pylori 
Helicobacter pylori : tests  
 
Urea breath test 
 patients consume a drink containing carbon isotope 13 (13C) enriched urea 
 urea is broken down by H. pylori  urease 
 after 30 mins patient exhale into a glass tube 
 mass spectrometry analysis calculates the amount of 13C CO2 
811

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    22 
  should not be performed within 4 weeks of treatment with an antibacterial or within 2 w eeks of 
an antisecretory drug (e.g. a proton pump inhibitor) 
 sensitivity 95-98%, specificity 97- 98% 
 the preferred method for testing eradication.  
Rapid urease test  (e.g. CLO test)

Rapid urease test  (e.g. CLO test) 
 biopsy sample is mixed with urea and pH indicator 
 colour change if H pylori urease activity 
 sensitivity 90-95%, specificity 95- 98% 
 Although rapid urease testing has a sensitivity of 93-97% the false negative rate incre ases 
significantly in the context of : 
 recent gastrointestinal haemorrhage ,  
 acid suppression therapy and  
 recent antibiotic treatment.  
 In this case a blood test for Helicobacter pylori  infection is required

 Serological markers would indicate the likelihood of Helicobacter 
pylori  infection and are  unaffected by the factors mentioned above.  
Serum antibody 
 remains positive after eradication 
 sensitivity 85%, specificity 80% 
Culture of gastric biopsy 
 provide information on antibiotic sensitivity 
 sensitivity 70%, specificity 100%  
 H. pylori  colonized on the surface of regenerative epithelium (silver stain) 
Gastric biopsy 
 histological evaluation alone, no culture

 histological evaluation alone, no culture 
 sensitivity 95-99%, specificity 95- 99% 
Stool antigen test 
 sensitivity 90%, specificity 95% 
 Whilst stool antigen testing is appropriate in the setting of initial diagnosis the NICE guidelines 
on dyspepsia do not recommend its use to confirm eradication  due to a lack of evidence.  
 it is important to be aware that testing may need to be delayed for three months 
after treatment to confirm eradication . 
 
 Test to confirm eradication :

Test to confirm eradication : 
 When to test for complete eradication? 
 Re-testing for Helicobacter pylori  is indicated only in the setting of peptic ulcer  
disease to confirm eradication where an initial test is positive. 
 Which test? 
 Carbon-13 urea breath testing is the only well validated method for confirming the 
successful eradication of Helicobacter pylori.  
 
 First-line treatment 
 eradication may be achieved with a 7 day course of

 not allergic to penicillin  PPI + amoxicillin + clarithromycin, or 
 allergic to penicillin  PPI + metronidazole + clarithromycin 
 allergic to penicillin + previous exposure to clarithromycin  PPI + bismuth + 
metronidazole + tetracycline  
  
 Second-line treatment 
 If still symptomatic after first-line  give a 7-day, twice-daily course of :  
 PPI + amoxicillin + either clarithromycin or metronidazole (whichever was not 
used first-line)

used first-line) 
 If there is a previous exposure to clarithromycin and metronidazole  PPI + 
amoxicillin + quinolone or tetracycline (whichever has the lowest acquisition 
cost).  
 allergic to penicillin + NO previous exposure to a quinolone   PPI + 
metronidazole + levofloxacin 
 allergic to penicillin + previous exposure to a quinolone  PPI + bismuth + 
metronidazole + tetracycline.  
 If there is inadequate response with initial H. pylori  eradication regime. Expert opinion

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    23 
  Re-testing for H. pylori  before second-line treatment  is considered to confirm 
eradication as there are serious side effects associated with antibiotics, e.g. Clostridium 
difficile  infection, and antibiotic resistance is increasing.  
 According to the British Infection Association , the carbon-13 urea breath test is the

most accurate method of re-testing for H. pylori .  
 This should be performed 4 weeks after the eradication therapy since antibiotics 
and proton pump inhibitors (PPIs) can suppress the bacteria causing a false 
negative result. 
 Eradication therapy is effective in 80-85% of cases and should not be repeated w ithout 
evidence of treatment failure. 
Peptic ulcer 
Basic

Basic 
Bleeding from Posterior duodenal ulcers are due to erosion of the gastroduodenal artery 
 
 The right and left gastroepiploic arteries  (gastro-omental arteries)  supply the greater 
curvature of the stomach. 
 The source of ulcer bleeding in the greater curvature of the stomach  Left 
gastroepiploic artery  
 The right gastric artery  arises from the hepatic artery or the left hepatic artery, supplies the

pylorus and travels along the lesser curvature of the stomach , supplying it, and 
anastomosing with the left gastric artery.  
 the cause of ulcer bleeding in the lesser curvature of the stomach  right gastric 
artery 
 The pancreaticoduodenal artery  (a branch of the gastroduodenal artery) supplies mainly the 
upper and lower duodenum and the head of the pancreas. 
 The right hepatic artery  supplies the right lobe of the liver and part of the caudate lobe. 
The golden notes

Sources of bleeding in peptic ulcers: 
 greater curvature of the stomach  Left gastroepiploic artery 
 lesser curvature of the stomach  right gastric artery 
 Posterior duodenal ulcers  gastroduodenal artery  
 pancreaticoduodenal artery (a branch of the gastroduodenal artery) supplies mainly the 
upper and lower duodenum. 
 
Sites of peptic ulcers: 
 80%  are duodenal.  
 The most common site  near the pylorus, on the duodenal side

 The less frequent site  lesser curvature of stomach or at the point at which the esophagus 
enters the stomach.  
 
Risk factors for peptic ulceration include 
 Helicobacter pylori  (H. pylori ) infection,  
 non-steroidal anti-inflammatory drug (NSAID) use,  
 cigarette smoking and  
 genetic factors - Lewis blood group antigens facilitate H. pylori  attachment to the mucosa. 
 
Interventions for peptic ulcer disease (NICE 2012)

 peptic ulcer + H pylori    H pylori  eradication therapy 
 peptic ulcer + H pylori  retesting for H pylori  6 to 8 weeks after beginning treatment, 
 gastric ulcer + H pylori   repeat endoscopy 6 to 8 weeks after beginning treatment 
 In people at high risk (previous ulceration) and for whom NSAID continuation is necessary, 
consider a COX-2 selective NSAID instead of a standard NSAID  with a PPI.

  The Two highly selective or specific in their ability to inhibit COX-2 while having little or 
no COX-1 affinity are rofe coxib  and cele coxib .  
 Offer H 2RA therapy if there is an inadequate response to a PPI. 
The effect of Helicobacter eradication on healing and recurrence of peptic ulcer: 813

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    24 
  The effects is dependent upon whether ulceration is gastric or duodenal and whether th e 
patient is taking non-steroidal anti-inflammatory drugs or not. 
 For duodenal ulcers  eradication slightly increases healing  (additional 5.4% over acid 
suppression alone) but dramatically decreases recurrence  (increases the number of

patients ulcer free at 12 months by 52%). 
 For gastric ulcers  eradication therapy has no effect on healing but does decrease 
recurrence (an additional 32% of patients are ulcer free at 12 months compared to acid 
suppression alone). 
 In patients taking non-steroidal anti-inflammatory drugs  eradication therapy has no 
effect on peptic ulcer healing (gastric or duodenal), but will decrease ulcer 
recurrence

recurrence   
 continued non-steroidal anti-inflammatory drug use markedly reduces the size of 
effect that eradication therapy has on reducing ulcer recurrence. 
 
Endoscopic appearance of ulcers: 
 
 The endoscopic appearances are of two small duodenal ulcers ( A) without evidence of recent 
haemorrhage.  There is some co-existent duodenitis.   
 The presence of villi identifies this as the duodenum.

 The mucosal appearances are not consistent with that of the stomach (absence of  rugae, paler 
squamous epithelium rather than redder columnar epithelium) or the oesophagus (pa le pink 
non-villous squamous epithelium). 
 
Following endoscopic intervention  
 immediately post-endoscopy, patients should be commenced on a high dose oral or 
intravenous proton pump inhibitor , this reduces the risk of rebleeding.

 Amoxicillin and clarithromycin may be indicated if there is evidence of Helicobacter p ylori 
infection. This need not be started immediately post-endoscopy but treatment should not be 
unnecessarily delayed. 
Zollinger-Ellison syndrome 
 
 gastrinoma (Zollinger-Ellison syndrome) is a gastrin-secreting neuroendocrine tumor that is  
most often localized to the duodenum and pancreas.

 Gastrin is released by G cells in the antrum under normal physiological conditions. 
 
Tumor location 
814

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    25 
  Duodenum ( ∼ 70% of cases) 
 Most ulcers   are located in the first part of the duodenum. 
 Pancreas ( ∼ 25% of cases): typically the head 
 Ectopic locations (5 –15% of cases) 
Causes 
 Most gastrinomas occur sporadically. 
 Around 30% occur as part of MEN type I syndrome  
 
 Sex: ♂ > ♀ (2:1)

 Age of onset: 30 –50 years  
 Hypergastrinemia ĺ stimulation of parietal cells ĺ gastric acid hypersecretion, which leads to:  
 Peptic ulcer disease 
 Inactivation of pancreatic enzymes ĺ diarrhea, steatorrhea ĺ malabsorption  
Features  
 multiple gastroduodenal ulcers 
 diarrhoea 
 malabsorption 
Diagnosis 
 Best initial test: esophagogastroduodenoscopy 
 Important to rule out H. pylori  infection and malignant ulcers

 Typically reveals multiple ulcers and thick gastric folds  
 Ļ Gastric pH  
 
 Fasting gastrin levels: the single best screen test  
 fasting gastrin test > 1000 with low PH < 2 is diagnostic  
 if level < 1000 and the diagnosis is suspected, then secretin stimulation testing  or 
calcium stimulation testing  
 secretin stimulation test   
 rise > 200 after 15 minute of dosing is considered positive  
 calcium stimulation test  
 rise > 395 is considered positive

 rise > 395 is considered positive  
 Secretin stimulation test  (if fasting serum gastrin test is inconclusive) 
 
The presence of multiple, large (> 2 cm) ulcers in atypical locations (e.g., the jejunum) should raise 
suspicion of gastrinoma. 
 
Treatment 
 Reduce acid production 
 PPIs  (e.g., omeprazole), H2 antagonists (e.g., ranitidine) 
 Octreotide (a somatostatin analog) may be used in refractory cases.  
 Non-metastatic disease:  
 surgical resection of the gastrinoma

 surgical resection of the gastrinoma 
 Metastatic disease:  
 chemotherapy 
 In approximately 50% of cases, the tumor has already metastasized at the time  of 
diagnosis 
Gastric MALT lymphoma 
Overview 
  lymphoma of Mucosa- Associated Lymphoid Tissue (MALT)  
 (MALT) is typically a low-grade, B-cell neoplasia  originating from mucosa-associated lymphoid 
tissue   
 associated with H. pylori  infection in 95% of cases

 good prognosis 
 Within the stomach the antrum is most commonly involved  
815

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    26 
  MALT lymphoma   
 7% to 8% of all B-cell lymphomas  
 the third most common type of non-Hodgkin's lymphoma 
 the most common type of primary extra-nodal  lymphoma and represents up to 50% of 
primary gastric lymphomas.  
 Gastric MALT lymphomas   
 account for about 30% of all MALT lymphomas,  
 median age of 57 years

 median age of 57 years  
 no sex predilection.  
Features 
 paraproteinaemia may be present 
  infiltrate of small-size lymphocytes that destroy gastric glands, configuring the  so-called 
‘lymphoepithelial lesion ’ which is pathognomonic of lymphoma  
 The common cytogenetic abnormalities demonstrated in MALT lymphomas is t(11;18) ,  
 seen in 30% to 40% of gastric and lung MALT lymphomas 
 This is clinically important, as t(11;18)-positive cases are less likely to respond to H

pylori -eradication therapy  
 there is a high incidence of t(11;18) in H pylori -negative gastric MALT lymphoma,  
 t(11;18)-positive cases are more likely to present with advanced-stage disease  
associated with aberrant expression of nuclear BCL10 
 t(11;18)-positive cases are less likely to transform to aggressive lymphomas , as 
they are unlikely to develop secondary chromosomal abnormalities. 
Treatment 
 if low grade then 80% respond to H. pylori  eradication

 low grade localised gastric helicobacter pylori positive : 
 first line   antibiotics plus a proton-pump inhibitor (PPI) 
 second line  radiotherapy  
 Patients are considered to have failed H pylori  eradication when: 
 there is no regression at repeat endoscopy 2 months after treatment,  
 or when there is lack of complete regression at approximately 18 months 
after treatment. 
 low grade localised gastric helicobacter pylori negative: 
 first line  radiotherapy

 first line  radiotherapy 
 low grade advance gastric (Disease not confined to the stomach) 
 first line  chemotherapy  
 If H pylori  -positive,  add eradication therapy. 
 High grade histological transformation: 
 First line  chemotherapy  
 MALT lymphoma is defined as a low-grade neoplasm. However, gastric MALT 
lymphoma can show a component of high-grade transformation.  
 This is characterised by an increase in the number of transformed blasts , which can

eventually lead to complete effacement of the original MALT lymphoma . 
 
Ref: bestpractice.bmj.com. 2017 
Gastric cancer 
 Sex: ♂ > ♀ (2:1) 
 Peak incidence: 70 years 
 Geographical distribution: 
 strong regional differences 
 High incidence in South Korea, china and Japan 
 Declining incidence in the United States and Europe  
 overall incidence is decreasing, but incidence of tumours arising from the cardia is

increasing  
 adenocarcinoma  is the most common gastric cancer (90% of cases) 
Features 
 often presents late, with weight loss, early satiety, 
816

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    27 
  postprandial vomiting  
 in some cases acanthosis nigricans  
 or Leser -Trélat sign.  
 multiple seborrheic keratoses, often with an inflammatory base (see below). 
 Associated with gastrointestinal adenocarcinomas as part of a paraneoplastic 
syndrome.

syndrome. 
 Sister Mary Joseph nodule  is a feature of gastric carcinoma and involves  metastasis to the 
periumbilical region.  
 metastasis  
 The liver is the most common site of metastasis of gastric carcinoma. 
 When first diagnosed with gastric cancer, ∼ 70% of patients already show metastatic 
spread to the lymph nodes 
 The lymph node most commonly involved in the spread of gastric carcinoma  is the left 
supraclavicular node (Virchow node). 
Types of gastric adenocarcinoma

Types of gastric adenocarcinoma 
 diffuse gastric adenocarcinoma  
 characterized by thickening and rigidity of the gastric wall.  
 It often remains asymptomatic until an advanced stage.  
 Unlike the intestinal type of gastric adenocarcinoma, it is more common in women a nd 
individuals less than 50 years old. 
 associated with signet ring cells and linitis plastica.  
 Linitis plastica  is a particularly aggressive form of diffuse adenocarcinoma.

 It is also known as "leather bottle stomach" because the stomach is diffusely 
thickened, with a small lumen that cannot expand, leading to the symptom o f 
early satiety. This thickening can be seen on the CT image.  
 These tumors infiltrate the submucosa , so that mucosal sampling may not show 
neoplastic cells.  
 The lesions are described as scirrhous, referring to the desmoplastic reaction that 
results in indurated, abundant fibrous tissue in the dense stroma.

 Scirrhous infiltration of the submucosa 
 Histologically, signet ring  cells are seen (named this way 
because mucin vacuoles displace the nucleus to the periphery). 
 Intestinal type of gastric adenocarcinoma 
 the most common  type  of gastric adenocarcinoma.  
 presents as a large, irregular ulcer with heaped up margins,  
 typically at the lesser curvature of the antrum. 
Histology 
 signet ring cells  may be seen in gastric cancer.

 They contain a large vacuole of mucin which displaces the nucleus to one side.  
 Higher numbers of signet ring cells are associated with a worse prognosis  
 H. pylori  infection  
 The most common cause (> 60%) 
 blood group A: g Astric c Ancer 
 gastric adenomatous polyps 
 pernicious anaemia  Chronic atrophic gastritis  become gastric adenocarcinoma. 
 smoking 
 achlorhydria  (decrease in gastric acid production)

 diet: salty, spicy, nitrates (dietary nitrosamines (smoked foods)) 
 Associations with decreased risk of gastric tumours   
 may be negatively associated with duodenal ulcer  
 NSAID  use is associated with decreased risk of certain gastric tumours. 
 diagnosis: endoscopy with biopsy 
 staging: CT or endoscopic ultrasound - endoscopic ultrasound has recently been shown to 
be superior to CT  
Treatment 
 gastrectomy

Treatment 
 gastrectomy 
 Iron deficiency is a possible complication of gastrectomy .  
 The body of the stomach  is the primary location for parietal cells , 
 Parietal cells produce gastric acid and intrinsic factor 
 Intrinsic factor is necessary for the absorption of vitamin B12.  817

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    28 
  Gastric acid  aid the absorption of iron  low pH environment is 
necessary for the reduction of Fe3+ (ferric iron) to Fe2+ (ferrous iron) the 
absorbable form of iron. 
 
Prognosis 
 Early diagnosis of gastric carcinoma results in a five year survival rate of 90%

  At diagnosis, 60% of cancers have already reached an advanced stage that do es not allow for 
curative treatment. 
 5-year survival  
 confined to the mucosa and submucosa (> 90%) 
 extended beyond the submucosa ( < 10%). 
 
seborrheic keratoses on the back of a person with Leser –Trélat sign  
Gastrointestinal stromal tumour (GIST) 
 common type of sarcoma; it develops in the gastrointestinal (GI) tract

 occur most often in adults over the age of 50 years  
 Location of GISTs:  
 most commonly involve the stomach (60%),  
 jejunum and ileum (30%),  
 duodenum (4% –5%), and  
 colorectal (< 5%). 
 Tumours in the small bowel and rectum appear to be more aggressive than thos e occurring in 
the stomach.  
 the cell of origin of gastric GISTs   Interstitial cells of Cajal  within Auerbach's plexus 
 the interstitial cells of Cajal act as pacemaker cells of the GIT, with regulation of

peristalsis in the adult intestine  
 Approximately 80% –95% of GISTs harbor an activating mutation in the KIT gene 
 about 80% of KIT-negative GISTs have an activating mutation in the PDGFRA gene . 
 a mutation in PDGFRA may make the tumour resistant to the standard drugs to 
treat GIST. 
  tumours with a PDGFRA mutation are usually less aggressive than the more 
common ones with KIT mutation. 
 50% are present with metastatic disease, ( commonly liver metastases) ,  
 Features

 Features 
 Mostly asymptomatic. 
 Tumor induce GI bleed and anemia 
 Other symptoms secondry to mass effects: 
 Abdominal discomfort, early satiety, palpable abdominal mass 
 Bowel obstruction or perforation 
 Dysphagia 
 Gold standard test is endoscopy with biopsy 
 Histopathology: Spindle cell  in 70 to 80%, epitheliods cells in 20 to 30 
 CT and endoscopic ultrasound allow tumour staging to plan further 
management.  
818

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    29 
  Immunohistochemical Stainning 
 Up to 95% of GISTs are positive for KIT expression (CD117)  
 60%–70% are positive for CD34 expression. 
 all GISTs ≥ 2 cm  surgery 
 Surgery is usually the first treatment method used for GIST. 
 If the tumour is too large to be removed at the time of diagnosis, it may be

treated initially with imatinib. If sufficient shrinkage has occurred after 6- 12 
months, it may be operated . 
 incidentally encountered GISTs < 2 cm  watchful waiting and surveillance for such 
very small GISTs might be reasonable. 
 for patients with KIT-positive unresectable and/or metastatic GIST   Medical 
Management:   
 first line  Imatinib  mesylate is an oral adenosine triphosphate (ATP) –
competitive TKI that selectively inhibits the activity of KIT, PDGFRA.

 It is effective in 80% of patients and on average will control the disease for 
about two years. 
 imatinib may be used as an adjuvant therapy after surgery  to reduces the 
risk of the cancer returning 
 second-line  In case of imitanib resistance:  patients can be switched 
directly from low-dose imatinib (400 mg/day) to another TKI, such as the only 
approved second-line  therapy, s unitinib . 
 3rd line  Regorafenib (if imatinib and sunitinib are not effective or not tolerated)

Menetrier's disease 
 A rare condition associated with giant gastric folds , predominantly in the fundus and body 
of the stomach.  
 Histologically there is hyperplasia of the gastric pits, gland atrophy and an increase 
in overall mucosal thickness.  
 Hypochlorhydria is usually present.  
 Patients often complain of epigastric pain 
 protein loss from the gastric mucosa can result in mild hypoalbuminaemia.

 some patients improve spontaneously,whereas in others this can be a premalignant state.  
 Antisecretory drugs such as proton-pump inhibitors can be tried for symptom relief. 
 
Bowel conditions 
Dyspepsia 
Causes of dyspepsia  
 Gastro-oesophageal reflux disease (GORD) (15 - 25%) 
 Gastric and duodenal ulcers (15 - 25%) and 
 Stomach cancer (2%). 
 The remaining 60% are classified as non-ulcer dyspepsia (NUD). 
 Drugs causing dyspepsia

 Drugs causing dyspepsia  
 NSAIDs ( ibuprofen is associated with the  lowest risk  of peptic ulcer disease ) 
 bisphosphonates 
 steroids 
 The following drugs may cause reflux by reducing lower oesophageal sphincter 
(LOS) pressure 
 calcium channel blockers* 
 nitrates* 
 *calcium channel blockers and nitrates are occasionally used in the 
management of achalasia, itself a cause of dyspepsia, because of their 
effect on the LOS. 
 theophyllines

 theophyllines 
 
Indications of Urgent  referral for an endoscopy (i.e. within 2 weeks). (NICE 2015) 
 upper abdominal mass  consistent with stomach cancer 
 Any sign of chronic gastrointestinal bleeding 819

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    30 
  Persistent vomiting 
 Iron deficiency anaemia, 
 Suspicious barium meal. 
 Progressive unintentional weight loss 
 Patients aged ≥ 55 years who've got weight loss , AND any of the following: 
 upper abdominal pain 
 reflux 
 dyspepsia 
Non-urgent 
 Patients with haematemesis  
 Patients aged >= 55 years who've got:

 Patients aged >= 55 years who've got: 
 treatment-resistant dyspepsia  or 
 upper abdominal pain with low haemoglobin levels or 
 raised platelet count  with any of the following: nausea, vomiting, weight loss, reflux, 
dyspepsia, upper abdominal pain 
 nausea or vomiting with any of the following: weight loss, reflux, dyspepsia, u pper 
abdominal pain 
Managing patients who do not meet referral criteria ('undiagnosed dyspepsia')  
 This can be summarised at a step-wise approach

 This can be summarised at a step-wise approach 
1. Review medications for possible causes of dyspepsia 
2. Lifestyle advice 
3. Trial of full-dose proton pump inhibitor for one month OR a 'test and treat' approa ch 
for H. pylori  
 lifestyle advice 
 avoid known precipitants: eg: smoking, alcohol, coffee, chocolate, fatty foods and  being 
overweight 
 Raising the head of the bed and having a main meal well before going to bed ma y help 
some people. 
 Testing for H. pylori  infection

 Testing for H. pylori  infection 
 initial diagnosis: NICE recommend using a carbon-13 urea breath test or a stool antigen 
test, or laboratory-based serology 'where its performance has been locally validate d' 
 test of cure: carbon-13 urea breath test 
 cognitive behavioural therapy and psychotherapy, may reduce dyspeptic symptoms in  the 
short term in individual people.  
 If H pylori  has been excluded and symptoms persist, offer either a low-dose PPI  or an H 2RA

for 4 weeks. 
Malabsorption 
Malabsorption is characterised by diarrhoea, steatorrhoea and weight loss. 
Causes  may be broadly divided into: 
1. intestinal (e.g. villous atrophy), 
2. pancreatic (deficiency of pancreatic enzyme production or secretion) 
3. biliary (deficiency of bile-salts needed for emulsification of fats) 
Intestinal causes of malabsorption  
 coeliac disease 
 tropical sprue

 tropical sprue 
 Giardiasis 
 brush border enzyme deficiencies (e.g. lactase insufficiency) 
Pancreatic causes of malabsorption 
 chronic pancreatitis 
 cystic fibrosis 
 pancreatic cancer 
Biliary causes of malabsorption 
 biliary obstruction 
 primary biliary cirrhosis 
 bacterial overgrowth (e.g. systemic sclerosis, diverticulae, blind loop) 
 lymphoma 820

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    31 
  short bowel syndrome   
 Does not develop unless more than two thirds of the small intestine  have been 
removed. 
 features inclu de: 
 Abdominal pain 
 Diarrhea and steatorrhea  
 Fluid depletion 
 Weight loss and malnutrition 
 Fatigue 
 complications caused by malabsorption of vitamins and minerals 
D-xylose test

D-xylose test 
 D-xylose is a monosaccharide which is absorbed through the small 
intestines and excreted through the kidneys.  
 D-xylose test is helpful in differentiating between structural and functional causes 
of malabsorption.  
 structural (e.g. Celiac disease, Crohn disease) or functional (e.g. pancreatic 
insufficiency) 
  An abnormally low excretion of D-xylose is indicative of a structural pathology.

 This test distinguishes between malabsorption due to small-intestinal diseases and 
malabsorption due to pancreatic exocrine insufficiency.  
 A 5-hour urinary excretion of 5 g or greater is normal following the oral administration of 25 
g of D-xylose to a well-hydrated subject. 
 Decreased xylose absorption and excretion are found:  
 In patients with damage to the proximal small intestine 
 When there is bacterial overgrowth in the small intestine (the bacteria catabolise the 
xylose)

xylose) 
 Patients with pancreatic steatorrhoea ( chronic pancreatitis ) usually have  normal 
xylose absorption .  
 Abnormal results might be encountered in renal failure, in the elderly and in patients with 
ascites due to an excretion defect rather than malabsorption. 
Diarrhoea (NICE 2012)  
 Diarrhoea is defined as the abnormal passage of loose or liquid stools more than 3 times  
daily or a volume of stool greater than 200 g/day .

 Diarrhoea is considered to be chronic if it persists for more than 4 weeks . 
Jejunal villous atrophy 
 
Causes  
 hypogammaglobulinaemia 
 gastrointestinal lymphoma 
 cow's milk intolerance 
Coeliac disease  
 
 Caused by sensitivity to the protein gluten.

 Caused by sensitivity to the protein gluten.  
  due to T cell  mediated hypersensitivity reaction  
 Mechanism: repeated protein gluten exposure  villous atrophy  malabsorption. 
821

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    32 
  Conditions associated with coeliac disease include dermatitis herpetiformis (a vesicular, 
pruritic skin eruption) and autoimmune disorders (type 1 diabetes mellitus and autoimmune 
hepatitis). 
 It is strongly associated with HLA-DQ2 (95% of patients) and HLA-B8 (80%) as well as HLA-
DR3 and HLA- DR7

DR3 and HLA- DR7 
 The prevalence of coeliac disease in Europe between 1:100 and 1:300. 
 It presents at any age but in adults the commonest age of presentation is 20s and 30s. 
 Women are slightly more commonly affected. 
 The action of tissue transglutaminase on alpha-gliadin generates epitopes to  CD4+ T-
lymphocytes, which provoke an inflammatory response in the intestinal wall. 
 
In 2009 NICE suggest that the following patients should be screened for coeliac disease :

Signs and symptoms Conditions 
 Chronic or intermittent diarrhoea 
 Failure to thrive or faltering growth (in children) 
 Persistent or unexplained gastrointestinal 
symptoms including nausea and vomiting 
 Prolonged fatigue ('tired all the time') 
 Recurrent abdominal pain, cramping or distension 
 Sudden or unexpected weight loss 
 Unexplained iron-deficiency anaemia, or other 
unspecified anaemia  Autoimmune thyroid disease 
 Dermatitis herpetiformis 
 Irritable bowel syndrome

 Irritable bowel syndrome 
 Type 1 diabetes 
 First-degree relatives (parents, siblings or 
children) with coeliac disease 
 
Diagnosis  
 Diagnosis is made by a combination of immunology and jejunal biopsy. Villous atrophy an d 
immunology normally reverses on a gluten-free diet. 
 If patients are already taking a gluten-free diet they should be asked, if possible, to reintroduce 
gluten for at least 6 weeks prior to testing. 
Immunology

Immunology  
 tissue transglutaminase (TTG) antibodies (IgA) are the first-choice  
 Selective IgA deficiency is more common in patients with coeliac disease. 
 For this reason IgA levels should be checked when serological tests are ordered.  
 If the patient has selective IgA deficiency   tissue transglutaminase IgG can be 
measured. 
 Patients normally need to be following a gluten-free diet for at least 6 months before 
the serology becomes negatives . 
822

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    33 
  endomyseal antibody (IgA)   90% sensitive and almost 100% specific.  
 Anti-endomysial antibodies are sensitive and specific, but miss the disease in 
about 5% of the population who are IgA deficient.  
 anti-gliadin antibody (IgA or IgG) tests are not recommended by NICE

 anti-casein antibodies are also found in some patients 
Jejunal biopsy 
 duodenal biopsies are the gold standard for diagnosis : 
 villous atrophy 
 crypt hyperplasia 
 increase in intraepithelial lymphocytes 
 lamina propria infiltration with lymphocytes 
 Appearances may resemble severe tropical sprue  
 
Rectal gluten challenge has been described but is not widely used 
Subtotal villous atrophy  is seen in a number of conditions other than coeliac disease such as:

 Severe tropical sprue 
 Cow's milk/soya sensitivity in children 
 Gastroenteritis 
 Hypogammaglobulinaemia 
 Neomycin therapy 
 Laxative abuse 
 Norwalk agent. 
Other investigations 
 Imaging 
 Which would  most likely seen on abdominal radiograph with barium contrast? 
 Decreased  jejunal folds, increased  ileal folds  
 imaging and biopsy of the GI mucosa show a characteristic blunting

of jejunal villi. This is often associated with a compensatory" jejunization" 
of the ileum to enhance nutrient absorption.  
 Screen for other related autoimmunities  
 In a patient with newly diagnosed celiac disease , it is important to screen for other 
related autoimmunities as well, e.g. type 1 diabetes mellitus and autoimmune  thyroiditis. 
 
 gluten-free diet.  
 Gluten containing cereals include: 
 wheat: bread, pasta, pastry 
 barley: beer

 barley: beer 
 whisky is made using malted barley. Proteins such as gluten are however 
removed during the distillation process making it safe to drink for patients 
with coeliac disease 
 rye 
 oats (some patients with coeliac disease appear able to tolerate oats) 
 Some notable foods which are gluten-free include: 
 Rice 
 Potatoes 
 corn (maize) 
 
follow- up  
 Tissue transglutaminase antibodies may be checked to check compliance with a gluten free

diet. 
 
Associations and Complications 
If the patient still symptomatic despite being compliant 
with a gluten free diet  think of T Cell lymphoma  
 
 Enteropathy associated T Cell lymphoma  (EATL) 
 is a form of Non-Hodgkins lymphoma  
 coeliac disease increase the risk of developing EATL within the 1st year of diagno sis, 
however with a strict gluten free diet, the risk returns to that of the general popu lation 
after this point. 823

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    34 
  Recurrent mouth ulcers 
 Hyposplenism ( Splenic atrophy ): seen in 50% of cases and responds poorly to gluten 
 selective Ig A deficiency 
 Small-bowel ulceration is associated with ulcerating jejunitis, but not colonic or gastric ulcers.

January 2016 exam: Why do patients with coeliac disease require regular immunisations? Functional 
hyposplenism  
 
Whipple's disease 
Whipple's disease: jejunal biopsy shows deposition of macrophages containing Periodic acid-
Schiff (PAS) granules 
 
 Whipple's disease is a rare multi-system  disorder  
 Caused by Tropheryma whippelii , a Gram positive  bacterium 
 more common in those who are HLA-B27 positive

 more common in those who are HLA-B27 positive  
 most common in white males aged 40-50 years 
 rarely is described in women (M:F ratio 9:1).  
 Malabsorption in Whipple disease is caused by macrophages in the small bowel lamina pro pria 
compressing the lacteals.  
 
Features 
 malabsorption: diarrhoea, weight loss 
 large-joint arthralgia 
 lymphadenopathy 
 skin: hyperpigmentation and photosensitivity 
 pleurisy, pericarditis

 pleurisy, pericarditis 
 neurological symptoms (rare): ophthalmoplegia, dementia, seizures, ataxia, myoclonus , 
characteristic oculo-masticatory movements  
 jejunal biopsy  shows deposition of macrophages containing Periodic acid-Schiff (PAS)  
granules 
 presence of T. whippelei  DNA in tissue by PCR. 
 oral co-trimoxazole for a year is thought to have the lowest relapse rate, sometimes prece ded 
by a course of IV penicillin 
 other option:

 other option:  
 initial two week course of parenteral penicillin  and streptomycin; followed by a 
prolonged course (one year) of tetracycline.  
Tropical Sprue  
 most common in the Carribbean and the Far-East.  
 occurs in tropical regions, predominantly central America and South-Eastern Asia. 
 characterized by a picture of small intestinal malabsorption and the cause is thought to b e

infectious in origin. 
 It is thought that an initial GI infection results in small bowel stasis, opportunistic 
colonisation by organisms such as coliforms, and then a degree of villous atrophy 
leading to malabsorption and B12, folate deficiency.  
 deficiency in folate contributes to greater mucosal injury . 
Features 
 Patients classically have a history of recent travel to a tropical area  
 present with indigestion, cramps within 2 or 3 weeks after an acute enteric infection.

 Megaloblastic anemia due to folate or B12 deficiency is a common finding.  
 
Diagnosis:   
 Jejunal biopsy reveals: 824

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    35 
  Mild villous atrophy 
 ↑↑ villous crypts 
 Mononuclear cellular infiltrates 
 Enlarged epithelial cells 
 Large nuclei caused by folate and/or vitamin B12 deficiency. 
  barium swallow may show thickening of mucosal folds 
Treatment :

Treatment : 
 The main treatment for tropical sprue is broad-spectrum antibiotics (i.e., tetracycline) and 
vitamin supplementation (i.e.,  folic acid, vitamin B12).  
 Tetracyclines 250mg qds up to 6 months 
 Ampicillin may be used as an alternative in patients who are intolerant of tetracyclin es. 
 Folate and B12 deficiencies should also be corrected 
 Complete recovery is possible with appropriate therapy. 

Irritable bowel syndrome (IBS)  
 
Feature 
 features supporting a diagnosis of IBS  include: 
 A long history with a relapsing and remitting course 
 Exacerbations triggered by life events 
 Symptoms aggravated by eating, and 
 Coexistence of anxiety and depression. 
 features which suggest organic disease rather than IBS  include: 
 Fever 
 Onset of symptoms in old age 
 Progressive deterioration 
 Rectal bleeding (not due to fissures or haemorrhoids)

 Steatorrhoea, and 
 Dehydration. 
 
Diagnosis  (NICE 2008)  
 The diagnosis of IBS should be considered  if the patient has had the following for at least 6 
months: 
1. abdominal pain, and/or 
2. bloating, and/or 
3. change in bowel habit 
 A positive diagnosis of IBS should be made  if the patient has abdominal pain relieved by 
defecation or associated with altered bowel frequency stool form, in addition to 2 of  the 
following 4 symptoms:

following 4 symptoms: 
1. altered stool passage (straining, urgency, incomplete evacuation) 
2. abdominal bloating (more common in women than men), distension, tension or 
hardness 
3. symptoms made worse by eating 
4. passage of mucus 
 
 Features such as lethargy, nausea, backache and bladder symptoms may also support the 
diagnosis 
 Red flag features  should be enquired about: 
1. rectal bleeding 
2. unexplained/unintentional weight loss 
3. family history of bowel or ovarian cancer

3. family history of bowel or ovarian cancer 
4. onset after 60 years of age 
 Also on clinical examination the other ' red flag'  indicators are: 
 Anaemia 
 Abdominal mass 
825

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    36 
  Rectal mass, and 
 Inflammatory markers for inflammatory bowel disease. 
 Suggested primary care investigations  are: 
 full blood count 
 ESR/CRP 
 coeliac disease screen (tissue transglutaminase antibodies) 
Management  (NICE 2015). 
 
First-line  pharmacological treatment - according to predominant symptom

 pain: antispasmodic agents 
 Pinaverium is used to reduce the pain duration associated with (IBS). 
 diarrhoea: loperamide is first-line 
 constipation: laxatives but avoid lactulose  
 For patients with constipation who are not responding to conventional laxatives linaclotide may 
be considered, if: 
 optimal or maximum tolerated doses of previous laxatives from different classes have 
not helped and 
 they have had constipation for at least 12 months

Second-line  pharmacological treatment 
 low-dose tricyclic antidepressants (e.g. amitriptyline 5-10 mg) are used in preference to 
selective serotonin reuptake inhibitors 
Other management options 
 psychological interventions - if symptoms do not respond to pharmacological treatments after 
12 months and who develop a continuing symptom profile (refractory IBS), consider refe rring 
for cognitive behavioural therapy, hypnotherapy or psychological therapy

 complementary and alternative medicines: 'do not encourage use of acupunctur e or 
reflexology for the treatment of IBS' 
General dietary advice 
 have regular meals and take time to eat 
 avoid missing meals or leaving long gaps between eating 
 drink at least 8 cups of fluid per day, especially water or other non-caffeinated drinks such  as 
herbal teas 
 restrict tea and coffee to 3 cups per day 
 reduce intake of alcohol and fizzy drinks

 reduce intake of alcohol and fizzy drinks 
 consider limiting intake of high-fibre food (for example, whole meal or high-fibre flour a nd 
breads, cereals high in bran, and whole grains such as brown rice) 
 reduce intake of 'resistant starch' often found in processed foods 
 limit fresh fruit to 3 portions per day 
 for diarrhoea, avoid sorbitol 
 for wind and bloating consider increasing intake of oats (for example, oat-based breakfast

cereal or porridge) and linseeds (up to one tablespoon per day). 
Fibre  
 There are two main types of fibre - soluble fibre (which dissolves in water) and insoluble fibre.  
  It is soluble fibre  rather than insoluble fibre that seems to help ease symptoms in some 
cases.  
 A diet high in soluble fibre is often prescribed for the treatment of IBS 
 Dietary sources of soluble fibre include oats, ispaghula (psyllium), nuts and seeds, 
some fruit and vegetables and pectins.

some fruit and vegetables and pectins.  
 A fibre supplement called ispaghula powder is also available from pharmacies a nd 
health food shops. This seems to be the most beneficial type of suppleme nt. 
 Insoluble fibre  is chiefly found in corn (maize) bran, wheat bran and some fruit and 
vegetables. In particular, avoid bran as a fibre supplement.  
Malnutrition 

 Food intolerance ( in 30-60% of patients with (IBS). ) 
826

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    37 
  increased intestinal contractile and electrical activity with increased sensitivity to visceral 
stimulation.  
 Proliferation of intestinal mast cells is a proposed mechanism by which food and stress 
may trigger symptoms. 
 definition : NICE define malnutrition as the following:

1. a Body Mass Index (BMI) of less than 18.5; or 
2. unintentional weight loss greater than 10% within the last 3-6 months; or 
3. a BMI of less than 20 and unintentional weight loss greater than 5% within the last 3- 6 
months 
 Around 10% of patients aged over 65 years are malnourished, the vast majority of th ose living 
independently, i.e. not in hospital or care/nursing homes. 
 Screening  for malnutrition if mostly done using MUST (Malnutrition Universal Screen 
Tool).

Tool).  
 
 it should be done on admission to care/nursing homes and hospital, or if the re is 
concern. For example an elderly, thin patient with pressure sores (The Waterlow score is 
used to estimate the risk of a patient developing a pressure sore ) 
 it takes into account BMI, recent weight change and the presence of acute disease 
 categorises patients into low, medium and high risk 
 Management  of malnutrition is difficult. NICE recommend the following points:

 dietician support if the patient is high-risk 
 a 'food-first' approach with clear instructions (e.g. 'add full-fat cream to mashed potato'), 
rather than just prescribing oral nutritional supplements (ONS) such as Ensure 
 if ONS are used they should be taken between meals, rather than instead of meals 
 
 Waterlow score  is used to estimate the risk of a patient developing a pressure sore , this 
includes an assessment of malnutrition as one of it's components

Lactose intolerance   
 Lactase acts on lactose to generate glucose and galactose. 
 more common in Asian, and East Asian races. 
 South-east Asian people, like the Vietnamese, Thais, and Chinese, have a very high 
prevalence of lactase deficiency.  
 Any GI infection may precipitate the diagnosis of lactose intolerance,  as gut flora may be

altered by large bowel bacterial or viral load, as well as the treatment of infection. 
 A change from an Eastern to a Western high lactose diet may also reveal lactose intolerance . 
 Many patients labelled as having IBS may suffer from undiagnosed lactose intoleran ce  
 many medications use lactose as a binding and stabilising agent. 
 Diagnosed with  a DNA assay of the lactase gene along with a hydrogen breath test.

 Treatment  of lactose intolerance is with careful replacement of lactase. 
 
Functional constipation  
 The Rome III criteria for functional constipation is as follows (it must include two or more of  the 
following): 
 straining during at least 25% of defecations 
 lumpy or hard stools in at least 25% of defecations 
 sensation of incomplete evacuation for at least 25% of defecations

 sensation of anorectal obstruction/blockage for at least 25% of defecations 
 manual manoeuvres to facilitate at least 25% of defecations (e.g., digital eva cuation, 
support of the pelvic floor) 
 fewer than three defecations per week 
 loose stools are rarely present without the use of laxatives, and 
 insufficient criteria for irritable bowel syndrome. 
 These criteria must be fulfilled for the last three months with symptom onset at least six 
months prior to diagnosis. 
 
 827

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    38 
 _____________________________________________________________________________  
Energy from food 
 The amount of energy that may be derived from 1 gram of food is as follo ws: 
 carbohydrates: 4 kcal 
 protein: 4 kcal 
 fat: 9 kcal 
 The amount of energy a food product contains is expressed in calories (kcal).

In simple terms, per unit weight, fats contain twice as many calories as protein or 
carbohydrates. 
Enteral feeding 
 
Key points 
 Identify patients as malnourished or at risk (see below) 
 Identify unsafe or inadequate oral intake with functional GI tract 
 Consider for enteral feeding 
 Gastric feeding unless upper GI dysfunction (then for duodenal or jejunal tube)

 Check NG placement using aspiration and pH (check post pyloric tubes with AXR) 
 the most important first line investigation that will establish correct positioning of the 
tube in the stomach? 
 The first line investigation to confirm correct placement of a nasogastric tube is 
 pH testing of gastric aspirate using indicator paper  
 If the pH is between 1 and 5.5 then this is confirmatory evidence of correct 
placement.

placement.  
 If the pH reading is between 5.5 and 6 it is recommended that a second 
independent reading is made to confirm. 
 if aspirate pH ≥6   nasogastric feeding tubes feeding cannot be commenced 
 If there is any doubt, then an appropriately interpreted chest x ray is a second line 
investigation.  
 Gastric feeding > 4 weeks consider long-term gastrostomy 
 Consider bolus or continuous feeding into the stomach

 ITU patients should have continuous feeding for 16-24h (24h if on insulin) 
 Consider motility agent in ITU or acute patients for delayed gastric emptying. If this doesn't 
work then try post pyloric feeding or parenteral feeding. 
 PEG can be used 4 hours after insertion, but should not be removed until >2 weeks after 
insertion. 
Surgical patients due to have major abdominal surgery: if malnourished, unsafe swallo w/inadequate

oral intake and functional GI tract then consider pre operative enteral feeding. 
 
Patients identified as being malnourished  
 BMI < 18.5 kg/m2 
 unintentional weight loss of > 10% over 3-6/12 
 BMI < 20 kg/m2 and unintentional weight loss of > 5% over 3-6/12 
AT RISK of malnutrition  
 Eaten nothing or little > 5 days, who are likely to eat little for a further 5 days 
 Poor absorptive capacity 
 High nutrient losses 
 High metabolism

 High metabolism 
Refeeding syndrome 
Refeeding syndrome  hypophosphataemia  
 
Definition :  
 Refeeding syndrome describes the metabolic abnormalities which occur on feeding a p erson 
following a period of starvation ( ≥ 5 days) .  
 
828

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    39 
 Pathophysiology: 
 When malnourished, the body uses endogenous fuel stores for energy an d maintains serum 
electrolytes by redistribution from intracellular spaces. 
 Exogenously administered glucose results in insulin release. This results in rapid

uptake of glucose, potassium, phosphate and magnesium into cells, with dramatic falls 
in the extracellular concentrations.  
 
Features 
 Hypophosphataemia ( symptoms are due predominantly to hypophosphataemia, ) 
 hypomagnesaemia 
 abnormal fluid balance 
 Due to understood reasons, the body retain fluid  ↑ extracellular space  ↑cardiac work   
acute heart failure. 
 neurological problems resulting in: 
 Oedema 
 Lethargy 
 Confusion  Coma 
 Convulsions, and

 Convulsions, and 
 Death. 
 
 Nausea and diarrhoea is also common due to gut intolerance. 
Prevention  (NICE 2006) 
 Identify patients at a high-risk of developing refeeding syndrome 
 Patients are considered high-risk:  
 if one or more of the following : 
1. BMI < 16 kg/m2 
2. unintentional weight loss >15% over 3-6 months 
3. little nutritional intake > 10 days 
4. hypokalaemia, hypophosphataemia or hypomagnesaemia prior to feeding 
(unless high)

(unless high) 
 If two or more of the following: 
1. BMI < 18.5 kg/m2 
2. unintentional weight loss > 10% over 3-6 months 
3. little nutritional intake > 5 days 
4. history of: alcohol abuse, drug therapy including insulin, chemotherapy, 
diuretics and antacids 
 Decrease oral calorific intake to less than 50% of the recommended amount. 
 NICE recommend that if a patient hasn't eaten for > 5 days, aim to re-feed at no 
more than 50% of requirements for the first 2 days.

 limit initial dietary intake to 1000 –1500 kcal/day  
 Correcting electrolyte abnormalities aggressively 
 it may be preferable to provide electrolyte replenishment prior to commencing calorific 
intake  
 
A patient with a history of alcoholism  is admitted for re-feeding . Which component of the feed may 
need to be reduced to avoid encephalopathy ? 
 Protein 
 protein content of feeds should be strictly managed in patients with alcoholism.

 Protein rich feeds  Ĺ total ammonia burden  ↑ risk of encephalopathy .  
 
Melanosis coli 
 
 Melanosis coli is a disorder of pigmentation of the bowel wall.  
 Causes 
 It is associated with laxative abuse, especially anthraquinone compounds such as 
senna 
829

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    40 
  This phenomenon is seen in over 70% of persons who use anthraquinone 
laxatives (for example, cascara sagrada, senna, and frangula) within several 
months of use. 
 Also alternative "medicine" drugs contain ingredients like cascara which contain 
anthraquinones.

anthraquinones. 
 The modern laxatives such as liquid paraffin and polyethylene glycol do no t 
cause these changes. 
 Chronic use of anthraquinone laxatives cause injury to the colonic epithelium, with 
generation of lipofuscin pigment.  This pigment is subsequently engulfed by the 
macrophages to give rise to the histological picture.  
 Melanosis coli is a histological diagnosis made from rectal biopsy material which shows

numerous macrophages filled with brown pigment within the lamina propria.  
 Histology demonstrates pigment-laden macrophages  
 The macroscopic appearance varies from deep black pigmentation to reticulated 
brown discolouration. 
 The condition is benign and reversible on stopping the laxatives. 
Mesenteric ischaemia (ischaemic colitis) 
 
The two most common symptoms of ischemic colitis are severe abdominal

pain and hematochezia  (passage of fresh blood through the anus).   
 
 Mesenteric ischaemia is primarily caused by arterial embolism resulting in infarction of the 
colon. 
  More likely occur in areas such as the splenic flexure  that are located at the borders of the 
territory supplied by the superior and inferior mesenteric arteries. 
 especially the superior mesenteric artery . 
 
Predisposing factors  
 other causes of emboli: endocarditis

 other causes of emboli: endocarditis 
 cardiovascular disease risk factors: smoking, hypertension, diabetes 
Features 
 rectal bleeding 
 fever 
 bloods typically show an elevated WBC associated with acidosis 
 Acute mesenteric ischaemia is a cause of elevated amylase that is unrelated to pancre atitis. 
  Elevated serum lactate also suggests ischaemic aetiology.  
Diagnosis

Diagnosis 
 CT scanning : the imaging modality of choice , with a sensitivity and specificity over 90%. 
 Angiography: if the diagnosis is in doubt. 
 Mucosal edema can be seen as the thumbprinting sign  on plain abdominal radiograph  
and barium enema.  
 
 supportive care 
 balloon angioplasty and stenting 
 the preferred treatment for hemodynamically stable patients with acute mese nteric 
ischemia who do not present with signs or symptoms of advanced intestinal

ischemia (peritonitis, sepsis) because this procedure is minimally invasive and studies 
suggest similar efficacy to open surgical treatment.  
 laparotomy and bowel resection 
  laparotomy is reserved for acutely ill patients who are hemodynamically unstable or 
have evidence of peritonitis (rebound tenderness and involuntary gua rding).  830

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    41 
 ___________________________________________________________
Small bowel bacterial overgrowth syndrome (SBBOS) 
  (SBBOS) is a disorder characterised by excessive amounts of bacteria in the small bowel 
resulting in gastrointestinal symptoms  of bloating, abdominal distension and diarrhoea  
.Risk factors for SBBOS

.Risk factors for SBBOS  
 neonates with congenital gastrointestinal abnormalities 
 absent gastric acid secretion 
 small bowel diverticulae 
 fistulae between the small and large bowel 
 small bowel strictures 
 diabetes mellitus (diabetic neuropathy) 
 adhesions. 
Features : It should be noted that many of the features overlap with irritable bowel synd rome:  
 chronic diarrhoea 
 bloating, flatulence 
 abdominal pain

 Biochemically there is classically a low vitamin B 12 level and normal or elevated folate 
level as a result of bacterial metabolism of B 12 to folate . 
 
Steatorrhoea and flatulence are classic presenting features of small bowel bacterial 
overgrowth. 
 
 The gold standard investigation of bacterial overgrowth is small bowel aspiration and 
culture  
 Other possible investigations include: 
 hydrogen breath test

 hydrogen breath test 
 14C-xylose breath test 
 14C-glycocholate breath test: used increasingly less due to low specificity 
 In practice many clinicians give an empirical course of antibiotics as a trial 
 
 correction of underlying disorder 
 antibiotic therapy: rifaximin  is now the treatment of choice  due to relatively low resistance.  
 Co-amoxiclav or metronidazole are also effective in the majority of patients.

Spontaneous bacterial peritonitis (SBP) 
 
  (SBP) is a form of peritonitis usually seen in patients with ascites secondary to liver cirrhosis.  
most commonly seen in alcoholic cirrhosis 
  typically caused by aerobic  gram negative bacteria. (usually Escherichia coli, Klebsiella) 
 sponteanous bacterial peritonitis is almost without exception caused by a single 
organism. 

organism. 
 Diagnosis  
 paracentesis: neutrophil count > 250 cells/ul  
 Sending some ascitic fluid in blood culture bottles increases the yield. 
 high serum ascites albumin gradient (SAAG) (>11 g/L) ascitic fluid and the white cells 
will be predominantly neutrophils (>500 WBCs/mm3and >50% neutrophils).  
 Management : 
 intravenous cefotaxime  is usually given 
 other option: IV piperacillin-tazobactam

 other option: IV piperacillin-tazobactam  
 It is important to start antibiotics promptly pending the results of an ascitic 
analysis. 
 Antibiotic prophylaxis should be given if: 
831

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    42 
  patients who have had an episode of SBP 
 patients with fluid protein <15 g/l and either Child-Pugh score of at least 9 or 
hepatorenal syndrome 
 Norfloxacin  is recommended for short term prophylaxis . 
 Alcoholic liver disease is a marker of poor prognosis in SBP.

 Has poor prognostic significance with a one year survival after a diagnosis of between 
30-50%. 
 pancreatic ascites (eg. Acute pancreatitis) 
 elevated fluid amylase helps confirm this (particularly the characteristic way in 
which it is in excess of the serum value). 
 The low lactate dehydrogenase ( <225 IU/L) helps exclude a polymicrobial ascitic 
fluid infection which has similar findings  
 no mention of finding any organisms on the Gram stain.

 Bacterial growth occurs in about 80% of specimens with 
polymorphonuclear (PMN) count of >250 cells/mm3. 
 Ascitic fluid analysis demonstrates a low serum albumin ascites gradient (SAAG) 
(<11 g/L).  
 Cirrhosis and spontaneous bacterial peritonitis are both characterised by a 
high SAAG ( >11 g/L) and are differentiated from each other on the basis 
of white cell count, Gram stain and culture results. 
 secondary bacterial peritonitis (ruptured viscus or loculated abscess).

 Lactate dehydrogenase >225mU/L, glucose <50mg/dL, total protein >1g/dL and 
multiple organisms on gram stain suggest secondary bacterial peritonitis  
(ruptured viscus or loculated abscess).  
 Chylous ascites  
 A high level of triglycerides confirms chylous ascites.  
 elevated amylase level suggest pancreatitis or gut perforation.  
 elevated bilirubin level suggest biliary or gut perforation. 
Tubercular peritonitis

Tubercular peritonitis 
Features 
 risk of tuberculosis  
 extensive lymphadenopathy.  
Diagnosis  
 The most sensitive test to establish the diagnosis is visually directed (laparoscopic) 
peritoneal biopsy with histology and culture for TB.  
 An alternative in this setting might be to perform fine needle aspiration or excisio n biopsy of 
one of the palpable lymph nodes.  
VIPoma 
VIP (vasoactive intestinal peptide)

VIPoma 
VIP (vasoactive intestinal peptide) 
 source: small intestine, pancreas 
 stimulation: neural 
 actions: 
 stimulates  water and electrolytes  secretion by pancreas and intestines,  
 inhibits gastric  acid and pepsinogen secretion  
 peripheral vasodilation ,  
 potentiates acetylcholine action on salivary glands. 
VIPoma 
 90% arise from pancreas 
 large volume diarrhoea, secretory diarrhoea ('pancreatic cholera')

A stool volume of <700 mL/d excludes the diagnosis of VIPoma. 
 hypokalaemia,  hypochlorhydia. Achlorhydria  832

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    43 
  hypokalaemic acidosis (loss of alkaline secretions) 
 mildly raised glucose. 
 raised plasma pancreatic polypeptide 
 abdominal colic 
 cutaneous flushing 
 raised plasma VIP 
Volvulus

Volvulus 
 Volvulus defined as torsion of the colon around it's mesenteric axis resulting in compromised 
blood flow and closed loop obstruction. 
 Sigmoid volvulus (around 80% of cases ) describes large bowel obstruction caused by the 
sigmoid colon twisting on the sigmoid mesocolon. A similar problem may also occur at the 
caecum (20% of cases).  
 In most people (around 80%) the caecum is a retroperitoneal structure so not at risk of

twisting. In the remaining minority there is however developmental failure of peritoneal f ixation 
of the proximal bowel putting these patients at risk of caecal volvulus. 
 
Sigmoid volvulus associations Caecal volvulus associations 
 older patients 
 chronic constipation 
 Chagas disease 
 neurological conditions e.g. Parkinson's disease, Duchenne 
muscular dystrophy 
 psychiatric conditions e.g. schizophrenia   all ages 
  adhesions 
  pregnancy 
 
Features 
 constipation

Features 
 constipation 
 abdominal bloating 
 nausea/vomiting 
 
Diagnosis 
 usually diagnosed on the abdominal film 
 The most helpful early diagnostic tool of intestinal obstruction is the plain 
abdominal X-ray.  
 sigmoid volvulus: large bowel obstruction (large, dilated loop of colon, often with air-fluid  
levels) + coffee bean sign 
 caecal volvulus: small bowel obstruction may be seen 
 
 sigmoid volvulus: rigid sigmoidoscopy with rectal tube insertion 
 caecal volvulus: management is usually operative. Right hemicolectomy is often nee ded 
 
Imaging in bowel obstruction 
Looking for small and large bowel obstruction is one of the key indications for performing a n 
abdominal film. 
 
Small bowel Large bowel 
Maximum normal diameter = 35 mm  
 
Valvulae conniventes extend all the way 
across Maximum normal diameter = 55 mm

across Maximum normal diameter = 55 mm 
 
Haustra extend about a third of the way 
across 
 
 833

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    44 
  
Radiology: pneumoperitoneum 
 An erect chest x-ray is a useful investigation in patients with an acute abdomen as it may 
demonstrate free air in the abdomen (pneumoperitoneum) - an abnorm al finding suggestive of 
a perforated abdominal viscus (e.g. a perforated duodenal ulcer).

 Rigler's sign (double wall sign) may be seen on an abdominal film. 
 CT is now the preferred method for detecting free air in the abdomen. 
 
Erect chest x-ray with air visible under the diaphragm on both sides. 
 
Abdominal x-ray demonstrates numerous loops of small bowel outlined by gas b oth within the lumen 
and free within the peritoneal cavity. Ascites is also seen, with mottled gas densities over bilate ral

paracolic gutters. In a normal x-ray only the luminal surface (blue arrows) should be visib le outlined 
by gas. The serosal surface (orange) should not be visible as it is normally in contact with  other intra-
abdominal content of similar density (other loops of bowel, omentum, fluid). In this case ga s abuts the 
serosal surface rendering it visible. As this film has been obtained supine (note absenc e of air-fluid

levels), ascites pools in the paracolic gutters, with fluid mixed in with gas bubbles (green arrows).  
Dumping syndrome  
 occur in up to 50% of patients who have undergone gastric bypass when high levels of  simple 
carbohydrates are ingested. 
 early dumping syndrome  
 rapid onset , usually within 15 minutes of eating   
 results from rapid emptying of food into the small bowel. 
834

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    45 
  Due to the hyperosmolality of the food there are rapid fluid shifts from the p lasma into 
the bowel leading to hypotension and a sympathetic nervous system response.  
 The presenting symptoms are often colicky abdominal pain, diarrhoea, nause a, and 
tachycardia. 
 Treatment:

 Treatment: 
 usually self-limiting and resolves within 7 to 12 weeks. 
 Patients should avoid foods high in simple sugar and replace them with high 
fibre, complex carbohydrates and protein-rich foods. 
 Small, frequent meals  
 leaving a 30 minute gap between solids and liquids  
 Late dumping syndrome   
 occurs as a result of the hyperglycaemia and subsequent insulin response 
leading to hypoglycaemia which takes place  two to three hours after a meal.

  Symptoms include dizziness, fatigue, sweating, and weakness.  
 Management is similar to early dumping syndrome. 
Small bowel lymphoma  
Pain  is the most common presenting feature of small bowel lymphoma 
 Lymphoma comprises 15-20% of all small bowel tumours with the ileum most common ly 
affected. 
  Primary lymphomas of the small bowel include 
 mucosa-associated lymphoid tissue (MALT) lymphoma

 diffuse large B cell lymphoma 
 immunoproliferative small intestinal disease (IPSID), and 
 enteropathy-associated T cell lymphoma (EATL). 
 Patients with coeliac disease are at higher risk of T cell lymphoma. 
 There is a male predominance 
 the median age at presentation of 25 years.  
 Patients may present with: 
 anorexia 
 weight loss 
 chronic pain 
 abdominal fullness 
 early satiety, and 
 constipation.

 constipation. 
 Findings on CT vary and may include multiple tumours, narrowing of the bowel lumen 
and mesenteric nodal masses. 
 
Pancreatic conditions 
Acute pancreatitis 
  
 acute inflammation of the pancreas, results in release of exocrine enzymes that cause  auto-
digestion .  
 Sequence of events leading to pancreatitis:  
 Intrapancreatic activation of pancreatic enzymes : secondary to pancreatic ductal

outflow obstruction (e.g., gallstones, cystic fibrosis) or direct injury to pancreatic acinar 
cells (e.g., alcohol, drugs) 
 Enzymatic autodigestion of pancreatic parenchyma  
 Attraction of inflammatory cells (neutrophil s, macrophages) ĺ release of inflammatory 
cytokines ĺ pancreatic  inflammation (pancreatitis) 
 Sequelae of pancreatitis  (depending on the severity of pancreatitis) 
835

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    46 
  Capillary leakage : Release of inflammatory cytokines and vascular injury by pancreatic 
enzymes ĺ vasodilation and increased vascular permeability ĺ shift of fluid from the  
intravascular space into the interstitial space (third space loss) 
ĺ hypotension, tachycardiaĺ  distributive shock

ĺ hypotension, tachycardiaĺ  distributive shock  
 Pancreatic necrosis : Uncorrected hypotension and third space loss ĺ decreased 
organ perfusion ĺ  multiorgan dysfunction (mainly renal) and pancreatic necrosis  
 Hypocalcemia : Lipase breaks down peripancreatic and mesenteric fat ĺ  release of 
free fatty acids that bind calcium ĺ hypocalcemia  
 
Causes 
The vast majority of cases in the UK are caused by gallstones and alcohol 
 
Popular mnemonic is GET SMASHED  
 Gallstones

 Gallstones 
 account for 50% of cases, with the majority of the rest being associated with alcohol. 
 For prediction of a biliary etiology, an ALT level has the highest positive predictive 
value of any biochemical test.  
 Ethanol 
 Amylase/lipase levels are markedly  elevated in gallstone  pancreatitis (thousands),  
whereas less increased in alcoholic  (hundreds )  
 raised mean corpuscular volume (MCV) suggests chronic high alcohol use  
 Trauma

 Trauma 
 Steroids 
 Mumps (other viruses include Coxsackie B) 
 Autoimmune (e.g. polyarteritis nodosa), Ascaris infection 
 Scorpion venom 
 Hypertriglyceridaemia, Hyperchylomicronaemia, Hypercalcaemia, Hypothermia 
 ERCP  (acute pancreatitis following ERCP should be treated with I.V fluids + analgesia ) 
ERCP is the third commonest cause of pancreatitis after alcohol and biliary tract disease .

 Drugs (azathioprine, mesalazine, didanosine, bendroflumethiazide, furosemide, pentamidine, 
steroids, sodium valproate) 
 pancreatitis is 7 times more common in patients taking mesalazine than sulfasalaz ine 
Hypertriglyceridaemia 
 Considered a risk factor for pancreatitis when triglyceride levels are above 11.2 
mmol/L . 
 In a patient with hypertriglyceridaemia and acute abdominal pain, an amylase should be 
checked to exclude acute pancreatitis.

checked to exclude acute pancreatitis.   
 The third commonest cause of acute pancreatitis after alcohol and gallstone s.  
 The definition of hypertriglyceridaemia is a level greater than 1.7 mmol/L. Severe 
hypertriglyceridaemia is defined as 11.2-22.4 mmoL/L and very severe as abo ve 22.4 mmol/L.  
 pancreatitis secondary to hypertriglyceridaemia has greater severity and is associated with a  
higher complication rate.  
Features

Features 
 Patients typically present with severe epigastric pain which radiates to the back, and vomiting.  
 there is often a systemic inflammatory response (SIRS)   
 Serum amylase is classically raised three or more times normal,  
 hypocalcaemia is relatively common.   
 Raised bilirubin and/or serum aminotransferase suggest underlying gallstones.  
 Cirrhosis results in a small shrunken liver, and raised ALT and ALP (and gamma-GT if the

cause is alcohol).  
 Rare features associated with pancreatitis include: 
 ischaemic (Purtscher) retinopathy - may cause temporary or permanent blindness 
 Skin changes (rare)  
 Cullen's sign: periumbilical ecchymosis and discoloration (bluish-red)  
 Grey Turner's sign: flank ecchymosis with discoloration  
 Fox's sign: ecchymosis over the inguinal ligament 
Marker of severity  
 CRP  is now a widely used marker of severity in acute pancreatitis.

 Other methods which have to correlate with prognosis include the Ranson criteria and 
APACHE II score  836

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    47 
 Prognosis 
 Criteria of poor prognosis 
 There are a number of scoring systems which can be used to guide prognosis, but t hey 
are unreliable within the first 48 hours of the illness.  
 Ranson's scoring system reflect prognosis associated with acute pancreatitis.

 Ranson's criteria  on admission that signify a worse prognosis  include: 
 Criteria present at 0 hours: 
 Age >55 years old - 1 point 
 WBC >16 ×109 - 1 point 
 Glucose >11.1 mmol/L  - 1 point 
 LDH >350 U/L - 1 point 
 AST >250 U/L - 1 point 
 Criteria present at 48 hours: 
 Hematocrit fall of 10% or greater - 1 point 
 Urea rise of 1.8 mmol/L or more despite fluids - 1 point 
 Serum Calcium <2 mmol/L - 1 point 
 pO2 <60 mmHg - 1 point   (PaO2 of < 8.0 kPa)

 pO2 <60 mmHg - 1 point   (PaO2 of < 8.0 kPa)  
 Base deficit >4 meq/L - 1 point 
 Fluid sequestration >6000 mL - 1 point 
 The mortality associated with severe acute pancreatitis  20%  
 often due to sepsis or multiorgan failure.  
 Hematocrit (Hct) 
 Should be conducted at presentation as well as 12 and 24 hours after admissio ns 
 Ĺ Hct (due to hemoconcentration) indicates third space fluid loss and inadequate fluid 
resuscitation

resuscitation 
 Ļ Hct indicates the rarer acute hemorrhagic pancreatitis  
 The following portend a poor prognosis  in patients with acute pancreatitis: 
WCC >15 
Urea >16 
Calcium <2.0 
Glucose >10 
CRP  >150 
 
 ARDS (adult respiratory distress syndrome),  
 acute kidney injury  
 disseminated intravascular coagulation (DIC).  
 due to pancreatic enzymes entering the blood and acting on coagulation fa ctors, 
thereby activating them. 
 Pancreatic pseudocyst

 Pancreatic pseudocyst 
 lab 
 Tests to confirm clinical diagnosis  
 Amylase is markedly raised , often in excess of four times the normal value. 
 nonspecific 
 Lipase : if ≥ 3 x  the upper reference range ĺ highly indicative of 
acute pancreatitis 
 The enzyme levels are not directly proportional to severity or prognosis 
 Tests to assess severity  
 Hematocrit (Hct) 
 Should be conducted at presentation as well as 12 and 24 hours after 
admissions 837

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    48 
  ↑ Hct  (due to hemoconcentration) indicates third space fluid loss and 
inadequate fluid resuscitation  
 Ļ Hct indicates the rarer acute hemorrhagic pancreatitis  
 WBC count 
 Blood urea nitrogen 
 Ĺ CRP and procalcitonin levels  
 Ĺ ALT  
 Images  
 Ultrasound 
 the most useful initial test

 the most useful initial test 
 Main purpose: detection of gallstones and/or dilatation of the biliary tract 
(indicating biliary origin) 
 Signs of pancreatitis 
 Indistinct pancreatic margins (edematous swelling) 
 Peripancreatic build-up of fluid ; evidence of ascites in some cases 
 Evidence of necrosis, abscesses, pancreatic pseudocysts 
 CT  
 not routinely indicated 
 only when the diagnosis is in doubt

 only when the diagnosis is in doubt 
 would be preferable to ultrasound in establishing the presence of inflamma tion 
(acute or chronic) of the pancreas and severity of disease  
 Abdominal x ray  
 has NO role in acute pancreatitis  
 Sentinel loop sign: 
 dilatation of a loop of small intestine in the upper abdomen 
(duodenum/jejunum)  
 Colon cut off sign:  
 gaseous distention of the ascending and transverse colon that abruptly 
terminates at the splenic flexure

terminates at the splenic flexure  
 Evidence of possible complications:  
 pleural effusions,  
 pancreatic calcium stones;  
 helps rule out intestinal perforation with free air 
 may demonstrate calcification in chronic  pancreatitis.  
 
Treatment  
 supportive, and monitoring (often in the intensive care unit).  
 Fluid resuscitation: aggressive hydration with crystalloids (e.g., normal saline)  
 Analgesia: IV opioids (e.g., fentanyl)

 Analgesia: IV opioids (e.g., fentanyl) 
 Bowel rest (NPO)and IV fluids are recommended until the pain subsides  
 Nasogastric tube insertion:  
 not routinely recommended;  
 indicated in patients with vomiting and/or significant abdominal distention 
 Nutrition 
 Begin enteral feeding  (oral/nasogastric/naso-jejunal) as soon as the pain 
subsides  
 Total parenteral nutrition:  
 only in patients who cannot tolerate enteral feeds  (e.g., those with

persistent ileus and abdominal pain) 
 if there is gallstones : 
 urgent ERCP  when stable.  
 All should have a cholecystectomy  either during the same admission  or within four 
weeks depending on their clinical progress.   
 
 838

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    49 
  
Systemic inflammatory response syndrome (SIRS) 
Causes 
 sepsis  
Criteria  
 SIRS is defined as two or more  of the following: 
1. Temperature more than 38°C or less than 36°C 
2. Heart rate more than 90 beats/min 
3. Respiratory rate more than 20 breaths/min or PaCO2 less than 4.3 kPa

4. WBC count 12,000/mm3, less than 4000/mm3 , or more than 10% immature (bands) 
form. 
 resuscitation of the sick patient still follows the ABC algorithm: 
1. Airway 
2. Breathing 
3. Circulation. 
 Airway control and oxygen to maintain normal saturations is the first part of that 
algorithm.  
 Subsequent fluid resuscitation and treatment of the underlying cause can then b e 
initiated.  
 The need for invasive monitoring and intensive care is then assessed, dependi ng on the

response to initial treatment. 
 Early goal-directed therapy (EGDT ) in cases of SIRS or septic shock is becoming 
increasingly recognised as potentially beneficial.  
 EGDT  aims to: 
 increase organ perfusion through restoration of mean arterial pressure using 
inotropes if necessary,  
 maintaining central venous pressure (CVP),  
 maintaining oxygenation 
 using SjVO2 (jugular venous oxygen saturation) as a guide to oxygen 
utilisation at the tissue level.

utilisation at the tissue level.  
 If fluids are not achieving haemodynamic stability, and there is hypoperfusion  (in dicated 
by oliguria or lactataemia)  the most appropriate course of action   central line   
vigorous resuscitation is indicated. 
 Insertion of a central line allows measurement of CVP, SjVO2 and the use of 
inotropes. 
 SjVO2 higher than 70% is indicative of organ hypoperfusion, as oxygen is not being 
extracted.

extracted. 
 Obtain blood cultures prior to antibiotic administration  
 
Pancreatic pseudocysts  
 encapsulated collection of pancreatic fluid which  develops 4 weeks after an acute attack of 
pancreatitis ; can occur in both acute and chronic pancreatitis  
 pancreatic secretions leak from damaged ducts ĺ inflammatory reaction of surroun ding tissue 
ĺ encapsulation of secretions by fibrous tissue

ĺ encapsulation of secretions by fibrous tissue  
 Often asymptomatic 
 Painless abdominal mass 
 Pressure effects 
 Gastric outlet obstruction (early satiety, non-bilious vomiting, abdominal pain) 
 Bile duct obstruction with jaundice 
Diagnostics  
 abdominal ultrasound/CT/MRI ĺ extrapancreatic fluid collection withinwell -defined 
wall/capsule, no solid cyst components detectable 
Treatment 839

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    50 
  Surgical/endoscopic; ultrasound/CT-guided percutaneous drainage  
 
Chronic pancreatitis 
 
 Chronic pancreatitis is an inflammatory condition, which can ultimately affect both the ex ocrine 
and endocrine functions of the pancreas. 
Causes

Causes 
 alcohol excess ( 80%)  
 what is the general mechanism by which alcohol induces the likely condition? 
 Alcohol increases acinar cell sensitivity to CCK (cholecystokinin), 
stimulating trypsinogen production in the cell 
 Unexplained (20%) 
 PRSS-1 mutation  can cause a hereditary form of the disease.  
 It does this by allowing trypsin to be activated in the pancreas, thus causing enzyma tic 
damage.

damage.  
 SPINK-1 mutation  can cause a hereditary form of the disease.  
damage. 
Features  
 pain is typically worse 15 to 30 minutes following a meal 
 steatorrhoea:  
 symptoms of pancreatic insufficiency usually develop between 5 and 25 years afte r the 
onset of pain 
 Late manifestation  (after 90% of the pancreatic parenchyma is destroyed)

 diabetes mellitus develops in the majority of patients. It typically occurs more than 20 ye ars 
after symptom begin 
 abdominal x-ray shows pancreatic calcification in 30% of cases. 
 CT is more sensitive at detecting pancreatic calcification.   
 Sensitivity is 80%, specificity is 85% 
 More sensitive in moderate to advanced chronic pancreatitis   
 Malabsorption is only present in moderate to advanced chronic pancreatitis 
 abnormalities include:

 abnormalities include: 
 pancreatic calcification,  
 pseudocyst formation and  
 ductal distortion.  
 CT scanning is much less effective in the diagnosis of early chronic pancreatitis  and a 
normal scan does not exclude the diagnosis. 
 functional tests: faecal elastase  may be used to assess exocrine function if imaging 
inconclusive 
 Both 72-hour faecal fat estimation and D-xylose absorption testing are used for their ab ility to

indicate the presence, or absence, of malabsorption, neither is diagnostic of an underl ying 
condition. 
 pancreatic enzyme supplements  
 Pancrelipase (Creon)  
 Analgesia 
 In a patient with chronic liver disease presented with features of decompensation 
associated with chronic pancreatitis  Naloxone   
 Patients with alcoholic liver disease are often surprisingly sensitive to opiate 
analgesia which should only be used with caution.

 antioxidants: limited evidence base - one study suggests benefit in early disease 
 
 Pancreatic pseudocysts 
 Splenic vein thrombosis 
 Can occur in 10% of patients with chronic pancreatitis 
 Pathophysiology: inflammation of the splenic vein  ĺ thrombus formation ĺ left -sided 
portal hypertension ĺ gastric varices   840

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    51 
  Clinical features: can present with upper GI bleeding, ascites, and splenomegaly 
 Diagnosis: ultrasound with doppler, CT/MR angiography 
 Treatment 
 Acute: anticoagulation and/or thrombectomy 
 Chronic and symptomatic: splenectomy 
 
 Pancreatic ascites 
 Pancreatic diabetes

 Pancreatic diabetes  
 Pancreatic cancer (especially in patients with hereditary pancreatitis) 
 
Pancreatic cancer 
 Pancreatic cancer is often diagnosed late as it tends to present in a non-specific wa y. 
  Over 80% of pancreatic tumours are adenocarcinomas  
  typically occur at the head of the pancreas. 
 most often found in the ductal cells  in the head of the pancreas . 

 smoking 
 diabetes 
 chronic pancreatitis (alcohol does not appear an independent risk factor though) 
 hereditary non-polyposis colorectal carcinoma 
 multiple endocrine neoplasia 
 BRCA2 gene 
 Jewish or African descent. 
Features 
 classically painless jaundice 
 however, patients typically present in a non-specific way with anorexia, weight loss, epig astric 
pain 
 loss of exocrine function (e.g. steatorrhoea) 
 atypical back pain is often seen

 atypical back pain is often seen 
 the first symptom is often pain that radiates to the back. 
 because it is found very late when it has already impinged on other structures. 
 migratory thrombophlebitis (Trousseau sign) is more common than with other cancers 
 Migratory thrombophlebitis causes recurrent tender, palpable small blood clots that  
come and go in various locations on the body,  
 ultrasound has a sensitivity of around 60- 90%

 ultrasound has a sensitivity of around 60- 90% 
 high resolution CT scanning is the investigation of choice  if the diagnosis is suspected 
 Carbohydrate Antigen 19-9  (CA-19-9) is a tumour marker is usually used to monitor 
response to treatment  and possible recurrance,  rather than for diagnosis. 
 less than 20% are suitable for surgery at diagnosis 
 a Whipple's resection (pancreaticoduodenectomy) is performed for resectable lesions in the 
head of pancreas.

head of pancreas.  
 Side-effects of a Whipple's include dumping syndrome and peptic ulcer disease 
 adjuvant chemotherapy is usually given following surgery 
 ERCP with stenting is often used for palliation 
 relief of symptoms as soon as possible is the main objective of therapy. 
 Stenting relieves symptoms of itching and reverses jaundice in about 85% of patients.  
 Stents can be inserted during an ERCP or percutaneously in those with extensive

disease or in those otherwise unsuitable for surgery. 
Prognosis 
 It has a very high mortality rate (approximately 1 year from diagnosis), usually because  it is 
found very late when it has already impinged on other structures. 
 
 841

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    52 
  
Biliary conditions 
Ascending cholangitis 
 Ascending cholangitis is a bacterial infection of the biliary tree.  
 The most common predisposing factor is gallstones. 
Features 
 Charcot's triad  (occurs in about 20-50% of patients) 
1. right upper quadrant (RUQ) pain, (70%)  
2. fever  (the most common feature, seen in 90%)

2. fever  (the most common feature, seen in 90%) 
3. jaundice ( 60%) 
 hypotension  and confusion  are also common 
 Combining these two additional symptoms to Charcot ’s triad results in Reynold ’s 
pentad.  
 elevated alkaline phosphatase and elevated direct bilirubin suggest obstruc tion of the biliary 
tree 
 The initial imaging study is ultrasonography. 
 The gold standard for diagnosis is (ERCP)  endoscopic retrograde cholangiopancreatography. 

 intravenous antibiotics 
 endoscopic retrograde cholangiopancreatography (ERCP)  after 24-48 hours  to relieve any 
obstruction 
Gallstones (Cholelithiasis) 
Risk factors for biliary stones  
 Cholesterol gallstones are thought to arise as a result of a triple defect: 
1. Super saturation of gallbladder bile (high in cholesterol, low in bile salts) 
2. Increased rate of cholesterol nucleation in the gallbladder

3. Reduction in gallbladder contractility 
 Predisposing factors to gallstone formation: 
 Older age 
 Female sex (oestrogens) 
 Oral contraceptive use 
 Cirrhosis (bile pigment stones) 
 ileal resection  (by reducing entero-hepatic circulation and increasing bile salt loss) 
 Clofibrate (by increasing biliary supersaturation) 
  Cholestyramine (by binding bile salts) 
 Crohn's disease  
Features 
 most will be asymptomatic

Features 
 most will be asymptomatic 
 Classic symptoms include biliary colic, nausea, and/or vomiting 
 biliary colic: sharp, colicky pain made worse with fatty food 
 
 liver function tests : obstructive jaundice 
 Ultrasound  
 abdominal/right upper quadrant ultrasound is the test of choice for gallstone diseas e  
  ultrasound finding of a common bile duct dilatation is suggestive of an ob structing 
stone

stone 
 Whilst ultrasound is a good preliminary investigation for common bile duct sto nes it 
lacks sensitivity. 
  The sensitivity of ultrasound for detecting stones is significantly reduced during an 
episode of acute pancreatitis (around 70%) so repeating an ultrasound is a reasonable 
suggestion as it would perform better in the current clinical context than it had done  
previously. However, its ability to detect CBD stones remains poor.

 MRI is highly effective in confirming the presence of common bile duct stones,  842

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    53 
  endoscopic ultrasound (EUS) is a suitable alternative. 
  CT does not perform well when compared to MRI. 
 
 Radiographs 
 cannot rule out stone with negative radiograph because cholesterol stones are 
radiolucent 
 pigment stones are radiopaque so may show up on radiograph

 Endoscopic retrograde cholangiopancreatography (ERCP),  along with intra-operative 
cholangiography, is considered the gold standard for diagnosis of common bile duct 
stones . 
 However it is an invasive procedure associated with significant morbidity; thus it should 
ideally be performed as a therapeutic rather than diagnostic  procedure. 
 The indication for ERCP is for the removal of ductal stones (predominantly CBD 
stones).  
 Magnetic resonance cholangiopancreatography (MRCP)

 The presence of a CBD calculus should be confirmed prior to subjecting the patient t o a 
potentially dangerous procedure such as an ERCP - MRCP would be the most 
appropriate test to do this.  
 the most sensitive for a diagnosis of gallstones 
 In terms of sensitivity for determining the presence of stones anywhere within 
the biliary tract, MRCP and EUS would be the most sensitive investigations with 
little to choose between them (ERCP may well miss small stones in the 
gallbladder).

gallbladder). 
 In patients with severe gallstone pancreatitis   ERCP and endoscopic stone extraction 
should be performed within 72 hours of the onset of pain.  
 In patients with mild gallstone pancreatitis , in the absence of cholangitis, there is no 
evidence to support ERCP and stone extraction in the acute setting; however arrangeme nts 
must be made for definitive management of common bile duct stones on t he same admission 
or within two weeks of recovery .

or within two weeks of recovery .  
 Asymptomatic gallstones  which are located in the gallbladder are common and  do not 
require treatment.  
 However, if stones are present in the common bile duct there is an increased risk of 
complications such as cholangitis or pancreatitis and surgical management should be 
  endoscopic retrograde cholangiopancreatography ( ERCP ) for biliary sphincterotomy and 
stone extraction.

stone extraction. 
 the most common procedure-related complication is  Pancreatitis  
 risks of developing this complication: 
 Female sex,  
 age less than 60 and  
 a low probability of structural disease (suggested by a normal bilirubin, 
non-dilated ducts or suspected sphincter of Oddi dysfunction) 
 Percutaneous transhepatic cholangiography is an interventional radiological procedure which 
is generally reserved for therapeutic decompression of an obstructed biliary system where

ERCP is unsuccessful or not possible. 
 
 Cholecystitis 
 Acute pancreatitis 
 Gallbladder cancer 
 Choledocolithiasis 
 calculi in the common bile duct 
 Fistula between gallbladder and small intestine 
 passed gallstone can obstruct the ileocecal valve 
Glasgow score for Pancreatitis: 
1. PaO 2 <7.29 kPa 
2. Glucose >10 mmol/L 
3. Age >55 years 
4. WBC >15 
5. Calcium <2.0 mmol/L 
6. Urea >16 mmol/L 843

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    54 
 7. LDH >600 IU/L 
8. Albumin <32 g/L 
Interpretation of glasgow score for pancreatitis: 
 The presence of three or more  of these criteria within the first 48 hours is indicative of severe 
pancreatitis.  
 If the score ≥3, severe pancreatitis is likely Referral to the HDU/ICU is suggested in this case.

If the score <3, severe pancreatitis is unlikely. 
Functional gall bladder pain  
 The Rome III criteria for functional gall bladder pain are as follows: 
 episodes lasting 30 minutes or longer 
 recurrent symptoms occurring at different intervals (not daily) 
 the pain builds up to a steady level 
 the pain is moderate to severe enough to interrupt the patient's daily activities or lead t o 
an Emergency Department visit

an Emergency Department visit 
 the pain is not relieved by bowel movements 
 the pain is not relieved by postural change 
 the pain is not relieved by antacids, and 
 exclusion of other structural disease that would explain the symptoms. 
 The pain may present with one or more of the following supportive criteria: 
 associated with nausea and vomiting 
 radiates to the back and/or right infra subscapular region, and 
 awakens from sleep in the middle of the night.

 awakens from sleep in the middle of the night. 
Choledochal cysts 
 Choledochal cysts are congenital bile duct anomalies, cystic dilatations of the biliary t ree 
 The classic triad in adults with choledochal cysts is: 
1. abdominal pain, (Most common symptom) 
2.  jaundice, and  
3. palpable right upper quadrant abdominal mass.  
 However, this triad is found in only 10-20% of patients.

 Adults may present with complications (eg, hepatic abscesses, cirrhosis, portal hypertension , 
recurrent pancreatitis, cholelithiasis) 
 Abdominal ultrasonography is the investigation  of choice 
 Choledochal cysts are usually diagnosed in the neonatal period but a few are delayed  until 
adulthood. The Todani classification is used to define these: 
 Type 1 - a fusiform dilation of the common hepatic duct (CHD) - the most common  
 Type 2 - a diverticulum of the CHD

 Type 2 - a diverticulum of the CHD 
 Type 3 - a choledochcele 
 Type 4 - describes extension into the intrahepatic ducts (the second most common)  
 Type 5 - intrahepatic cystic disease only. 
  Treatment  
 Resection and reconstruction is advised to prevent recurrent cholangitis, pancreatitis, 
and malignant change. 
Sphincter of Oddi dysfunction 
 Type 1 Sphincter of Oddi dysfunction (SOD) is characterised by:

  abdominal pain,  
 deranged liver function tests,  
 a dilated biliary tree without strictures, and  
 delayed emptying of contrast at ERCP.  844

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    55 
  Delayed excretion of contrast is definitive and Sphincter of Oddi manometry need not be  
carried out with this finding. 
 Type 2 SOD 
 pain with only one or two other criteria from the type 1 definition  
 type 3 SOD 
 biliary type pain only.

 type 3 SOD 
 biliary type pain only.  
 Diagnosis in type 3 is supported by abnormal manometry although this will only be 
present in 12-28% of these patients so the diagnosis is most often one of exclusion . 
Post-cholecystectomy syndrome 
 Post-cholecystectomy syndrome is a recognised complication of cholecystectomies.  
 Typically symptoms of dyspepsia, vomiting, pain, flatulence and diarrhoea occur in up to 40%

patients post surgery. 
 The pathology behind the syndrome isn't completely clear, however there is some association 
with remnant stones and biliary injury.  
 Pain is often due to sphincter of Oddi dysfunction and the development of surgical adhesio ns.  
 Management: 
 low-fat diet  
 bile acid sequestrants, such as Cholestyramine, to bind the excess bile acids and thus 
preventing lower gastrointestinal signs.

preventing lower gastrointestinal signs.  
 Proton-pump inhibitors like Lansoprazole do play a role, if the patient is complaining of 
dyspeptic like symptoms .  
Bile-acid malabsorption  
 
 Although a small proportion of bile acids (3%) are excreted in the faeces, about 9 7% of bile 
acids are recycled.  
 Bile-acid malabsorption is a cause of chronic diarrhoea.

 the bile, with no gall bladder to store it, is excreted directly into the gut  diarrhoea  
 In people with bile acid malabsorption, excess bile in the colon stimulates electrolyte and water 
secretion, which results in chronic watery diarrhoea.  
 May affect 10% of patients following cholecystectomy. 
 Typically it is post-prandial 
 There is evidence suggesting that up to one-third  of people with a diagnosis of IBS with 
diarrhoea (IBS- D) have bile acid malabsorption 
 
mechanisms

mechanisms  
 Bile acid malabsorption causes diarrhoea by 1 of the following mechanisms:  
 inducing secretion of sodium and water increasing colonic motility  
 stimulating defecation 
 inducing mucus secretion  
 damaging the mucosa, thereby increasing mucosal permeability. 
 
Types : divided into 3 types depending on aetiology:  
 type 1: following ileal resection, disease or bypass of the terminal ileum  
 type 2: primary idiopathic malabsorption

 type 2: primary idiopathic malabsorption  
 type 3: associated with cholecystectomy, peptic ulcer surgery, chronic pancreatitis, coeliac 
disease or diabetes mellitus. 
 
Causes:  
1. Prima ry: due to an excessive production of bile acid,  
 
2. Secondary:  Due to an underlying gastrointestinal disorder, causing reduced bile acid 
absorption  
 often seen in patients with ileal disease, such as with  Crohn's . 
 cholecystectomy 
 small intestinal bacterial overgrowth

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    56 
  Ileal resection  
 drugs:  
 Biguanides (metformin) ,  
 Colchicine, used for treating gout in patients where (NSAIDs) are 
contraindicated 
 the test of choice is SeHCAT  
 nuclear medicine test using a gamma-emitting selenium molecule in selenium

homocholic acid taurine or tauroselcholic acid (SeHCAT)   (75Selenium HomotauroCholic 
Acid Test ) 
 scans are done 7 days apart to assess the retention/loss of radiolabelled75SeHCAT 
 Retention values of less than 15% have been considered abnormal and 
indicative of bile acid malabsorption. 
 retention values of 10 –15% (mild bile acid malabsorption)  
 retention values of 5 –10% (moderate bile acid malabsorption)  
 retention values of 0 –5% (severe bile acid malabsorption). 

 bile acid sequestrants e.g. cholestyramine 
Primary biliary cirrhosis  
Primary biliary cirrhosis  - the M rule 
 
 IgM 
 anti-Mitochondrial antibodies, M2 subtype 
 Middle aged females 
 
 Aetiology: not fully understood although it is thought to be an autoimmune cond ition.  
 Mechanism: chronic inflammatory process  damage to interlobular bile ducts  cholestasis & 
 female: male ratio  9:1

 female: male ratio  9:1  
 classic presentation  itching in a middle-aged woman 
 
 Sjogren's syndrome (seen in up to 80% of patients) 
 systemic sclerosis 
 thyroid disease 
The two main conditions causing pigmentation  and chronic liver disease  are: 
1. primary biliary cirrhosis (PBC) and 
2.  Haemochromatosis. 
 
 early: may be asymptomatic (e.g. raised ALP on routine LFTs) or fatigue, pruritus

 cholestatic jaundice 
 hyperpigmentation , especially over pressure points 
 xanthelasmas, xanthomata 
 also: clubbing, hepatosplenomegaly 
 Fat malabsorption leading to deficiency of the vitamins A, D, E, K (hence osteomalacia and  
also bruising). 
 Back pain  due to osteomalacia resulting from malabsorption or osteoporosis - hepatic 
osteodystrophy. 
 late: may progress to liver failure 
 
Diagnosis

Diagnosis 
 anti-mitochondrial antibodies (AMA) M2 subtype are present in 98% of patients and are hig hly 
specific   
 (AMAs) targeted against pyruvate dehydrogenase. 
 Pyruvate dehydrogenase (PD) is found in the mitochondria. required for the 
generation of acetyl-CoA from pyruvate for entry into the tricarboxylic acid (TCA) 
cycle. 
 smooth muscle antibodies in 30% of patients 846

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    57 
  raised serum IgM 
Liver functon tests correlate poorly with histology in PBC – the disease may progress insidiously with 
normal or near-normal LFTs.  
 malabsorption: osteomalacia, coagulopathy 
 Osteoporosis  is a common complication, possibly due to vitamin D malabsorption and/or

premature ovarian failure. All patients with PBC should be screened for the condition   The 
patient should undergo bone mineral densitometry.  
 sicca syndrome occurs in 70% of cases 
 portal hypertension: ascites, variceal haemorrhage 
 hepatocellular cancer (20-fold increased risk)  
 pruritus: cholestyramine 
 fat-soluble vitamin supplementation 
 ursodeoxycholic acid ( UDCA ) 
 UDCA delays the need for liver transplantation

 UDCA delays the need for liver transplantation 
 improves liver biochemistry and may slow disease progression. 
 The effectiveness of UDCA is monitored by improvements in ALP and GGT, but 
ALP is more widely used than GGT. 
 liver transplantation  
 e.g. if bilirubin > 100 (PBC is a major indication)   
 Liver transplantation has a good prognosis (90 –95% survival)  
 recurrence in graft can occur but is not usually a problem 
 occur in 10% to 40% of patients

 occur in 10% to 40% of patients  
 but recurrent PBC does not affect either graft or patient survival rates. 
 contraindication to liver transplantation: 
 Psychological factors that may impair compliance with 
immunosuppression  
Primary sclerosing cholangitis (PSC) 
 
Primary sclerosing cholangitis is a biliary disease of unknown aetiology characterised by inflamma tion 
and fibrosis of intra and extra-hepatic bile ducts

 ulcerative colitis: 4% of patients with UC have PSC, 80% of patients with PSC have UC 
 Crohn's (much less common association than UC) 
 HIV 
Features 
 50 % of patients with primary sclerosing cholangitis (PSC) will have a normal physical 
examination at the time of diagnosis  
 cholestasis:  (alkaline phosphatase greater than transaminases)  jaundice and pruritus 
 right upper quadrant pain 
 fatigue 
 intermittent diarrhoea. 

 ERCP  is the standard diagnostic tool , showing multiple biliary strictures giving a 'beaded' 
 Non-invasive magnetic resonance cholangiopancreatography ( MRCP ) is often performed 
initially . 
 MRCP would be the initial diagnostic investigation of choice particularly given a lower 
complication rate and its ability to image ducts proximal to obstructing strictures.

 Antibodies: ANCA may be positive (pANCA 84%,  aCL 66%, , and ANA 53% ) 
 increase in IgM  
 there is a limited role for liver biopsy, which may show fibrous, obliterative cholangitis often 
described as 'onion skin' 
 cholangiocarcinoma (in 10%) 
 increased risk of colorectal cancer 
847

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    58 
 Prognosis 
 The median time to liver failure around 12 years. 
 
Cholangiocarcinoma 
 The vast majority of cholangiocarcinomas (70%) are sporadic.  
 Primary sclerosing cholangitis (PSC) is the most common risk factor 
 Others 
 diabetes 
 fatty liver disease, and

 Others 
 diabetes 
 fatty liver disease, and 
 inflammatory bowel disease without PSC. 
 Alcohol 
 Smoking 
 Chronic hepatitis B 
 obesity 
 The imaging characteristics of a cholangiocarcinoma are hypovascularity with scarring 
and calcification. 
 CT contrast is delivered in early (hepatic arterial) phase and delayed (portal venous) 
phase.  
 80% of normal liver tissue derives its blood supply from the portal vein, but tumours

generally derive their blood supply from the hepatic artery and are therefore 
hypervascular. 
 Cholangiocarcinomas are an exception as hypovascular lesions .  
 The Bismuth-Corlette classification is as follows: 
 Type I - below confluence of left and right hepatic ducts 
 Type II - reaching confluence but not involving left or right hepatic ducts 
 Type III - occluding common hepatic duct and either right (IIIa) or left (IIIb) hepatic duct

 Type IV - multicentric or bilateral intrahepatic segmental involvement; or involving 
confluence and both right and left hepatic ducts. 
 It is commonly used but does not take into account factors such as distant metastases 
or vessel involvement. 
 
hypervascular lesions on CT scan  (most prominent on arterial phase imaging): 
 Breast cancer metastasis 
 Focal nodular hyperplasia 
 Hepatic adenoma 
 HCC   
 
Liver conditions

Liver conditions 
Hepatomegaly 
Common causes  of hepatomegaly 
 Cirrhosis: if early disease, later liver decreases in size. Associated with a non-tender, firm li ver 
 Malignancy: metastatic spread or primary hepatoma. Associated with a hard, irregular. liver 
edge 
 Right heart failure: firm, smooth, tender liver edge. May be pulsatile 
 viral hepatitis 
 glandular fever 
 malaria 
 abscess: pyogenic, amoebic

 malaria 
 abscess: pyogenic, amoebic 
 hydatid disease  haematological malignancies 
 sarcoidosis, amyloidosis 
 
 848

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    59 
Hepatosplenomegaly 
Causes of hepatosplenomegaly 
 chronic liver disease* with portal hypertension 
 infections: glandular fever, malaria, hepatitis 
 lymphoproliferative disorders 
 myeloproliferative disorders e.g. CML 
 amyloidosis

*the latter stages of cirrhosis are associated with a small liver 
 
Gaucher's disease  is a lysosomal storage disease,  due to deficiency of the 
lysosomal hydrolase beta-glucosidase . most commonly seen in Ashkenazi Jews. 
Its features include hepatosplenomegaly, haematological abnormalities and skeletal 
involvement.  
Liver function test 
 Gamma-glutamyl-transferase (GGT)

 Gamma-glutamyl-transferase (GGT)   
 ↑↑ by drugs such as phenytoin and alcohol. 
 Mild raises in GGT can occur with any alcohol intake, and a rise does not always 
indicate liver pathology. 
 ↑↑ in fatty liver 
 Alkaline phosphatase  (ALP)  typically ↑↑ in pregnancy.  
 Only ischaemic hepatitis and paracetamol overdose tend to produce transaminase l evels that 
are raised to very high degree (250 times the upper limit of normal).

 Remember that the level to which transaminases are elevated cannot be used to judge  the 
degree of liver damage and impairment of hepatic function.  
Alkaline phosphatase 
Causes of raised alkaline phosphatase (ALP)  
 liver: cholestasis, hepatitis, fatty liver, neoplasia 
 Paget's 
 osteomalacia 
 bone metastases 
 hyperparathyroidism 
 physiological: pregnancy , growing children, healing fractures 
 
The table below splits the causes according to the calcium level

Raised ALP and raised calcium Raised ALP and low calcium 
• Bone metastases  
• Hyperparathyroidism  • Osteomalacia  
• Renal failure  
Liver biopsy 
Contraindications to percutaneous liver biopsy 
 deranged clotting (e.g. INR > 1.4) 
 Percutaneous liver biopsy should be avoided if the INR is greater than 1.3 (prothrombin 
time greater than three seconds above normal).

time greater than three seconds above normal).  
 If the INR is >1.4, fresh frozen plasma  (FFP) may be administered and liver biopsy 
then carried out if the INR is less than 1.4. 
 low platelets (e.g. < 60 * 109/l) 
 The minimum safe lower limit of platelets is 60.  
 Where the platelet count is 40-60 biopsy can be performed immediately after  platelet 
transfusion provided there has been an increment to the recommended level. 
 Anti-platelet medication

 Anti-platelet medication  
 should be stopped for at least one week prior to liver biopsy. 
 anaemia 849

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    60 
  extrahepatic biliary obstruction 
 hydatid cyst 
 haemoangioma 
 uncooperative patient 
 ascites 
 Significant volume ascites is a contraindication to percutaneous liver biopsy but a 
transjugular biopsy can be performed as an alternative.  
Acute liver failure

Acute liver failure  
Acute liver failure describes the rapid onset of hepatocellular dysfunction leading t o a variety of 
systemic complications. 
Causes  
 paracetamol overdose 
 alcohol 
 viral hepatitis (usually A or B) 
 acute fatty liver of pregnancy 
Features* 
 jaundice 
 coagulopathy: raised prothrombin time 
 hepatic encephalopathy 
 renal failure is common ('hepatorenal syndrome')

*remember that 'liver function tests' do not always accurately reflect the synthetic function of t he liver. 
This is best assessed by looking at the prothrombin time and albumin level.  
Ascites 
Causes  
 The serum ascites albumin gradient (SAAG) is the most sensitive and specific method 
of categorising ascites.  
 To calculate the ascitic fluid albumin should be subtracted from the serum albumin.

 A value that is ≥11 g/L (high SAAG) indicates a transudate (e.g. cirrhosis, cardiac 
failure), 
  <11 g/L (low SAAG) indicates an exudate (e.g. malignancy, pancreatitis). 
 
 The causes of ascites can be grouped into those with a serum-ascites albumin gradient 
(SAAG) <11 g/L or a gradient >11g/L as per the table below: 
 
SAAG > 11g/L SAAG <11g/L 
Cirrhosis 
Alcoholic hepatitis 
Cardiac ascites 
Mixed ascites 
Massive liver metastases 
Fulminant hepatic failure 
Budd-Chiari syndrome

Budd-Chiari syndrome 
Portal vein thrombosis 
Veno-occlusive disease 
Myxoedema 
Fatty liver of pregnancy Peritoneal carcinomatosis 
Tuberculous peritonitis 
Pancreatic ascites  
Bowel obstruction 
Biliary ascites 
Post operative lymphatic leak 
Serositis in connective tissue diseases 
Characteristics of ascitic fluid 
 Causes of a transudate (protein < 30 g/l, assuming a normal albumin level):  
 Hepatic cirrhosis 
 Right-sided cardiac failure

 Right-sided cardiac failure 
 Hypoalbuminaemia (nephrotic syndrome) 
 Acute nephritis 
 Budd-Chiari syndrome 
 Causes of an exudate (protein > 30 g/l): 
 Infection (tuberculosis, peritonitis) 850

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    61 
  Inflammation (vasculitis) 
 inhaler.  
Treatment  
 Large, symptomatic ascites  therapeutic paracentesis.  
 Several large randomised, controlled trials have shown that repeated large volume 
paracentesis (4-6 L) is safer and more effective for the treatment of tense ascites

compared with larger than usual doses of diuretics. 
 Paracentesis is relatively contraindicated if the patient is encephalopathic,  
 Paracentesis is less likely to be successful if the patient has peripheral oedema 
 Whilst therapeutic paracentesis will be necessary in light of the large volume tense 
ascites it would be advisable to consider doing this with FFP cover. 
 Not large, asymptomatic ascites  dietary salt restriction (to no more than 90 mmol/day) + 
spironolactone.

spironolactone. 
 The initial management would be spironolactone 
 Initial dose of spironolactone is 100 mg/day and may be titrated up to 400 mg/da y.  
 Once the maximum dose of spironolactone has been reached furosemide can  be added 
if there is still significant ascites accumulation and the renal function and electrolytes will 
tolerate further diuresis.  
 Doses of furosemide are advised start at 40 mg/day titrating up to 160 mg/day as 
tolerated or needed.

tolerated or needed. 
 Furosemide alone has poor efficacy in cirrhosis. 
 A major reason for so-called diuretic-resistant ascites is an excess sodium intake 
 Spironolactone is more effective than furosemide because  the site of sodium retention 
in cirrhosis is the distal nephron 
 The ideal weight loss is 0.5 kg/day 
  transcutaneous liver biopsy is contraindicated with ascites (use transjugular biopsy if 
absolutely necessary).

absolutely necessary). 
 Management of hyponatraemia in patients with chronic liver disease and ascites: 
 serum sodium is 126-135 mmol/L  No specific intervention other than monitoring   
 serum sodium is 121-125 mmol/L + normal creatinine  Reduce diuretics  
 serum sodium is 121-125 mmol/L + high creatinine  Stop diuretics + give volume 
expansion 
 serum sodium is ≤120 mmol/L   Stop diuretics + give volume expansion   with 
colloid or normal saline.

colloid or normal saline. 
 Management of hypoproteinemia in patients with chronic liver disease 
 Cirrhotic ascites has significantly lower protein and complement levels than non-cirrhotic 
ascites.  
 This can result in less opsonic activity of the peritoneal fluid predisposing to 
spontaneous bacterial peritonitis. 
 indications for the use of albumin in cirrhosis: 
 post-paracentesis circulatory dysfunction,  
 spontaneous bacterial peritonitis, and  
 hepatorenal syndrome.

 hepatorenal syndrome. 
 Albumin replacement treatment is warranted in this diagnosis and can also decrease 
the development of the hepatorenal syndrome. 
 20% salt poor albumin (human albumin solution)  
 The salt-poor preparation of albumin is particularly important in this scenario as 
high salt load will encourage fluid to shift into the extravascular compartment 
resulting in fluid overload. 851

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    62 
  
Summary table of the current uses of albumin in hepatology, according to the main international 
guidelines and looking at future perspectives ( PPCD : post-paracentesis circulatory dysfunction; SBP: 
spontaneous bacterial peritonitis; HRS : hepatorenal syndrome; HE: hepatic encephalopathy; ACLF :

acute- on-chronic liver failure). 
 
Meig's syndrome  ovarian fibroma associated with a pleural effusion and ascites 
Liver cirrhosis 
 
 which hepatic cells  are central to the process of fibrosis? 
 The hepatic stellate cells  are central to the process of fibrosis within the liver.

 What is the pro-inflammatory factor in fibrotic liver injury which activate the stellate ce lls? 
 Tumour necrosis factor-a  is a pro-inflammatory effector in fibrotic liver injury, through 
activation of the stellate cells . These cells then secrete the fibrillar collagen constituting 
the defining features of hepatic fibrosis. 
 Interleukin-10 is thought to exert anti-inflammatory effects on the stellate cell.

 Which mediator is released by stellate cel ls that causes fibrosis seen in cirrhosis?.  
 Transforming growth factor-beta  is the mediator released by stellate cells  that 
causes fibrosis 
 Which factor that causing contraction of the hepatic stellate cells?  
 Endothelin  is a vasoconstrictor in the hepatic sinusoids  (similarly in the 
endothelium of the systemic circulation) and functions by causing contraction of the

hepatic stellate cells  thus increasing intrahepatic sinusoidal resistance  and 
promoting portal hypertension . 
 Nitric oxide antagonises the effects of endothelin in the liver. 
 Pathogenesis includes the replacement of type IV collagen in the perisinusoida l space (space 
of Disse) with type I and III collagen. 
Features  
 Cardiac  
 Cardiac output is often elevated 
 The cardiomyopathy of alcoholism is a dilated or congestive form. 
 Dilated cardiomyopathy

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    63 
  systemic vasodilatation 
 ĻĻ vascular resistance,  
 increased plasma volume  low serum sodium. 
 Most patients have sodium and water retention . 
 Secondary hyperaldosteronism will result in total body sodium overload but not 
necessarily hypernatraemia.

necessarily hypernatraemia.  
 Remember that the sodium level is a concentration, therefore if the amount of 
solvent (water) is increased then it will not necessarily rise. 
 Abdominal symptoms 
 Hepatomegaly (possibly causing RUQ pain)  
 Splenomegaly  
 Ascites  
 Portal hypertension   
 Hepatic intrasinusoidal pressure is elevated  
 Which features is most indicative of decompensated portal hypertension? 
 Caput medusae

 Caput medusae 
 Which sign is a direct result of decreased hepatic oncotic  function in cirrhotic patients? 
 Lower limb swelling 
 Hormone disorders 
 Hyperestrogenism  
 Gynecomastia, decreased body hair (e.g., chest hair) 
 Gynaecomastia  
 What is the cause of gynaecomastia in cirrhosis? 
 Altered oestrogen metabolism 
 ↓↓ metabolism of sex steroids  ĹĹ oestrogen level.  
 there is associated testicular atrophy and loss of body 
hair.

hair. 
 May occur as a result of spironolactone therapy (an 
aldosterone antagonist). 
 Hypogonadism (testicular atrophy) 
 Reduced libido, erectile dysfunction, infertility 
 Amenorrhea  
Classifications   
 Child-Pugh classification of liver cirrhosis 
 The Child-Pugh classification is a scoring system to assess the severity  of liver 
cirrhosis 
Score 1 2 3 
Bilirubin ( m mol/l) <34 34-50 >50 
Albumin (g/l) >35 28-35 <28 
Prothrombin time, 
prolonged by (s) <4 4-6 >6

prolonged by (s) <4 4-6 >6 
Encephalopathy None mild marked 
Ascites None mild marked 
 Summation of the scores allows the severity to be graded either A, B or C: 
 < 7 = A 
 7- 9 = B 
 9 = C 
 Cirrhosis can be micro- or macronodular in type. 
1. micronodular  form: the nodules are less than 3 mm across with uniform liver 
involvement - seen in alcohol  or biliary disease . 
2. macronodular form: there are larger nodules, classically seen in chronic viral 
hepatitis .

hepatitis . 
 ALT is more specific than other liver enzymes in diagnosing hepatic injury.  853

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    64 
  the most important immediate investigation for patient with hepatic cirrhosis presented 
in a confused and drowsy state  Blood glucose ( hepatic gluconeogenesis can be 
significantly down-regulated)  
 ĹĹ plasma volume  
 ↓↓  serum sodium  
 Patients with cirrhosis are frequently hyponatraemic.

 This is a function of an inability to excrete free water (increased ADH levels and 
systemic vasodilation contribute, but the underlying mechanism is complex and 
not entirely understood).  
 Urinary sodium concentration is usually less than 10 mmol/l  
 Reduced urinary sodium excretion  
 Patients with cirrhosis are frequently hyponatraemic. This is a function of an 
inability to excrete free water (increased ADH levels and systemic vasodilation

contribute, but the underlying mechanism is complex and not entirely 
understood).  
 
Thrombocytobenia is a common finding in chronic liver disease.  
 
Sex hormones in liver cirrhosis 
 Clinical features of male cirrhotic subjects are feminization(gynecomastia etc) and 
hypogonadism(testicular atrophy, reduced fertility, loss of libido, impotence etc).  
 sex hormones  
 decrease in serum testosterone levels  
 increase in serum estrogen levels

 increase in serum estrogen levels  
 increase in ratio of estrogen to testosterone  
 Hyperestrogenization may be related with feminization of male cirrhotic subjects, 
whereas hypogonadism is the result of alcohol abuse per se, rather than the indirect 
consequence of liver cirrhosis.  
 
Prognosis 
 Five year survival after liver transplantation is now 75%. 
liver transplant

liver transplant  
Guidelines for referral to a liver unit following paracetamol overdose  include 
 Metabolic acidosis ( pH <7.3  or bicarbonate <18 mmol/L). 
 INR >3 (or prothrombin time >50 seconds) 
  INR >2.0 at or before 48 hours or >3.5 at or before 72 hours should prompt 
referral to a specialist unit.  
 Peak elevation occurs around 72-96 hours. 
 Oliguria 
 Creatinine >200 µmol/L, 
 (use haemodialysis if >400 μmol/L)  
 Hypoglycaemia.

 Hypoglycaemia. 
 Systolic BP <80 mm Hg despite adequate fluid resuscitation 
  Any degree of encephalopathy 48 hours after ingestion. 
 raised intracranial pressure (ICP)  
 signs of CNS oedema include: 
 BP >160/90 mmHg (sustained) or brief rises (systolic >200 mmHg),  
 bradycardia,  
 decerebrate posture,  
 extensor spasms, and  
 poor pupil responses 
Criteria for liver transplant in fulminant failure in cases of paracetamol overdose  include: 
 arterial pH lower than 7.3 or

 arterial pH lower than 7.3 or  
 all of the following: 
 Prothrombin time greater than 100 seconds 
 Creatinine greater than 300 µmol/L, and 
 Grade 3-4 encephalopathy. 854

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    65 
 Criteria for liver transplant in fulminant failure in non-paracetamol  cases include: 
 INR greater than 6.7 or  
 prothrombin time greater than 100 seconds, or  
 any three of the following: 
 Aetiology that is not due to hepatitis A, hepatitis B or a drug reaction 
 Age less than 10 years or more than 40 years

 Age less than 10 years or more than 40 years 
 Jaundice more than seven days before encephalopathy 
 INR greater than 4 or prothrombin time greater than 50 seconds, and 
 Bilirubin greater than 300 µmol/L. 
Portal hypertension  
Basics 
 The liver receives approximately 1500 ml of blood each minute, two-thirds of which is 
provided by the portal vein . 
 
Definition:

 abnormally high pressure in the hepatic portal vein ( hepatic venous pressure gradient of 10 
mm Hg or more).  
 Portal hypertension is present when the wedged hepatic vein pressure is more than 5 mmHg 
higher than the inferior vena cava pressure. 
Mechanism of porto-systemic collaterals  
 Because the veins in the portal system lack valves , increased resistance to flow at any

point between the splanchnic venules and the heart will increase the pressure in all vessels on  
the intestine site of the obstruction.  
 This is manifest clinically by the development of porto-systemic collaterals (oesophageal 
varices), splenomegaly and/or ascites. 
 
Causes :  (Vascular resistance and blood flow are 2 important factors in its development).  
Pre-hepatic - (pre-sinusoidal) blockage of the portal vein before the liver  
 Congenital atresia or stenosis.

 Congenital atresia or stenosis. 
 Portal vein thrombosis  (idiopathic, umbilical and portal sepsis , malignancy, hypercoagulable 
states, pancreatitis). 
 Longstanding portal vein thrombosis is a well recognised complication in 
premature neonates due to cannulation of the umbilical vein during neonata l 
intensive care. 
 the best initial investigation is  Ultrasound with Doppler  
 Splenic vein thrombosis. 
 Extrinsic compression - eg, tumours. 
Hepatic  (sinusoidal)

Hepatic  (sinusoidal) 
 Cirrhosis. (the most common cause)  
 Chronic hepatitis. 
 Schistosomiasis. 
 Myeloproliferative diseases. 
 Idiopathic portal hypertension. 
 Granulomata - eg, sarcoid. 
 Nodular (nodular regenerative hyperplasia, partial nodular transformation). 
 Toxins (arsenic, vinyl chloride). 
 Fibropolycystic disease (including congenital hepatic fibrosis). 
Post-hepatic - (post-sinusoidal) blockage of hepatic veins or venules

 Budd-Chiari syndrome (hepatic vein obstruction). 
 Constrictive pericarditis. 
 Right heart failure. 855

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    66 
  Veno-occlusive disease of the smaller hepatic veins/venules (due to ingestion of pyrrolizidine  
alkaloids; antileukaemic drugs, radiation). 
 Sclerosing hyaline necrosis. 
 
Portal hypertension measurement:   
 Portal pressure is indirectly measured in clinical practice by the hepatic venous pressure gradient 
(HVPG).

(HVPG). 
 The HVPG is calculated by subtracting the free hepatic venous pressure (which reflects intra-
abdominal pressure) from the wedged hepatic venous pressure (which reflects portal venous 
pressure). These values are obtained by hepatic venous catheterization.  
 Normal HVPG values are <5 mm Hg.  
 HVPG >10 mm Hg predicts the development of oesophageal varices. 
 However, HVPG is moderately invasive and its clinical role is uncertain.

 The normal hepatic venous pressure gradient (normal HVPG = 1-5 mmHg) means that the p ortal 
hypertension is not related to post-sinusoidal intrinsic liver disease such as cirrhosis (caused in 
children by metabolic disorders such as A1ATD) or post-hepatic venous obstruction (HV 
thrombosis). 
 The haemodynamic goal of treatment is reduce the HVPG by 20% or to less than 12 mmHg, 
using a non-selective beta blocker. If this is not achievable despite titrating the beta-blocker

dose, then endoscopic variceal ligation must be considered. 
 Wedged hepatic venous pressure  
 the pressure recorded by a catheter wedged in a hepatic vein. It reflects the portal venou s 
pressure in the hepatic sinusoids.  
 ↑↑ in sinusoidal and post-sinusoidal portal hypertension,  
 remains normal in pre-sinusoidal portal hypertension.  
 
Complications of portal hypertension: 
 Haematemesis or melaena - suggest bleeding varices.

 Lethargy, irritability and changes in sleep pattern - suggest encephalopathy. 
 Increased abdominal girth, weight gain - suggest ascites. 
 Abdominal pain and fever - suggest spontaneous bacterial peritonitis. 
 Pulmonary involvement is common in patients with portal hypertension 
 
Trans-jugular intrahepatic porto-systemic shunt  (TIPSS)  
 Indications are:  
 Diuretic resistant ascites ( Intractable ascites  ) 
 Intractable portal hypertensive bleeding and 
 Hepato-renal failure.

 Hepato-renal failure. 
 contraindications to shunting: 
 Severe hepatic encephalopathy 
 Severe heart failure  
 Septicaemia 
Hepatic encephalopathy 
 Hepatic encephalopathy may be seen in liver disease of any cause.  
 The aetiology is not fully understood but is thought to include excess absorption of amm onia 
from bacterial breakdown of proteins in the gut 
Features  
 confusion, altered GCS (see below) 
 hepatic flap 856

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    67 
  Asterixis (also called the flapping tremor, or liver flap) is a tremor of the hand when the 
wrist is extended, sometimes said to resemble a bird flapping its wings. 
 hepatic encephalopathy is unlikely to be present if a liver flap (asterixis) cannot be 
detected. 
 constructional apraxia: inability to draw a 5-pointed star

 triphasic slow waves on EEG 
 raised ammonia level (not commonly measured anymore) 
Grading of hepatic encephalopathy 
 Grade I: mood changes like depression or irritability, and sleep abnormalities (typically sleep 
inversion)  
 Grade II: Confusion, inappropriate behaviour 
 Grade III: Incoherent, restless 
 Grade IV: Coma 
Precipitating factors 
 infection e.g. spontaneous bacterial peritonitis 
 GI bleed 
 drugs: sedatives, diuretics 
 hypokalaemia

 increased dietary protein (uncommon) 
Treatment  
 Treat precipitating cause ( e.g., give K+ if hypokalemic)  
 Lactulose  
 metabolized to lactic acid by colonic flora, converts NH3 to NH4+ which can be absorbed 
 Neomycin  
 replaced with rifamixin, neomycin no longer routinely used 
 antibiotics kill colonic flora leading to decreased NH 3 production 

Hepatorenal syndrome: 
 
 vasoactive mediators cause  splanchnic vasodilation   ↓↓ systemic vascular resistance 
 'underfilling' of the kidneys  activation of the renin-angiotensin-aldosterone system by the 
juxtaglomerular apparatus  renal vasoconstriction which is not enough to counterbalance 
the effects of the splanchnic vasodilation.  
Types 
 Hepatorenal syndrome has been categorized into two types: 
Type 1 HRS Type 2 HRS 
Rapidly progressive

Rapidly progressive 
Doubling of serum creatinine to > 221 mmol/L or a 
halving of the creatinine clearance to less than 20 ml/min 
over a period of less than 2 weeks 
Very poor prognosis Slowly progressive 
Prognosis poor, but patients may live for longer 
characterised by a moderate and stable 
reduction in renal function, hypotension and 
diuretic resistance.  

 The ideal treatment  is liver transplantation but patients are often too unwell to have surgery 
and there is a shortage of donors 
 Other Management options 
 agonists of vasopressin V1 receptors such as terlipressin   vasoconstriction of the 
splanchnic circulation 
 volume expansion with 20% albumin 
 transjugular intrahepatic portosystemic shunt 
 
857

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    68 
  
Wilson's disease 
Wilson's disease - serum caeruloplasmin is decreased   
 
 Wilson's disease is an autosomal recessive disorder characterised by impaired copper 
transport via caeruloplasmin results in excessive copper deposition in the tissues.

 Wilson disease  is a disorder resulting from impaired copper excretion into bile . Copper 
overload and deposition in tissues leads to predominantly hepatic and neuropsychiatri c 
symptoms. 
  Metabolic abnormalities include increased copper absorption from the small intestine a nd 
decreased hepatic copper excretion. 
Aetiology and pathophysiology 
 autosomal recessive  
 caused by a defect in the ATP7B gene located on chromosome 13.

 Mutations within the ATP7B gene result in disruption of an ATPase within hepato cytes which is 
responsible for the movement of copper across intracellular membranes. This results in 
hepatic retention of copper, and low serum levels.   
 The mechanism of tissue damage in Wilson disease is copper-mediated hydroxyl free radical 
tissue damage. 
 
Features   
 The onset of symptoms is usually between 10 - 25 years.

 Children usually present with liver disease whereas the first sign of disease in young adults 
is often neurological disease  
 liver: hepatitis, cirrhosis 
 neurological:  
 basal ganglia degeneration, speech and behavioural problems are often the first 
manifestations .  
 The most common early neurological sign is an asymmetrical tremor ,  
 Also: the initial sign is usually increased clumsiness. 
 parkinsonism,  
 dystonia . 
 asterixis,  
 chorea,  
 dementia

 chorea,  
 dementia 
 Kayser-Fleischer rings   
 Golden corneal rings 
  in the posterior surface of the retina, within its Descemet ’s membrane.    
 Detected by Slit lamp examination  
 Present in up to 90% of symptomatic patients, but is not pathognomonic.  
 renal tubular acidosis (esp. Fanconi syndrome) 
 haemolysis 
 blue nails 
Diagnosis 
 Reduced serum caeruloplasmin 
 Ļ Total  serum copper 
 increased 24hr urinary copper excretion

 increased 24hr urinary copper excretion 
 greater than 1.6 μmol/day  
 Liver biopsy   
 The most reliable investigation to confirm the diagnosis 
 Shows:  
 increased hepatic parenchymal copper concentration 
858

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    69 
  steatosis, glycogenated nuclei, focal hepatocellular necrosis, fibrosis and 
 MRI of the brain 
  commonly shows increased density in the basal ganglia. 
 Genetic testing for ATP7B mutation   
 usually reserved for patients where the diagnosis is in doubt, or for screening of 
siblings. 

siblings. 
 higher risk of hepatocellular carcinoma.  
 
 General management 
 Low-copper diet: avoid foods such as organs, shellfish, nuts, and chocolate  
 Hepatotoxic drugs, alcohol and foods high in copper (liver, chocolate, shellfish etc.) 
should be avoided.  
 Regular check-ups: liver biochemical tests every 6 months if disease is stable[9] 
 Liver transplantation in cases of fulminant liver failure 
 Medical therapy

 Medical therapy 
 Initial therapy : chelating agents   
 Penicillamine :  
 first-line treatment  
 side effects in ∼ 30% of cases  
 (e.g., sensitivity reactions) 
 bone marrow suppression 
 Alternatives: trientine or zinc salts 
 Trientine  
 may become first-line treatment in the future 
 better tolerated than penicillamine, and is therefore used as an 
alternative where side effects are seen when penicillamine is 
initiated.

initiated. 
 Maintenance therapy : zinc salts  or low dose chelating agents 
 
 Zinc acetate is the intervention of choice for patients with asymptomatic Wilson ’s 
disease (i.e. those who present with elevated transaminases without evidence of 
cirrhosis or neurological dysfunction). 
 screening of first degree relatives  
 Once a diagnosis of Wilson's disease is made, screening of first degree relatives (with 
genetic testing) should be done.

genetic testing) should be done.  
Treatment with a chelating agent should be administered gradually over the course of 3 to 6 
months, as mobilizing the copper stored in tissues too rapidly may exacerbate neurological 
symptoms 
Prognosis 
 Early treatment allows a normal length of life,  
  however without treatment Wilson's disease is usually fatal by the age of 40 yea rs. 
September 2014 exam: A 23-year-old woman developed unilateral hand tremor at rest,

behaviour & mood changes, speech problems & bradykinesia. Dark circular marks noted 
around the iris. her uncle died of liver cirrhosis at the age of 40 years. Given the likely 
diagnosis, what is the mode of inheritance? Autosomal recessive  
Hyponatraemia in Patients with chronic liver disease  
 Patients with chronic liver disease and ascites often develop hyponatraemia, the management 
of which can be difficult.

of which can be difficult. 
  Diuretic therapy for the management of ascites often contributes to the hyponatrae mia. 
 The British Society of Gastroenterology guidelines  suggest that: 
 serum sodium is ≤120 mmol/L  normal saline + stop diuretic  
 serum sodium is 126-135 mmol/L  No intervention other than careful monitoring. 859

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    70 
  serum sodium is 121-125 mmol/L + normal serum creatinine  reduce diuretics or stop 
it if necessary  
 serum sodium is 121-125 mmol/L + ↑↑ serum creatinine  volume expansion + stop 
diuretics  
 fluid restriction should only be used in patients who are clinically euvolaemic, not on

diuretics and have severe hyponatraemia with a normal serum creatinine. 
Alcohol  
 After drinking excessive amounts alcohol  
 Mechanism of polyuria  Ethanol inhibits ADH secretion  
 Mechanism of nausea  vagal stimulation to the vomiting centre.  
 Mechanism of tremors  increase glutamate production by neurones to compensate for the 
previous inhibition by ethanol.

previous inhibition by ethanol. 
 Mechanism of hypoglycemia  hepatic sequestration of Reduced nicotinamide adenine 
dinucleotide (NADH) 
 In the liver alcohol dehydrogenase converts ethanol to acetaldehyde but to do so 
requires the reduction of oxidized nicotinamide adenine dinucleotide (NAD+) to reduced 
nicotinamide adenine dinucleotide (NADH).  
 Acetaldehyde is then further oxidized to acetate to aldehyde dehydrogenase, w hich 
requires the reduction of another NAD+ to NADH.

requires the reduction of another NAD+ to NADH.  
 When excess alcohol is consumed then the system becomes overwhelmed and NADH 
accumulates in hepatocytes. 
 This sequestration of NADH reduces the amount of NAD+ available to oxidize 
gluconeogenic precursors  hypoglycemia  
 
Alcohol - drinking problems: management 
Nutritional support 
 SIGN recommends alcoholic patients should receive oral thiamine if their 'diet may be 
deficient'   
Drugs used 
 benzodiazepines for acute withdrawal

 benzodiazepines for acute withdrawal 
 disulfram: promotes abstinence - alcohol intake causes severe reaction due to inhibition of  
acetaldehyde dehydrogenase. Patients should be aware that even small  amounts of alcohol 
(e.g. In perfumes, foods, mouthwashes) can produce severe symptoms. Contraindication s 
include ischaemic heart disease and psychosis 
 acamprosate: reduces craving, known to be a weak antagonist of NMDA receptors, improve s 
abstinence in placebo controlled trials

abstinence in placebo controlled trials 
 
Alcoholic liver disease  
The recommended maximum alcohol intake per week is 21 units for men and 14 units for wome n. 
 Governmental guidelines suggest that women should not have more than 2-3  units per day and men 
should not have more than 3-4 units per day 
Alcoholic liver disease includes fatty liver, alcoholic hepatitis and cirrhosis.  
 fatty liver  (hepatic steatosis) 
 accumulation of fat within the hepatocytes.

 accumulation of fat within the hepatocytes.  
 asymptomatic and detected incidentally. 
  Elevated transaminases and a background of alcoholism are clues to the diagnosis.  
 macro vesicular fatty changes.  
 Microvesicular fatty changes are not found in hepatic steatosis. 
 An ultrasound demonstrates hyperechogenicity and a bright liver. 
 This is reversible with abstention from alcohol.  
 Alcoholic hepatitis  presents as: 
 acute right upper quadrant (RUQ) pain

 acute right upper quadrant (RUQ) pain  
 Tender hepatosplenomegaly 
 jaundice  
 fever  
 frequently occurs on a background of cirrhosis 
 marked derangement of LFTs 
 LFT typically show an AST elevated greater than the ALT with at least a 2:1 
ratio 860

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    71 
  AST:ALT ratio can be useful in diagnosing alcoholic liver disease, because more 
than two-thirds of patients will have a ratio greater than 2. 
  transaminases are typically only slightly elevated rarely over 300 and virtually 
never over 500.  
 The alkaline phosphatase may well be significantly elevated giving the liver

profile an 'obstructive' appearance. 
 High IgA levels are seen in alcoholic liver disease. 
 At a microscopic level there is inflammation of the liver. 
 In liver cirrhosis , the hepatocytes are damaged so much that they are replaced by scar tissue 
which is permanent. The cardiomyopathy of alcoholism is a dilated or congestive form.  
 Alcoholic hepatitis and cirrhosis may co-exist. 
 Alcoholic hepatitis and cirrhosis may lead to encephalopathy, portal vein hypertension and

hepato-renal syndrome, increase risk of infections and they are usually malnourished.  
 Treatmen t involves: 
 good nutrition and abstinence from alcohol. 
 There is no specific therapy for alcohol-related hepatitis and cirrhosis.  
 treat the complications which include: 
 ascites  high doses of diuretics 
 spontaneous bacterial peritonitis, 
 hepatic encephalopathy  
 and oesophageal varices.  
 
Chronic alcohol abuse is typically associated with 

Increased carbohydrate deficient transferrin (CDT) 
 
Which feature would suggest a diagnosis of hepatic steatosis rather than non-alcoholic fatty 
liver disease? 
 Reversible hepatic damage after discontinuing alcohol consumption  
 
The common abnormalities in chronic alcohol dependence: 
 Macrocytosis 
 Elevated GGT - this is due to enzyme induction but does not necessarily indicat e that there is 
liver damage 
 Hypertriglyceridaemia - can contribute to pancreatitis

 Hyperuricaemia - can cause gout 
 Hypoglycaemia - can contribute to seizures and coma 
 Hypomagnesaemia 
 Hypogonadism 
 Thiamine deficiency 
 Increased carbohydrate deficient transferrin - considered a marker of chronic abuse and 
sometimes checked to ensure abstinence, for example, while awaiting liver transplantation  
 Iron levels are variable in alcohol dependence: hepatitis causes increased serum iron while  
poor diet can result in iron deficiency

poor diet can result in iron deficiency 
 Ferritin can be elevated in the acute phase response, but reduced in advanced  liver disease 
due to possible reduced synthesis rates 
 Hyponatraemia and hypokalaemia are often seen in established liver disease 
 ALT is elevated in liver disease and hepatocellular damage 
 AST is elevated (but can also be increased in cardiac or muscular damage). 
 AST:ALT ratio can be elevated due to the mitochondrial effects of alcohol causing  a

disproportionate increase in AST. However, this is not specific.   
 
Alcoholic ketoacidosis 
 Alcoholic ketoacidosis is a non-diabetic euglycaemic form of ketoacidosis.  
 It typically presents with a pattern of:  
 Metabolic acidosis 
 Elevated anion gap 
 Elevated serum ketone levels 
 Normal or low glucose concentration 861

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    72 
  The most appropriate treatment is an infusion of saline & thiamin e. Thiamine is required 
to avoid Wernicke encephalopathy or Korsakoff psychosis. 
 
Disulfiram  
 Indication : used as an aid to stopping alcohol abuse. 
 Mode of action : irreversible inhibitor of aldehyde dehydrogenase, therefore if alcohol is

ingested, aldehyde accumulates causing unpleasant reactions including vomiting, palpitations 
and breathlessness.  
 The reaction with alcohol only occurs at least 12 hours after the start of disulfiram  therapy 
and may occur up to 10 days after stopping disulfiram  therapy.  
 Disulfiram is active against scabies,  although other treatments are usually preferred. 
 
Ref : medical-masterclass.2017 part 2 

Non-alcoholic fatty liver disease 
 
 Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of liver disease in 
the developed world. 
  It is largely caused by obesity and describes a spectrum of disease ranging from: 
 steatosis - fat in the liver 
 steatohepatitis - fat with inflammation, non-alcoholic steatohepatitis (NASH), see b elow 
 progressive disease may cause fibrosis and liver cirrhosis

 NAFLD is thought to represent the hepatic manifestation of the metabolic syndrome and hence  
insulin resistance is thought to be the key mechanism leading to steatosis 
 Non-alcoholic steatohepatitis (NASH)   
 liver changes similar to those seen in alcoholic hepatitis in the absence of a history of 
alcohol abuse.  
 the diagnosis is made only by histology of liver biopsy which shows lesions 
suggestive of ethanol intake in a patient known to consume less than 40 g of 
alcohol per week.

alcohol per week. 
 The diagnosis is supported by the presence of obesity, hyperglycaemia and 
hyperechogenic hepatic parenchyma on US. 
 relatively common and though to affect around 3-4% of the general populat ion.  
 The progression of disease in patients with NASH may be responsible for a proportion 
of patients previously labelled as cryptogenic cirrhosis 
Associated factors  
 obesity 
 type 2 diabetes mellitus 
 jejunoileal bypass

 jejunoileal bypass 
 sudden weight loss/starvation 
Features 
 usually asymptomatic 
 hepatomegaly 
 ALT is typically greater than AST 
 increased echogenicity on ultrasound 
 The hallmark of the condition on liver biopsy is the association of inflammation with fatty 
infiltration of the liver. This can progress to fibrotic change and eventually to cirrho sis. 

 the mainstay of treatment is lifestyle changes (particularly weight loss) and monitoring 
 there is ongoing research into the role of gastric banding and insulin-sensitising drugs (e.g. 
Metformin) 
Prognosis 
 Approximately 20% develop cirrhosis  
 
862

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    73 
Liver abscess  
Pyogenic liver abscess 
 The most common organisms found in pyogenic liver abscesses are Staphylococcus aureus  in 
children and Escherichia coli  in adults. 
  usually complicates pre-existing biliary and gastrointestinal tract infections.

 Ideally, a penicillin- based β -lactamase antibiotic combined with metronidazole 
to provide anaerobic cover would be the treatment of choice. 
 amoxicillin + ciprofloxacin + metronidazole 
 if penicillin allergic: ciprofloxacin + clindamycin 
 
The CT demonstrates a hypodense lesion (A) with surrounding oedema (B).  
 
Amoebic liver abscess  
 A solitary abscess in the right lobe of the liver is typical of amoebic liver abscess.

 A history of chronic diarrhoea might be elicited in patients with amoebic liver 
abscess.  
 
CT showing a pyogenic liver abscess in the right lobe of the liver. 
Hydatid cysts 
Asymptomatic, calcified cystic lesions in the liver are typical of hydatid cysts. 
 Hydatid cysts are endemic in Mediterranean and Middle Eastern countries.  
 Hydatid infection was endemic in sheep farming regions (such as Wales or New Zealand) in

the past and sheep dogs were infected by eating infected offal. Humans contract hydatid s via 
faecal/oral spread from dogs. 
863

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    74 
  most commonly seen in farming and rural communities 
 They are caused by the tapeworm parasite Echinococcus granulosus .  
 Up to 90% cysts occur in the liver and lungs 
 An outer fibrous capsule is formed containing multiple small daughter cysts.

 These cysts are allergens which precipitate a type 1 hypersensitivity reaction . 
Clinical features : 
 Can be asymtomatic, or symptomatic if cysts > 5cm in diameter 
 The liver cysts are usually asymptomatic and calcification usually denotes a non-v iable 
cyst. 
 Morbidity caused by cyst bursting, infection and organ dysfunction (biliary, bronchial, renal and 
cerebrospinal fluid outflow obstruction)

cerebrospinal fluid outflow obstruction) 
 In biliary ruputure there may be the classical triad of; biliary colic, jaundice, and urticaria 
 
 Ultrasonography is the most helpful initial test  since it can usually differentiate a simple cyst 
from other cystic lesions. It should also be used for follow up studies. 
  CT scan shows characteristic daughter cysts. 
 Hydatid serology has a sensitivity of 80-90%.

 If hydatid serology is negative then further imaging (CT/MRI) +/- aspiration may be 
required to make a diagnosis. 
 CT is the best investigation to differentiate hydatid cysts from amoebic and pyogenic 
cysts. 
Treatment 
 Surgery is the mainstay of treatment (the cyst walls must not be ruptured during removal a nd 
the contents sterilised first). 
 benzimidazoles 
Drug-induced liver disease

Drug-induced liver disease 
 
Drug-induced liver disease is generally divided into hepatocellular, cholestatic or mixed. Th ere is 
however considerable overlap, with some drugs causing a range of changes to the liver  
The following drugs tend to cause a hepatocellular  (hepatocellular pattern of injury with 
transaminases elevated in excess of alkaline phosphatase. ) picture: 
 paracetamol 
 sodium valproate, phenytoin 
 MAOIs 
 halothane

 MAOIs 
 halothane 
 anti-tuberculosis: isoniazid, rifampicin, pyrazinamide 
 statins 
 alcohol 
 Statins   
 nitrofurantoin  cause chronic active hepatitis.  
The following drugs tend to cause cholestasis  (+/- hepatitis): 
 oral contraceptive pill 
 antibiotics: flucloxacillin, co-amoxiclav, erythromycin (risk may be reduced with erythromycin 
stearate) 
 anabolic steroids, testosterones 
 phenothiazines: chlorpromazine, prochlorperazine

 sulphonylureas 
 fibrates 
 rare reported causes: nifedipine 
 methotrexate 
864

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    75 
  amiodarone 
Triad of abdominal pain, ascites and liver enlargement.  
 obstruction of the main hepatic veins by thrombus. 
 Budd-Chiari syndrome, or hepatic vein thrombosis, is usually seen in the context of underl ying

haematological disease or another procoagulant condition 
 
Causes  
 polycythaemia rubra vera 
 thrombophilia: activated protein C resistance, antithrombin III deficiency, protein C & S 
deficiencies 
Features 
 abdominal pain: sudden onset, severe 
 ascites 
 tender hepatomegaly  
 Signs of portal hypertension are present and patients may develop acute variceal 
haemorrhage as a complication.  
Diagnosis

Diagnosis 
 Ultrasound Doppler or contrast CT scan is often used to make the diagnosis.  
 Hypertrophy of the caudate lobe on imaging is a characteristic sign but is seen in only 
50% of cases.  
 Ascitic tap usually demonstrates a high SAAG (>11 g/L). 
 Thrombolysis and subsequent anticoagulation 
Prognosis 
 Three year survival in patients with chronic Budd-Chiari syndrome has been reported as 
50%.

50%.  
Gilbert's syndrome 
 Gilbert's syndrome is an autosomal recessive* condition of defective bilirubin conjugation du e 
to a deficiency of UDP glucuronyl transferase .  
 The prevalence is approximately 1-2% in the general population 
Features  
 unconjugated hyperbilinaemia (i.e. not in urine) 
  normal dipstix urinalysis excludes Dubin-Johnson and Rotor syndrome as these both pro duce 
a conjugated bilirubinaemia.

a conjugated bilirubinaemia. 
 jaundice may only be seen during an intercurrent illness 
 rise in bilirubin following prolonged fasting or IV nicotinic acid  
 no treatment required 
*the exact mode of inheritance is still a matter of debate 
Crigler-Najjar syndrome 
 Crigler-Najjar syndrome refers to a condition of absent UDP -glucuronyl transferase.  
 This condition presents early in life with jaundice, increased unconjugated bilirub in and 
kernicterus.

kernicterus.  
 This disease is life threatening and the only cure is liver transplant. 
Dubin-Johnson syndrome 
 benign autosomal recessive disorder 
 Resulting in hyperbilirubinaemia (conjugated, therefore present in urine). 
 It is due to a defect in the canillicular multispecific organic anion transporter (cMOAT) protein. 
This causes defective hepatic bilirubin excretion

 patients have a black liver on gross examination  of the tissue.  865

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    76 
  On microscopic examination, patients have epinephrine metabolite accumulations in their 
hepatocytes.   
 No treatment is necessary. 
Autoimmune hepatitis 
The combination of deranged LFTs  combined with secondary amenorrhoea  in a young female

strongly suggest  autoimmune hepatitis  
 Autoimmune hepatitis is condition of unknown aetiology which is most commonly seen in  
young females.  
 T-cell mediated progressive necro-inflammatory process resulting in fibrosis and cirrhosis.  
 Other autoimmune disorders including:  
 coeliac disease,  
 pernicious anaemia,  
 thyroiditis  
 type 1 diabetes mellitus. 
 IgG hypergammaglobulinaemia

 IgG hypergammaglobulinaemia  
 sicca syndrome (xerostomia/dry eyes, keratoconjunctivitis sicca) may occur.  
 HLA B8, DR3 and Dw3. 
 
Types 
 Three types of autoimmune hepatitis have been characterised according to the t ypes of 
circulating antibodies present 
Type I Type II Type III 
Anti-nuclear antibodies (ANA) and/or 
anti-smooth muscle antibodies  (SMA ). 
Affects both adults and children  Anti-liver/kidney microsomal 
type 1 antibodies (LKM1)

type 1 antibodies (LKM1) 
Affects children only  Soluble liver-kidney antigen 
 
Affects adults  in middle-age 
Features 
 may present with signs of chronic liver disease 
 acute hepatitis: fever, jaundice etc (only 25% present in this way) 
 amenorrhoea (common) 
 ANA/SMA/LKM1 antibodies,  
 raised IgG levels 
 liver biopsy:  
 The gold standard for diagnosis  
 inflammation extending beyond limiting plate 'piecemeal necrosis' , bridging necrosis  

 steroids, other immunosuppressants e.g. azathioprine 
 Prednisolone (with or without azathioprine) is better than azathioprine alone. 
 Steroid therapy produce symptomatic, biochemical and histological improvement, with 
improvement in survival.  
 It does not, however, prevent progression to frank cirrhosis. 
 liver transplantation   
Prognosis 
 The prognosis with long-term immunosuppression is excellent even in the presence of

cirrhosis and few patients subsequently develop liver failure.  
866

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    77 
Ischaemic hepatitis 
 Ischaemic hepatitis is a diffuse hepatic injury resulting from acute hypoperfusion (sometimes 
known as 'shock liver').  
 It is diagnosed in the presence of an inciting event (eg: cardiac arrest) and marked

increases in aminotransferase levels (exceeding 1000 international unit/L or 50 times 
the upper limit of normal).  
 Often, it will occur in conjunction with acute kidney injury (tubular necrosis) or other end organ 
dysfunction. 
Pregnancy: jaundice 
Physiological liver changes during pregnancy; 
 albumin level decreases earlier in 1st  trimester due to hemodilution

 ALT& AST aminotransferase remains normal.  Thus, serum aminotransferase levels is the 
most useful test for the routine diagnosis of liver diseases during pregnancy.  
 total and free bilirubin decreases during all three trimesters . Conjugated bilirubin ↓↓in 2nd & 
3rd  trimesters.  
 ALP ↑↑ in late pregnancy,  due both to the production of the placental isoenzyme and to the 
increase in bone isoenzyme. (Thus ALP levels is not a suitable test for the diagnosis of

cholestasis during pregnancy).  
 Serum gamma-glutamyl transferase ↓↓ in 2nd & 3rd  trimesters,  
 serum 5'nucleotidase slightly ↑↑ in 2nd & 3rd  trimesters.  
 Serum total bile acid concentrations not changed during pregnancy. Measurement of serum 
bile acids may be useful for the diagnosis of cholestasis, especially when serum 
aminotransferase levels are within normal limits.  
 Intrahepatic cholestasis of pregnancy would not occur in the first trimester.

Gilbert's &  Dubin-Johnson syndrome , 
 may be exacerbated during pregnancy  
HELLP syndrome  
 HELLP syndrome is a mnemonic that stands for Hemolysis, Elevated Liver enzymes, and 
Low Platelets in a patient with severe preeclampsia.  
 HELLP syndrome is a manifestation of severe preeclampsia that can lead to  hepatic 
subcapsular hematoma formation.

subcapsular hematoma formation. 
 Schistocytes are an erythrocyte variant that may be seen in HELLP syndrome. 
 Immediate delivery is the only definitive treatment  
Obstetric cholestasis 
 Obstetric cholestasis affects around 0.7% of pregnancies in the UK 
 most common in the third trimester  
 Caused by a bile acid transporter defect  
Features

Features  
 pruritus - may be intense - typical worse palms, soles and abdomen 
 Jaundice occurs in less than 10% of patients. 
Diagnosis (cholestatic picture of (LFTs) with a high ALP and, with a lesser rise in ALT.) 
 ↑ Total Serum bile acid levels  (cholic acid and chenodeoxycholic acid) >10 micromol/L 
 ↑↑ GGT   
 Ĺ ALT, AST  
 Ĺ direct bilirubin  
 bilirubin < 100 
 only slightly elevated in about 10% 
 Ĺ ALP  867

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    78 
  ALP is not useful as it is normally raised in late pregnancy anyway. 
 prothrombin time may be prolonged in any cholestatic process due to vit k deficiency    
Complicatio ns 
 increased risk of prematurity and still birth.  
Differential diagnosis:

Differential diagnosis:   
 Viral hepatitis is the commonest cause of jaundice in pregnancy but the elevated bile acids  
make this unlikely  
 ursodeoxycholic acid  
 First-line medication 
 widely used but evidence base not clear 
 early therapy with ursodeoxycholic acid reduces the risk of preterm birth and stillbirth. 
 Cholestyramine 
  SE: may cause a deficiency in fat-soluble vitamins 
 Rarely, there are cases of cerebral hemorrhage associated with vitamin

K shortage under cholestyramine therapy. 
 induction of labour at 37 weeks is common practice but may not be evidence based  
 vitamin K supplementation 
 phenobarbital 
Prognosis 
 fully reversible postpartum 
 Recurrence in following pregnancies (40 –60%) 
 
Cardiac output and blood volume increase in pregnancy but hepatic blood flow does not.  
Acute fatty liver of pregnancy (AFLP)  

 a rare disease most common in the third trimester characterized by extensive fatty inf iltration of 
the liver, which can result in acute liver failure  
 older maternal age,  
 primiparity,  
 multiple pregnancies,  
 pre-eclampsia,  
 male foetus  
 previous AFLP. 
 dysfunction of fatty acid β-oxidation  microvesicular fat deposition.   
Features  
 nausea & vomiting 
 headache 
 jaundice 
 hypoglycaemia

 headache 
 jaundice 
 severe disease may result in pre-eclampsia 
 Coagulopathy  with an increased risk of disseminated intravascular coagulation (DIC)  
 Hypoalbuminemia  ĺ ascites  
 encephalopathy later. 
 ALT is typically elevated e.g. 500 u/l 
 Ĺ WBC, Ļ platelets  
 support care 
 once stabilised delivery is the definitive management 
 
 868

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    79 
Haemochromatosis 
 
 Haemochromatosis is an autosomal recessive  disorder of iron absorption and metabolism 
resulting in iron accumulation.  
Aetiology 
 It is caused by inheritance of mutations in the HFE gene  on both copies of chromosome 6 *.

 *there are rare cases of families with classic features of genetic haemochromatosis but no 
mutation in the HFE gene  
 90 % of cases are caused by the substitution of tyrosine for cysteine at position 282  of the 
HFE gene found on chromosome 6. 
 HLA-A3 is associated with haemochromatosis 
 1 in 10 people of European descent carry a mutation genes affecting iron meta bolism, mainly 
HFE 
 prevalence in people of European descent = 1 in 200

 Haemochromatosis is the most prevalent genetic condition in Caucasian population, with a 
carrier rate of 1 in 10 and is present in about 1 in 200-400 people 
 Males and females are affected equally but females are often 'protected' from th e clinical 
features by menstrual blood loss. 
 Iron absorption is regulated in the duodenal crypts. 
 HFE is a protein that regulates iron absorption ,

 HFE  forms a complex at the basolateral membrane that if bound to transferrin + ir on at the 
basolateral membrane of the duodenal crypt cells prevents maturation and consequ ently 
absorption of iron in the bowel.  
 mutation in the HFE gene  failure of complex formation and constant maturation of duodenal 
crypt cells  subsequent unregulated uptake of iron.  
Presenting features 
 often asymptomatic in early disease 
 early symptoms include  
 fatigue, 
 erectile dysfunction

 fatigue, 
 erectile dysfunction  
 arthralgia (often of the hands) 
 Joint x-rays characteristically show chondrocalcinosis 
 'bronze' skin pigmentation 
 liver: stigmata of chronic liver disease, hepatomegaly, cirrhosis, hepatocellular deposition)  
 cardiac failure (2nd to dilated cardiomyopathy) 
 hypogonadism (2nd to cirrhosis and pituitary dysfunction - hypogonadotrophic hypogonadism)

 arthritis (especially of the hands). Joint x-rays characteristically show chondrocalcinosis 
Questions have previously been asked regarding which features are reversible with treatment:  
Reversible complications 
 
 Cardiomyopathy 
 Skin pigmentation 
 Irreversible complications 
 
 Liver cirrhosis** 
 Diabetes mellitus 
 Hypogonadotrophic hypogonadism 
 Arthropathy 
 
**whilst elevated liver function tests and hepatomegaly may be reversible, cirrhosis is not 

The best investigation to screen for haemochromatosis 
 General population : transferrin saturation is considered the most useful marker.  
869

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    80 
  Ferritin should also be measured but is not usually abnormal in the early stages of ir on 
accumulation.   
 testing family members: genetic testing for HFE mutation 
These guidelines may change as HFE gene analysis become less expensive 
Diagnostic tests  
 liver biopsy:  Perl's stain

 liver biopsy:  Perl's stain 
 the gold standard investigation (as it quantifies iron deposition and also stages the 
amount of fibrosis)  
 molecular genetic testing for the C282Y and H63D mutations 
 found in 90% 
 there is substitution of tyrosine for cysteine at position 282 of the HFE gene on 
chromosome 6.  
 However there is low penetrance of clinical disease and haemochromatosis also occurs 
in patients who are negative for this mutation.

in patients who are negative for this mutation. 
 MRI has high specificity but low sensitivity for demonstrating iron overload in the liver - it has 
not replaced the need for biopsy in the majority of cases. 
 
Typical iron study profile in patient with haemochromatosis 
 transferrin saturation > 55% in men or > 50% in women 
 raised ferritin (e.g. > 500 ug/l) and iron.  Ferritin is measured to help guide further investigation

and treatment: if more than 1000 a liver biopsy should be performed and treatm ent initiated. 
 low TIBC 
 Early diagnosis and treatment is critical in haemochromatosis as survival and morbidity are 
improved if phlebotomy is initiated prior to the development of cirrhosis. 
 weekly or twice weekly (if tolerated)  venesections  of 500 cm3 until the serum ferritin is less 
than 50 ng/mL & Transferritin saturation less than 50%

 When iron overload and anaemia are present concomitantly chelation with desferoxamine  
may be required.  
 Patients should be told to avoid vitamin C  supplementation as this can enhance iron toxicity. 
 End stage liver disease, portal hypertension and hepatocellular carcinoma (which is increased 
up to 200-fold) may necessitate liver transplantation . 
Monitoring adequacy of venesection 
 BSCH recommend 'transferrin saturation should be kept below 50% and the serum ferritin

concentration below 50 ug/l' 
 
May 2005 exam : Which feature of haemochromatosis may be reversible with treatment?  
Cardiomyopathy  
 
 May 2014 exam:  H/O fatigue and arthralgia. The joint pain is worse around his metacarpop halangeal joints and 
knees. polyuria and polydipsia. An x-ray of his knees reveals chondro calcinosis. What is the mode of inheritance of 
the likely underlying diagnosis? Autosomal recessive  (This patient has typical symptoms of haemochromatosis: 1/

Lethargy. 2/arthralgia, with evidence of chrondrocalcinosis. 3/diabetes mellitus (polyu ria and polydipsia)  
 
Hepatocellular carcinoma (HCC) 
 
 Hepatocellular carcinoma (HCC) is the third most common cause of cancer worldwide.  
 Chronic hepatitis B is the most common cause of HCC worldwide with chronic hepatitis C 
being the most common cause in Europe. 
Risk factors   
 The main risk factor  for developing HCC is

 The main risk factor  for developing HCC is  
 Liver cirrhosis, for example secondary* to hepatitis B & C, alcohol, haemochromatosis 
and primary biliary cirrhosis.  
 *Wilson's disease is an exception 
 75% to 90% of patients with HCC have cirrhosis.  
870

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    81 
  HCC develops in 4% of cirrhotics per year. 
  Patients with chronic hepatitis B have 100-fold higher risk of developing HCC.  
 
 Other risk factors  include: 
 alpha-1 antitrypsin deficiency 
 hereditary tyrosinosis 
 glycogen storage disease 
 aflatoxin 
 drugs: oral contraceptive pill, anabolic steroids

 porphyria cutanea tarda 
 male sex 
 diabetes mellitus, metabolic syndrome 
Features 
 tends to present late 
 features of liver cirrhosis or failure may be seen: jaundice, ascites, RUQ pain, hepa tomegaly, 
pruritus, splenomegaly 
 possible presentation is decompensation in a patient with chronic liver disease 
Screening  with ultrasound (+/- alpha-fetoprotein) should be considered for high risk groups such as:

 patients liver cirrhosis secondary to hepatitis B & C or haemochromatosis 
 men with liver cirrhosis secondary to alcohol 
Management  options 
 early disease: surgical resection 
 liver transplantation 
 radiofrequency ablation 
 transarterial chemoembolisation 
 sorafenib: a multikinase inhibitor 
Management of liver capsule pain 
 Stretching of the liver capsule by a primary hepatoma or metastases within the liver can cause  
chronic cancer pain.

chronic cancer pain.  
  This commonly presents as dull, right-sided subcostal pain.  
  Referred pain at the top of the ipsilateral shoulder occurs due to diaphragmatic irritation i f the 
superior aspect of the capsule is involved.  
 Corticosteroids can be used in the management of liver capsule pain and dexameth asone is 
usually the choice of steroid.  
 Which analgesics would be most suitable for the management of liver capsule pain?  
 Dexamethasone

 Dexamethasone  
Carcinoid syndrome  
 
Which biochemical markers is most likely depleted in carcinoid syndrome? 
 Biosynthesis of serotonin begins with tryptophan, so tryptophan depletion  is most 
likely. 
 
 usually occurs when metastases are present in the liver and release serotonin into the 
systemic circulation 
 may also occur with lung carcinoid as mediators are not 'cleared' by the liver 
Features

Features  
 flushing (often earliest symptom) 
 bronchospasm 
 right heart valvular stenosis (left heart can be affected in bronchial carcinoid) 
 (mostly tricuspid insufficiency) and pulmonary stenosis, 
 Endocardial fibrosis is due to constant exposure of the right heart to serotonin.  
 other molecules such as ACTH and GHRH may also be secreted resulting in, for example, 
Cushing's syndrome

Cushing's syndrome 
 pellagra can rarely develop as dietary tryptophan is diverted to serotonin by the tumour  
871

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    82 
  urinary 5-hydroxy-indole-acetic acid (5-HIAA) ( specificity  100% ,  sensitivity 70% ) 
 plasma chromogranin A y ( The most  sensitive marker 100%  ) 
 somatostatin analogues e.g. Octreotide ( Side effects of octreotide therapy include increased 
risk of gallstones )

risk of gallstones ) 
 The best treatment for symptoms of carcinoid is the somatostatin analogue, 
octreotide , which improves symptoms and prognosis 
 Other potential treatments following resistance or failure of octreotide include  hepatic artery 
embolisation.  
 diarrhoea: cyproheptadine may help 
 the treatment for the diarrhoea will be through treating the underlying diagnosis, 
which is carcinoid  octreotide

which is carcinoid  octreotide 
 Cyproheptadine is not a first line treatment for diarrhoea and in fact may cau se 
diarrnoea as a side effect. 
 Telotristat inhibits tryptophan hydroxylase, which mediates serotonin biosynthesis. It 
is indicated for carcinoid syndrome diarrhea in combination with somatostatin analog 
(SSA) therapy in adults inadequately controlled by SSA therapy. 
 Telostristat approved by (FDA) in 2017 for carcinoid syndrome diarrhea in

combination with somatostatin analog (SSA) therapy in adults inadequately 
controlled by an SSA. 
 
Which vitamin deficiency may be associated with carcinoid syndrome? 
 Vitamin B 3 
 Vitamin B 3, niacin, is used to make NAD and is derived from tryptophan.  
 In carcinoid syndrome, the increased synthesis of serotonin would deplete the 
supply of tryptophan needed to make niacin.  
 A deficiency of niacin would result in pellagra, which is characterized by diarrhea,

dermatitis, and dementia  
 
May 2007 exam: If the patient develops carcinoid syndrome, which one of the following 
symptoms is most likely to occur first? Facial flushing  
 
Viral hepatitis 
Hepatitis A 
Diagnosis  
 Anti-hepatitis A  IgM antibody will confirm the diagnosis   
 IgG antibody would suggest:  
  a previous hepatitis A infection or  
 another underlying cause such as cytomegalovirus. 
Indicator of poor prognosis

 Hepatitis A infection on a background of hepatitis C (but not B) has very poor 
prognosis. 
Hepatitis B 
 
 Hepatitis B is a double-stranded DNA hepadnavirus  
Spread through  
 vertical transmission from mother to child.  
 Perinatal transmission is the most common route of hepatitis B infection  
worldwide

worldwide   
 the infection rate is 90% in infants born to HBeAg (hepatitis B envelope antigen) positive 
mothers. 
 exposure to infected blood or body fluids,  
 Sexual transmission comprises 30% of hepatitis B infections in developed countries.  
Incubation period  
872

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    83 
  6-20 weeks. 
Features:  
 fever,  
 jaundice  
 elevated liver transaminases. 
 
 Symptoms of decompensated liver disease include: 
 ascites,  
 encephalopathy and  
 gastrointestinal haemorrhage. 
 
Complications   
 chronic hepatitis (5-10%) 
 fulminant liver failure (1%) 
 hepatocellular carcinoma

 hepatocellular carcinoma 
 glomerulonephritis 
 polyarteritis nodosa 
 cryoglobulinaemia 
 
Immunisation against hepatitis B 
 contains what?: 
 HBsAg adsorbed onto aluminium hydroxide adjuvant  
 prepared from what? 
 prepared from yeast cells using recombinant DNA technology 
 schedule? 
 give 3 doses of the vaccine + one-off booster 5 years following the initial primary 
vaccination 
 At risk groups who should be vaccinated  include:  
 healthcare workers,

 healthcare workers,  
 intravenous drug users,  
 sex workers,  
 close family contacts of an individual with hepatitis B,  
 individuals receiving blood transfusions regularly,  
 chronic kidney disease patients who may soon require renal replacement therapy,  
 prisoners,  
 chronic liver disease patients 
 failure to respond or respond poorly to 3 doses of the vaccine  
 occur in 10-15% of adults.  
 Risk factors include: 
 age over 40 years,  
 obesity,  
 smoking,

 obesity,  
 smoking, 
 alcohol excess and  
 immunosuppression 
 how to check response? 
 testing for anti-HBs levels 
 testing for anti-HBs is only recommended for : 
 those at risk of occupational exposure (i.e. Healthcare workers) and  
 patients with chronic kidney disease.  
 In these patients anti-HBs should be checked  1-4 months after primary 
immunisation  
 how to interpret anti-HBs levels? the table below shows 
 
 873

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    84 
  
Anti-HBs level 
(mIU/ml) Response 
> 100 Indicates adequate response , no further testing required. Should still receive booster 
at 5 years 
10 - 100 Suboptimal response  - one additional vaccine dose should be given.  
If immunocompetent no further testing is required

< 10 Non-responder . Test for current or past infection. Give further vaccine course (i.e. 3 
doses again) with testing following. If still fails to respond then HBIG would be 
required for protection if exposed to the virus 
 
Hepatitis B serology  
Interpreting hepatitis B serology : It is important to remember a few key facts: 
 surface antigen (HBsAg) 
  is the first marker to appear and causes the production of anti-HBs

 appears in the serum 1 to 10 weeks following acute exposure , even  before 
symptoms or (ALT) rise. 
 normally implies acute disease (present for 1-6 months) 
 if present for > 6 months then this implies chronic disease (i.e. Infective) 
 In those who  recover HBsAg will usually become undetectable after 4 to 6 months . 
  
 Anti-HBs  
 implies immunity (either exposure or immunisation).  
 It is negative in chronic disease 
 Anti-HBc  
 implies previous (or current) infection.

 implies previous (or current) infection.  
 IgM anti-HBc appears during acute or recent hepatitis B infection and is present 
for about 6 months.  
 Anti-HBc IgM is detectable between 6 and 32 weeks after exposure  
 IgG anti-HBc persists 
 HbeAg  
 results from breakdown of core antigen from infected liver cells as is therefore a marker 
of infectivity  
 HBeAg is a marker of infectivity in all patients except those who have Hepatitis B virus

(HBV) pre-core mutant  or the core promoter mutant, because they do not synthesise 
HbeAg ,  
 this is most commonly due to a stop-codon mutation at nucleotide 1896.  
 So the learning here is that although the e antigen is negative, the patient may still 
be infective.  
 previous immunisation: anti-HBs positive, all others negative  
 previous hepatitis B (> 6 months ago), not a carrier: anti-HBc positive, HBsAg negative

 previous hepatitis B, now a carrier: anti-HBc positive, HBsAg positive  
 
 IgM anti- HBc jointing HBV-DNA is most effective and most practicable in distinguishing Acute 
Hepatitis B from Chronic Hepatitis B With Acute Flare.  
 
874

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    85 
  
  Acute 
Infection  Chronic 
Carrier  Window 
Period  Complete 
Recovery  Immunized  
HBs  + + - - - 
Anti-HBs  - - - + + 
Anti-HBc  + (IgM)  + (IgG)  + + (IgG)  - 
 
Distinguish between acute HBV and a flare of chronic disease  
 originates from  an area of the world with a high prevalence of HBV infection

 In areas of low HBV prevalence, such as the United Kingdom, a combination of HBsAg 
positivity and features of acute hepatitis usually indicates acute self-limiting hepatitis B 
 In countries with high prevalence of hepatitis B the majority of infection is acquired 
vertically during childhood and leads to chronicity rather than acute infection. 
 Anti- HBc-IgM is typically found in acute HBV  infection, however it can be found in10-15% of

patients with chronic HBV. This is especially true when considering acute flares of chronic 
hepatitis.  
 The sensitivity and specificity for HBc-IgM to distinguish between acute HBV and a 
chronic flare has been reported as low as 77% and 70% respectively.  
 Using high titres to determine cut-offs (1:10,000 or greater) does improve this 
significantly however. 
 Flares of chronic HBV  are typically associated with higher levels of HBV DNA and AFP  
than acute self-limiting disease.

than acute self-limiting disease.  
 The alpha-fetoprotein is commonly elevated during acute hepatitis due to hepatic 
regeneration. 
 flares of chronic HBV  tend to be associated with less necroinflammation, and thus ALT tends 
to be as raised as in acute HBV, but hepatic synthetic dysfunction  is more common. 
 
Assessment of liver disease in secondary specialist care for adults 
with chronic hepatitis B

with chronic hepatitis B 
  The initial test  for liver disease in adults newly referred for assessment is  transient 
elastography  
 Transient elastography (FibroScan) is a new, non ‐invasive, rapid method allowing 
evaluation of liver fibrosis by measurement of liver stiffness. 
 Interpretation of transient elastography score 
 ≥ 11 kPa  antiviral treatment without a liver biopsy 
 between 6 and 10 kPa   liver biopsy to confirm the level of fibrosis

 < 6 kPa   liver biopsy ,  if the : 
 Age < 30 years and HBV DNA > 2000  IU/ml and abnormal ALT  (≥30 IU/L 
for males and  ≥ 19 IU/L for females) on 2 consecutive tests conducted 
3 months apart. 
 < 6 kPa   NO liver biopsy , if the :  
 HBV DNA <  2000 IU/ml and normal ALT. 
 Offer annual reassessment of liver disease using transient elastography to adults who 
are not taking antiviral treatment. 
 Acute HBV  
 the majority of patients wi ll resolve spontaneously,

 treatment with an oral anti-HBV agent is not necessary. 
Patients who are positive for HBsAg for more than six months but are HBeAg negative, HBV DNA 
negative and have normal ALT do not require liver biopsy nor do they require antiviral therapy, but 
hepatitis B serology and ALT should be monitored annually. 
 Chronic HBV 
 Indications of antiviral treatment in adults with chronic hepatitis  B (NICE 2013) 
 age ≥ 30 years  + HBV DNA > 2000 IU/ml + abnormal ALT (≥30  IU/L in males

≥19 IU/L in females) on 2 consecutive tests conducted 3 months apart. 
 Age < 30 years + HBV DNA > 2000  IU/ml + abnormal ALT if there is : 
 evidence of necro-inflammation or fibrosis on liver biopsy   875

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    86 
  or a transient elastography  score > 6 kPa. 
 HBV DNA > 20,000 IU/ml + abnormal ALT regardless of age or the extent of liver 
disease. (on 2 consecutive tests conducted 3 months apart) 
 cirrhosis + detectable HBV DNA, regardless of HBeAg status, HBV DNA and ALT 
levels.

levels. 
 HBV DNA greater than 2000 IU/ml + evidence of necro-inflammation or fibrosis 
on liver biopsy. 
 
 First-line   pegylated interferon-alpha   
 ↓↓ viral replication in up to 30% of chronic carriers.  
 better response  is predicted by being female, < 50 years old, low HBV DNA levels, 
non-Asian, HIV negative, high degree of inflammation on liver biopsy 
 Interferon alfa is usually given short term and is not very effective in patients 
without an elevated ALT.

without an elevated ALT.   
 other antiviral medications  (examples include tenofovir, Adefovir  and entecavir)  
 are increasingly used with an aim to suppress viral replication (not in a dissimilar way to 
treating HIV patients) 
 would be of most value for long-term treatment  of his HBV 
  Lamivudine would be an alternative, although resistance develops commonly.  
 adults with HBeAg-positive chronic hepatitis B and compensated liver disease

 first-line   48-week course of peg-interferon alfa- 2a 
 stopping peginterferon alfa-2a 24 weeks after starting treatment if HBV DNA level 
has decreased by less than 2 log 10 IU/ml and/or if HBsAg is greater than 
20,000 IU/ml  2nd line 
 second-line   tenofovir  disoproxil  ( nucleo tide analogue, reverse transcriptase 
inhibitor (NRTI) 
 to people who  do not undergo HBeAg seroconversion or who relapse (revert to

being HBeAg positive following seroconversion) after first-line treatment with 
peginterferon alfa- 2a. 
 Offer  entecavir  ( nucleo side  analogue , reverse transcriptase inhibitor ) as 
an alternative second-line treatment to people who cannot tolerate tenofovir 
disoproxil or if it is contraindicated. 
 Entecavir is a pro-drug and requires phosphorylation to the triphosphate 
form before it becomes active. 
Nucleoside = Sugar + Base  
Nucleotide = Sugar + Base + Phosphate

Nucleotide = Sugar + Base + Phosphate  
 
 If HBV DNA remains detectable at 96 weeks: 
 If No history of lamivudine resistance  add lamivudine to tenofovir 
disoproxil. 
 With a history of lamivudine resistance  add entecavir to tenofovir 
 When to consider stopping nucleoside or nucleotide analogue treatment? 
 without cirrhosis  12 months after HBeAg seroconversion 
 with cirrhosis  do not stop

 with cirrhosis  do not stop  
 Adults with decompensated liver disease (portal hypertension, bleeding varices, ascites 
and encephalopathy)  
 Do not offer peginterferon alfa- 2a  worsen hepatic decompensation  
 First-line  entecavir  (if there is no history of lamivudine resistance). 
 people with a history of lamivudine resistance  tenofovir  disoproxil   
 Co-infection with chronic hepatitis B and C  peginterferon alfa + ribavirin

Hepatitis B and pregnancy 
Basics 
 all pregnant women are offered screening for hepatitis B 
 Without intervention the vertical transmission rate is around 20%, which increases to 90% if 
the woman is positive for HBeAg. 876

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    87 
  babies born to mothers who are chronically infected with hepatitis B or to mothers who've h ad 
acute hepatitis B during pregnancy should receive a complete course of vaccination + 
hepatitis B immunoglobulin  
  (nice 2013)  Offer  tenofovir disoproxil  to women with HBV DNA greater than 107 IU/ml in

the third trimester to reduce the risk of transmission of HBV to the baby . stopped at 4 to 
12 weeks after the birth 
 there is little evidence to suggest caesarean section reduces vertical transmission rates 
 hepatitis B cannot be transmitted via breastfeeding (in contrast to HIV) 
Hepatitis C  
 
 Hepatitis C is likely to become a significant public health problem in the UK in the next decad e.

  It is thought around 200,000 people are chronically infected with the virus.  
 The most common route of transmission of hepatitis C in the United States is intravenous 
drug use.   
 Hepatitis C virus genotypes 
 There are 6 genotypes and more than 50 subtypes.  
 In England and Wales genotypes 1 and 3 account for more than 90% of a ll diagnosed 
infections.   
 In Japan, North America, and western Europe, the majority of infections are with 
genotypes 1, 2, and 3.

genotypes 1, 2, and 3.   
 Subtype  1a is the most predominant genotype in the US,  
 subtype 1b predominates in Asia and Europe. 
 Genotype 4 is more prevalent in the middle east and in northern and central Africa.  
 Genotypes 5 and 6 have been identified in South Africa and southeast Asia,  
respectively.  
 Differences in subtype can result in subtle differences in response to antiviral therapies. 
 Hepatitis C genotype 3 is associated with insulin resistance and hepatic steatosis

 Genotype 3a is most strongly associated with a positive response to therapy  
 Genotypes 2 and 3 respond reasonably well to polyethylene glycol (PEG) interferon and 
ribavirin; genotypes 1and 4 less well. 
 At risk groups include: 
 intravenous drug users  
 and patients who received a blood transfusion prior to 1991 (e.g. haemophiliacs). 
 hepatitis C is a RNA flavivirus 
 incubation period: 6-9 weeks 
The risk o f Transmission:

The risk o f Transmission: 
 vertical transmission rate from mother to child is about 6%.  
 sexual intercourse is probably less than 5% (in contrast to hepatitis B, sexual transmission 
is uncommon).  
 needle stick injury is about 2% 
 The risk is higher if there is coexistent HIV 
 breast feeding is not contraindicated in mothers with hepatitis C 
 
Features 
 after exposure to the hepatitis C virus less than 20% of patients develop an acute hepa titis

 Chronic hepatitis C is a very common cause of minor elevations in serum 
transaminases. Other liver function tests can be entirely normal  
Diagnosis 
 first  Arrange an anti-HCV antibody test  
 HCV RNA tests are normally only ordered following a positive antibody test .  
 chronic hepatitis C associated with insulin resistance  
 insulin sensitising drugs may improve response to anti-viral therapy 
Extrahepatic association of hepatitis C 
 Sjögren's syndrome

 Sjögren's syndrome 
 Porphyria cutanea tarda 
 Lichen planus 
877

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    88 
  Cryoglobulinaemia (mixed essential type)  
 myeloma and monoclonal gammopathies 
 Lymphoma 
 
 chronic infection (80-85%) - only 15-20% of patients will clear the virus after an acute infection 
and hence the majority will develop chronic hepatitis C 
 cirrhosis (20-30% of those with chronic disease)

 hepatocellular cancer 
 porphyria cutanea tarda (PCT): it is increasingly recognised that PCT may develop in patients 
with hepatitis C, especially if there are other factors such as alcohol abuse 
Management of chronic infection 
 chronic hepatitis C is defined as infection that lasts for more than 6 months.  
 The effectiveness of antiviral treatment depends on the viral genotype; the resp onse is

generally better in people infected with genotypes 2 or 3 than in those infected with g enotypes 
1, 4, 5 or 6. 
 The recommended treatment duration is 24 weeks (genotypes 2 or 3) or 48 weeks (all 
other genotypes)  
 Combination therapy with interferon-alfa and ribavirin is generally recommended for thos e with 
moderate-sever disease (histological diagnosis of significant scarring and/or significant 
necrotic inflammation).

necrotic inflammation). 
 In cases where a liver biopsy carries a high risk (e.g. haemophilia), treatment can be initiated 
without histological confirmation. 
 Both treatment-naïve (new) patients and those who have relapsed following initial resp onse to 
interferon-alfa should be considered for 6 months of combination therapy. 
 currently a combination of pegylated interferon-alpha, ribavirin and a protease in hibitor (e.g. 
boceprevir, simprevir and telaprevir) is used

boceprevir, simprevir and telaprevir) is used 
 cure rates are now approaching 90%, including for some strains which have been previously 
difficult to treat 
 Genotype 1 hepatitis C have low rates of viral clearance with dual interferon and ribavirin 
therapy alone.  the recommended duration of therapy is 48 weeks  
 the aim of treatment is sustained virological response (SVR), defined as undetectable se rum 
HCV RNA six months after the end of therapy

HCV RNA six months after the end of therapy 
 treatment is not generally recommended in those patients who consume large 
quantities of alcohol , given the increased risk of liver damage. 
 the best way to assess response to treatment  Viral load  
 relapse occurs in approximately 5% of people after 5 years. 
Complications of treatment 
 ribavirin - side-effects: haemolytic anaemia, cough. Women should not beco me pregnant 
within 6 months of stopping ribavirin as it is teratogenic

 interferon alpha - side-effects: flu-like symptoms, depression, fatigue, leukopen ia, 
thrombocytopenia.  
 For this reason close monitoring of FBC is recommended, with initial review after 4 
weeks of therapy. 
 Peginterferon alfa 2a and  2b are contraindicated in severe psychiatric conditions. 
                   
 878

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    89 
  
Factors Associated With Accelerated Fibrosis Progression 
Host Viral 
Nonmodifiable  
 Fibrosis stage 
 Inflammation grade 
 Older age at time of infection 
 Male sex 
 Organ transplant 
  
Modifiable  
 Alcohol consumption 
 Nonalcoholic fatty liver 
disease 
 Obesity 
 Insulin resistance  Genotype 3 infection

 Insulin resistance  Genotype 3 infection 
 Coinfection  with 
hepatitis B virus or 
HIV 
Hepatitis D 
 Hepatitis D is a single stranded RNA delta virus  
 It is an incomplete RNA virus that requires hepatitis B surface antigen to complete its 
replication and transmission cycle.  
 It is transmitted in a similar fashion to hepatitis B (exchange of bodily fluids)

 and patients may be infected with hepatitis B and hepatitis D at the same time.  
 Hepatitis D terminology: 
 
 Co-infection: Hepatitis B and Hepatitis D infection at the same tim e. 
 Superinfection: A hepatitis B surface antigen positive patient subsequently 
develops a hepatitis D infection. 
 Superinfection is associated with high risk of fulminant hepatitis, chronic hepatitis status and 
cirrhosis. 
 Diagnosis is made via reverse polymerase chain reaction of hepatitis D RNA.

 Interferon is currently used as treatment, but with a poor evidence base. 
Hepatitis E 
 
 RNA hepevirus 
 spread by the faecal-oral route 
 incubation period: 3-8 weeks 
 common in Central and South-East Asia, North and West Africa, and in Mexico 
 causes a similar disease to hepatitis A, 
  does not result in a carrier state  
 carries a significant mortality (about 20%) during pregnancy

 does not cause chronic disease or an increased risk of hepatocellular cancer 
 In general, hepatitis E is a self-limiting viral infection followed by recovery . Prolonged 
viraemia or faecal shedding are unusual  
 a vaccine is currently in development*, but is not yet in widespread use 
 
Hepatitis histology 
 hepatitis E  Marked cholestasis  
 chronic hepatitis   Ground-glass hepatocytes (large hepatocytes containing surface 
antigen).  
879

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    90 
  hepatitis C  Lymphoid aggregates and a marked increase in the activation of sinusoidal 
lining cells  
 hepatitis D  Microvesicular steatosis  
Colorectal conditions 
Colorectal cancer 
 
 Colorectal cancer is the third most common type of cancer in the UK and the second mos t 
cause of cancer deaths

cause of cancer deaths 
 Adenocarcinomas  comprise the vast majority (98%) of colon and rectal cancers 
 Location of cancer  (averages) 
 rectal: 40% 
 sigmoid: 30% 
 descending colon: 5% 
 transverse colon: 10% 
 ascending colon and caecum: 15% 
Colorectal cancer: genetics 
There are three types of colon cancer: 
 Sporadic (95%) 
 Hereditary non-polyposis colorectal carcinoma (HNPCC, 5%) 
 Familial adenomatous polyposis (FAP, <1%) 
Sporadic colon cancer

Sporadic colon cancer 
 may be due to a series of genetic mutations. For example: 
 allelic loss of the APC gene  more than half of colon cancers 
  further gene abnormalities e.g.  
 activation of the K-ras  oncogene, 
 RAS is an intracellular signaling molecular that acts downstream of the 
epidermal growth factor receptor (EGFR) to stimulate cell division and 
growth 
 present in 30-50% of colorectal cancers 
 associated with failure to respond to EGFR based therapies such as the

monoclonal antibodies Cetuximab  and Panitumumab.  
 The presence of a KRAS  mutation is a contraindication to 
treatment with these agents. 
 deletion of p53 and DCC  tumour suppressor genes lead to invasive carcinoma 
Hereditary non-polyposis colorectal carcinoma (HNPCC)  
 also known as (Lynch syndrome)  
 autosomal dominant mutation of DNA mismatch repair  genes with microsatellite instability . 
 most common form of inherited colon cancer.

 most common form of inherited colon cancer.  
 Around 90% of patients develop cancers, often of the proximal colon, which are usually  poorly 
differentiated and highly aggressive.  
 The most common genes involved are: 
 MSH2  (60% of cases)  the function of this gene  DNA mismatch repair  
 MLH1 (30%) 
 Patients with HNPCC are also at a higher risk of other cancers, with endometrial cancer  
being the next most common association, after colon cancer.

 The Amsterdam criteria  are sometimes used to aid diagnosis: 
 at least 3 family members with colon cancer 
 the cases span at least two generations 
 at least one case diagnosed before the age of 50 years 
 Torre-Muir syndrome , a type of hereditary nonpolyposis colorectal cancer (HNPCC), is 
characterized by sebaceous adenomas.  
 These lesions are usually present on the face, near the eyes and forehead and appear 
as yellow papules/nodules. 
880

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    91 
  
sebaceous adenomas  associated with Torre-Muir syndrome  a type of HNPCC 
 
 Polyp cancers represent T1 disease and have been s ub-classified.  
 The Haggitt system is used for pedunculated polyps and describes the deepest 
invasion of carcinoma cells within the polyp : 
 Level 1 is limited to the head of the polyp

 Level 1 is limited to the head of the polyp 
 Level 2 is extension into the neck 
 Level 3 is invasion of the stalk, and 
 Level 4 is invasion beyond the stalk but above the muscularis propria. 
 The Kicuchi system describes the depth of invasion in sessile polyp cancers. 
 
Familial adenomatous polyposis (FAP)  
 FAP is a rare autosomal dominant condition which leads to the formation of hundreds o f polyps 
by the age of 30-40 years.  
 Patients inevitably develop carcinoma.

 Patients inevitably develop carcinoma.  
 It is due to a mutation in a tumour suppressor gene called adenomatous polyposis co li gene 
(APC ), located on chromosome 5.  
 Genetic testing can be done by analysing DNA from a patients white blood cells. 
  Patients generally have a total colectomy with ileo-anal pouch formation in their tw enties.  
 Patients with FAP are also at risk from duodenal tumours. 
 Oesophagogastroduodenoscopy (OGD) surveillance is recommended.

  A variant of FAP called Gardner's syndrome  can also feature: 
 osteomas of the skull and mandible,  
 retinal pigmentation,  
 thyroid carcinoma  
 and epidermoid cysts on the skin 
Carcinoembryonic antigen  may be used to monitor for recurrence in patients post-operatively or 
to assess response to treatment in patients with metastatic disease 
 
Colorectal cancer: screening 
 
Overview 
 most cancers develop from adenomatous polyps. Screening for colorectal canc er has been

shown to reduce mortality by 16% 
 the NHS now has a national screening programme offering screening every 2 years to all men  
and women aged 60 to 74 years. Patients aged over 74 years may request screening  
 eligible patients are sent faecal occult blood (FOB) tests through the post 
 patients with a single positive results are offered a colonoscopy 
 An uncertain or unclear result will result in a request to repeat up to a maximum of two furth er

tests. Persistent unclear results require further investigation with consideration of colonoscopy.  
 A negative faecal occult blood does not exclude an underlying diagnosis of colorectal canc er. 
881

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    92 
  Any patient with symptoms, irrespective of a negative faecal occult blood test, should be 
investigated for the possibility of underlying bowel cancer as appropriate. 
At colonoscopy, approximately: 
 5 out of 10 patients will have a normal exam

 5 out of 10 patients will have a normal exam 
 4 out of 10 patients will be found to have polyps which may be removed due to their 
premalignant potential 
 1 out of 10 patients will be found to have cancer 
  
Streptococcus bovis  bacteraemia and endocarditis is associated with colon cancer  (in around 
half of cases). All patients should, therefore, undergo colonoscopy  
Colorectal cancer: referral guidelines

Colorectal cancer: referral guidelines 
NICE updated their referral guidelines in 2015. The following patients should be referred urgently  
(i.e. within 2 weeks) to colorectal services for investigation: 
 patients >= 40 years with unexplained weight loss AND abdominal pain 
 patients >= 50 years with unexplained rectal bleeding 
 patients >= 60 years with iron deficiency anaemia OR change in bowel habit 
 tests show occult blood in their faeces (see below)

An urgent referral (within 2 weeks) should be 'considered' if: 
 there is a rectal or abdominal mass 
 there is an unexplained anal mass or anal ulceration 
 patients < 50 years with rectal bleeding AND  any of the following unexplained 
symptoms/findings: 
 -ĺ abdominal pain  
 -ĺ change in bowel habit  
 -ĺ weight loss  
 -ĺ iron deficiency anaemia  
Faecal Occult Blood Testing (FOBT)  
This was one of the main changes in 2015. Remember that the NHS now has a nation al screening

programme offering screening every 2 years to all men and women aged 60 to 74 years. Patients 
aged over 74 years may request screening. 
 
In addition FOBT should be offered to: 
 patients >= 50 years with unexplained abdominal pain OR weight loss 
 patients < 60 years with changes in their bowel habit OR iron deficiency anaemia 
 patients >= 60 years who have anaemia even in the absence of iron deficien cy 
 
Risks for colorectal carcinoma 
Population risk  1 in 40

Population risk  1 in 40 
One first-degree relative more than 45 years old  1 in 17 
One first-degree plus one second-degree relative  1 in 12 
Two first-degree relatives  1 in 6 
Familial polyposis  1 in 2 
 
Which drugs may reduce the risk of colon cancer? 
 Vitamin D  
 Aspirin  and NSAID  
 
The Dukes' System 
 The Dukes' staging system has now largely been replaced with the TNM system, however 
it is still used.

it is still used.  
 The Dukes' staging system has been proven to correlate well with a patient's chance of 
survival. 
 It is classified as following: 
 Dukes' A:  
 Invasion into but not through the bowel wall,  
 80%+ 5 year survival 
 Follow-up of a Dukes' A colon cancer 882

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    93 
  Colonoscopy - indicated on an annual basis for the first 2 years, then 
this should be done 3-yearly 
 Faecal occult blood - should be tested 6-monthly for the first 4 years and 
then once yearly 
 Carcinoembryonic antigen (CEA) - can be used to monitor for recurrence if 
it is elevated initially  
 Dukes' B:

 Dukes' B:  
 Invasion through the bowel wall but not involving lymph nodes,  
 60-70% 5 year survival 
 Dukes' C:  
 Involvement of lymph nodes,  
 30-40% 5 year survival 
 Dukes' D:  
 Widespread metastases,  
 0% 5 year survival 
 
AJCCC  (American Joint Committee)  Staging of Colorectal Cancer  
Primary Tumor (T)   
TX Primary tumor cannot be assessed 
T0 No evidence of primary tumor 
Tis Carcinoma in situ: intraepithelial or invasion of lamina propria

T1 Tumor invades submucosa 
T2 Tumor invades muscularis propria 
 
T3 Tumor invades through the muscularis propria into pericolorectal tissues 
T4a Tumor penetrates to the surface of the visceral peritoneum 
T4b Tumor directly invades or is adherent to other organs or structures 
 
Regional Lymph Nodes (N)  
NX Regional lymph nodes cannot be assessed 
N0 No regional lymph node metastasis 
N1 Metastasis in 1-3 regional lymph nodes 
 
N1a Metastasis in one regional lymph node

N1a Metastasis in one regional lymph node 
N1b Metastasis in 2-3 regional lymph nodes 
 
N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pe ricolic or perirectal tissues without 
regional nodal metastasis 
N2 Metastasis in 4 or more regional lymph nodes 
N2a Metastasis in 4-6 regional lymph nodes 
N2b Metastasis in 7 or more regional lymph nodes 
 
Distant Metastasis (M)  
M0 No distant metastasis 
M1 Distant metastasis

M1 Distant metastasis 
M1a Metastasis confined to one organ or site (for example, liver, lung , ovary, nonregional node) 
M1b Metastases in more than one organ/site or the peritoneum 
 883

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    94 
 Residual tumour (R) classification  exists in addition to the TNM classification and the 
histological grade (G): 
 RX presence of residual tumour cannot be assessed 
 R0 no residual tumour 
 R1 microscopic residual tumour 
 R2 macroscopic residual tumour. 
 
Management of metastatic lesions

Management of metastatic lesions 
 Metastatic lesion resection:  
 Colorectal carcinoma is one of the only oncological diseases where the presence of a 
metastatic deposit can be treated with curative intent.  
 A solitary liver lesion should be surgically resected.  
 In fact, the purpose of following patients with CEA is to identify patients with solitary 
metastatic lesions amenable to surgical resection.

 Transarterial chemoembolization & Radiofrequency ablation are used as palliative proced ures 
when the lesions are too numerous or large to resect.  
January 2015 exam: A man has hereditary non-polyposis colorectal cancer secondary to a mutation in 
the MSH2 gene. which other cancers his daughter will most be at risk from? Endometrial cancer  
Dysplastic colonic polyps

Dysplastic colonic polyps 
The British Society of Gastroenterology (BSG) published guidelines on the follow-up period for 
dysplastic colonic polyps in 2002: 
 5-year interval is indicated for low-risk patients (one to two adenomas that are both small, 
ie <1 cm) 
 3-year follow up is recommended for medium-risk patients (three to four adenomas 
or one or two adenomas where one adenoma bigger than or equal to 1 cm)

 1-year follow-up is recommended for high-risk patients (five or more small adenomas or 
more than three with at least one at or above 1 cm in size).  
Polyp characteristics : associated with a higher risk of malignant change:  
 polyps greater than 1.5 cm, which are sessile or flat   
 Histology demonstrating severe dysplasia, predominantly villous architecture or squamous 
metaplasia  
Peutz-Jeghers syndrome

Peutz-Jeghers syndrome 
 Peutz-Jeghers syndrome is an autosomal dominant  condition 
 Characterised by: 
 numerous hamartomatous polyps in the gastrointestinal tract. 
 pigmented freckles on the lips, face, palms and soles.  
 Around 50% of patients will have died from a gastrointestinal tract cancer by the age of  60 
years. 
  incidence of 1:50,000 live births. 
Genetics  
 responsible gene encodes serine threonine kinase LKB1  or STK11  
Features

Features 
 hamartomatous polyps in GI tract (mainly small bowel) 
 pigmented lesions on lips, oral mucosa, face, palms and soles 
 intestinal obstruction e.g. intussusception 
 gastrointestinal bleeding 
 conservative unless complications develop 
 colonoscopy every two years  after the age of 25 for evaluation of the presence of polyps 
and polypectomy. 884

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    95 
  
Sigmoid volvulus  
The most important feature of a sigmoid 
volvulus rather than a large redundant 
distended loop of sigmoid colon is the absence 
of haustra. 
 
Capsule endoscopy

Capsule endoscopy  
 Capsule endoscopy is currently used in UK to identify the source of occult gastrointestinal 
bleeding when an OGD and colonoscopy and failed to show a cause.  
 It is particularly useful for identifying pathology in the ileum. 
Pseudomyxoma peritonei 
 Pseudomyxoma peritonei is a rare mucinous tumour most commonly arising from the 
appendix.

appendix.  
 The disease is characterised by the accumulation of large amounts of mucinous ma terial in the 
abdominal cavity. 
  It is rare, with an incidence of 1-2/1,000,000 per year 
Treatment  
 usually surgical and consists of cytoreductive surgery (and often peritonectomy) combined with 
intra-peritoneal chemotherapy with mitomycin C. 
Villous adenoma

Villous adenoma 
 
Villous adenomas are colonic polyps with the potential for malignant transformation . They 
characteristically secrete large amounts of mucous , potentially resulting in electrolyte 
disturbances. 
 
Features : The vast majority are asymptomatic. Possible features: 
 non-specific lower gastrointestinal symptoms 
 secretory diarrhoea may occur 
 microcytic anaemia 
 
885

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    96 
Carcinoid tumours 
Carcinoid syndrome 
Left-sided valvular lesions are not observed in carcinoid syndrome because the lung 
metabolizes serotonin (5-HT). Remember the symptoms of carcinoid syndrome as   "Be FDR " :

Bronchospasm , Flushing , Diarrhoea, and Right-sided valvular lesions.  
 Carcinoid syndrome occurs in only 5% of patients with carcinoid tumour 
 The most common originating sites of carcinoid is the small bowel, particularly the 
ileum ;  
 Around 55% of all carcinoid tumours arise from the GI tract,

 the most common site of origin is the small bowel (45% of those arising within the GI 
tract). 
 Within the small bowel, the most common site of origin is the distal ileum. 
 carcinoid tumors  are the most common  malignancy of the appendix.  
 5-HT, kinins, prostaglandins and other vasoactive substances are secreted. 
 the caecal-appendiceal region is the commonest location for a carcinoid primary.

 These tumours are  slow growing 
 
Features  
 flushing (often earliest symptom)  the most common feature ( occurring in 85% of patients ) 
.often provoked by alcohol. 
 diarrhoea  ( 75% )and abdominal cramps in the majority of patients. 
Cardiac abnormalities develop in 50% of patients and consist of tricuspid regurgitation 
or pulmonary stenosis.

or pulmonary stenosis. 
Fibrosis of the heart valves is a recognised feature  
 other molecules such as ACTH and GHRH may also be secreted resulting in, for 
example, Cushing's syndrome  
 urinary 5-HIAA 
 24-hour urine collection for 5-hydroxy-indole-acetic acid (5-HIAA) - excretion is greater 
than 0.3 mmol. 
 plasma chromogranin A y

 plasma chromogranin A y 
 Biopsy of the lesion show cells staining for chromogranin A on histology  consistent with a 
neuroendocrine tumour 
 Octreotide scanning  is positive in up to 85% of cases, however a negative scan does not rule 
out liver metastases.  
 The liver should be imaged by  high resolution CT with fine cuts or by USS .  
 The sensitivity of USS may be increased by the use of microbubble contrast mediu m 
(levovist), which is available at some centres.

(levovist), which is available at some centres.  
 Fasting gut hormones  should be measured as neuroendocrine tumours may co-secrete other 
hormones such as VIP, which may contribute to the diarrhoea. 
 somatostatin analogues e.g. octreotide 
 Octreotide is less likely to be effective if octreotide scan negative , but other analogues 
such as lanreotide  have different affinities for different somatostatin receptor subtypes, 
which may be present on the tumour.

which may be present on the tumour. 
 Other Symptomatic management may include hepatic embolisation, hepatic chemo-
embolisation and chemotherapy.  
 echocardiography to screen for carcinoid heart disease (right-sided valvular lesions). 
 Prognosis   
 generally good. 
 
Ref: 886

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    97 
  Ref  www.medical-masterclass.com  (mrcp part 2)  
 
Gorlin syndrome  causes: 
1. gastric hamartomas,  
2. basal cell carcinomas,  
3. mandibular bone cysts,  
4. intracranial calcification,  
5. pits on the palms and soles.

5. pits on the palms and soles.  
 
Diverticular disease  
 Diverticulosis  presence of diverticula which are asymptomatic. 
 Diverticular disease  diverticula associated with symptoms  typically painless bleeding  
 Diverticulitis  diverticular inflammation (fever, tachycardia) with or without localised 
symptoms and signs  painful , No bleeding  
Overview

Overview 
 Diverticula  are bulging sacs that push outward on the colon wall.can occur anywhere in the 
colon, but most commonly form near the end of the colon on the left side (sigmoid 
colon).  
 A diverticulum consists of a herniation of mucosa through the thickened colonic muscle.  
 most common in industrialized countries where diets are lower in fiber and higher in processed 
carbohydrates.  
 Diverticular disease is by far the commonest cause of severe fresh bleeding per rectum.

Causes : It is believed diverticula form when there is increased pressure in the colon 
 Diets low in fiber cause hard stool and slower "transit time" through the colon, increasing 
pressure. 
 repeated straining during bowel movements also increases pressure. 
 Drugs: diuretics, and narcotic pain relievers, can increase constipation and increase pressure 
in the colon.  
 Approximately 50% of all people have diverticula by the time they are 50 years of a ge, and

nearly 70% of all people have diverticula by the time they are 80 years of age 
 Diverticular disease is rare in people younger than 40 years  
 Disease is more virulent in young patients, with a high risk of recurrences or 
 The most common fistula is colovesicular and then colovaginal fistulas.  
 The main risk factors are age over 50 years and low dietary fibre. 
 Obesity is an important risk factor in young people.

 Complicated diverticular disease has an increased frequency in: 
 patients who smoke, 
 use non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol,  
 and those who are obese and have low-fibre diets 
Features 
 Approximately 75% of people with diverticula have asymptomatic diverticulosis 
 Pain is generally exacerbated by eating and diminished with defecation or flatus. 
 Other symptoms, such as bloating, constipation or rectal bleeding, may also occur. 
 Diverticulitis 


 
multiply and cause infection.  
 Generally presents with left lower quadrant pain. Asian patients have predominantly 
right-sided diverticula and will usually present with right lower quadrant pain. 
 Pain may be intermittent or constant and may be associated with a change in bowel 
habits. 
 Fever and tachycardia are present in most patients 
 One third of patients who develop diverticulitis will develop further complications

(perforation, abscess, fistula, stricture/obstruction) 
Diagnosis :  colonoscopy 
 sensitivities and specificities for CT are significantly better than for contrast enemas.  887

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    98 
  When an abscess is suspected, CT scanning is the best modality for making the diagnosis an d 
following its course. 
 Because of risk of perforation, endoscopy is generally avoided in initial assessment of the 
patient with acute diverticulitis. 
 Haemorrhage :

 Haemorrhage : 
 Flexible sigmoidoscopy is an appropriate initial approach to rule out an obvious 
rectosigmoid lesion. 
 If no cause is identified, further assessment with non-invasive (nuclear scintigraphy) or 
invasive (angiography, colonoscopy) techniques can be undertaken in an attempt to 
localise and treat the bleeding source. 
 asymptomatic  
 No treatment or follow-up needs 
 there may be a prophylactic benefit of a high-fibre diet.

 The risk of perforation may be increased by the use of NSAIDs and long-term us e 
of opioids. 
 Calcium-channel blockers are associated with a reduction in diverticular perforation but  
there is insufficient evidence to recommend their use. 
 Broad-spectrum antibiotics to cover anaerobes and Gram-negative rods - eg, co-
amoxiclav or a combination of ciprofloxacin and metronidazole (if allergic to penici llin).  
 Paracetamol should be used for pain.

 Paracetamol should be used for pain. 
 Recommend clear liquids only; gradually reintroduce solid food as symptoms improve 
over 2-3 days. 
 Review within 48 hours, or sooner if symptoms deteriorate. Hospital admission should 
be arranged if symptoms persist or deteriorate. 
 Mesalazine has been shown to be more effective in improving the severity of sym ptoms, 
bowel habit, and in preventing symptomatic recurrence of diverticulitis, than antibiotics 
alone

alone 
 Most patients admitted with acute diverticulitis will respond to conservative treatm ent, 
but 15-30% will need surgery. 
 The indications for surgery are: 
 Purulent or faecal peritonitis. 
 Uncontrolled sepsis. 
 Fistula. 
 Obstruction. 
 Inability to exclude carcinoma. 
 CT-guided percutaneous drainage of abdominal abscesses is now used in preference to  
surgery when feasible. 
 Risk of recurrent symptoms after an attack of acute diverticulitis is about one in three.

 Recurrent attacks are less likely to respond to medical treatment and they have a high 
mortality rate.  
 Haemorrhage 
 Haemorrhage ceases spontaneously in 70-80% of patients .. Subsequent colonoscopy 
should be performed to establish the source of the bleeding and to exclude n eoplasia. 
 Intra-arterial vasopressin at angiography can control haemorrhage in more than 90% of 
patients. The benefit is usually only temporary but may allow time to prepare t he patient

adequately for surgery. 
 Angiographic embolisation of very distal bleeding branches is also effective and safe. 
 Surgery in lower gastrointestinal bleeding is usually reserved until endoscopic or 
angiographic treatments fail. 
 Segmental resection is most usually done if the bleeding site is clearly identified from  a 
therapeutically unsuccessful angiographic or endoscopic procedure. In patients with 
persistent bleeding and no angiographic or endoscopic identification of a definite

bleeding site, subtotal colectomy may be required. 
 The chance of a third bleeding episode can be as high as 50%, so many authori ties 
recommend surgical resection after a second bleeding episode. 
 Approximately three quarters of patients with anatomical diverticulosis remain 
asymptomatic. 
 Most complications of diverticulitis are associated with the initial attack, after which the 
disease tends to run a benign course. 888

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    99 
  Mortality and morbidity are related to complications of diverticulosis, which are mainly 
diverticulitis and lower gastrointestinal bleeding. These occur in 10-20% of patients with 
diverticulosis during their lifetime. 
 Prevention  
 Dietary fibre may prevent development of diverticular disease but, once symptoms

develop, the benefit from fibre supplementation is unclear. 
 Physical exercise has also been shown to help prevent the development of d iverticular 
disease. 
 
Meckel's diverticulum  
 Meckel's diverticulum is the vestigial remnant of the omphalomesenteric duct.  
 It is normally located in the terminal ileum within ~60 cm of the ileocaecal valve a nd it averages 
6 cm in length.

6 cm in length. 
 the diverticulum is frequently located near the ileocecal valve in the small bowel. 
 In Meckel diverticulum, there is persistence of the vitelline duct, an embryologic structure 
necessary for receiving nutrients. When this structure persists, the Meckel diverticulum may 
contain ectopic tissue, such as the acid-secreting gastric mucosa 
 Although it occurs much more commonly in children it is an important differential consid eration 
for gastrointestinal bleed in adults.

for gastrointestinal bleed in adults. 
 also quite common in Down's syndrome.  
Features 
 About 50% of these contain ectopic gastric mucosa, commonly leading to clinical presentati ons 
of peptic ulceration and haemorrhage. 
 Other complications of Meckel's diverticulum include   
 Diverticulitis 
 Intussusception 
 Perforation 
 Obstruction. 
Diagnosis 
 Technetium99m pertechnetate scintigraphy  
 Tc-99m pertechnetate accumulates in gastric mucosa and is the study of choice for

identifying ectopic gastric mucosa in a Meckel's diverticulum. 
889

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    100 
  
The picture shows an excised Meckel's diverticulum.  
 
Meckel diverticula: rule of 2’s 
 occurs in 2% of the population,  
 commonly located within 2-feet of the ileocecal valve, 
 2-inches in length,  
 commonly occurs before the age of two. 
Intussusception

Intussusception  
 Hirschsprung disease is aganglionosis of colon, causing obstruction. It usually presents in 
neonatal period.  
 common cause of intestinal obstruction in children in general and in Down's syndrome in 
particular.  
 There is a classic triad in intussusception of:  
1. acute abdominal pain,  
2. currant jelly stool and  
3. palpable abdominal mass, usually in right iliac fossa.  
Aorto-enteric fistulae (AEF)

Aorto-enteric fistulae (AEF)   
 known to occur following endovascular repair of abdominal aortic aneurysms (AAA) and 
secondary to aortic grafting of any kind, presumably because of mechanical forces of  
dislodged or migrating devices. 
 May occur after aorto-bifemoral graft as treatment for peripheral vascular disease. 
 Strongly positive faecal occult blood (FOB) suggests significant GI haemorrhage in 
spite of normal upper GI endoscopy.

spite of normal upper GI endoscopy.  
Anal fistula  
 Goodsall's rule describes the likely location of the internal opening of a fistula- in-ano based on 
its external opening.  
 If the external opening is anterior to the 9-3 o'clock  plane then the fistula forms a 
direct radial tract and opens  internally  at the same clock face point .  
 If the external opening is posterior to this line then it will generally follow a more

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    101 
Angiodysplasia  
Angiodysplasia is associated with aortic stenosis 
 Angiodysplasia is a vascular deformity of the gastrointestinal tract which predisposes to 
bleeding and iron deficiency anaemia.  
 generally seen in elderly patients

 generally seen in elderly patients  
 Second most common cause of lower GI bleeding in patients >60 years of age. 
 There is thought to be an association with aortic stenosis, although this is debated.  
 predominantly located in the proximal colon (77%)  (located most commonly in the 
ascending colon  and caecum) but is also found in the jejunum and ileum (15%) and 
transverse colon.  
 In Heyde's syndrome, a syndrome of aortic valve stenosis and colonic angiodysplasia, a

possible mechanism is the induction of von Willebrand's disease type IIA by the v alvular 
stenosis. 
 Bleeding stops spontaneously in >90% of cases. 
Diagnosis  
 colonoscopy 
 mesenteric angiography if acutely bleeding 
 The repeated negative upper and lower GI endoscopies suggest that small bowel 
angiodysplasia  may be the cause, in an area which is difficult to image via conventional 
endoscopy. In this situation capsule endoscopy has a higher yield and would be the

appropriate next step.  
 The pathophysiology of angiodysplasia in this situation isn't known, although it may be  
due to changes in pressure within the mesenteric venous plexus, as the condition ofte n 
resolves once the valve is treated. 
 endoscopic cautery or argon plasma coagulation 
 antifibrinolytics e.g. Tranexamic acid 
 oestrogens may also be used 
Heyde's syndrome  gastrointestinal bleeding from angiodysplasia in the presence of 
aortic stenosis.

aortic stenosis.  
Anal fissure 
 
Anal fissures are longitudinal or elliptical tears of the squamous lining of the distal anal can al. If 
present for less than 6 weeks they are defined as acute, and chronic if present for m ore than 6 
weeks. Around 90% of anal fissures occur on the posterior midline 
 
Management of an acute anal fissure (< 6 weeks)  
 dietary advice: high-fibre diet with high fluid intake

 bulk-forming laxatives are first line - if not tolerated then lactulose should be trie d 
 lubricants such as petroleum jelly may be tried before defecation 
 topical anaesthetics 
 analgesia topical steroids do not provide significant relief 
Management of a chronic anal fissure (> 6 weeks) 
 the above techniques should be continued 
 topical glyceryl trinitrate (GTN) is first line treatment for a chronic anal fissure

 if topical GTN is not effective after 8 weeks then secondary referral should be considered for 
surgery or botulinum toxin 
 
891

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    102 
  
Inflammatory bowel disease 
Crohn's disease 
 Crohn's disease is a form of inflammatory bowel disease.  
 Commonly affects the terminal ileum and colon but may be seen anywhere from the  mouth to 
anus. 

anus. 
 IBD is more common in white people than in African-Caribbean people or those of Asian 
origin.  
 has a lower incidence in non-white races; people of Jewish origin are more prone to 
inflammatory bowel disease than non-Jews; and  Ashkenazi Jews are at higher risk than 
Sephardic Jews.  
 slightly more common in females (male to female ratio is 1:1.2) 
 typically presents in late adolescence or early adulthood.  The highest incidence of Crohn's

disease in the 15 –30 year age  
 The ratio of Crohn's disease to ulcerative colitis varies between adults and children. In 
adults, the ratio of Crohn's disease to ulcerative colitis is 2:3, whil e the ratio in children is 
much higher (2.3:1).  
Pathology  
 cause is unknown but there is a strong genetic susceptibility 
 inflammation occurs in all layers, down to the serosa. This is why patients with Crohn's are 
prone to strictures, fistulas and adhesions 
Features

Features  
 presentation may be non-specific symptoms such as weight loss and lethargy 
 diarrhoea:  
 the most prominent symptom in adults.  
 Crohn's colitis may cause bloody diarrhea.   
 Nocturnal diarrhoea is indicative of organic disease and is typical of a Crohn's disease 
flare.  
 abdominal pain: the most prominent symptom in children.  often in the lower right quadrant 
 perianal disease: e.g. Skin tags or ulcers

 perianal disease: e.g. Skin tags or ulcers 
 An abdominal mass is often palpable in the presence of small bowel disease which can 
lead to Vitamin K malabsorption. 
 extra-intestinal features are more common in patients with colitis or perianal disease 
 
Extra-intestinal manifestations of  IBD  A PIE SAC : 
 Aphthous ulcers  
 Pyoderma gangrenosum  
 Iritis  
 Erythema nodosum  
 Sclerosing cholangitis  
 Arthritis  
 Clubbing of fingertips 
 
 892

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    103 
  
Questions regarding the 'extra-intestinal' features of inflammatory bowel disease  are common: 
Common to both Crohn's disease (CD) 
and Ulcerative colitis (UC) Notes 
Related to 
disease activity  Aphthous oral ulcers  
Arthritis: pauciarticular, asymmetric 
Erythema nodosum 
Episcleritis

Episcleritis 
Osteoporosis Arthritis is the most common extra-intestinal 
feature in both CD and UC 
Episcleritis is more common in CD 
Interstitial lung disease is more common in 
CD 
Unrelated to 
disease activity  Arthritis: polyarticular, symmetric 
Uveitis 
Pyoderma gangrenosum 
Clubbing 
Primary sclerosing cholangitis Primary sclerosing cholangitis is much more 
common in UC  
Uveitis is more common in UC  
 
Smoking in IBD

Smoking in IBD 
 Smoking associated with earlier age of onset of disease and more frequent need for 
immunosuppression among women  with Crohn's disease but not men . 
 Smoking cessation is associated with an increased risk of ulcerative colitis.  
Bloods 
 C-reactive protein correlates well with disease activity 
Faecal calprotectin 
 Calprotectin  is a protein belonging to the S100 family and occurring in large amounts in

neutrophil granulocytes 
 Increased faecal calprotectin indicates increased migration of neutrophils to intestinal m ucosa 
 ĹĹ Calprotectin in stool is the direct consequence of neutrophil degranulation due to mu cosal 
damage .  
 The logical next step in excluding inflammatory bowel disease 
  Recommended by NICE to distinguish between inflammatory bowel diseases and  non-
inflammatory bowel diseases, such as irritable bowel syndrome  in people presenting with

any of the following lower gastrointestinal symptoms for at least 6 weeks: ab dominal 
pain or discomfort, bloating, or change in bowel habit.  
   ĹĹ when there is any intestinal inflammation  Crohn ’s disease or ulcerative 
colitis.  
 normal value is approximately 25 mg/kg. 
  in IBS values may be slightly higher than those of healthy subjects , but in IBD signi ficantly ↑↑ 
 Calprotectin  exceeding 50 mg/kg should be considered positive  do endoscopy to confirm 
IBD

IBD 
 Non-invasive screen for IBD 
 Normal faecal calprotectin  makes IBD unlikely  
 ↑↑ faecal calprotectin  drive further imaging  
Stool culture 
 should be performed first 
 Even if the presentation is highly suggestive of inflammatory bowel disease. However, it is 
unforgivable not to do a stool culture in a case of diarrhoea and that should  be the starting 
point before considering the other investigations 
Endoscopy 
 colonoscopy is the investigation of choice

 colonoscopy is the investigation of choice 
 Crohn's disease most typically affects the terminal ileum and proximal colon, therefo re 
the investigation of choice would be ileo-colonoscopy. A flexible sigmoidoscopy 
may not identify any areas of disease.   
 features suggest of Crohn's include deep ulcers, skip lesions 
Histology  
 inflammation in all layers from mucosa to serosa 
 goblet cells 
 granulomas 893

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    104 
  Patchy inflammation 
Small bowel enema 
 high sensitivity and specificity for examination of the terminal ileum 
 strictures: 'Kantor's string sign' 
 proximal bowel dilation 
 'rose thorn' ulcers 
 fistulae 
 
Barium study is shown from a patient with 
worsening Crohn's disease. Long segment of

worsening Crohn's disease. Long segment of 
narrowed terminal ileum in a 'string like' 
configuration in keeping with a long stricture 
segment. Termed 'Kantor's string sign' .  
 
The picture shows the typical ' cobblestone 
mucosa' of Crohn's disease with isolated areas 
of normal mucosa surrounded by deep ulceration 
(ulcerative colitis does not result in such deep 
ulceration). 
Thumb printing

Thumb printing  
 thumb printing is a predominantly radiological finding due to inflamed, oedematous  folds of 
bowel as a result of mucosal oedema caused by inflammation. Thumb printing may be see n in 
either Crohn's disease or ulcerative colitis. 
Management (NICE 2012)  
 CD UC 
Inducing remission 
 1st line  glucocorticoids  (oral, 
topical or I.V) , OR Budesonide. 
Fear of steroid S.E (e.g in children)  
enteral feeding (in addition to or 
instead of)

instead of)   
 
 Mild & moderate UC 
1st line: 
 Rectal & distal colitis  
rectal (topical) 
Aminosalicylates is 
superior to rectal 
steroids 
 Proximal colitis  oral 
Aminosalicylates 
Sever UC   hospital  1st line 
( I.V steroid) 
 
2nd line  5-ASA drugs (e.g. 
mesalazine 2nd line  oral prednisolone 
 
Maintaining remission Stop smoking 
1st line  azathioprine  or 
mercaptopurine 
2nd line  methotrexate 
previous surgery  5-ASA drugs (e.g. 
mesalazine)  oral 5-ASA e.g.

mesalazine)  oral 5-ASA e.g. 
mesalazine 
 azathioprine and 
(methotrexate is NOT 
recommended for UC) 
 
894

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    105 
 General points  
 patients should be strongly advised to stop smoking 
 some studies suggest an increased risk of relapse secondary to NSAIDs and the combined 
oral contraceptive pill but the evidence is patchy 
  dietary advice  
 Short-term use of TPN may be helpful in severe cases

 There is a significant portion of Crohn ’s patients who are lactose intolerant, and hence a 
dairy free diet may reduce the frequency of diarrhoea . 
 glucocorticoids (oral, topical or intravenous) are generally used to induce remission. 
Budesonide is an alternative in a subgroup of patients 
 enteral feeding with an elemental diet may be used in addition to or instead of other me asures

to induce remission, particularly if there is concern regarding the side-effects of steroids (for 
example in young children) 
 5-ASA drugs (e.g. mesalazine) are used second-line  to glucocorticoids but are not as 
effective 
 azathioprine or mercaptopurine* may be used as an add- on medication to induce remission 
but is not used as monotherapy. Methotrexate is an alternative to azathioprine 
 infliximab is useful in refractory disease and fistulating Crohn's . Patients typically continue

on azathioprine or methotrexate 
 metronidazole is often used for isolated peri-anal  disease 
Maintaining remission 
 stopping smoking is a priority  
 (remember: smoking makes Crohn's  worse, but may help ulcerative colitis)  
 first-line   azathioprine or mercaptopurine  
 second-line    methotrexate  
 if a patient has had previous surgery    5-ASA drugs (e.g. mesalazine) should be 
Surgery 
 around 80% of patients with Crohn's disease will eventually have surgery

 Loss of the terminal ileum frequently leads to  bile salt malabsorption and treatment 
with the bile salt chelator cholestyramine  quickly relieves the problem. 
Treatment during pregnancy 
 For relapse during pregnancy  
 1st line    Prednisolone is the most appropriate initial treatment  
 2nd line (in patients who not responds to corticosteroids )  Infliximab 
 Infliximab is thought to be low risk in pregnancy although it does cross the 
placenta.

placenta.  
 Patients on maintenance infliximab therapy should stop treatment by week 26 
gestation.  
 In patients who require treatment in the last trimester, live vaccines should be 
avoided in the newborn for the first 6 months. 
 For maintenance therapy   azathioprine or 6MP 
 
Complications:  There are 3 main serious intestinal complications in Crohn's disease: 
1. Stricture (narrowing) of the bowel  intestinal obstruction

2. Fistulas, which are abnormal connections between sections of the bowel, or between the 
bowel and bladder.  
3. colorectal cancer  
Prognosis :( Nice 2013) 
Prognostic feature  Crohn's disease ulcerative colitis 
prolonged remission Only 10% 50% 
surgery within 10 years of 
diagnosis 50% 20–30% 
risk of mortality compared with 
the general population slightly increased Not increased 
General outlook worse than ulcerative colitis Better than Crohn's

*assess thiopurine methyltransferase (TPMT) activity before offering azathiopri ne or mercaptopurine 
 
 895

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    106 
  
Renal calculi are increased in Crohn's due to a mixture of dehydration and increased oxalate 
due to small bowel pathology and previous surgery. (Non-contrast helical CT abdomen is the 
investigation of choice for suspected renal calculi.)  

Crohn's-like enterocolitis with mycophenolate mofetil  
 Reported in renal transplant patients who have received mycophenolate mofetil.  
 Investigations will reveal mucosal ulceration and skip lesions ordinarily seen in Crohn's. 
 Treatment  Withdrawal of mycophenolate  resolution of symptoms  
Ulcerative colitis  (Nice guidelines 2013)  
 
 Ulcerative colitis (UC) is a form of inflammatory bowel disease.

  Inflammation always starts at rectum (hence it is the most common site for UC),  
 never spreads beyond ileocaecal valve and is continuous.  
 The peak incidence of ulcerative colitis is in people aged 15-25 years and in those aged  55-65 
years. 
Features  
The initial presentation is usually following insidious and intermittent symptoms: 
 bloody diarrhoea 
 urgency 
 tenesmus 
 abdominal pain, particularly in the left lower quadrant 
 extra-intestinal features (see below)

 extra-intestinal features (see below) 
 
Severity of ulcerative colitis (Mild, moderate and severe)  
 In adults the severity criteria are based on the Truelove and Witts' severity ind ex 
 In children (≤ 11  years) and young people (12 to 17 years) these categories are based on th e 
Paediatric Ulcerative Colitis Activity Index (PUCAI) 
 
Truelove and Witts' severity index 
 
 Mild Moderate Severe 
Bowel movements 
(no. per day) < 4 4–6 ≥ 6 + at least one of the features of systemic

upset (Pyrexia, Pulse > 90, anaemia,  ĹESR ) 
Blood in stools small 
amounts  Between mild 
and severe Visible blood 
Pyrexia (> 37.8°C)  No No Yes 
Pulse > 90 bpm  No No Yes 
Anaemia 
Haemoglobin <105 
g/L  No No Yes 
ESR ≤ 30 ≤ 30 > 30 
 
C reactive protein  ≤ 30 ≤ 30 >30  
 
Pathology 
 red, raw mucosa, bleeds easily 
 no inflammation beyond submucosa (unless fulminant disease) 
 widespread ulceration with preservation of adjacent mucosa which has the appearance of

polyps ('pseudopolyps') 
 inflammatory cell infiltrate in lamina propria 
 neutrophils migrate through the walls of glands to form crypt abscesses 
 depletion of goblet cells and mucin from gland epithelium 
 granulomas are infrequent 
Barium enema 
896

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    107 
  loss of haustrations 
 superficial ulceration, 'pseudopolyps' 
 long standing disease: colon is narrow and short -'drainpipe colon' 
 
Abdominal x-ray from a patient with ulcerative colitis showing lead pipe appearance  of the colon (red

arrows). Ankylosis of the left sacroiliac joint and partial ankylosis on the right (yellow arrow), 
reinforcing the link with sacroilitis.   
Ulcerative colitis: flares  
 Non-steroidal anti-inflammatory drugs (NSAIDs) cause flares of inflammatory bowel 
disease. 
 Cytomegalovirus is an uncommon cause of non-responsive colitis. 
Flares of ulcerative colitis are usually classified as either mild, moderate or severe: 
Mild Moderate Severe 
Fewer than four stools 
daily, with or without 
blood

blood 
 
No systemic disturbance 
 
Normal erythrocyte 
sedimentation rate and 
C-reactive protein values Four to six stools a day, 
with minimal systemic 
disturbance More than six stools a day, containing blood 
 
Evidence of systemic disturbance, e.g. 
 fever 
 abdominal tenderness, distension or reduced 
bowel sounds 
 anaemia 
Patients with evidence of severe disease should be admitted to hospital.

Risk factors for the precipitation of toxic colonic dilatation 
ulcerative colitis identify the following as risk factors for the precipitation of toxic colon ic 
dilatation: 
 Under-treatment 
 Purgative bowel preparations for colonoscopy 
 Non-steroidals 
 Opioids 
 Anti-cholinergics, and 
 Anti-diarrhoeal agents. 
 inappropriately delayed 
Ulcerative colitis: management

Ulcerative colitis: management 
Treatment can be divided into inducing and maintaining remission. NICE released guidelines on  the 
management of ulcerative colitis in 2013. 
The severity of UC is usually classified as  being mild, moderate or severe: 
897

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    108 
  mild: < 4 stools/day, only a small amount of blood 
 moderate: 4-6 stools/day, varying amounts of blood, no systemic upset 
 severe: >6 bloody stools per day + features of systemic upset (pyrexia, tachycardia, anaemia , 
raised inflammatory markers) 
Inducing remission

 treatment depends on the extent and severity of disease 
 rectal (topical) aminosalicylates or steroids: for distal colitis rectal mesalazine has been shown 
to be superior to rectal steroids and oral aminosalicylates 
 oral aminosalicylates 
 oral prednisolone is usually used second-line  for patients who fail to respond to 
aminosalicylates. NICE recommend waiting around 4 weeks before deciding if first-line 
treatment has failed

treatment has failed 
 severe colitis should be treated in hospital. Intravenous steroids are usually given first-
line 
 oral aminosalicylates e.g. mesalazine 
 azathioprine and mercaptopurine 
 methotrexate is not recommended for the management of UC (in contrast to Crohn's disease)  
 there is some evidence that probiotics may prevent relapse in patients with mild to mod erate 
disease 
Inactive (quiescent) colitis: 
 (ESR) is not raised in quiescent UC

 (ESR) is not raised in quiescent UC 
 If the ESR, CRP and platelet counts are not raised, indicating that the patient's 
symptoms are not due to active disease. 
 Neutrophilic infiltrate is present if disease is active  
 Involves epithelium of surface and crypts 
 Frequently forms crypt abscesses 
Ulcerative colitis: colorectal cancer 
Overview 
 risk of colorectal cancer is significantly higher than that of the general population although  
studies report widely varying rates

studies report widely varying rates 
 the increased risk is mainly related to chronic inflammation 
 worse prognosis than patients without ulcerative colitis (partly due to delayed diagnosis) 
 lesions may be multifocal 
Factors increasing risk of cancer 
 disease duration > 10 years 
 patients with pancolitis 
 onset before 15 years old 
 unremitting disease 
 poor compliance to treatment 
Colonoscopy surveillance & Risk stratification of IBD

 All patients with a diagnosis of colitis should have a screening colonoscopy 10 years after 
index presentation, preferably when they are in remission. 
 patients should be decided following risk stratification. 
 Lower risk   5 year follow up colonoscopy 
 Extensive colitis with no active endoscopic/histological inflammation 
 left sided colitis 
 Crohn's colitis of <50% colon 
 Intermediate risk   3 year colonoscopy

 Intermediate risk   3 year colonoscopy 
 Extensive colitis with mild active endoscopy/histological inflammation 
 post-inflammatory polyps 
 OR family history of colorectal cancer in a first degree relative aged 50 or over 
 Higher risk   1 year follow up colonoscopy 
 Extensive colitis with moderate/severe active endoscopic/histological 
inflammation 
 stricture in past 5 years 
 dysplasia in past 5 years declining surgery

 dysplasia in past 5 years declining surgery 
 primary sclerosing cholangitis  / transplant for primary sclerosing cholangitis 
 family history of colorectal cancer in first degree relatives aged <50 years 
___________________________________________________________  898

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    109 
 Inflammatory bowel disease: key differences 
 The two main types of inflammatory bowel disease are Crohn's disease and Ulcerative colitis.  
 They have many similarities in terms of presenting symptoms, investigation findings and 
management options.

management options.  
 There are however some key differences which are highlighted in table below: 
 
Venn diagram showing shared features and differences between ulcerative colitis and Crohn's 
disease. Note that whilst some features are present in both, some are much more commo n in one of 
the conditions, for example colorectal cancer in ulcerative colitis 
 
Crohn's disease (CD) Ulcerative colitis (UC) 
Features  Diarrhoea usually non-bloody  
Weight loss more prominent

Weight loss more prominent  
Upper gastrointestinal symptoms, mouth ulcers, 
perianal disease 
Abdominal mass palpable in the right iliac fossa Bloody diarrhoea more common 
Abdominal pain in the left lower quadrant 
Tenesmus 
Extra-intestinal  Gallstones are more common secondary to 
reduced bile acid reabsorption  
Oxalate renal stones* Primary sclerosing cholangitis more common 
Complications  Obstruction, fistula, colorectal cancer Risk of colorectal cancer high in UC than CD

Pathology  Lesions may be seen anywhere from the mouth 
to anus  
 
Skip lesions may be present Inflammation always starts at rectum and never 
spreads beyond ileocaecal valve 
 
Continuous disease 
Histology  Inflammation in all layers from mucosa to 
serosa 
 increased goblet cells 
 granulomas No inflammation beyond submucosa (unless 
fulminant disease) - inflammatory cell infiltrate in 
lamina propria 
 neutrophils migrate through the walls of 
glands to form crypt abscesses

glands to form crypt abscesses 
 depletion of goblet cells and mucin from 
gland epithelium 
Endoscopy  Deep ulcers, skip lesions - 'cobble-stone' 
appearance Widespread ulceration with preservation of 
adjacent mucosa which has the appearance of 
Radiology  Small bowel enema 
 high sensitivity and specificity for 
examination of the terminal ileum 
 proximal bowel dilation Barium enema

 proximal bowel dilation Barium enema 
 loss of haustrations 
 long standing disease: colon is narrow 
and short -'drainpipe colon' 
899

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    110 
 Crohn's disease (CD) Ulcerative colitis (UC) 
 fistulae 
 
*impaired bile acid rebsorption increases the loss calcium in the bile. Calcium normally  binds oxalate. 
IBD: histology 
This histological differences between Crohn's and ulcerative colitis are summarised below: 
Crohn's

Crohn's  
 inflammation occurs in all layers, down to the serosa. This predisposes to strictures, fistulas 
and adhesions 
 oedema of mucosa and submucosa, combined with deep fissured ulcers ('rose-thorn') lea ds to 
a 'cobblestone' pattern 
 lymphoid aggregates 
 non-caseating granulomas 
Ulcerative colitis  
 inflammation in mucosa and submucosa only (unless fulminant disease) 

 crypt abscesses 
 
900

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    111 
  
feature Ulcerative colitis Crohn's 
Most common site  Rectum  Terminal ileum  
Distribution  Rectum to colon “backwash ” ileitis Mouth to anus  
Spread  Continuous  Discontinuity “skip” lesions  
Gross features  Extensive ulceration 
 Pseudo-polyps 
   Focal aphthous ulcers with 
intervening normal mucosa

intervening normal mucosa 
  Linear fissures 
  Cobblestone appearance 
  Thickened bowel wall “linitis plastic ” 
  Creeping fat  
Micro  Crypt abscess Noncaseating granulomas  
Inflammation  Limited to mucosa and 
submucosa Transmural 
Complication   Toxic megacolon 
   Strictures 
  String sign on barium study 
  Obstruction 
  Abscess 
  Fistula 
  Sinus tract   
Genetic Association  HLA-B27   
Extraintestinal 
manifestation Common Uncommon  
Cancer risk 5-25% Slight 1- 3%

Cancer risk 5-25% Slight 1- 3% 
Presentation Bloody diarrhea Variable : Pain, diarrhea, weight 
loss 
 
Pseudopolyps are seen in both  ulcerative colitis and Crohn's disease. 
 
history of previously well-controlled ulcerative colitis, treated with mesalazine 1.2 g daily. presented 
with a 5-day history of increasing bowel frequency. A diagnosis of active proctitis was made . What is 
the most appropriate treatment?  
 increase mesalazine dosage

 increase mesalazine dosage  
Microscopic colitis (Collagenous colitis and Lymphocytic colitis)   
 Microscopic colitis (MC) is an inflammatory condition of the colon that presents with two 
subtypes: collagenous ( CC) and lymphocytic colitis (LC) .  
 Both types of MC present with watery diarrhea,  and normal endoscopic findings. Differentiation 
is made by histological examination but treatment is the same.

 Risk factors  for MC are female gender, higher age, concomitant autoimmune disease, pas t 
and current diagnosis of malignancy of organ transplant 
 Among all autoimmune disorders, celiac disease appears to have the strongest 
association. 
 The use of proton pump inhibitors (PPIs) (lansoprazole), low dose aspirin, β -blockers, 
angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (NSAIDs),

selective serotonin reuptake inhibitors (SSRI), statins, and bisphosphonates have all 
been associated with MC 
 histological evaluation through lower endoscopy.  
 The histology found in MC (both CC and LC) demonstrates lymphocytic 
infiltration of the lamina propria and the epithelium .  
 CC differs from LC in that there is marked thickening of the subepithelial 
layer .  
 Intraepithelial lymphocytosis (IEL)  can be found in both CC and LC, but is

more pronounced in LC : ≥ 20 intraepithelial lymphocyte per 100 surface 
epithelial cells are needed to make the diagnosis  901

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    112 
  Both MC respond well to oral budesonide. 
 Prognosis is good with resolution of symptoms after medical therapy. 
 38% of the patients achieve spontaneous remission with either no treatment or with simple 
anti-diarrheals. 
 
Histological features of collagenous colitis and lymphocytic colitis

Collagenous colitis  Lymphocytic colitis  
Lamina propria  Lymphocytic infiltration of the lamina propria with little or no damage in mucosal 
architecture 
Subepithelial 
layer  Thickening of subepithelial layer > 10 µm  Subepithelial collagen layer not 
present or < 10 µm  
Intraepithelial  Intraepithelial lymphocytosis could be 
present, but necessary for the diagnosis Intraepithelial lymphocytosis (≥ 20 IEL 
per 100 surface epithelial cells) 
 
 discontinue any potentially offending drug. 
 mild and intermittent symptoms can be treated with anti-diarrheal medication 
(loperamide).  
  moderate to severe symptoms: only budesonide has strong supporting evidence and 
should be the first-line treatment in inducing and maintaining clinical remission in both 
CC and LC 
 Prednisone is an alternative corticosteroid that has shown some efficacy in 
treating MC. however it is less effective than budesonide.

Collagenous colitis  
 Collagenous colitis is one of the forms of microscopic colitis, i.e. a condition in which 
the colon appears normal on colonoscopy, but where the diagnosis is made based on 
the abnormal histology of colonic biopsies.  
 predominantly affects women (male: female of 1: 4) in the fifth and sixth decade s of life.  
 aetiology is unknown,  
 although associated with  
 several medications – in particular, non-steroidal anti-inflammatory drugs  
902

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    113 
  coeliac disease and other autoimmune disorders. 
 chronic watery diarrhoea (which tends to be worse during the day than at night), a nd is also 
often accompanied by crampy, diffuse abdominal pain.  
 normal blood tests, radiological and macroscopic appearances .

 The diagnosis is made based on the typical histological appearances of a thickened 
subepithelial collagen band, a moderate inflammatory cell infiltrate, and an in crease in 
intraepithelial lymphocytes. 
 Treatments include antidiarrhoeal agents (such as Loperamide), 5-aminosalicyclate drugs, 
corticosteroids, and bile acid sequestrants, all of which are variably effective. 
 
Lymphocytic colitis  
 Associations

 occur in patients with other forms of GI pathology, including Crohn ’s and Coeliac.  
 Sertraline also appears to be associated with the development of lymphocytic 
colitis.  
 Withdrawal of the offending agent is preferable,  
 loperamide is often used as a first line therapy to reduce the severity of diarr hoea, with 
cholestyramine an alternative if there is bile salt malabsorption.

 Other alternatives include immune modulating agents such as azathioprine, although  a 
response to therapy may take many months to appear.  
 
Toxic megacolon ( Toxic dilatation of the colon ) 
DON ’T GIVE ANTI-DIARRHEAL Rx FOR ACUTE COLLITIS  TOXIC MEGACOLON  
 
Flexible sigmoidoscopy is the best investigation - safer than colonoscopy (relative

contraindication in active colitis), allowing biopsies to be taken and the viewing of a possible 
pseudomembrane. Occasionally the mucosa has a characteristic appearance. 
 
 Usually associated with severe colitis. 
 usually due to severe UC but also with Crohn's colitis and rarely ischaemic or infective 
colitis 
 The transverse or right colon is usually the most dilated part in toxic megacolon, often greater 
than 6 cm and occasionally up to 15 cm on supine films. 
 Diagnostic criteria

 toxic megacolon  transverse colon dilatation ≥ 6 cm +  signs of systemic toxicity.  
 
 Radiographic evidence of colonic distension  
 plus at least three of the following: 
 Fever >38.6°C 
 Heart rate >120 beats per minute  (The most reliable sign is the pulse rate) 
903

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    114 
  Neutrophilic leucocytosis  >10.5 × 109/L, or 
 Anaemia. 
 Plus,  at least one of the following: 
 Dehydration 
 Altered mental status 
 Electrolyte disturbances, or 
 Hypotension. 
 The most helpful investigation is a plain abdominal X-ray.

 Radiological colonic dilatation - widest diameter ≥ 6 cm in the transverse colon . 
 Other radiological findings include: 
 loss of haustral pattern,  
 mucosal oedema and  
 thumbprinting. 
Treatment   
The treatment of choice for established dilatation is colectomy . 
 
 Treatment includes 3 main goals:  
1. reduce colonic distention to prevent perforation (5-fold increase in mortality after free 
perforation) 
 Rolling techniques (knee-elbow and prone) may be performed to assist in

redistribution of colonic gas and decompression 
 Medical treatment:  
 antibiotics to cover the colonic bacterial flora, gram-negative and 
anaerobic bacteria  
 steroids: either hydrocortisone 100 mg IV every 6 hours or 
methylprednisolone 60 mg IV every 24 hours is acceptable. The latter has 
greater relative anti-inflammatory potency and less relative 
mineralocorticoid potency.  
 cyclosporine may be effective

 cyclosporine may be effective  
 colectomy: Most authors recommend colectomy if persistent dilatation is present 
or if no improvement is observed on maximal medical therapy after 24-72 hours. 
2. correct fluid and electrolyte disturbances  
 fluid replacement, electrolyte repletion, and transfusion should be aggressive. 
3. treat toxemia and precipitating factors. 
 Broad-spectrum (IV) antibiotics with coverage equivalent to ampicillin, 
gentamicin, and metronidazole should be initiated.

 Possible triggers for TM  should be stopped, including: 
 narcotics  
 antidiarrheals  
 anticholinergics  
Prognosis 
 The mortality rate for non-perforated, acute toxic colitis is about 4%; if perforation occurs, the 
mortality is approximately 20%.  
 
 904

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    115 
  
Gastroenteritis and food poisoning 
Diarrhoea  
 Osmotic diarrhoea  occurs in patients with diabetes who ingest too much sorbitol (a 
common substitute for glucose in so-called 'diabetic foods'.  
 Secretory diarrhoea  commonly occurs in response to endotoxin-producing bacteria, (eg 
cholera or Escherichia coli).

cholera or Escherichia coli). 
 
 Chronic radiation enteritis is diagnosed if diarrhoea and abdominal pain persist for 3 or more 
months following irradiation.   
 
Gastroenteritis 
 
Travellers' diarrhoea   
 defined as at least 3 loose to watery stools in 24 hours with or without one of more o f 
abdominal cramps, fever, nausea, vomiting or blood in the stool.  
  The most common cause is Escherichia coli

  The most common cause is Escherichia coli  
 Ciprofloxacin is recommended for first line antibiotic therapy (when needed) before 
stool culture results are available.  
Acute food poisoning 
 Sudden onset of nausea, vomiting and diarrhoea after the ingestion of  a toxin.  
  typically caused by Staphylococcus aureus , Bacillus cereus  or Clostridium perfringens . 
 Clostridium perfringens :  
 a Gram-positive, rod shaped, anaerobic, spore-forming bacterium.

 The spores can withstand (يقاومcooking temperatures, so if food (meat and poultry) is 
left to stand for a long time, germination of spores can occur, causing food poisoning.  
 The CPE (clostridium perfringens enterotoxin) can be detected in food that has be en 
improperly prepared.  
 Clostridium perfringens can also cause gas gangrene, a necrosis of tissues with 
gas production. The toxin responsible for gas gangrene is called alpha-toxin. 
 reservoir for this pathogen

 reservoir for this pathogen  
 Vibrio species are most commonly found in seafood (Fish), are comma-shaped, 
and prefer alkaline media. 
 Improperly canned foods  are reservoirs for Clostridium botulinum . This is an 
anaerobic gram-positive organism that creates spores. If the can is bulging, it is 
probably contaminated and should not be eaten. 
 Honey can be a reservoir for Clostridium botulinum . Newborn babies are at risk for

contracting spores from eating honey since their immune systems are poorly developed. 
This can lead to “floppy baby ” syndrome. 
 Mayonnaise and other cream-based dishes  are often reservoirs for Staphylococcus 
aureus . 
 
905

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    116 
  
Stereotypical histories 
Infection Typical presentation 
Escherichia coli  Common amongst travellers 
Watery stools 
Abdominal cramps and nausea 
Giardiasis  Prolonged, non-bloody diarrhoea 
Cholera  Profuse, watery diarrhoea 
Severe dehydration resulting in weight loss 
Not common amongst travellers

Not common amongst travellers 
Shigella  Bloody diarrhoea 
Vomiting and abdominal pain 
Staphylococcus 
aureus  Severe vomiting 
Short incubation period 
Campylobacter  commonest cause of bacterial gastroenteritis in the UK   
A flu-like prodrome is usually followed by crampy abdominal pains (often a 
prominent feature), 'pseudoappendicitis' (RIF pain), fever and diarrhoea which may 
be bloody. 
 the most appropriate therapy  IV fluids

 the most appropriate therapy  IV fluids  
 most units advocate no antibiotic treatment. 
 Antibiotic of choice in this infection is erythromycin, though ciprofloxacin 
and tetracycline may also be appropriate. 
Complications  include Guillain-Barre syndrome 
Salmonella  After Campylobacter, Salmonella  is the most commonly isolated bacterial 
pathogen when laboratory diagnosis of diarrhea is sought. 
 acute onset of fever, diarrhea, and cramping

 acute onset of fever, diarrhea, and cramping 
 antibiotic treatment of patients with nontyphoidal salmonellosis may actually 
prolong, rather than limit, fecal shedding of these organisms. 
 the likely sources are poultry (دواجنand eggs.  
Bacillus cereus  Two types of illness are seen 
 vomiting within 6 hours, stereotypically due to rice 
 diarrhoeal illness occurring after 6 hours 
Amoebiasis  Gradual onset bloody diarrhoea, abdominal pain and tenderness which may last for

several weeks 
Incubation period 
 1-6 hrs: Staphylococcus aureus , Bacillus cereus * 
 12-48 hrs: Salmonella , Escherichia coli  
 48-72 hrs: Shigella , Campylobacter  
 > 7 days: Giardiasis, Amoebiasis 
Amoebic dysentery  
 Acute amoebic dysentery is managed with: 
1. a course of oral metronidazole  or tinidazole,  
2. followed by a ten day course of diloxanide to eradicate colonisation of the gut.

 Amoebic liver abscess may appear at any time from eight weeks after infection, and  presents 
with night sweats, anorexia and right upper quadrant pain. 
 mortality from amoebiasis is less than 1%. 
 
 906

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    117 
Giardiasis 
 Giardiasis is caused by the flagellate protozoan Giardia lamblia .  
 It is spread by the faeco-oral route 
  
Features  
 often asymptomatic (carriers) 
 lethargy, bloating, abdominal pain 
 non-bloody diarrhoea

 non-bloody diarrhoea 
 chronic diarrhoea, malabsorption and lactose intolerance can occur 
 steatorrhoea  
Diagnosis 
 stool microscopy for trophozoite and cysts are classically negative, therefore duodenal fluid 
aspirates or 'string tests' (fluid absorbed onto swallowed string) are sometimes needed 
 initial investigation for Giardia  is microscopy  three stool samples  
 if repeated stool samples are negative and symptoms continue, current NHS guideli nes

suggest that endoscopy is the best way to confirm the diagnosis.   
 It is diagnosed by stool microscopy; if negative  duodenal aspirates or biopsy.  
 Testing of serum antibodies against G. lamblia  trophozoites is not useful in diagnosing current 
 immunoassays using antibodies against cyst or trophozoite antigen  have greater sensitivity 
and faster  than conventional stool microscopy methods.  
  the specificity o f a number of different immunoassays (eg: ELISA) was ≥98%.

Treatment  
 Metronidazole  
 Alternatives  (quinacrine, tinidazole, ornidazole, furazolidone, paromomycin).    
Clostridium perfringens  
The food poisoning with Colicky abdominal pain and diarrhoea without vomiting  after incubation 
period between 9-13 hours is typical of Clostridium perfringens . 
Bacillus cereus

Bacillus cereus 
typical case of Bacillus cereus, profuse vomiting occurs one to five hours after eating (rice ). 
 
B.cereus  can cause two patterns of disease: 
1. classic emetic form: 
 caused by the ingestion of toxin   
 Characterised by nausea and vomiting, similar to Staphylococcus aureus .  
 Rice products are generally the cause of this form. 
2. diarrhoeal form: 
 less common  
 Caused by the ingestion of the organism , which releases toxin within the stomach.

 Produce an illness similar to C. perfringens (but the incubation period is classically 
shorter (1-6 hours) with watery diarrhoea and abdominal cramps.  
 Meats, milk, vegetables and fish have been associated with this form.  
 
*vomiting subtype, the diarrhoeal illness has an incubation period of 6-14 hours 
Shigella  
 causes bloody diarrhoea, abdominal pain

 causes bloody diarrhoea, abdominal pain 
 severity depends on type: S sonnei (e.g. from UK) may be mild, S flexneri or S d ysenteriae 
from abroad may cause severe disease 
 treat with ciprofloxacin 
 Reactive arthritis and Reiter's syndrome can develop following infection with a number of 
enteric pathogens including Shigella , Salmonella , Campylobacter and Yersinia . 
 907

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    118 
 ___________________________________________________________   
Yersinia enterocolitica   
 gram-negative bacillus 
 the second most common cause of bacterial gastrointestinal infection in children.  
 most frequently associated with enterocolitis, acute diarrhea, terminal ileitis,  mesenteric

lymphadenitis and pseudoappendicitis  
 Pseudoappendicitis syndrome is more common in older children and young adults.  
 Enterocolitis, the most common presentation of Y enterocolitica, occurs primarily in young 
children,  Most cases are self-limited. 
 Y enterocolitica  is potentially transmitted by contaminated unpasteurized milk and milk 
products, raw pork, tofu, meats, oysters, and fish. 
 The usual presentation of Y enterocolitica  infection includes diarrhea (the most common

clinical manifestation of this infection), low-grade fever, and abdominal pain lasting 1-3  weeks. 
Diarrhea may be bloody in severe cases. Vomiting is present in approximately 15-40% of 
cases  
 Stool culture is the best way to confirm the diagnosis  
 Ultrasonography or computed tomography (CT) scanning may be useful in delineating tru e 
appendicitis from pseudoappendicitis  
 Complications  
 After an incubation period of 4-7 days, infection may result in mucosal ulceration

(usually in the terminal ileum and rarely in the ascending colon), necrotic lesions in 
Peyer patches, and mesenteric lymph node enlargement.  
 In persons with human leukocyte antigen (HLA) –B27, reactive arthritis is not 
uncommon, possibly because of the molecular similarity between HLA-B27 antigen 
and Yersinia  antigens.  
 First-line drugs used against the bacterium include aminoglycosides and trimethoprim-

sulfamethoxazole (TMP-SMZ). Other effective drugs include third-generation cephalospo rins, 
tetracyclines (not recommended in children < 8 y), and fluoroquinolones (not approved for u se 
in children < 18 y).  
 
 Yersinia pestis  is the causative agent of the plague. 
 Yersinia  bacteria has an ability to survive, and actively proliferate at temperatures as low a s 1–
4°C (e.g., on food products in a refrigerator).  
 Yersinia is one of the causes of reactive arthritis

 Yersinia  may be associated with Crohn's disease 
 Iranian sufferers of Crohn's disease were more likely to have had earlier exposure to 
refrigerators at home, consistent with its unusual ability to thrive at low temperatures. 
 Which bacteria can multiply and produce endotoxin even in refrigerated blood? 
 Yersinia  
 it is a prominent cause of life-threatening post-transfusion infection.  
 Endotoxins can result in septic shock  
 
 908

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    119 
Gastrointestinal parasitic infections 
Common infections  
Organism Notes 
Enterobiasis   Due to organism Enterobius vermicularis  
 Common cause of pruritus ani 
 Diagnosis usually made by placing scotch tape at the anus, this will trap eggs that

can then be viewed microscopically 
 Treatment is with mebendazole 
Ancylostoma 
duodenale   Hookworms that anchor in proximal small bowel 
 Most infections are asymptomatic although may cause iron deficiency anaemia 
 Larvae may be found in stools left at ambient temperature, otherwise infection is 
difficult to diagnose 
 Infection occurs as a result of cutaneous penetration, migrates to lungs, coughed 
up and then swallowed 
 Treatment is with mebendazole

Ascariasis   Due to infection with roundworm Ascaris lumbricoides  
 Infections begin in gut following ingestion, then penetrate duodenal wall to 
migrate to lungs, coughed up and swallowed, cycle begins again 
 Diagnosis is made by identification of worm or eggs within faeces 
Strongyloidiasis   Due to infection with Strongyloides stercoralis  
 Rare in west 
 Organism is a nematode living in duodenum of host

 Initial infection is via skin penetration. They then migrate to lungs and are 
coughed up and swallowed. Then mature in small bowel are excreted and cycle 
begins again 
 An auto infective cycle is also recognised where larvae will penetrate colonic wall 
 Individuals may be asymptomatic, although they may also have respiratory 
disease and skin lesions 
 Diagnosis is usually made by stool microscopy 
 In the UK mebendazole is used for treatment 
Cryptosporidium   Protozoal infection

Cryptosporidium   Protozoal infection 
 Organisms produce cysts which are excreted and thereby cause new infections 
 Symptoms consist of diarrhoea and cramping abdominal pains. Symptoms are 
worse in immunosuppressed people 
 Cysts may be identified in stools 
 Treatment is with metronidazole 
Giardiasis   Diarrhoeal infection caused by Giardia lamblia (protozoan) 
 Infections occur as a result of ingestion of cysts

 Symptoms are usually gastrointestinal with abdominal pain, bloating and passage 
of soft or loose stools 
 Diagnosis is by serology or stool microscopy 
 First line treatment is with metronidazole 
Exotoxins and endotoxins 
Exotoxins are secreted by bacteria where as endotoxins are only released following lysis o f the cell. 
Exotoxins are generally released by Gram positive bacteria  with the notable exceptions of Vibrio

cholerae  and some strains of E. coli  
It is possible to classify exotoxins by their primary effects: 
 pyrogenic toxins 
 enterotoxins 
 neurotoxins 
 tissue invasive toxins 909

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    120 
  miscellaneous toxins 
Pyrogenic toxins  
Pyrogenic toxins stimulate the release of endogenous cytokines resulting in fever, rash etc. T hey are 
super-antigens which bridge the MHC class II protein on antigen-presenting cells with th e T cell 
receptor on the surface of T cells resulting in massive cytokine release.

Organism Toxin Notes 
aureus  Toxic shock syndrome (TSST-1 
superantigen) toxin Results in high fever, hypotension, 
exfoliative rash 
Streptococcus 
pyogenes  Streptococcal pyrogenic exotoxin A & C Results in scarlet fever 
Enterotoxins  
Enterotoxins act on the gastrointestinal tract causing one of two patterns of illness:  
 diarrhoeal illness 
 vomiting illness ('food poisoning') 
Organism Toxin Notes

Vibrio cholerae  Cholera toxin Causes activation of adenylate cyclase (via G s) leading to 
increases in cAMP levels, which in turn leads to increased 
chloride secretion and reduced sodium absorption 
Shigella 
dysenteriae  Shiga toxin Inactivates 60S ribosome ĺ epithelial cell death  
Escherichia coli  1. Heat labile toxin 
 
2. Heat stabile toxin 1. Activates adenylate cyclase (via G s), increasing cAMP ĺ 
watery diarrhoea

watery diarrhoea 
 
2. Activates guanylate cyclase, increasing cGMP ĺ watery  
diarrhoea 
aureus  Staphylococcus 
aureus enterotoxin Vomiting and diarrhoeal illness lasting < 24 hours 
Bacillus cereus  Cereulide Potent cytotoxin that destroys mitochondria. Causes a vomiting 
illness which may present within 4 hours of ingestion 
Neurotoxins  
 
Neurotoxins act on the nerves (tetanus) or the neuromuscular junction (botulism) causing paralysis. 
 
Clostridium 
tetani  Tetanospasmin Blocks the release of the inhibitory neurotransmitters GABA and glycine 
resulting in continuous motor neuron activity ĺ continuous muscle 
contraction ĺ lockjaw and respiratory paralysis  
botulinum  Botulinum 
toxin Blocks acetylcholine (ACh) release leading to flaccid paralysis 
Tissue invasive toxins  
 
perfringens  α-toxin, a

perfringens  α-toxin, a 
lecithinase Causes gas gangrene (myonecrosis) and haemolysis 
aureus  Exfoliatin Staphylococcal scalded skin syndrome 
 
 910

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    121 
  
Miscellaneous toxins 
Corynebacterium 
diphtheriae  Diphtheria 
toxin ADP ribosylates elogation factor (EF-2), resulting in inhibition, causing 
a 'diphtheric membrane' on tonsils caused by necrotic mucosal cells. 
Systemic distribution may produce necrosis of myocardial, neural and 
renal tissue

renal tissue 
Pseudomonas 
aeruginosa  Exotoxin A Also inhibits EF-2 by the same mechanism as above 
Bacillus anthracis  Oedema 
factor (EF) Forms a calmodulin-dependent adenylate cyclase which increases 
cAMP, impairing the function of neutrophils/macrophages ĺ reduced 
phagocytosis 
Bordetella 
pertussis  Pertussis 
exotoxin Inhibits G i leading to increases in cAMP levels, impairing the function 
of neutrophils/macrophages ĺ reduced phagocytosis  
Endotoxins

Endotoxins  
Endotoxins are lipopolysaccharides that are released from Gram-negative bacteria suc h as Neisseria 
meningitidis . 
Pseudomembranous colitis (Clostridium difficile)  
 Clostridium difficile  is a Gram positive  rod 
  often encountered in hospital practice.  
 It produces an exotoxin which causes intestinal damage leading to a syndrome calle d 
pseudomembranous colitis.

pseudomembranous colitis. 
  Clostridium difficile  develops when the normal gut flora are suppressed by broad-spectrum 
antibiotics.  
 Clindamycin is historically associated with causing Clostridium difficile  but the aetiology has 
evolved significantly over the past 10 years.  
 Second and third generation cephalosporins  are now the leading cause of Clostridium 
difficile . 
 symptoms can occur up to 10 weeks  following antibiotic therapy. 
Features  

Features  
 a raised white blood cell count  is characteristic 
 if severe toxic megacolon may develop 
Diagnosis   
 is made by detecting Clostridium difficile  toxin (CDT) in the stool  
 the most widely used diagnostic tool.  
 ELISA tests are specific but not as sensitive.  
 Culture is sensitive but often does not differentiate between toxigenic and non-toxig enic 
strains.

strains. 
 sigmoidoscopy may show  multiple white plaques adhered to the gastrointestinal 
mucosa 
 The classic sigmoidoscopic appearance of 2 to 10 mm raised yellow nodules are 
pathognomonic . 
  90% of cases can be detected macroscopically by flexible sigmoidoscopy 
 mild cases may not be evident macroscopically  microscopic examination of a 
biopsy sample 
 Plain AXR is useful for diagnosing toxic dilatation  
 would be the investigation of choice if there is abdominal distension.

 Toxic dilatation should be excluded prior to sigmoidoscopy .  
 However it does not establish the diagnosis. 
 first-line therapy is oral metronidazole for 10-14 days 
 if severe  or not responding to metronidazole then oral vancomycin may be used 911

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    122 
  The major advantage of vancomycin over metronidazole is that vancomycin is not 
absorbed, so maximal concentrations of the drug can act intracolonically at the site of 
 indicators for severe disease  include: 
 An age greater than 60 
 Albumin <25 g/L 
 Temperature >38.3°C 
 White cell count >15 ×109/L

 White cell count >15 ×109/L 
 Endoscopic evidence of pseudomembranous colitis and 
 Intensive care admission. 
 Intravenous metronidazole can be used where oral administration is impossible; intravenous 
vancomycin is not effective. 
 for life-threatening infections a combination of oral vancomycin and intravenous metronida zole 
should be used 
Amoebiasis 
 caused by Entamoeba histolytica  (an amoeboid protozoan)

 spread by the faecal-oral route.  
 10% of the world's population is chronically infected.  
 Features 
 can be asymptomatic,  
 May cause mild diarrhoea  
 Amoebic dysentery  
 profuse, bloody diarrhoea 
 stool microscopy may show trophozoites 
 treatment is with metronidazole 
 Complication 
 Amoebic liver abscess 
 usually a single mass in the right lobe (may be multiple) 
 features: fever, RUQ pain 
 serology positive in > 90%

 serology positive in > 90% 
Viral gastroenteritis  
 Most cases of acute infectious gastroenteritis are viral, 
 Causes  
 most common:  
 norovirus  is the most common cause of acute gastroenteritis  and the 
second most common cause of hospitalisation for acute gastroenteritis.  
 large outbreaks from consumption of contaminated food and water,  
 spread person- to-person.  
 other common 
 rotavirus,

 rotavirus,  
 enteric adenovirus and  
 astrovirus.  
 Features 
 Characteristics of the history that suggest a viral aetiology of acute gastroenteritis 
include:  
 intermediate incubation period (24 –60 h),  
 short infection duration (12 –60 h) and  
 high frequency of vomiting.  
Scombrotoxin food poisoning   
 Caused by the ingestion of foods that contain high levels of histamine  and possibly other

vasoactive amines and compounds. 
 Histamine and other amines are formed by the growth of certain bacteria and the sub sequent 
action of their decarboxylase enzymes on histidine and other amino acids in food, by spoil age 
of foods such as; 
 fishery products, particularly tuna  or mahi mahi . 912

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    123 
  dark meat fish such as tuna, mackerel and marlin.  
 The most common cause of scombroid poisoning is due to ingestion of spoiled fish  
following inadequate refrigeration or prolonged time at room temperature. Cooking do es 
not inactivate the toxin/histamines. 
 Incubation period  
 10-60 minutes . 
 Feature

 Feature 
 The symptoms are due to ingestions of amines, predominantly histamines , produced 
by bacterial decarboxylation of histidine in fish meat.  
 Onset is usually 10- 30 minutes post-ingestion of the implicated fish but a delayed onset 
may occur up to two hours. 
 Patients with pre-existing conditions such as bronchial asthma, and those taking 
isoniazid (a histaminase inhibitor) may be more symptomatic.

 Presented with diarrhoea, flushing, sweating and a hot mouth, minutes after 
eating  
 Urticarial rash , Bronchospasm 
Treatment 
 usually self-limiting  
 In severe cases, symptoms respond rapidly to antihistamines, for example, 
chlorpheniramine and intravenous cimetidine by slow intravenous injection over at least five 
minutes.  
Perforated viscus 
the most appropriate next step in making the diagnosis   abdominal CT scan

 Ascitic fluid analysis:  
 very bloody ascites  
 secondary bacterial peritonitis  
 very inflammatory (very high neutrophil count)  
 exudate (low serum albumin ascites gradient - <11 g/L).  
 Gram stain demonstrates multiple bacteria .  
 X-ray  
 distended bowel loops (dilated, oedematous) 
 Rigler ’s sign , which indicates a perforated viscus.  
 also known as the double wall sign, is seen on an X-ray of the abdomen when

 the air is present on both sides of the intestine, (luminal and peritoneal side of the 
bowel wall). 
 Dome sign    
 Air on the top of the liquid (fluid level) 
 pneumatosis coli which are suggestive of ischaemic bowel but not diagnostic of this or 
perforation. 
 913

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    124 
  
914

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    125 
  
Endoscopy in patients on antiplatelet or anticoagulant therapy  
British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines (2016)

 The risk of endoscopy in patients on antithrombotics depends on the risks of proce dural 
haemorrhage versus thrombosis due to discontinuation of therapy. 
 Where the endoscopic procedure carries a high risk of bleeding  and the indication for 
anticoagulation is low risk  for discontinuation then anticoagulation should be discontinued 
until the INR is <1.5 and restarted post-procedure. Bridging with heparin is not required.

 Bridging is only recommended if the indication for  anticoagulation is high risk  - for 
example, mechanical mitral valve, atrial fibrillation (AF) and prosthetic valve, recent 
venous thromboembolism (VTE) (less than three months), thrombophilia. 
 Low molecular weight heparin (LMWH) is relatively contraindicated in patients with 
an estimated glomerular filtration rate (eGFR) less than 30 mls/min , these patients 
may require admission for unfractioned heparin (UFH) infusion. 
915

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    126 
  Where an endoscopic procedure is associated with a low risk of haemorrhage then the BSG 
recommends continuation of anticoagulation at the current dosage  providing an INR within 
the last seven days is within the therapeutic range. 
 
916

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    127 
  
917

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    128 
  
918

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    129 
  
919

Notes & Notes for MRCP                                                                                          By Dr. Yousif Abdallah Hamad    130 
  
Proctitis 
 Proctitis is  inflammation of the lining of the rectal mucosa 
 Causes 
  radiation therapy or antibiotics 
 usually within 6 months of treatment with a total dose of greater than 50 Gy.

 can occur any time up to 30 years post irradiation. 
 sexually transmitted diseases (STDs) : anal intercourse 
 most commonly due to gonorrhea and chlamydia, 
 less commonly lymphogranuloma venereum or herpes virus 
  HSV types 1 and 2 infections : Symptoms may include: tenesmus, rectal 
pain, discharge, hematochezia and tender inguinal lymph nodes. 
  autoimmune disease of the colon, such as Crohn disease and ulcerative colitis 
920

Nephrology 
 
  1   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                    
                                                                                                                                                                                   
By
 
Nephrology
 
Updated 
 
2017
 
Contains:

Updated 
 
2017
 
Contains: 
 
 921

  2   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                    
                                                                                                                                                                                   
 Renal anatomy  The tables below show the anatomical relations of the kidneys: 
Right kidney  
Direct contact Layer of peritoneum in-between

Direct contact Layer of peritoneum in-between 
Right suprarenal gland 
Duodenum 
Colon Liver 
Distal part of small intestine 
 
Left kidney  
Left suprarenal gland 
Pancreas  
Colon Stomach 
Spleen 
 
Renal physiology 
 
Diagram showing the basic physiologic mechanisms of the kidney 
Renal blood flow (RBF)   
 Renal blood flow is 20-25% of cardiac output

 Renal blood flow is 20-25% of cardiac output  
 The 'Fick principle' can be used to estimate RBF  through clearance. 
 Sympathetic stimuli produce vasoconstriction and RBF should be increased in response to  
hypoxia. 
 Renal cortical blood flow > medullary blood flow (i.e. tubular cells more prone to ischaemia) 
  Glomerular filtration rate and renal blood flow increase by about 50% in pregnancy  
leading to decreased BUN and creatinine  on laboratory examination. 
922

  3   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                    
                                                                                                                                                                                   
  What is the effect of decrease in hematocrit on renal function? 
 Decreased Renal Blood Flow

 Decreased Renal Blood Flow 
 the relationships between Renal Blood Flow (RBF), Renal Plasma 
Flow (RPF), Hematocrit (Hct), and Glomerular Filtration Rate (GFR):  
 RBF = RPF / (1 - Hct).  
 Assuming that the GFR is stable, this equation suggests that a 
decrease in Hct would lead to an decrease in RBF .  
 
Renal tubular functions 
 
 Sodium, glucose, bicarbonate and amino acids are absorbed at the proximal tubule 
level

level 
 Sodium reabsorption is mostly through active transport in the loop of Henle with only a 
modest reabsorption facilitated by aldosterone.  
 Ammonia is secreted by the distal tubule 
 Regulation of water secretion is by the distal tubule and the collecting ducts under 
the influence of vasopressin  increase permeability to water.  
 The relative hyperosmolality of the medulla is maintained by a counter-current mecha nism

and is responsible for the flux of water across the renal tubule 
 descending loop of Henle  is permeable to water but impermeable to solutes, due to the 
presence of aquaporin 1 in its tubular wall  water moves to medullary space  hypertonic 
filtrate  
 ascending loop of Henle   is impermeable to water (because of a lack of aquaporin, a 
common transporter protein for water channels in all cells except the walls of the ascending

loop of Henle) but permeable to solutes, but here Na+, Cl−, and K+ are actively transported 
into the medullary space, making the filtrate hypotonic  
923

  4   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                    
                                                                                                                                                                                   
  What is the renal cellular mechanism that prevents a sodium load intake from 
drastically increasing  plasma osmolality?

drastically increasing  plasma osmolality? 
 Movement of aquaporin channels to the apical surface of collecting duct cells 
 An increase in sodium intake will cause an increase in plasma osmolality, 
triggering the release of antidiuretic hormone (ADH), a.k.a. vasopressin.  
 The immediate effect of ADH  (occurs over minutes)  movement 
of aquaporin channels to the apical surface of collecting duct cells .  
 the long-term effect of ADH  (occurs over days) Increase

in aquaporin gene expression by collecting duct cells. 
 
924

  5   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                    
                                                                                                                                                                                   
Renin-angiotensin –aldosterone system 
 
Renin

Renin 
 Released by juxtaglomerular cells in kidney in response to Ļ renal perfusion, low sodium  
 Hydrolyses angiotensinogen to form angiotensin I 
 when decreased cardiac output occurs, stimulation of renin release is the primary 
event which leads to peripheral oedema  
 renin ↓ in primary hyperaldosteronism due to negative feedback ( Ĺ Aldosterone  Ĺ BP 
 Ĺrenal perfusion  Ļ renin)

 Ĺrenal perfusion  Ļ renin)  
 
Which renal cells would respond first to this acute event of hypotension  to increase blood pressure? 
 Juxtaglomerular cells 
 
Factors stimulating renin secretion  
 Ļ BP ĺ Ļ renal  perfusion 
 Hyponatremia 
 renal artery stenosis  Sympathetic nerve 
stimulation 
 Catecholamines 
 Erect posture 
Factors reducing renin secretion  
 β-blockers 
 NSAIDS 
Angiotensin 
 ACE in lung converts angiotensin I → 
angiotensin II

angiotensin II 
 Vasoconstriction leads to raised BP  Stimulates thirst 
 Stimulates aldosterone and 
ADH   
 
Aldosterone 
 Released by the zona glomerulosa (the outer layer of adrenal cortex) in response to 
925

  6   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                   
                                                                                                                                                                                    
 raised angiotensin II, potassium, and ACTH levels 
 Act in distal tubule  retention of Na+ in exchange for K+/H+ :

 ↑ resorption of Na+  ↓Na+ loss in urine 
 ↑ resorption of water (osmotic effect due to ↑ Na+)   
 ↑ excretion of K+  
  
The counter -current concentrating mechanism in the kidney 
Urine is concentrated by a complex interaction between the loops of Henle, the medullary 
interstitium, vasa recta and the collecting tubules, collectively termed  'the counter-current 
mechanism' : 
 Vasa recta possess fenestrated walls that facilitate the movement of diffusible  substances

(free movement of water and electrolytes across the walls of the vasa recta)  
 Fine-tuning of the salt and water balance is achieved in the distal and collecting tubules 
under the influence of aldosterone and antidiuretic hormone 
 The ascending limb of the loop of Henle is impermeable to water but permeab le to sodium 
 All nephrons are involved in this process 
 The glomerular filtration rate ensures that the elimination of compounds such as urea  from

plasma can take place without losing large amounts of water as well 
________________________________________________________ 
Renal Investigations 
Urinalysis 
 
Significance of presence of casts in urine 
 Hyaline casts   may be seen in normal urine, particularly after exercise 
 Coarse granular casts   occur in glomerular and tubular disease 
 Tubular cell casts   may be seen in patients with acute tubular necrosis 
 The presence of 10 or more white blood cells/mm3   infection

 The presence of red-cell casts   characteristic of glomerulonephritis 
Red cell casts : Present in: 
 Acute glomerulonephritis 
 Renal vasculitis  Accelerated hypertension  
 Interstitial nephritis. 
Oliguria  
 Oliguria is defined as <400 ml urine/day. 
 a urine output of <0.5mL/kg/h. 
 
 926

  7   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                    
                                                                                                                                                                                   
comment Normal 
limits urinalysis 
"Significant pyuria " ≥ 10 leucocytes per microlitre   (µl)

or cubic millimeter (mm3)   < 10  (WBCs) / 
leukocytes / 
(pus cells) 
characteristic of glomerular origin  0 - 3   dysmorphic RBCs 
Suggestive of in vivo  hemolysis, but must be distinguished from  
 hematuria. In case of hemoglobinuria, a urine dipstick shows 
 presence of blood, but no RBCs are seen on microscopic 
examination. 0 hemoglobinuria 
a positive test suggests presence of bacteria in significant numbers 
(ie more than 10,000 per ml) , A negative result does not rule out a

UTI 0 nitrites 
 
Sterile pyuria 
Pyuria in the absence of bacteriuria 
 Causes
 partially treated UTI 
 urethritis  and sexually transmitted 
diseases e.g. Chlamydia  
 renal tuberculosis 
 renal stones   
 foreign body eg: urinary catheter, 
 appendicitis 
 bladder/renal cell cancer  adult polycystic kidney disease 
 Chemical cystitis (eg 
cyclophosphamide)  
 analgesic nephropathy 
 Acute glomerulonephritis  
 Tubulo-interstitial diseases 
Glycosuria in pregnancy

Glycosuria in pregnancy  
 The most likely mechanism of glycosuria in pregnant woman  Reduced renal 
reabsorption 
 patients with persistent glycosuria should be investigated with a glucose tolerance test at  
around 24 weeks 
 
Ketonuria in pregnancy 
 Ketonuria may also be seen in normal pregnancy, as a result of the increased met abolic 
requirements 
 
Urine pH   
 The range is 4.5 to 8. urine is commonly acidic (ie 5.5-6.5)  
 Acidic urine  (low pH) may be caused by:

 Acidic urine  (low pH) may be caused by: 
 diet (eg, acidic fruits such as cranberries)  
 uric acid calculi.  927

  8   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                   
                                                                                                                                                                                    
  Urine pH generally reflects the blood pH but in renal tubular acidosis (RTA) this is not the

case. In type 1 RTA (distal) the urine is acidic but the blood alkaline. In type 2 (proxima l) the 
urine is initially alkaline but becomes more acidic as the disease progresses. 
  Alkaline urine  (high pH) is seen in: 
 the initial stages of type 2 RTA  
 Infection with urease-splitting organisms,  
 and may be associated with the formation of stag-horn calculi. 
 Diet, with vegetarians having more alkaline urine when compared with omnivores.

 Animal proteins contained in meat, eggs and cheese are often converted into acidic 
products (for example, amino acids) during digestion, absorption or metabolism. T his 
provides a daily increase in the body's acid content, which has to be excreted by the  
kidneys.  
 For people eating a vegetarian diet, consumption of foods rich in citrate or carbonated 
drinks raise the urine pH. 
 Other situations can interfere with this balance, such as tubular function or bacterial

infection, which often promotes an alkaline urine pH due to the presence of bacterial 
enzymes converting urea to ammonia. 
 Effects of urine pH on stone formation: 
 Acidic urine  uric acid stones are more likely to form.  
 Alkaline urine  phosphate stones are more likely to form (calcium phosphate 
becomes less soluble at pH>6;). 
 Excretion of ammonium occurs when an acid urine is produced but the pH of u rine is of 
course determined by the concentration of H+ ions.

 Unable to lower the pH to less than 5.5  in type 1 RTA. 
 A pH of above 7.0 after prolonged and severe vomiting would be expected in an att empt to 
compensate for the loss of acid; however when there is extracellular fluid depletion t he 
retention of sodium takes priority.Instead of bicarbonate being excreted it is reabsorbe d in 
the proximal and distal nephron and this perpetuates the metabolic alkalosis until the f luid 
balance is restored with intravenous (IV) fluids.

Disproportionately raised creatinine compared with the urea level leads to suspicion of 
rhabdomyolysis. Additional clue is raised PO4 and K+ & renal failure.  
Disproportionately raised urea compared with creatinine level leads to suspicion of dehydration. 
 
 928

  9   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                   
                                                                                                                                                                                    
 ___________________________________________________ 
Renal investigations:

Renal investigations: 
 The most appropriate an urgent scan to exclude obstruction of the kidneys is 
Ultrasound renal tract 
 Retrograde urethro-graphy is the mainstay of investigation for urethral stricture  
disease  
 Renal scintigraphy with DMSA   
 Involves administration of radioactive isotope (dimercaptosuccinic acid) which is 
taken up by the renal parenchyma.  
 This identify regions of decreased uptake due to  acute inflammation (such as 
pyelonephritis) or renal scarring.

pyelonephritis) or renal scarring. 
 The technique of dimercaptosuccinic acid DMSA scan also allows detection of 
congenital renal disorder. 
 A small kidney with uniform uptake of DMSA is likely to represent congenital 
hypodysplasia, whereas a focal area of reduced cortical uptake associated with loss 
of contours is more likely to represent an infection-related scar. 
___________________________________________________ 
Renal Biopsy

Renal Biopsy   
 The hila of the kidneys lie at the L1 and L2 vertebral levels. 
 For a routine biopsy there is no preferable side to biopsy, but commonly it is the Lt 
Kidney .  
 Coagulation studies should always be performed prior to renal biopsy due to the risk of 
bleeding (e.g. in a case of alcohol excess, clotting studies may be deranged).  
 Macroscopic haematuria  can occur in up to 10% of renal biopsies.

 Nephrectomy is a rare but serious complication of renal biopsy required to control bleeding. 
It should be consented for that.  
Haematuria 
 Haematuria is defined as >3 RBC/high power field (hpf) of centrifuged sediment un der the 
microscope. 
 Non-visible (Microscopic) haematuria is found in around 2.5% of the population.  
 
Causes of transient or spurious non-visible haematuria 
 urinary tract infection

 urinary tract infection 
 menstruation   vigorous exercise (this normally settles after around 3 
days) 
 sexual intercourse  
 
 929

  10   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Causes of persistent n on-visible haematuria 
 cancer (bladder, renal, prostate) 
 stones 
 benign prostatic hyperplasia  prostatitis

 benign prostatic hyperplasia  prostatitis 
 urethritis e.g. Chlamydia  
 renal causes: IgA nephropathy, thin 
basement membrane disease 
 
Spurious causes - red/orange urine, where blood is not present on dipstick 
 foods: beetroot, rhubarb 
 drugs: rifampicin, doxorubicin 
 
what is the pathophysiology of  Exercise-induced hematuria? 
 Extracorpuscular mechanical trauma  causing hemolysis  
 patients present after the event with rust-colored urine. 

 Current evidence does not support screening for haematuria.  
 The incidence of non-visible haematuria is similar in patients taking aspirin/warfarin to the 
general population hence these patients should also be investigated. 
 
Testing 
 urine dipstick is the test of choice for detecting haematuria 
 persistent non-visible haematuria is often defined as blood being present in  2 out of 3 
samples tested 2-3 weeks apart

samples tested 2-3 weeks apart 
 The incidence of non-visible haematuria is similar in patients taking aspirin/warfarin 
to the general population hence these patients should also be investigated as 
normal.  
 renal function, albumin: creatinine (ACR) or protein: creatinine ratio (PCR) and blood 
pressure should also be checked 
 urine microscopy may be used but time to analysis significantly affects the numbe r of red 
blood cells detected

blood cells detected 
 in an elderly presented with  painless macroscopic haematuria . the most important 
thing to exclude after infection would be a bladder tumour initially before embarking upon 
a renal biopsy.  Therefore cystoscopy is the best initial investigation.  
 
NICE urgent cancer referral guidelines  (updated in 2015). 
 Urgent referral (i.e. within 2 weeks)  
 Aged ≥ 45 years AND: 
 unexplained visible haematuria without UTI, or

 unexplained visible haematuria without UTI, or 
 visible haematuria that persists or recurs after successful treatment of UTI. 
 Aged ≥ 60 years AND have unexplained nonvisible haematuria and either dysuria or 
a raised white cell count on a blood test. 
 Non-urgent referral  
 Aged ≥ 60 years with recurrent or persistent unexplained UTI. 
 patients under the age of 40 years with normal renal function, no proteinuria an d who are

normotensive do not need to be referred and may be managed in prima ry care. 
 
 930

  11   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 May 2009 exam: A 62-year-old man with H/O hypertension & AF, on warfarin. A urine

dipstick showed blood + with no protein or leucocytes. This result repeated twice. What 
is the most appropriate action? Cystoscopy  (The incidence of non-visible haematuria is 
similar in patients taking warfarin to the general population therefore these patients sh ould be 
investigated as normal)  
_________________________________________________________ 
Acute interstitial nephritis (AIN) 
 
The rapid onset of renal failure , coupled with a rash and eosinophilia  is highly suspicious

of a diagnosis of interstitial nephritis 
Overview 
 Acute interstitial nephritis is inflammation of the renal tubulo-interstitium, secondary to a 
hypersensitivity reaction to drugs.  
 accounts for 25% of drug-induced acute renal failure 
 An acute allergic reaction with infiltration of immune cells occurs in response to the 
causative drug, causing direct cytotoxicity.  
 The onset of AIN occurs approximately 10-14 days after the initiation of the incitin g agent

and resolves with removal of the offending drug.   
  It is typically  characterized by eosinophilia and eosinophiluria  with elevated levels of 
IgE in the serum suggesting a type I hypersensitivity .  
 AIN may also be caused by type IV hypersensitivity with mononuclear interstitial infiltrate on  
renal biopsy. 
Features 
 fever, rash, arthralgia 
 Eosinophilia and Eosinophiluria.  
 in blood (50%) ,  
 in urine ( 70%) and in renal biopsy.

 in urine ( 70%) and in renal biopsy.  
 eosinophilia is common, and eosinophiluria is pathognomonic  
 Typically, eosinophilia is absent in AIN-induced by NSAIDs  
 mild renal impairment 
 Many patients are not oliguric despite moderately severe acute renal failure. Patients 
with non-oliguric acute renal failure should always be investigated for AIN  
 Proteinuria is dominant, 
 
Causes

Causes 
The drugs that most commonly cause acute interstitial nephritis are proton pump inhibitors , 
penicillins , NSAIDs  and thiazide  diuretics. 
 drugs:  (40-60% of cases of interstitial nephritis are due to drug hypersensitivity).  
 penicillin, rifampicin , cephalosporins, vancomycin, Co-trimoxazole , Sulphonamides  
 NSAIDs, (The most common causative drug) 
 allopurinol,  931

  12   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
   thiazides and furosemide 
 Phenytoin. 
 Ranitidine. Cimetidine .  Omeprazole  
 infection: Hanta virus , staphylococci 
Diagnosis

Diagnosis  
 A definite diagnosis can only be made with renal biopsy , which usually shows 
mononuclear cell infiltrate throughout the interstitium with associated oedema. 
 
Treatment  
 untreated AIN  results in interstitial fibrosis.  
 The mainstay of treatment is to withdraw any drug which may be causative.  The majority 
of patients recover following withdrawal of the offending drug  
 High-dose prednisolone is indicated in some cases to hasten recovery. There is no proof

that corticosteroids are effective in drug-induced AIN  
 Dialysis may be required in severe cases.  
_______________________________________________________ 
Acute kidney injury (AKI)  (previously termed acute renal failure or ARF) 
Nice guideline tells  what increases the risk of AKI : 
1. Emergency surgery, ie, risk of sepsis or hypovolaemia 
2. Intraperitoneal surgery 
3. CKD, ie if eGFR < 60 
4. Diabetes 5. Heart failure 
6. Age >65 years 
7. Liver disease 
8. Use of nephrotoxic drugs

8. Use of nephrotoxic drugs 
 
It also defines the criteria for diagnosing AKI  
 1. Rise in creatinine of 26 micromol/L or more in 48 hours OR 
 2. 50% + rise in creatinine over 7 days OR 
 3. Fall in urine output to less than 0.5ml/kg/hour for more than 6 hours in adults (8 ho urs in 
children) OR 
 4. 25% + fall in eGFR in children / young adults in 7 days. 
Refer to a nephrologist if any of the following apply: 
 1. Renal transplant

 1. Renal transplant 
 2. ITU patient with unknown cause of AKI 
 3. Vasculitis/ glomerulonephritis/ tubulointerstitial nephritis/ myeloma 
 4. AKI with no known cause 
 5. Inadequate response to treatment 
 6. Complications of AKI 
 7. Stage 3 AKI  
 8. CKD stage 4 or 5 
 9. Qualify for renal replacement hyperkalaemia / metabolic acidosis/ complications of 
uraemia/ fluid overload (pulmonary oedema) 932

  13   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Acute tubular necrosis vs. prerenal uraemia

Acute tubular necrosis vs. prerenal uraemia  
 
Pre-renal uraemia Acute tubular necrosis 
Pathology  due to hypoperfusion   due to circulatory compromise 
and/or nephrotoxins  
Urine sodium < 20 mmol/L > 30 mmol/L 
Urine osmolality  >500  <350  
Fractional sodium 
excretion* < 1% > 1% 
Fractional urea excretion** < 35% >35% 
Urine: plasma osmolality > 1.5 < 1.1 
Urine: plasma urea   > 10:1  < 8:1  
urine/plasma creatinine >40 <20 
Specific gravity > 1020 < 1010

Specific gravity > 1020 < 1010 
Urine 'bland' sediment A urine free of 
red blood cells or casts  brown granular casts 
Response to fluid challenge Yes No 
 *fractional sodium excretion = (urine sodium/plasma sodium) / (urine creatinine/pl asma creatinine) x 
100 
 **fractional urea excretion = (urine urea /blood urea ) / (urine creatinine/pl asma creatinine) x 100 
 80-90% Of the acute renal failure seen by physicians will fall into the cat egory of prerenal 
failure or ATN.

failure or ATN. 
 Normal plasma osmolality = 278 – 305 mOsmol/Kg  
 Normal urinary osmolality = 350 – 1000 mOsmol/Kg 
933

  14   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
September 2009 exam: Which test is most useful when determining whether there is

prerenal uraemia or acute tubular necrosis? Urinary sodium  
 
Acute tubular necrosis (ATN) 
Pathological mechanism 
 ATN usually arises following an acute ischaemic or nephrotoxic event  
 in ischemic causes of ATN  the thick ascending limb of the Loop of Henle is injured  
 in nephrotoxic event   the proximal convoluted tubule is affected.

 the injured tubular cells fail to reabsorb sodium, tubular concentrating ability is lost, and  
urea clearance is low   
Causes of ATN include 
 Hypertension: Accelerated hypertension can cause small vessel obstruction with 
proliferative endarteritis of intralobular arteries and fibrinoid necrosis of afferent arterioles 
and glomerular capillary tuft. 
 Rhabdomyolysis 
 Hepatic failure: Renal failure from ATN occurs in 25% of patients with severe hepatic 
damage.

damage. 
 Eclampsia  
 Drugs such as : 
 aminoglycosides ,  
 Aminoglycoside undergoes glomerular filtration and then reabsorption in the 
proximal tubule where  tubular cell injury/death occurs . 
 cephalosporins, 
  cisplatin, 
  amphotericin.   
 Heavy metal poisoning, carbon tetrachloride,  
 Heroin addicts . Associated furosemide is likely to increase the plasma 
concentration of toxic drugs and leads to (ATN).  
 Corticosteroid therapy has not been associated with ATN.

Phases:  (ATN) is characterised by 3 phases:  
1. Initiation phase , with acute decrease in GFR with sudden rise in serum creatinine ± 
oliguria 
2. Maintenance phase , with a sustained marked reduction in GFR and rising Cr (1-2 weeks) 
3. Recovery phase , in which tubular function is gradually restored and urine volume gradually 
rises, with concomitant decrease in Cr to pre-injury levels 
 
Features 
 Oliguria is common in the early stages of acute tubular necrosis (ATN)

 ATN after aminoglycoside  impairment in the concentrating ability, and most 
patients are non-oliguric  934

  15   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
   acute renal failure expected to begin more than five days after  the initiation of gentamicin

 Small amounts of 'tubular' proteinuria (<1 g/day) may be seen, but >3 g suggests a 
glomerular leak  
 Urinalysis often reveals brown granular casts , which are tubular epithelial cells. 
Precautions in management 
 After inappropriate attempts to initiate a diuresis by infusion of normal saline with out 
adequate monitoring of the patient's volume status, pulmonary oedema du e to salt and 
water retention is not uncommon

water retention is not uncommon 
 
 Aminoglycoside nephrotoxicity correlates with  Frequency of aminoglycoside 
dosing   
 
 Multiple human clinical trials (including meta-analysis) studies report less nephrotoxicity and 
equal efficacy when aminoglycosides are given once daily (supratherapeutic doses) rather 
than in conventional divided doses. 
 
Prognosis 
 Oliguria during the initial stages of ATN is followed by polyuria, and even afte r a relatively

minor insult, recovery may take up to 6 weeks 
 Creatinine clearance would be expected to be normal  in only 40% of cases  one year after the 
initial insult.  
 The mortality rate associated with ATN may be up to 50%, but this is largely dependen t on 
the precipitating illness 
 the chance of recovery of renal function to the level where dialysis is not required  
95 % 
 Sepsis, particularly Gram-negative septicaemia , is the most frequent complication

and cause of death in acute renal tubular necrosis while awaiting spontaneous recovery 
of renal function 
Papillary necrosis 
Causes 
 chronic analgesia use (concomitant diuretic use may exacerbate renal hypotension ) 
 sickle cell disease 
 TB 
 acute pyelonephritis 
Features 
 fever, loin pain, haematuria 
 IVU - papillary necrosis with renal scarring - 'cup & spill'

Consequences of ren al papillary necrosis 
 Ureteric obstruction may result if the papillae have sloughed off 
 
 935

  16   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Where there is obstruction,  review by a urologist is advised as ureteric stent placement 
may be required

may be required 
 If there is no obstruction  withdrawal of the offending agent  + adequate hydration  
Acute Pyelonephritis 
 The two peaks of incidence in adults occur in young sexually active women and in men > 
50 years of age  
Aetiology 
 Gram-negative bacilli such as Escherichia coli or Klebsiella  species are responsible in 
more than 95% of cases

more than 95% of cases  
 Unusual organisms may be responsible if there has been a history of urethral 
instrumentation 
 Staphylococcal urinary sepsis is usually indicative of haematological seeding of infection 
Symptoms 
 include fever, rigors, flank pain, dysuria, polyuria, haematuria, nausea and v omiting, 
headache and diarrhea.  The absence of fever rules out acute pyelonephritis  
 In young women with a first infection, urine culture may be all that is required

 Otherwise, work-up includes urea and electrolytes measurement, a full blood count and 
blood cultures, and renal ultrasound in compromised patients 
Treatment 
 trimethoprim or ciprofloxacin 
 Surgical opinion may be required for: 
 recurrent infections  
 evidence of vesicoureteric reflux on scanning   
Acute vs. chronic renal failure

Acute vs. chronic renal failure 
Best way to differentiate is renal ultrasound - most patients with CRF have bila teral small kidneys.  
(normal range for both kidneys 10-12 cm)  
 
Renal size 
Renal size asymmetry in the presence of hypertension and renal impairment suggest 
renovascular disease. 
 
 Small kidneys suggest 
chronic renal failure The usual range of kidney size measured 
longitudinally is between 9-12 cm. 936

  17   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Causes of Large kidneys  (chronic renal failure with normal/enlarged kidneys)  
 Stage 1 diabetic nephropathy

 Stage 1 diabetic nephropathy 
 Hydronephrosis 
 Rapidly progressive 
glomerulonephritis 
 HIV-associated nephropathy   Acromegaly 
 Renal vein thrombosis   
 Adult polycystic kidney disease 
 Scleroderma   
 
Causes of one small kidney  
 Renal arterial disease  
 or chronic renal scarring due to vesico-ureteric reflux   (associated with recurrent UTI )  
Voiding cysto-urethrogram (VCUG) is the investigation of choice to demonstrate 
potential reflux disease

potential reflux disease  
Other features suggesting CRF rather than ARF  
 hypocalcaemia (due to lack of vitamin D) 
 evidence of renal osteodystrophy on plain X-ray  
 skin pigmentation and peripheral neuropathy are the result of long-standing metabolic 
abnormality such as chronic renal failure 
Cholesterol embolization 
Overview  
 cholesterol emboli may break off causing renal disease

 seen more commonly in arteriopaths, abdominal aortic aneurysms 
Features 
 eosinophilia 
 purpura  renal failure 
 livedo reticularis 
 
May 2014 exam:  H /O impaired RFT +  purpuric rash on feet after coronary angiogram is performed 
for acute MI. What is the most likely diagnosis? Cholesterol embolization  (Cholesterol embolisation is 
a well-documented complication of coronary angiography)  
 
Chronic kidney disease (CKD)

Chronic kidney disease (CKD) 
 Impaired renal function for >3 months  based on abnormal structure or function,  
 OR GFR <60mL/min/1.73m2 for >3 months with or without evidence of kidney damage.  
Common causes   
 diabetic nephropathy (Type II  > type I) 
 chronic glomerulonephritis (commonly IgA nephropathy) 
 chronic pyelonephritis 
 adult polycystic kidney disease 
Risk factors 937

  18   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  NICE recommend that screening for chronic kidney disease should be offered to patients 
with: 
 Diabetes 
 Hypertension

with: 
 Diabetes 
 Cardiovascular disease 
 Structural renal tract pathology 
 Multisystem disease with potential renal involvement 
 Opportunistically detected haematuria or proteinuria 
 family history of stage 5 chronic kidney disease, or 
 Hereditary kidney disease. 
 In the absence of other risk factors the guidelines recommend that age, gender a nd 
ethnicity should not be used as risk markers to test people for chronic kidney disease.

 Obesity alone should not be used as a risk factor (features of the metabolic syndrome 
should also be present). 
 
eGFR and classification of CKD  
 
eGFR variables => CAGE => Creatinine, Age, Gender, Ethnicity  
Serum creatinine may not provide an accurate estimate of renal function due to diff erences in 
muscle. For this reason formulas were develop to help estimate the glomerular filtration rate 
(estimated GFR or eGFR). The most commonly used formula is the Modification of Diet in Renal

Disease (MDRD)  equation, which uses the following variables: 
1. serum creatinine 
2. age  ( GFR ↓↓ with age)  3. gender 
4. ethnicity  
 
Factors, which may affect the result 
 muscle mass (e.g. amputees , body-
builders) 
(Ļmuscle mass  overestimation. 
Ĺ muscle mass  underestimation of the 
GFR.)   eating red meat 12 hours prior to 
the sample being taken 
 
 Which advice should be delivered to the patient before the test?    avoid eat any 
meat in the 12 hours before

  19   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 CKD may be classified according to GFR: 
*Proteinuria, haematuria, or evidence of abnormal anatomy or systemic disease.

 One reason to classify renal impairment is to motivate secondary prevention, eg to 
‘mandate ’ ACE-i or ARB if BP >140/85 especially if proteinuria is present or stage ≥3. 
 Symptoms usually only occur once stage 4 is reached (GFR <30).  
 End-stage renal failure (ESRF) is defined as GFR <15 mL/min/1.73m2 or need for renal 
replacement therapy (RRT —dialysis or transplant). 
 A falling GFR is an independent risk factor for cardiovascular disease  this is the

chief cause of death from renal failure.   
 In CKD stages 1 and 2, risk from cardiovascular death is higher than the risk of reaching 
ESRF. 
 Cystatin c  represents a novel marker of estimating GFR 
 Estimating GFR is difficult and notoriously inaccurate. If in doubt, calculate using 24 hour 
creatinine clearance or radioisotope clearance. 
 If GFR is greater than 90 ml/min/1.73 m2 , Which test will indicate Ļ kidney function?  Ĺ 
creatinine more than 20%

creatinine more than 20% 
 If eGFR result is less than 60 ml/min/1.73 m2 in a person not previously tested, what 
is the next step?    Repeat the test within 2 weeks.    
  (GFR) can be estimated from serum creatinine using the modification of diet in rena l 
disease (MDRD). Cystatin C is less influenced by age, gender and muscle mass than 
serum creatinine, and it has been proposed as an alternative marker for (eGFR).

 estimates of GFR become less accurate as the true GFR increases (eGFR values of 
60 ml/min/1.73 m2 or more) 
 The CKD-EPI equation is more accurate than the MDRD Study equation  
 Less bias at eGFR >60  
  performs better in people aged 75 years and over. 
  use of the MDRD Study equation may over-diagnose CKD.  
 
939

  20   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Measuring kidney function  (Nice guidelines 2014)  
Creatinine-based estimate of GFR Cystatin C-based estimate of GFR

 avoid meat in the 12 hours before the 
test  
 Avoid delaying the blood sample (used 
within 12 hours of venipuncture). 
 
 use the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI)  
 Apply a correction factor to GFR values  
for African-Caribbean (multiply eGFR by 
1.159). 
  less reliable in: 
 acute kidney injury 
 pregnancy  
 oedematous states 
 muscle wasting disorders 
 malnourished  
 amputation 
 certain ethnic groups (eg: Asian

 certain ethnic groups (eg: Asian 
family origin).   have a higher specificity for significant 
disease outcomes than those based on 
serum creatinine.  
 When an improved assessment of risk 
is needed, the CKD-EPI cystatin C 
equation should be used to estimate 
GFR cystatin C 
 eGFR cystatin C  Ĺ in hypothyroidism 
&  Ļ in hyperthyroidism 
 
When to use a cystatin C-based estimate of GFR for diagnosis of CKD (Nice 2014)

 If eGFR creatinine is 45 –59 ml/min/1.73 m2, sustained for at least 90 days +  no proteinuria  
(albumin: creatinine ratio [ACR] less than 3 mg/mmol) or othere marker of CKD   do 
eGFR cystatin C , if it is more than 60 ml/min/1.73 m2  rule out CKD 
 
GFR vs creatinine level: 
 normal creatinine in an elderly patient is not indicative of normal renal function because  
serum creatinine does not increase due to age related muscle loss

 this may explain same creatinine levels with deferent GFR in some patients  
 (eGFR) is more accurate . 
 
January 2010 exam: Which factor is most likely to invalidate the use of the Modification of Diet  in 
Renal Disease (MDRD) equation to calculate a patients eGFR? Pregnancy  
 
May 2012 exam: Which factor is most likely to explain unexpectedly low result of eGFR? Large 
muscle mass secondary to body building  
 
Consequences of CKD

Consequences of CKD   
 Hypocalcaemia: secondary to reduced levels of 1,25(OH) 2 vitamin D  
 CKD  failure of the 1α -hydroxylation of vitamin D to form 1,25 
dihydroxycholecalciferol  (a step that usually occurs in renal tubular cells ) 940

  21   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 ↓↓1,25(OH) 2 vitamin D   ↓↓calcium absorption from the gut, which is often

exacerbated by poor oral intake of calcium in patients with CKD. 
 The kidneys are responsible for converting inactive vitamin D (25-
hydroxycholecalciferol) to its active form 1,25-dihydroxycholecalciferol via the 
enzyme 1-alpha-hydroxylase.  
 Serum alkaline phosphatase is raised  when renal osteodystrophy develops, specifically 
the bone isoenzyme rather than the liver form. 
 Hyperphosphataemia PO(4) ↑↑ :Reduced glomerular filtration rate results in reduced 
phosphate excretion.

phosphate excretion.  
 Dialysis is able to remove only about half of the phosphate that the healthy 
kidney would be able to do. 
 The healthy adult kidney excretes 5400 mg per week  of phosphate. 
 the maximum amount of phosphate that can be removed by dialysis in a 
patient with anuric renal failure who is dialysis dependent is 2700 mg / week.  
 calcium containing phosphate binder  such as calcium acetate  is the most

appropriate initial  treatment . In conjunction with dietary phosphate restriction this 
will help reduce the plasma phosphate. 
 calcium acetate should be taken with meals 
 the additional calcium in calcium acetate may be sufficient to increase t he 
plasma calcium into the normal range. 
 Aluminium hydroxide and sevelamer are both phosphate binders - whilst they wo uld 
help correct the elevated phosphate they would not have any impact on th e low 
calcium.

calcium. 
 Secondary hyperparathyroidism : hyperphosphataemia and hypocalcaemia  ↑↑ 
parathyroid hormone (secondary hyperparathyroidism)  renal osteodystrophy. 
 Secondary hyperparathyroidism arises in established renal failure due lack of vitamin 
D production and reduced ability to absorb and retain calcium. 
 Causes of ↑↑  (PTH) in CKD include: 
1. hypocalcaemia 
2. impaired 1,25-dihydroxyvitamin D production by the diseased kidneys 
3. hyperphosphataemia

3. hyperphosphataemia  
 In most patients on dialysis , the primary bone disease is osteitis fibrosa cystica , 
a disease of increased bone resorption caused by elevated PTH levels related 
to low levels of vitamin D and hyperphosphataemia.  
 Slightly elevated parathyroid hormone level is actually desirable in the managem ent 
of renal bone disease. Suppression is not generally necessary until levels exceed 
300 ng/L. 
 Reduced tubular secretion of urate

300 ng/L. 
 Reduced tubular secretion of urate  
 Hyperkalaemia is a classical finding due to metabolic acidosis and decreased glomerular 
filtration rate. 941

  22   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Metabolic acidosis  is a result of bicarbonate wasting and reduced ammonia and acid 
excretion.

excretion. 
 Hypertension  is seen due to sodium and water overload and direct renal effects secondary 
to the underlying renal disease. 
 Anaemia:  decreased erythropoietin production, low grade haemolysis, inadequate intake 
 Hypertriglyceridaemia:  decreased plasma lipoprotein lipase activity 
 Pericarditis and cardiomyopathy : uraemia leads to exudation of fibrin onto the 
epicardial and pericardial surfaces . 
 Glucose intolerance : tissue insulin resistance.

 Increased skin pigmentation  
 Extra-skeletal calcification:  Prolonged treatment with vitamin D (hence hypercalcaemia 
and hyperphosphataemia) increases  
 
chronic renal failure and hypocalcaemia with a raised parathyroid hormone (PTH)  
secondary hyperparathyroidism. 
 
Chronic renal failure leads to hyperphosphataemia, which triggers release of parathyroid 
hormone. 
 
Studies such as UKPDS reveal that:

hormone. 
 
Studies such as UKPDS reveal that: 
 improving glycaemic control  would reduce microvascular complications but this has 
no significant impact upon cardiovascular morbidity and mortality.  
 lowering blood pressure  significantly reduced morbidity from both microvascular and 
macrovascular disease. 
__________________________________________________________ 
Chronic kidney disease: hypertension 
 Hypertension is both a cause and consequence of chronic kidney disease.

 Pathogenesis of hypertension caused by CKD is multifactorial. It is caused by:  
 Increased intravascular volume (due to reduced glomerular filtration) 
 Excessive activity of the renin angiotensin system 
 Increased activity of the sympathetic nervous system 
 Endothelial dysfunction, and 
 Other neural and humoral factors. 
 The majority of patients with (CKD) will require more than two drugs to treat hypertension.

 ACE inhibitors  are first line and are particularly helpful in proteinuric renal disease (e.g. 
diabetic nephropathy).  942

  23   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  As these drugs tend to reduce filtration pressure a small fall in glomerular filtration

pressure (GFR) and rise in creatinine can be expected.  
 NICE suggest that a decrease in eGFR of up to 25% or a rise in creatinine of up 
to 30% is acceptable , although any rise should prompt careful monitoring and 
exclusion of other causes (e.g. NSAIDs). A rise greater than this may indicate 
underlying renovascular disease.   
 Furosemide  is useful as a anti-hypertensive in patients with CKD, particularly when

the GFR falls to below 45 ml/min*.( *the NKF K/DOQI guidelines suggest a lower cut-off of less than 
30 ml/min )  
 It has the added benefit of lowering serum potassium.  
 High doses are usually required.  
 If the patient becomes at risk of dehydration (e.g. Gastroenteritis) then consideration 
should be given to temporarily stopping the drug  
_____________________________________________________ 
Chronic kidney disease: proteinuria

Chronic kidney disease: proteinuria 
 Microalbuminuria is defined as a urine albumin excretion of between 30-300 mg per 
24 hours.  
 A concentration above 300 mg/24 hours signifies albuminuria and a concentration ab ove 
3.5 g/24 hours signifies overt proteinuria. 
 Proteinuria is an important marker of chronic kidney disease, especially for diabetic 
nephropathy. 
  NICE recommend using the albumin: creatinine ratio (ACR) in preference to the protein:

creatinine ratio (PCR) when identifying patients with proteinuria as it has greater sensitivity.  
 For quantification and monitoring of proteinuria, PCR can be used as an alternativ e, 
although ACR is recommended in diabetics. 
  Urine reagent strips are not recommended unless they express the result as an ACR 
 In the presence of mild to moderate hypertension, proteinuria indicates either unde rlying 
renal disease or renovascular disease . 
 NICE guidelines recommend BP target range:

 NICE guidelines recommend BP target range: 
 CKD patient who have proteinuria equivalent to ACR ≥70 mg/mmol  120-129/<80  
mmHg. The same target range should be used in patients with diabetes.  
 Non-diabetic patients with CKD and an ACR <70 mg/mmol  120-139/<90  mmHg  
 
Approximate equivalent values  
 
 Average individuals pass around 10mmol urinary creatinine each day. Therefore: 
 U PCR 50 = 500mg protein/day  
 U PCR 100 = 1000mg protein/day  
943

  24   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  a 24 hour urinary protein collection of 1g is therefore approximately equivalent to urina ry 
PCR of 100 mg/mmol.

PCR of 100 mg/mmol. 
 
Collecting an ACR sample  
 by collecting a 'spot' sample it avoids the need to collect urine over a 24 hour perio d in 
order to detect or quantify proteinuria 
 should be a first-pass morning urine specimen 
 if the initial ACR is greater than 30 mg/mmol and less than 70 mg/mmol, confirm by a 
subsequent early morning sample. If the initial ACR is greater than 70 mg/mmol a repeat 
sample need not be tested 
Interpreting the ACR results

Interpreting the ACR results 
 in non-diabetics  an ACR greater than 30 mg/mmol is considered clinically significant 
proteinuria 
 in diabetics  microalbuminuria (ACR greater than 2.5 mg/mmol in men and ACR greater 
than 3.5 mg/mmol in women) is considered clinically significant. 
 An elevated albumin- to-creatinine ratio should be confirmed with at least two additional 
tests performed over the subsequent 3 to 6 months, with confirmation of the di agnosis

requiring at least 2 of 3 positive samples .  
 
 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockres (ARBs)  
  ACEi and ARBs reduce intra-glomerular pressure  by inhibiting angiotensin II ̶ 
mediated efferent  arteriolar vasoconstriction. 
 Also have a proteinuria-reducing effect, which is independent of their 
antihypertensive effect. 
 reduce the breakdown of bradykinin (an efferent arteriolar vasodilator);

 restore the size and charge selectivity to the glomerular cell wall (GCW);  
 reduce the production of cytokines, such as transforming growth factor –beta (TGF-
beta), that promote glomerulosclerosis and fibrosis. 
 Spironolactone   
 The most likely therapy to reduce proteinuria after ACEi 
 Even if serum K is 5.2 mmol 
 Addition of aldosterone antagonist therapy to ACE inhibition further impacts to 
reduce proteinuria in diabetic renal disease.

reduce proteinuria in diabetic renal disease.  
 It may however worsen hyperkalaemia, and for this reason close monitoring of urea 
and electrolytes is required after commencing therapy. 
 A small reduction in glomerular filtration rate (GFR) is also seen during the first 12 
weeks after commencement of therapy. 
 
 944

  25   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 ___________________________________________________ __________ 
Diabetic nephropathy (See Endocrinology system)

Diabetic nephropathy (See Endocrinology system)  
___________________________________________________ __________ 
Chronic kidney disease: anaemia 
 normochromic normocytic anaemia  
 becomes apparent when the GFR is less than 35 ml/min (other causes of anaemia sho uld 
be considered if the GFR is > 60 ml/min).  
 Anaemia in CKD predisposes to the development of left ventricular hypertrophy - 
associated with a three fold increase in mortality in renal patients

Causes of anaemia in renal failure  
 reduced erythropoietin levels - the most significant factor 
 reduced erythropoiesis due to toxic effects of uraemia on bone marrow 
 reduced absorption of iron 
 anorexia/nausea due to uraemia 
 reduced red cell survival (especially in haemodialysis) 
 blood loss due to capillary fragility and poor platelet function 
 stress ulceration leading to chronic blood loss 
 The tubing of dialysis equipment causes continued low level blood loss

NICE guidelines 2015 :  Diagnostic tests to determine iron status and predict response to 
iron therapy in anaemia with CKD 
 Do it every 3 months  (1–3 months for people receiving haemodialysis). 
 Use percentage of hypochromic red blood cells (% HRC ; more than 6%), but only if 
processing of blood sample is possible within 6 hours. 
 If using % HRC  is not possible, use reticulocyte Hb content ( CHr; less than 29 pg)

 If these tests are not available or the person has thalassaemia or thalassaemia trait, use 
a combination  of transferrin saturation (less than 20%) and serum ferritin measurement 
(less than 100 micrograms/litre). [new 2015]  
 Do not request transferrin saturation or serum ferritin measurement alone  to assess 
iron deficiency status in people with anaemia of CKD. [new 2015]  
  
 It is important to correct anaemia, as it leads to ventricular hypertrophy, which increases the

cardiovascular morbidity and mortality. 
 NICE guidelines suggest a target haemoglobin of 10 - 12 g/dl 
 determination and optimisation of iron status should be carried out prior to the 
administration of erythropoiesis-stimulating agents (ESA). Many patients, especially those 
on haemodialysis, will require IV iron 
 If there is iron depletion, I.V  iron  transfusion  will be the most appropriate next step

 Once iron stores are restored and ferritin is in the normal range, if the patient is still 
anaemic then erythropoietin would be the next appropriate option 
 It is imperative that renal patients avoid repeated blood transfusion, unless in extremis, so 
that future renal transplantation will not be precluded by allo-sensitisation. 945

  26   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  If patient is exhibiting  symptoms and signs of severe anaemia, i.e. angina , the

treatment of choice is an urgent blood transfusion. If the patient did not have 
symptoms  the correct answer would be subcutaneous erythropoietin and intravenous iron. 
 ESAs such as erythropoietin and darbepoetin should be used in those 'who are likely t o 
benefit in terms of quality of life and physical function' 
 When receiving erythropoetin therapy, it is important to note that over-correction  of a low 
haemoglobin can have harmful effects such as cardiovascular problems and

thrombophlebitis. 
 
Targets for treatment  
 Hb :  maintain Hb range between 100 and 120 g/litre ( 10 - 12 g/dl ) (NICE 2015)  
 Ferritin :  
 in pre-dialysis and peritoneal dialysis patients   >100 μg/L,  
 in haemodialysis patients >200 μg/L  
 ferritin level maintained at 200-500 μg/L 
 NICE 2015  should not rise above 800 micrograms/litre (review the dose of 
iron when serum ferritin levels reach 500 micrograms/litre) 
 Transferrin saturation >20% 
 haematocrit <33%.

 haematocrit <33%. 
 percentage hypochromic red cells <6%. 
Chronic kidney disease: bone disease  
Renal osteodystrophy  (ROD) 
 consists of a mixture of osteomalacia, hyperparathyroid bone disease (osteitis fibrosa), 
osteoporosis and osteosclerosis 
 Pathogenesis of osteomalacia in renal osteodystrophy 
 Diminished activity of renal 1- α-hydroxylase    failure of converting

cholecalciferol to its active metabolite 1,25-dihydroxy-cholecalciferol  ↓ intestinal 
absorption of calcium  hypocalcaemia, hyperphosphataemia and stimulation of the 
parathyroid glands 
 The gold standard for the diagnosis and classification of ROD is bone biopsy   
 The preferred site of biopsy is 2 cm posterior and 2 cm inferior to the anterio r iliac 
crest. 
Metastatic calcification in CRF  
 mainly due to calcium phosphate deposition,

 mainly due to calcium phosphate deposition,  
 Increased prevalence with time on haemodialysis 
 CRF managed with dialysis is the commonest cause of secondary oxalosis  (acute arthritis 
of small joints with digital calcific deposits).  
 
 Aims 
 reduce hyperphosphataemia 
 reduce PTH level 946

  27   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  medications 
 phosphate binders 
 vitamin D 
 Phosphate binders 
 aluminium containing binders are no longer used

 calcium based binders much more common 
 problem is vascular calcification 
 non-calcium based agents currently being developed 
 
Calciphylaxis 
 Calciphylaxis is a rare complication of end-stage renal failure. The underlying mechanism is 
not clear  
 Results in deposition of calcium within arterioles causing microvascular occlusion and 
necrosis of the supplied tissue.

necrosis of the supplied tissue.  
 most commonly affects the skin and presents with painful necrotic skin lesions.  
 The risk of developing calciphylaxis is linked with hypercalcaemia, hyperphophataemia and  
 Warfarin is widely reported as causing/exacerbating calciphylaxis in high risk patients, 
however the underlying mechanism is not known.  
 Treatment focuses on: 
  reducing calcium and phosphate levels 
 controlling hyperparathyroidism

 controlling hyperparathyroidism  
 avoiding contributing drugs such as warfarin and calcium containing compounds. 
should People with CKD in the following groups (Nice 2014) :  Referral criteria - CKD 
be referred for specialist assessment: 
 GFR less than 30 ml/min/1.73 m2 (GFR category G4 or G5), with or without diabetes 
 ACR 70 mg/mmol or more, unless known to be caused by diabetes and already 
appropriately treated

appropriately treated 
 ACR 30 mg/mmol or more (ACR category A3), together with haematuria 
 sustained decrease in GFR of 25% or more, and a change in GFR category or sustained 
decrease in GFR of 15 ml/min/1.73 m2 or more within 12 months 
 hypertension that remains poorly controlled despite the use of at least 4 antihypertensive  
drugs at therapeutic doses. 
 known or suspected rare or genetic causes of CKD 
 suspected renal artery stenosis. 
 
 947

  28   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
CKD –management  (Nice 2014)  
 BP control:  
 aim for

 aim for  
 Patient with CKD < 140/90  
 Patient with CKD + DM or ACR ≥ 70  mg/mmol < 130/80 
 Do not offer a combination of renin –angiotensin system antagonists to people with 
CKD. 
 measure serum potassium & GFR before starting renin –angiotensin system 
antagonists. Repeat these measurements between 1 and 2 weeks after starting 
renin –angiotensin system antagonists and after each dose increase.

 If pretreatment serum potassium > 5.0 mmol/litre  Do not offer renin –angiotensin 
system antagonist 
 Stop renin –angiotensin system antagonists if the serum potassium ≥ 6.0  mmol/litre  
 If there is ↓eGFR or ↑creatinine after starting or increasing the dose of renin –
angiotensin system antagonists, but it is less than 25% (eGFR) or 30% (serum 
creatinine) of baseline:  
 repeat the test in 1 –2 weeks.  
 Do not modify the renin –angiotensin system antagonist dose if the change is

less than 25% (eGFR) or 30% (serum creatinine) of baseline 
 If the eGFR change is 25% or more, or the change in serum creatinine is 30% 
or more: 
i. Check other cause for the deterioration in renal function  such as 
volume depletion or concurrent medication (for example, NSAIDs) 
ii. if no other cause for the deterioration in renal function is found, stop the 
renin –angiotensin system antagonist or reduce the dose 
iii. add an alternative antihypertensive if required.

 Consider apixaban in preference to warfarin in people with a confirmed eGFR of 30 –
50 ml/min/1.73 m2 and non-valvular atrial fibrillation who have 1 or more of the following risk 
factors: 
 prior stroke or transient ischaemic attack 
 age 75 years or older 
 diabetes mellitus 
 symptomatic heart failure. 
 Bone metabolism and osteoporosis 
 Measure serum calcium, phosphate and PTH concentrations in people with a GFR of 
less than 30 ml/min/1.73 m2

less than 30 ml/min/1.73 m2 
 vitamin D deficiency  colecalciferol or ergocalciferol 948

  29   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  If vitamin D deficiency has been corrected and symptoms of CKD –mineral

and bone disorders persist, offer alfacalcidol (1-alpha-hydroxycholecalciferol) 
or calcitriol (1- 25-dihydroxycholecalciferol) 
  raised serum phosphate   Sevalamer  
 Sevalamer is a non-aluminium containing phosphate binder 
 Aluminium hydroxide was previously the drug of choice, but due to 
concern about accumulation of aluminium, leading to possible 
aluminium related dementia, it has now fallen out of favour. 
 management of metabolic acidosis

 management of metabolic acidosis 
 Consider oral sodium bicarbonate supplementation for people with both: 
 a GFR less than 30 ml/min/1.73 m2 (GFR category G4 or G5)  and 
 a serum bicarbonate concentration of less than 20 mmol/litre. 
 
Prescribing in patients with renal failure 
Questions regarding which drugs to avoid in renal failure are common 
 
Drugs to avoid in renal failure

Drugs to avoid in renal failure  
 antibiotics: tetracycline, nitrofurantoin 
 NSAIDs 
 NSAIDs reduce glomerular perfusion by inhibiting production of prostaglandins which 
dilate the afferent arteriole of the glomerulus. The reduction in blood supply to the 
kidney results in impairment of kidney function. 
 Thus, the most likely cause of renal decline is prostaglandin related.  
 NSAIDs can also cause an interstitial nephritis but this is often accompanied by a

nephrotic syndrome-like picture.  
 lithium 
 metformin 
Drugs likely to accumulate in chronic kidney disease  - need dose adjustment 
 most antibiotics including penicillins, cephalosporins, vancomycin, gentamicin, streptomy cin 
 digoxin, atenolol 
 furosemide 
 opioids 
 Alfentanil, buprenorphine  and fentanyl are the preferred opioids in patients 
with chronic kidney disease.

with chronic kidney disease. 
Drugs relatively safe  - can sometimes use normal dose depending on the degree of chronic 
kidney disease 
 antibiotics: erythromycin, rifampicin 
 diazepam 
 warfarin  
 Omeprazole  is principally dependent upon hepatic clearance and safe even with 
marked renal impairment. 
___________________________________________________ __________ 949

  30   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Erythropoietin 
 Erythropoietin is a haematopoietic growth factor that stimulates the production of 
erythrocytes.

erythrocytes.  
Sources of Erythropoietin 
 interstitial fibroblasts in the kidney (predominant during adulthood) 
 perisinusoidal cells in the liver (predominates in the fetal period) 
 Exogenous erythropoietin, or recombinant human erythropoietin (rhEPO), is produ ced 
by recombinant DNA technology . 
 
The main uses of erythropoietin  are  
 to treat the anaemia associated with chronic kidney disease 
 The best option to relieve fatigue in patient with end stage renal failure is

Treatment of  anaemia with erythropoietin   
 Improvement in haemoglobin level results in the increased well-being and 
better appetite.  
 Anaemia associated with cytotoxic therapy. 
 Prevention of anaemia in premature babies with low birth weight.  
Side effects of erythropoietin 
 accelerated hypertension  headache, 
encephalopathy & seizures (BP  ↑↑ in 
25%)  
 ischaemic stroke 
 bone aches 
 skin rashes, urticaria

 skin rashes, urticaria 
 pure red cell aplasia (PRCA)  raised PCV thrombocythaemia  Ĺ risk 
of thrombosis (e.g. Fistula) 
 iron deficiency 2nd to increased 
erythropoiesis 
 anaphylaxis 
 Hyperkalaemia in uraemic patients 
 Ĺmortality of patients with 
malignancy (e.g. renal cell 
carcinoma)  
 
Causes of response failure to erythropoietin therapy: 
 iron deficiency 
 inadequate dose 
 concurrent infection/inflammation 
 hyperparathyroid bone disease

 hyperparathyroid bone disease 
 aluminium toxicity  : if suspected, perform a 
desferrioxamine test 
 folate deficiency   marrow fibrosis 
 development of antibodies against 
the treatment 
 ESA-induced PRCA 
 testosterone deficiency in males 
 poor compliance 
 
ESA induced pure red cell aplasia (PRCA) 
 due to antibodies against erythropoietin 
 Indicated by a low reticulocyte count, together with anaemia and the presence of 
neutralising antibodies.

neutralising antibodies.  
 Confirmed by presence of anti-erythropoietin antibodies together with a lack of p ro erythroid 
progenitor cells in the bone marrow 950

  31   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  the risk is greatly reduced with  darbepoetin  
 
Treatment protocol

Treatment protocol  
 Ideally, before starting EPO in renal patients you should get their haematinics (iron, B1 2, 
folate) to ensure they are replete of all. If any are found to be low they shou ld be replaced. 
 Parameters commonly measured to assess iron status are: serum ferritin and transferrin 
saturation. 
 Both are indirect measures of iron and frequently do not permit an assessment of the 
adequacy of iron supply to the erythron.

adequacy of iron supply to the erythron.  
 direct measures by flow cytometry, cell volume and hemoglobin concentration can 
be measured in individual red blood cells and reticulocytes, using two parameters ( 
particularly useful in identifying iron-deficient erythropoiesis). 
 The percentage of hypochromic erythrocytes  (defined as red blood cells 
with a hemoglobin concentration of less than 28 g/dl)  
  the content of hemoglobin in reticulocytes (CHr)

 If there is Iron deficiency (NICE 2015) 
 For patient on haemodialysis or ESA  I.V iron therapy. 
 For patient not on haemodialysis  trial of oral iron  
 If they are intolerant of oral iron or target Hb levels are not reached within 3 
months   intravenous iron therapy.  (part 2 Exam July 2002)  
 offer maintenance iron to people with anaemia of CKD who are receiving ESAs  
 haemodialysis patients will need the equivalent of 50 –60 mg intravenous iron per

week (1 mg/kg/week). [NICE 2015] 
 If Ferritin is below the recommended level of  200 for patients receiving erythropoietin 
treatment  iron supplementation is recommended.  
 GI absorption of iron is suboptimal in patients with renal failure, and IV replacement 
is therefore the preferred intervention. 
 Erythropoietin is given subcutaneously at a dose of 25-50 U/kg three times per week 
 The blood pressure, haemoglobin and reticulocyte count should be monitored ev ery 2 
weeks

weeks  
 erythropoiesis-stimulating agent (ESAs): dose and frequency  
 adjusted to keep the rate of Hb increase between 10 and 20 g/litre/month.   
 Adjusting ESA treatment  
  if ACEi & ARB are used, an increase in ESA therapy should be considered.  
 
ferritin should be >200g/l in patients treated with EPO. 
 
Significance of erythropoietin levels (EPO test) 
 Low serum erythropoietin levels suggest  polycythaemia vera 
 raised serum erythropoietin level suggests   
 hypoxic cause

 hypoxic cause  
  autonomous production of erythropoietin (as in renal carcinoma). 
 erythropoietin abuse (Erythropoietin has been misused as a performance-
enhancing drug by some athletes ) 
 
May 2010 exam : H/O CKD patient started on erythropoietin. What is the main benefit of 
this treatment? Improved exercise tolerance  951

  32   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Erythropoietin can be detected in urine for few weeks after the latest dose 
 
Renal replacement therapy

Renal replacement therapy 
 
 Patients usually begin dialysis when their glomerular filtration rate (GFR) reaches 10 
ml/minute or 15 mL/minute if they are diabetic. 
Indications for dialysis  
 Refractory pulmonary oedema 
 Persistent hyperkalaemia (K+ >7mmol/L) 
 Severe metabolic acidosis (pH<7.2 or base excess <10) 
 Uraemic complications such as  
 encephalopathy or 
 Uraemic pericarditis (pericardial rub) 
 Uraemic peripheral neuropathy

 Uraemic peripheral neuropathy  
 Drug overdose —BLAST: Barbituates, Lithium, Alcohol (and ethylene glycol), Salicylates, 
Theophyline, 
 
Arterio-venous fistula is the first choice of vascular access for dialysis.  
 
Haemodialysis (HD)   
Assessment of haemodialysis adequacy: 
The adequacy of haemodialysis session is best measured by : 
  'Clearance' is used to indicate dialysis adequacy, and most commonly the clearance of  
urea is used.

urea is used. 
 Clearance is the ratio of removal rate to blood concentration.  
 Removal rate can be measured by sampling blood on either side of the dialyser and 
multiplying the difference by the inflow rate.  
 Clearance is the removal rate divided by the inflow concentration. 
  However, this only provides a measure of dialysis at one point in time .  
 The adequacy of an entire haemodialysis session  is best measured by the fall in solute

concentration from before dialysis to after.   
 This is calculated using complex equations and is expressed as Kt/V.  
 The current recommendation for adequate dialysis for three treatments per week are  
a Kt/V of 1.2.  
 (the 'urea reduction ratio').A more crude assessment of the adequacy of dialysis obtained 
by noting the magnitude of the decrease in blood urea concentration  
952

  33   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  It is standard practice in the UK to take biochemical and haematological measurements

before and after haemodialysis sessions at regular intervals (monthly in hospital HD 
patients and at least 3 monthly in home HD patients). Adequate HD is indicated by: 
 pre-dialysis serum bicarbonate levels of 18-24 mmol/L, 
  potassium 4.0-6.0 mmol/L,  
 phosphate 1.1-1.7 mmol/L,  
 calcium and albumin within normal range.  
Pre and post- dialysis values: 
 . A high pre-dialysis or inter-dialysis blood pressure may be related to:

 excessive sodium and water ingestion during the inter-dialysis period  
 or a high dialysate sodium level, 
 A high post-dialysis blood pressure may reflect inadequate achievement of dry weigh t. 
  Volume and blood pressure are linked and it is therefore important to optimise 
ultrafiltration and dry weight to control blood pressure.   
 A patient ’s dry weight is their normal weight when they are not fluid overloaded, also 
called euvolemia

called euvolemia 
 The rate of ultrafiltration  depends upon the porosity of the membrane and the 
hydrostatic pressure of the blood, which depends upon blood flow. This is very 
effective in removal of fluid and middle-sized molecules, which are thought to cause  
uremia.   
 Weight gain between dialyses of more than 4.8% is associated with increased mortality . 
 The combination of high pre- and post-dialysis blood pressure, and high pre-dialysis

potassium, indicate that the patient is receiving inadequate dialysis. 
 Both procedural issues (insufficient blood flow rate, dialysis time and frequency  
and needle size) and access issues should be addressed.  
 If these fail to improve the situation a different dialysis modality should be 
considered, such as more frequent or sustained haemodialysis.  
 It is recommended that pre-dialysis haemoglobin concentration should be maintained  
between 100-120 g/L.

between 100-120 g/L. 
 If his haemoglobin below the recommended level for a dialysis patient, you need  to 
measure haematinics initially prior rather than jumping in with EPO treatment. 
  Many haemodialysis patients are iron deplete, and in these cases intravenous iron 
is indicated rather than EPO in the first instance.  
 
Adverse effects of dialysis 
 Modem techniques of dialysis preclude chances of vitamin D or calcium deficiency, fluid

and electrolyte imbalance or risk of viral hepatitis 
 protein-calorie malnutrition is seen in up to 50% of patients   953

  34   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Dietary restriction of foods with high phosphate content (milk, eggs and cheese),

decreased protein intake, anorexia, nausea and vomiting, may all contribute to this 
condition 
 
Complications of rapid haemodialysis 
 Disequilibrium syndrome :  
 Caused by cerebral oedema, resulting from the rapid shifts of uraemic toxins 
associated with too-rapid haemodialysis in a severely uraemic patient  
 characterized by weakness, dizziness, headache, and in severe cases, mental 
status changes.  
 The diagnosis is one of exclusion;

 The diagnosis is one of exclusion;  
 a prime characteristic of this syndrome is that it is nonfocal.  
 
Long -term haemodialysis 
 associated with carpal tunnel syndrome this is due to beta-2 microglobulin 
deposition 
 Cardio-vascular disease is the commonest cause of death (50%) in dialysis patients 
 Carnitine deficiency  
 Patients on chronic hemodialysis may have carnitine deficiency.  
 Carnitine is essential for the transport of long-chain fatty acids from the cytosol into

the mitochondria.  
 chronic hemodialysis  carnitine deficiency  Impaired mitochondrial 
transport of long-chain fatty acids 
 Cardiomyocytes and skeletal muscle cells extensively use fatty acids as a fuel.  
 Carnitine deficiency leads to: 
 accumulation of long-chain fatty acids in the cytosol of cardiomyocytes 
(resulting in cardiac fatty change and cardiomegaly ) 
 accumulation of long-chain fatty acids in the cytosol of skeletal muscle cells 
(resulting in muscle cramps ).

(resulting in muscle cramps ).  
 Treatment  is via L-carnitine administration. 
 
Indications of Catheter removal : 
 Staphylococcus  aureus  bloodstream infection  
 Methicillin-resistant Staphylococcus aureus (MRSA) infection  
 vancomycin is the drug of choice  
 non-staphylococcus aureus catheter-related bloodstream infection in the following 
circumstances:  
 Severe sepsis 
 Haemodynamic instability 
 Endocarditis 
 Evidence of metastatic infection, or

 Evidence of metastatic infection, or 
 Persistence of bacteraemia after 48-72 hours of effective antibiotics. 
 954

  35   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Dialysis amyloidosis 
Aetio-pathogenesis  
 Occurs due to the failure of clearance of B2-microglobulin

 This protein, the light chain of class-1 HLA antigens, is usually freely filtered at th e 
glomerulus but is not cleared by cellulose-based dialysis membranes 
 There is resulting amyloid deposition within the synovium 
Clinical features: Amyloid deposition within the synovium results in:  
 clinical syndrome of median nerve compression  
 pain and stiffness in multiple joints  
Treatment & Prognosis 
 The syndrome resolves slowly after renal transplantation,

 some benefit is seen in switching patients to dialysis with a biosynthetic dialysis membrane 
Complications: 
 gastrointestinal haemorrhage caused by amyloid deposition around submucosal bloo d 
vessels   
Peritoneal dialysis 
 Peritoneal dialysis (PD) is a form of renal replacement therapy. It is sometimes used as a 
stop-gap to haemodialysis or for younger patients who do not want to have to v isit hospital 
three times a week.

three times a week. 
 The majority of patients do Continuous Ambulatory Peritoneal Dialysis (CAPD), which 
involves four 2-litre exchanges/day. 
 Peritoneal dialysis-associated peritonitis 
 sclerosing peritonitis 
 Adynamic bone disease (ABD) 
Peritoneal dialysis-associated peritonitis  
 Causes:  
 The most common cause  coagulase-negative staphylococci  such 
as Staphylococcus epidermidis (40-50% of cases) .  
 another common cause   Staphylococcus aureus

 is made by peritoneal fluid cell count ( neutrophils above 100/ml ).( White cell count 
> 100/mm3 in PD fluid sample )  
 PD fluid neutrophil percentage of greater than 50% is in keeping with PD peritonitis. 
 intraperitoneal antibiotics  (vancomycin) And oral quinolone (Before culture results 
are received).  
 the initial treatment of choice would be intraperitoneal antibiotics.  
 initial antibiotic regimes should cover Gram positive (including MRSA) and

Gram negative organisms. 
 Give intra-peritoneal vancomycin and gentamicin  
  Intravenous antibiotics  would be preferable if the clinical condition  worsened 
despite intraperitoneal antibiotics,  
 Recurrent Staph, epidermidis peritonitis may necessitate removal and 
replacement of the peritoneal dialysis catheter due to chronic colonisation   955

  36   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Adynamic bone disease (ABD)   (low bone turnover )

 Definition :  (ABD) is a variety of renal osteodystrophy characterized by reduced osteblasts 
and osteoclasts, no accumulation of osteoid and markedly low bone turnover ( ↓bone 
formation and resorption).  
 Distinguish ABD from the second low-turnover form, i.e. osteomalacia:  
 In ABD : Both the rate of collagen synthesis by osteoblasts and the subsequent 
mineralization of bone collagen are subnormal. there are few or no osteoblasts

 In osteomalacia : mineralization defect exceeds the defects in bone formation, 
resulting in a relative osteoid excess.  
 Bone alkaline phosphatase (BAP) is the single most useful biochemical parameter 
for the assessment of bone formation.  
 ↑↑  BAP exclude ABD  
 elevations of BAP along with total AP may be seen in severe osteomalacia. 
 Risk factors & Causes : overtreatment of secondary hyperparathyroidism associated with 
CKD  
(ABD is, at least in part, often iatrogenic)

(ABD is, at least in part, often iatrogenic)  
 commonly CKD patients on dialysis, either peritoneal or hemodialysis  
 ↑ in CAPD compared to haemodialysis 
 Especially prevalent in diabetic patients on peritoneal dialysis  
 ↑ in Increasing age of dialysis patients  
 Aluminum overload   
 Serum aluminium levels do not correctly reflect body aluminium stores and do 
not correlate well with signs of aluminium toxicity.  
 desferrioxamine (DFO) test increases the diagnostic accuracy

 High calcium load 
 Low PTH levels 
 Vitamin D over-treatment (eg : alfacalcidol) 
 High prevalence of diabetes mellitus 
 
 basically in CKD:  
 PTH serum levels are higher than normal   
 bone tissue is resistant to PTH  
 PTH serum levels decrease beyond relatively low levels, which would be considered 
normal in the general population.  
 So that a relative reduction of PTH  low turnover state.   
 Complications:  ( pain, fracture, Ĺ Ca+)  
 bone pain

 bone pain  
 increased incidence of hip fracture  
 hypercalcaemia as the bone loses its capacity to buffer serum calcium  
  
 Treatment: currently follows two principles:  
1. reduce calcium and vitamin D load  
 Stop calcium-containing phosphate binders and replace with non-calcium- , 
non-aluminium-containing phosphate binders 956

  37   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Assess oral dietary calcium intake and reduce to <2000 mg/day 
 Reduce or stop active vitamin D compounds

 Reduce or stop active vitamin D compounds 
 Lower dialysate calcium to 1.25 mmol/L or below 
 Avoid bisphosphonates, strontium and fluoride administration 
2. restore PTH activity  
 Follow- up 
 Changes of bone markers, such as bone-specific alkaline phosphatase, over time, 
may be suitable indicators for the assessment of therapeutic effects. 
 
Other complications of peritoneal dialysis 
 Worsening of diabetic control : 
 dialysis fluid contains a high glucose

 dialysis fluid contains a high glucose  
 patients with diabetes may require significantly more diabetes treatment to 
reduce their blood glucose once dialysis is commenced  
 Worsening of abdominal hernias : due to the large fluid volume expansion and should be 
surgically repaired 
 Stomas adhesions: 
 Stomas may be associated with significant adhesions and changes within the 
abdominal cavity making catheter placement impossible

Contraindication of continuous ambulatory peritoneal dialysis ( CAPD): 
 Colostomy.  
  increase the risk of peritonitis 
 Recent or prospective abdominal surgery  
 Complex abdominal surgery  and resultant extensive adhesion damage the 
peritoneal membrane (peritoneal fibrosis) and lead to compartments within the 
peritoneum.  
 Simple abdominal surgery, however, does not preclude peritoneal dialysis; examples 
include cholecystectomy, appendectomy or caesarian section.

May 2013 exam: A patient on Ambulatory Peritoneal Dialysis (CAPD). Feels generally unwell with 
abdominal pain and fever. Which organism is most likely to be responsible for this presentation? 
Staphylococcus epidermidis  
 
Renal transpla nt 
 
Hyperacute graft rejection is due to pre-
existent antibodies to HLA antigens 
mediated IgG and is therefore   DR  Renal transplant HLA matching 
is the most important 957

  38   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Some basic points on the HLA system   
 class 1 antigens include A, B and C. Class 2 antigens include DP,DQ and DR

 when HLA matching for a renal transplant the relative importance of the HLA antigens are 
as follows DR > B > A 
 Which HLA subtypes is usually implicated with respect to matching for avoiding 
hyperacute rejection? 
 HLA-C 
 Anti-HLA-C IgG antibodies are usually implicated in hyperacute rejection;  
 specifically, HLA-CW5 subtype antibodies have been implicated most in 
hyperacute rejection of renal transplant. 
 
Types of Transplants :  
 Autografts :

 Autografts :  
 same individual acts as both donor and recipient.  
 Isografts :  
 donor and recipient are genetically identical (twins).  
 Allografts :  
 donor and recipient are genetically dissimilar but belong to the same species (the 
commonest).  
 Xenografts :  
 donor and recipient belong to different species (between animal and human). 
 Orthotopic transplants :  
 the transplanted part is placed in its normal anatomical location.

 Heterotopic transplants :  
 the transplanted part is placed in different anatomical location.  
 
Graft survival 1 year 10 years 
Cadaveric transplants  90% 60% 
Living-donor transplants 95% 70% 
 Post- operative problems 
 ATN of graft 
 vascular thrombosis 
 urine leakage 
 UTI 
 
Hyper acute  rejection (minutes to hours) 
 due to pre-existent antibodies against donor HLA type 1 antigens (a type II hypersensitivity 
reaction)  and is therefore IgG mediated

reaction)  and is therefore IgG mediated 
 rarely seen due to HLA matching 
 antigen-antibody complexes  activate the complement system  causing massive 
thrombosis in the capillaries  avascularization of the graft.  
 the kidney is most susceptible to hyperacute rejection; the liver is relatively resistant, 
possibly because of its dual blood supply, but more likely because of incompletely 
understood immunologic properties.

understood immunologic properties. 
 
Reasons for deterioration in renal function  soon after a renal transplant : 
 Hyperacute rejection (which usually occurs in hours) 958

  39   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Acute tubular necrosis, and 
 Surgical complications (renal arterial or venous thrombosis and ureteric stenosis).

In the presence of a dropping urine output and rising creatinine, an urgent ultrasound scan 
should be obtained to exclude any mechanical obstruction of the renal tract before 
considering other options.  
 
Acute graft failure (< 6 months) 
 Approximately 25% of transplant patients will have at least one episode of reje ction mostly 
between days 7 and 21, and less commonly up to three months post-operatio n.  
 usually due to mismatched HLA. Cell-mediated (cytotoxic T cells)

 other causes include cytomegalovirus infection 
 Although CMV infection would not cause a sudden deterioration in renal 
function  
 Doppler ultrasound studies may show a sharp deterioration in graft perfusion, and kidney 
biopsy will show invading lymphocytes penetrating the tubular basement membrane, 
causing tubulitis.  
 It is often clinically silent, with only a sharp rise in serum creatinine pointing towards the 
diagnosis.  
 may be reversible with steroids and immunosuppressants

Chronic graft failure (> 6 months)  
 both antibody and cell mediated mechanisms cause fibrosis to the transplanted kidn ey 
(chronic allograft nephropathy) 
 caused by recurrence of original renal disease (MCGN > IgA > FSGS) 
 Recurrence of renal pathologies post-renal transplantation:  
1. Membranoproliferative GN: 40-90% recurrence rate, type 2 much greater 
than type 1).  
2. FSGS: 40%.  
3. Membranous GN: 30%. 
 
Differentiate between acute cellular rejection and CMV

Onset  Feature Renal function  
Acute cellular 
rejection Commonly between 
days 7 and 21 often clinically silent Sudden sharp rise 
in serum creatinine 
CMV Usually seen after 
four weeks Systemic feature (pulmonary, 
GIT and Retinitis). Gradual rise in 
serum creatinine 
 
Risk factors of chronic rejection  include : 
 number of previous acute rejection episodes 
 presence of anti-HLA antibodies 
 anti-endothelial antibodies 
 CMV infection 
 dyslipidaemia 
 hypertension 959

  40   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  functional mass of the donor kidney, and 
 delayed graft function (a clinical manifestation of ischaemia/reperfusion injury). 
 
Type

Type 
of transplant 
rejection Hyperacute 
rejection Acute rejection Chronic rejection 
Frequency  < 1%   50%   50%  
Onset after 
transplantation   < 48  
(usually within 
minutes to hours)  < 6 months  
(usually within days to 
weeks)  > 6 months   
(usually after a few years) 
Pathophysiology  Preformed 
antibodies  
against class 
I HLA   ĺ 
activation 
of complement 
system and 
adhesion to 
granulocytes ĺ  
thrombosis of 
vessels ĺ 
graft ischemia  T-lymphocyte 
induced cell-

mediated and/or 
humoral immunity  Irreversible 
intimal fibrosis and 
obstruction of vessels  
Clinical findings  Intraoperative 
assessment : 
swelling of the 
organ as soon as 
perfusion is 
restored  Pain in the graft region 
 Graft edema 
 Fever and 
deterioration of general 
condition 
 In kidney transplants : Ĺ 
BP and RFT; ↓urine 
output  Slow, progressive loss of 
organ function 
Diagnosis  Biopsy:  
small vessel 
thrombosis and

thrombosis and 
graft infarction  Biopsy (confirmatory 
test) 
 Heterogenous 
mononuclear 
aggregates±  
antibody  
 C4d staining 
indicates 
humoral  graft 
rejection  Biopsy 
 Kidney:  
Glomerular sclerosis 
 Heart: 
accelerated coronary 
artery disease 
 Liver: vanishing bile 
duct syndrome 960

  41   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Type 
 Negative C4d  
staining indicates

staining indicates 
cellular  rejection 
Prevention  Preoperative  
cross-  matching, 
ABO grouping 
and 
HLA  matching  Post-transplant 
immunosuppressive 
therapy  Irreversible process with 
no known prevention 
Treatment  Graft removal  Change or increase 
dosage of 
therapy   Graft removal, and 
retransplantation 
 
Graft versus host disease (GVHD)   
presents with liver abnormalities, significant diarrhoea and skin changes.  

 damage to the host as a result of a systemic inflammatory reaction induced by T 
lymphocytes present in the graft 
Etiology 
 Allogenous hematopoietic stem-cell transplantation 
 Small bowel transplantation  
 Transfusion of non-irradiated blood products 
 Products implicated in cases of transfusion associated GVHD include:   
 Non-irradiated whole blood   
 Packed red blood cells   
 Platelets   
 Fresh non-frozen plasma   
 Granulocytes

 Granulocytes    
 The following have not been implicated:   
 Frozen deglycerolised red blood cells   
 FFP and   
 Cryoprecipitate 
 
 961

  42   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Types of graft-versus-host disease  
 Acute graft-versus-host disease Chronic graft-versus-host disease

Onset  < 100 days  after transplantation  > 100 days  after transplantation 
Pathophysiology  Donor T lymphocytes react with the 
recipient's organs  Mostly unknown 
Clinical 
presentation  Pruritic or painful maculopapular rash  
 Nausea, vomiting, diarrhea , and/or 
cramping abdominal pain   
 Hepatic dysfunction: jaundice 
 
  Scleroderma-like and lichenoid 
skin changes  
 Sicca syndrome: 
xerophthalmia, xerostomia, dry 
pruritic skin  
 Chronic enteritis (similar

 Chronic enteritis (similar 
to inflammatory bowel disease): 
bloody diarrhea, abdominal pain, 
weight loss 
 Bronchiolitis obliterans : 
chronic cough, wheezing, 
and dyspnea that is not 
responsive  to bronchodilator 
therapy    
 Myasthenic  symptoms 
 polymyositis: weakness, 
muscle pain 
Diagnostics  CBC:  anemia, thrombocytopenia, leukope
nia 
 ↑ ALP   
 Confirmatory test: biopsy of skin, rectum,

 Confirmatory test: biopsy of skin, rectum, 
or liver  Spirometry: obstructive lung 
disease 
 Confirmatory test: biopsy of 
the skin, oral cavity, liver, or 
lung 
Prevention  Antithymocyte globulin  
 Cyclosporine  and one of the following: 
 Methotrexate 
 Mycophenolate mofetil 
Treatment  Optimize GvHD prophylaxis 
(e.g., cyclosporine levels) 
 Corticosteroids 
 < 50% skin involvement: topical 
steroids  
 Involvement of the GI tract, liver, 
or > 50% of skin: systemic

or > 50% of skin: systemic 
steroids  ± topical steroids  First-line: corticosteroids  
 Second-line : cyclosporine and 
increased corticosteroid dose 
 962

  43   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Post-transplant problems  
Cytomegalovirus (CMV) infection 
Renal transplant + infection  CMV

Renal transplant + infection  CMV  
 
 Over 50% of renal transplant patients have a significant infection within the first 12 mon ths 
of having a renal transplant.  
 (CMV) infection occur as a result of immunosuppression 
 Usually seen after four weeks as before this time the immune system has not been 
fully affected by the immunosuppressants. 
 At the time of transplant the CMV-serological status of the donor and recipient are noted.

The highest risk is seen in CMV-seronegative recipients who receive a kidney from a CMV-
seropositive donor. These patients are usually given antiviral prophylaxis.  
 associated with increased graft rejection and renal artery stenosis in renal transplant 
recipients. 
 Typical manifestations of infection would include 
 Interstitial pneumonitis 
 Oesophagitis 
 Peptic ulceration 
 Colitis and 
 Retinitis. 

 Ganciclovir (synthetic guanine derivative) is the most appropriate treatment 
for CMV   
 concomitant use with ciclosporin leads to elevated creatinine 
 Pancytopenia may occur as a result of ganciclovir toxicity  
 Foscarnet is the drug of choice for ganciclovir-resistant cytomegalovirus 
retinitis . 
 
the two most common causes of declining renal function post renal transplant are: 
 graft rejection and  
 ciclosporin toxicity .

 ciclosporin toxicity . 
Acute pyelonephritis :  
 high risk of acute episode of pyelonephritis in the transplanted kidney, due to the 
immunosuppression, the neuropathic bladder and self-catheterisation.   
 present like an acute rejection episode, with a tender swollen graft, low-grade pyrexia, an d 
deteriorating graft function. 
 Especially in the intermediate stage of the post-transplantation immunosuppression, wh en

the patient is most immunocompromised (three to six months post-transplant). 
 
Interstitial pneumonia 
 Cytomegalovirus is the predominant cause of infection in patients within a perio d 
of 1-4 months after renal transplantation 963

  44   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  A chest X-ray will show a bilateral interstitial or reticulonodular infiltrate that begins in

the periphery of the lower lobes and spreads centrally and peripherally 
 
BK virus :  
 C4d staining is used for detection of BK virus after renal transplantation   
 
Epstein-Barr virus (EBV)  
 Epstein-Barr virus (EBV)-associated lymphoproliferative disease  (e.g: non-Hodgkin's 
lymphoma) may occur in individuals with inherited or acquired immunodeficiency 
syndromes. 
 Approximately 1% of renal transplant recipients develop post-transplant

lymphoproliferative disease (PTLD) in the first year following their transplant. 
skin cancer  
 Kidney transplant recipients have a high risk of developing non-melanoma skin cancer , 
therefore,  cancer surveillance is an important consideration in kidney transplant recipients  . 
 The patient may has a malignant melanoma  with liver metastases , hence the deranged 
liver function tests and liver capsule pain.

liver function tests and liver capsule pain.  
 The patient is often unaware of the melanoma lesion, and the primary lesion may in fact 
disappear as the disease progresses. Patient may present with RUQ pain and high LFT. 
 Post-transplant patients are much more prone to develop malignancy compared to n ormal 
population. 
 Cyclosporine is one of the main reasons for development of post-transplant 
malignancy.

malignancy. 
 Non-melanoma skin cancers (NMSC) are the commonest malignancies in post-transplant 
state. Of these, squamous cell Ca is the commonest.  
 
Kidney donation 
 Providing there is a sibling who is proven not to have polycystic kidney disease, living 
related donation should be considered as this would ensure a better match and bett er graft 
survival. 
 Siblings are close genetically, and therefore usually are a better match than spouses. The

husband should not be accepted for kidney donation until all siblings have been 
 The age difference is not, however, a contraindication to kidney donation. 
 Living unrelated kidney donation could also be considered, and is increasing in use in the 
UK. 
 Adults should be considered as doner prior to children because renal cysts usually develop 
during teenage years, so one cannot be confident a child has not been a ffected until they 
are at least 20.

are at least 20. 
Autosomal dominant polycystic kidney disease (ADPKD) 
 
964

  45   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 (ADPKD) is the most common inherited cause of kidney disease, 
  affecting 1 in 1,000 Caucasians.

  affecting 1 in 1,000 Caucasians.   
 Accounting for approximately 8% of cases of end-stage renal disease (ESRD).  
 Two disease loci have been identified, PKD1 and PKD2, which code for polycystin-1 an d 
polycystin-2 respectively 
 Typically presents between the ages of 30-50. 
 As it is an a utosomal dominant, the chance of passing this condition from affected 
patient to his son is 50%.  
 
ADPKD type 1 ADPKD type 2 
85% of cases 15% of cases 
Chromosome 16 Chromosome 4

Chromosome 16 Chromosome 4 
Presents with renal failure earlier, reach ESRF by 
50s. Have a slower course, reaching ESRF by 
70s. 
 
ADPKD: features  
 Hypertension (the earliest  manifestation of ADPKD) 
 recurrent UTIs 
 abdominal pain ( loin pain due to a cyst haemorrhage  or infection)  
 renal stones 
 haematuria ( rupture cysts  presents with visible haematuria ) (Gross haematuria in 
ADPKD carries a poor prognosis however microscopic haematuria may be a complication)

 chronic kidney disease 
 
Renal Complications 
 CKD 
 ADPKD is like a CKD with high phosphate, low calcium but with normal/high Hb due 
to excess erythropoietin secretion. 
 Excessive erythropoietin production  polycythaemia. 
 Renal cell carcinoma with lung metastasis: it is very rare but recognized complication of 
ADPCKD >>> CT Thorax & Abdomen. 
 
Extra-renal manifestations 
 Liver cysts (70%) 
 Berry aneurysms (8%)

 Berry aneurysms (8%) 
 Subarachnoid haemorrhage may be a cause of mortality in 9% of patients with 
ADPKD,  
 8% of patients have an asymptomatic intracranial aneurysm  
965

  46   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  screening for cerebral aneurysms should only be carried out in high risk patients. 
These include factors such as:

These include factors such as:  
1. Previous rupture of aneurysm  
2. Concerning neurological symptoms (for example, severe headache) 
3. Positive family history of haemorrhagic stroke or aneurysm.  
 Even if aneurysms are found, the rupture risk can still be low and the morbidity 
implications of curative surgery may outweigh conservative management. 
 Cardiovascular system: mitral valve prolapse  (25%)    (needs echo screening),

mitral/tricuspid incompetence, aortic root dilation, aortic dissection 
 Colonic diverticula (with any related symptoms, screen by barium enema) 
 cysts in other organs: pancreas, spleen; very rarely: thyroid, oesophagus, ovary 
 Ultrasound (Sensitivity for ADPKD1 is 99% for at-risk patients older than 20 years)  
 Sonographic diagnostic criteria  (in patients with positive family history):  
 age < 30 years  2 unilateral or bilateral cysts

 age 30-59 years  2 cysts in each kidney  
 age > 60 years  4 cysts in each kidney  
 Sensitivity of these criteria   
 nearly 100% for patients 30 years of age or older and for younger patients 
with PKD1 mutations,  
 67% for patients with PKD2 mutations younger than 30 years of age.   
 CT scan or MRI should therefore be used in the latter group.  
 one cannot be confident a child has not been affected until they are at least 
20:

20:  
 a normal ultrasound scan at 20 years of age means you can be 90% 
confident they are not affected,  
 a normal scan at 30 increases the confidence level to 98%.  
 Screening is not usually recommended in children because the presence or absence 
of cysts does not affect management (tight blood pressure control), and the absence 
of cysts in children does not exclude the disease.  
 All children of affected patients should have their blood pressure monitored at least

annually, from early childhood (around age 3) onwards. 
 If cysts are not seen in a younger with a positive family history, the ultrasound should 
be repeated every five years until the age of 30.  
 Contrast-enhanced CT scan or MRI   
 Abdominal CT is sensitive for the detection of cysts however the high radiation dose, 
particularly in young patients, means it is not widely used as a screening test. 
 should be used if ultrasound is equivocal, especially in patients with PKD2 mutations

younger than 30 years of age.  
 CT: More sensitive than USS and may aid in diagnosis in younger patients.  
 MR angiography : In patients with a family history of intracranial aneurysm - to 
screen for cerebral aneurysms. 
 Genetic testing   
 The most appropriate strategy to investigate younger with a family history of 
ADPK is genetic counselling (referral)  966

  47   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  The major indication for genetic screening in (ADPKD) is for subjects who are

considering donating a kidney to a relative affected by the disease 
 sequence analysis  can identify only around 70% of known mutations and linkage 
analysis requires the availability of sufficient family members. 
 can be used in the following cases: 
 The imaging results are equivocal or inconclusive. 
 To confirm a presumed diagnosis in the absence of family history of the 
disease (conclusive proof of the diagnosis in these patients relies on mutation 
analysis).

analysis). 
 When a definite diagnosis is required in a younger patient, such as a potential 
living related kidney donor.  
 Renal biopsy is contraindicated  due to a high risk of haemorrhage into a cyst 
 
Treatment  
 high fluid intake (to prevent the formation of renal stones or blood clots) 
 non-NSAID-based analgesia are the cornerstones of management 
 IV fluids, paracetamol and codeine  
 Hypertension  ACE inhibitors or angiotensin receptor antagonists

  ACE inhibitors reduce proteinuria and may reduce cyst formation in ADPKD, 
 aliskiren, the direct renin inhibitor, also has early data which show promise with 
respect to reducing new cysts. 
 A new therapy ( tolvaptan ) to delay disease progression (recommended by NICE in 2015) 
 Action:  selective vasopressin antagonist  inhibit the binding of vasopressin to the 
V2 receptors  reduces cell proliferation, cyst formation and fluid excretion.

  adverse reactions:  thirst, polyuria, nocturia, pollakiuria (frequent urination), ↑ liver 
enzyme.  
 Urinary tract infections should be treated with lipophillic drugs (for example, ciprofloxacin , 
trimethoprim-sulphamethoxazole) as they have the best penetration into cyst fluid.  
 End- stage renal disease ĺ Transplantation  
Prognosis 
 the renal function usually deteriorates in a gradual fashion, usually with a drop in 
creatinine clearance of 5/6 ml/min/year

creatinine clearance of 5/6 ml/min/year  
 Approximately half of patients require dialysis by the age of 60  
 
January 2016 exam: You are reviewing a patient with adult polycystic kidney disease. 
Which cardiovascular feature are you most likely to find on examination? Mitral valve 
prolapse  
 
 967

  48   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Autosomal recessive polycystic kidney disease (ARPKD)

 Autosomal recessive polycystic kidney disease (ARPKD) is much less common than 
autosomal dominant disease (ADPKD). 
  It is due to a defect in a gene located on chromosome 6  
 Diagnosis may be made on prenatal ultrasound or in early infancy with abdominal m asses 
and renal failure. Newborns may also have features consistent with Potter's syndrome 
secondary to oligohydramnios. 
  End-stage renal failure develops in childhood.

  Patients also typically have liver involvement, for example portal and interlobular fibrosis.  
  Renal biopsy typically shows multiple cylindrical lesions at right angles to the cortical 
surface. 
Medullary sponge kidney   
 is a disorder characterised by dilatation of the collecting ducts in the papillae, with 
accompanying cystic changes

accompanying cystic changes   
 It is often associated with calculi , which can result in pyelonephritis and renal tract 
obstruction. 
 Typically not inherited but is a congenital condition.  The aetiology is uncertain, but it is 
thought to be a developmental abnormality, possibly resulting from tubular or collecting duct 
obstruction at any early age.  
 The kidneys size are normal or increased. 
  The age of presentation is usually in the third or fourth decade

 The majority of cases are sporadic, although a rare autosomal dominant familial form exists 
with onset in adulthood, and a juvenile autosomal recessive form is also recognised . 
Recent research has identified a possible defect in the development of the proton  pump 
mechanism in the kidney. 
 Diagnosis is made via excretion urography, showing small calculi in the papillary 
zones with surrounding increase density; this is because the dilated collecting

ducts are filled with contrast medium 
 About 20% of patients have associated hypercalciuria or renal tubular acidosis 
 Skeletal hemihypertrophy may be associated 
 Renal failure is highly unusual 
Alport's syndrome 
 
968

  49   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Alport syndrome is the second most common inherited cause of renal failure (after 
polycystic kidney disease)

polycystic kidney disease)  
 usually inherited in an X-linked dominant  pattern.    
 Inheritance is variable, but the majority are X linked dominant (85%) ;  
 Therefore, as only the Y chromosome is passed from father to son there is no 
chance of the son having the disease. 
 15% are autosomal recessive with rare autosomal dominant variants  
 Most cases arise from the COL4A 5 gene on the X chromosome  .

 It is due to a defect in the gene which codes for type IV collagen  resulting in an 
abnormal glomerular-basement membrane (GBM).  
 Patients with Alport syndrome are  at risk of developing antiglomerular basement 
membrane disease ( Goodpasture's  disease) following transplantation , as their 
immune systems have never been exposed to type IV collagen and hence lack 
tolerance. 
 What is the most likely reason for the decline in graft function?

 Anti-glomerular-basement membrane antibodies (Goodpasture's 
syndrome ) 
 There is a high spontaneous mutation rate, which means 20% of patients have no family  
history.  
 Prevalence is around 1 in 5000  
 The disease is more severe in males with females rarely developing renal failure  
 usually presents in childhood.  
 more severe in males 
 females do not develop progressive renal failure with this condition.

 A favourite question is an Alport's patient with a failing renal transplant. This may be 
caused by the presence of anti-GBM antibodies leading to a Goodpasture's 
syndrome like picture  
Features  
"Can't see, can't pee, can't hear a bee." 
 microscopic haematuria 
 Most common and earliest manifestation 
 progressive renal failure  
 bilateral sensorineural deafness ( usually occurs before the onset of renal failure ) 
 ocular 
 Anterior lenticonus

 ocular 
 Anterior lenticonus  
 protrusion of the lens surface into the anterior chamber  
 Occurs in 25% of patients  
 is the pathognomonic  feature of Alport syndrome  
 Dot-and-fleck retinopathy 
 Most common ocular manifestation  of patients with Alport syndrome, 
(occurring in 85%) 
 retinitis pigmentosa 
 renal biopsy:  969

  50   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
   Light microscopy  
 usually unremarkable and electron microscopy is usually required.  
 Electron microscopy

 Electron microscopy  
 splitting of lamina densa   
 basket weave pattern of glomerular basement membrane 
 foam cells 
 produced by lipid accumulation in visceral epithelial cells 
 slit lamp examination: 
  bilateral thin lens capsules  
 conical protrusions on the anterior aspect of the lens,  
 subcapsular cataracts.  
Treatment  
 Rigorous control of hypertension may delay the onset of end stage renal failure,

  angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers if they 
have proteinuria   
 Renal transplant  
Prognosis  
 ESRF seen in 90% of patients with Alport's by the age of 40 years. 
 
September 2009 exam: What is the mode of inheritance of Alport's syndrome in the 
majority of cases? X-linked dominant  
 
January 2008 exam: Alport's syndrome is due to a defect in:? Type IV collagen  

Haemolytic uraemic syndrome 
The presence of thrombocytopenia  and evidence of haemolysis  in association with  bloody  
diarrhoea  should make you think of haemolytic uraemic syndrome (HUS). 
 
Haemolytic uraemic syndrome is generally seen in young children and produces a triad of:  
 acute renal failure 
 microangiopathic haemolytic anaemia 
 thrombocytopenia with normal clotting.  
Causes 
 post-dysentery - classically E coli 0157:H7  ('verotoxigenic', 'enterohaemorrhagic')

.Toxins produced in the intestine enter the blood and bind to endothelial cells in t arget 
organs. Endothelial cell damage leads to platelet and fibrin deposition with resu ltant 
fragmentation of circulating red blood cells and microvascular occlusion.  
The syndrome has also been reported after infections with coxsackie, echovirus 
and Shigella . 
 tumours 
970

  51   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  pregnancy 
 ciclosporin, the Pill 
 systemic lupus erythematosus 
 HIV

 HIV 
 Inherited recurrent HUS has been described with both dominant and recessive patte rns of 
inheritance  
 full blood count: anaemia, ĻĻSerum haptoglobins (which bind haemoglobin), 
thrombocytopaenia, fragmented blood film  
 The hallmark of HUS is the appearance of  schistocytes  (fragmented, deformed, 
irregular, or helmet shaped red cells) on the blood film.  
 There is normal coagulation and fibrinogen. 
 U&E: acute renal failure

 U&E: acute renal failure 
 stool culture 
Major differential diagnosis  is: 
1. Sepsis with DIC - presents with abnormalities of clotting parameters.  
2. TTP - thrombotic thrombocytopenic purpura presents with microangiopathic haemoly tic 
anaemia, thrombocytopenic purpura, neurologic abnormalities, fever, and renal diseas e. 
 Patients with TTP lack a plasma protease that is responsible for the breakdown of von

Willebrand factor (vWF) multimers and these accumulate in the plasma. The activity o f this 
protease is normal in patients with HUS. 
 Until the test for vWF protease activity becomes available, differentiation between HUS an d 
TTP is based on the presence of central nervous system involvement in TTP and the m ore 
severe renal involvement in HUS. 
 In HUS 90% of patients are children and a history of prodromal diarrhoeal illness is more 
common. 
 
feature HUS                  TTP

common. 
 
feature HUS                  TTP 
Acute kidney injury  more severe Less severe 
Neurological symptoms  less common  More common 
 Complications  include: 
 Stroke, seizure and coma occur in 25% of patients 
 Rarely pancreatitis, and 
 Pleural and pericardial effusions. 
 Approximately 5% of patients will develop end stage renal failure. 
 
 treatment is supportive e.g. Fluids, blood transfusion and dialysis if required

 there is no role for antibiotics, despite the preceding diarrhoeal illness in many patients 
 the indications for plasma exchange in HUS are complicated. As a general rule plasma 
exchange is reserved for severe cases of HUS not associated with diarrhoea 971

  52   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Non-steroidal anti-inflammatory drugs and anti-diarrhoeals should be avoided 
Prognosis

Prognosis 
 
 Most children recover spontaneously from the illness, but mortality may be high  in the 
elderly.  
 Unfortunately fatality rates from HUS remain high, at between 5 and 10%. 
 
MRCPUK- part-1- September 2012 exam:  H/O bloody diarrhea and dehydration +  ↓Platelet 
, ↑WBC, ↑urea & creatinine. Given the likely diagnosis, which organism is the most likely 
cause?   
 E. coli   
 
MRCPUK- part-1- May 2010 exam: Feature of  diarrhoea , lethargy & acute renal failure.

There is a known local outbreak of E coli 0157:H7. Given the likely diagnosis, which one 
of the following investigation results would be expected? 
 Fragmented red blood cells (∆ haemolytic uraemic syndrome )  
 
Renal tubular defects 
 thick ascending limb of Henle's loop : Bartter syndromes are renal tubular salt-wasting 
disorders in which the kidneys cannot reabsorb chloride in the thick ascending limb of 
Henle's loop

Henle's loop  
 distal convoluted tubule : Gitelman  syndrome are renal tubular salt-wasting disorders in 
which the kidneys cannot reabsorb chloride due to defect of thiazide-sensitive Na-CI 
cotransporter in the distal convoluted tubule 
 proximal tubule : Carbonic anhydrase is expressed in the proximal tubule and is inhibited 
by acetazolamide; this is manifested biochemically by normal anion-gap metabo lic acidosis

Fanconi syndrome refers to a proximal tubular defect that results in wasting of phosphate, 
calcium and amino acids .It is an important feature of cystinosis and is also seen in 
myeloma kidney and Wilson's disease 
 collecting ducts  :Aquaporin channels are expressed in the cortical collecting ducts and are 
involved in water handling; defects result in diabetes insipidus 
Fanconi syndrome

Fanconi syndrome   
 Fanconi's syndrome characterised by generalised dysfunction of the proximal tubule , 
with the resultant urinary loss of bicarbonate, calcium, phosphate, urate, amino acids,  
glucose, and other organic acids and bases. 
 Most diseases associated with Fanconi syndrome are inherited in an autosomal recessive  
pattern. Consequently: 
 the child of 2 heterozygous parents, whether male or female, has a 25% cha nce of 
being homozygous.

being homozygous.  
 The children of an affected individual (homozygous) are all heterozygous and can be 
affected only if the other parent is heterozygous, a very rare event. 
 Fanconi's syndrome is marked by the appearance in the urine of all amino acids . 
Specific amino aciduria as seen in isolated cystinuria, glucose loss in isolated glycosuria, 
and isolated phosphaturia do not constitute Fanconi's syndrome. 972

  53   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Causes 
 cystinosis (most common cause in children) 
 multiple myeloma 
 Wilson's disease

Feature 
 type 2 (proximal) renal tubular acidosis (RTA) 
 polyuria 
 aminoaciduria 
 glycosuria 
 phosphaturia 
 
 In children , Fanconi's syndrome results in growth retardation, renal rickets, and severe 
metabolic acidosis.  
 Adult cases exhibit similar urinary losses, but the clinical impact is largely restricted to 
_________________________________________________________

Gitelman's syndrome 
 
 Gitelman's syndrome is due to a defect in the thiazide-sensitive Na+ Cl- transporter in 
the distal convoluted tubule.   
 Caused by loss- of-function mutations in the SLC12A3 gene  
 It is the most common congenital renal tubular disorder  in Caucasians, with a 
prevalence of 1 in 40,000 
Features  
 patients may be highly symptomatic (eg salt craving, dizziness, fatigue, muscle weakness

and cramps, paraesthesiae, non-specific aches and pains) or may have minimal 
symptomatology 
 hypomagnesaemia  (which is pathognomic ) 
 hypocalciuria    
 normotension 
 salt wasting leads to activation of the renin-angiotensin system also leading to raised 
aldosterone levels. 
 The  most useful investigation in pointing to the diagnosis is  Renin and 
aldosterone levels  
 
Bartter syndrome and Gitelman syndrome 
973

  54   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Clinical diagnosis of Bartter or Gitelman syndrome: 
1. Unexplained hypokalemia and metabolic alkalosis 
2. Normal or low blood pressure,

2. Normal or low blood pressure,  
3. Other, more common, etiologies are ruled out (ie, surreptitious vomiting and diuretic 
use). 
  Laboratory diagnosis 
 Urine chloride concentration, (typically greater than 25 meq/L) 
 In contrast, patients with hypokalemia and metabolic alkalosis caused by 
vomiting have a urine chloride concentration that is usually less than 25 
meq/L 
 Urine diuretic screen. 
 The practicality of genetic testing is limited.

 Patients who secretively take diuretics have a variable urine chloride concentration; it is 
high when the diuretic effect is present and low when it dissipates. A urine diuretic screen  
should be sent. 
 Treatment of patients with Bartter and Gitelman syndromes: 
 life-long administration of a drug that blocks distal tubule sodium-potassium 
exchange (eg,spironolactone)  
 supplementation with potassium chloride and magnesium. 
 NSAIDs. 
 
Bartter syndrome  Gitelman syndrome

Bartter syndrome  Gitelman syndrome  
SLC12A 1  
(Bartter syndrome type I)  SLC12A 3 
 Gene affected   
 
1 in a million. 1 in 40,000 prevalence 
 
sodium chloride reabsorption in 
the thick ascending limb of 
Henle's loop (NKCC2) thiazide-sensitive Na-CI 
cotransporter in the distal 
convoluted tubule Site of defect 
Most cases are discovered in 
infancy or early adolescence 
(more severe symptoms) present in  adolescence and early 
adulthood 
 ( milder symptoms)   presentation

adulthood 
 ( milder symptoms)   presentation 
Concentrating capacity reduced 
and diluting capacity reduced Concentrating capacity 
normal/near normal and diluting 
capacity reduced Concentrating and 
diluting abilities 
increased reduced Urinary calcium 
either normal or mildly reduced severe hypomagnesemia is 
common serum magnesium 
 
 974

  55   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Bartter syndrome  
 
Basics

Basics 
 Bartter syndrome is a childhood disease inherited as an autosomal recessive trait 
 Leads to tubular defects in Na-K-Cl cotransporter  and increased intrarenal production of 
ProstaglandinE2 (PGE2) 
 The defect located in the thick ascending limb of the loop of Henle  
 usually diagnosed at school age or later. 
Aetio-pathogenesis 
 ↓Chloride  reabsorption ↓loop (NaCl) reabsorption  ↑renin & aldosterone secretion with 
juxtaglomerular (JGA) hyperplasia

juxtaglomerular (JGA) hyperplasia  
 ↑ (NaCl) in collecting duct   ↑K+ & H+ secretion  hypokalaemia & metabolic alkalosis 
 High levels of aldosterone also enhance potassium and hydrogen exchange for sodi um. 
 ↑ kinin & prostaglandins secretion  vascular unresponsiveness to presser effect 
 K+  ↑PGE2  afferent arteriole dilation ↓Renal Perfusion Pressure (RPP)  chronic 
renin secretion with no effect on GFR, RPP, Na, Cl, K reabsorption (because PGE2

overcome this reaction) JGA hypertrophy due to excess of work.  
Features 
 usually presents in children, polyuria, Polydipsia ,dehydration, mimics loop diuretic use  
 nocturnal enuresis,  
 Hypokalaemia  muscle weakness 
 Alkalosis 
 Hypercalci uria  
 normal to low BP :  
 ↑renin and aldosterone NOT  ↑ BP because of  vascular unresponsiveness to 
presser effect  
 growth retardation. 
 rarely sensorineural defects

 rarely sensorineural defects 
 Other symptoms, which appear during late childhood, include fatigue, muscle wea kness, 
cramps, and recurrent carpopedal spasms. 
Investigations ( Exclude diuretic abuse ) 
 urinary chloride: high (>20 mmol/L or 20 mEq/L)  
 urinary calcium : high (normal range 100 – 300 mg/day) 
 Urinary sodium: high  
 serum potassium: low (hypokalaemic alkalosis) 
 increased plasma renin and aldosterone levels.  
 Hyponatraemia and hypochloraemia may also be present.

 Renal biopsy  Hyperplasia of the juxtaglomerular apparatus is characteristic  
 Gitelman  
975

  56   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Gitelman  hypocalciuria 
 Bartter  hypercalciuria + high renin, high aldosterone

 While Bartter may or may not have hypomagnesemia, it is pathognomon ic for 
Gitelman.  
 Chronic vomiting  
 Chronic vomiting:  low urine chloride levels  
 Bartter's  higher urine chloride levels. 
 Abuse of diuretic medications (water pills):  
 The physician must screen urine for multiple diuretics before diagnosis is made. 
 
Treatment  
 K+-sparring diuretic (eg: spironolactone) 
 Treatment is aimed at preventing potassium wasting

 NSAID (eg: Indomethacin) ↓ production of prostaglandins  restores the normal 
physiological vascular response. 
Liddle's syndrome  
 
hypokalaemic alkalosis + suppressed renin and aldosterone + hypertension  Liddle ’s 
syndrome 
 
Overview 
  mutation in genes mapped to chromosome 16.  
 Caused by  increased sodium reabsorption due to increased activity of

epithelial sodium channels in the distal tubules  from gain- of-function mutations . This 
leads to activation of sodium/potassium exchange independent of circulating 
mineralocorticoid.  
Features 
 hypertension  
 caused by increased sodium reabsorption. 
 hypokalaemia  
 metabolic alkalosis.  
Treatment  
 potassium-sparing diuretics 
 either amiloride  or triamterene ( epithelial sodium channel (ENaC) antagonists)

 Hypertension and hypokalaemia respond well to amiloride but not spironolactone , 
because amiloride acts directly on the sodium channel , whereas spironolactone 
acts on the mineralocorticoid receptor.  
 Amiloride specifically inhibits overactive sodium channels and effectively 
controls blood pressure in Liddle ’s syndrome, in which hypertension is caused 
by separate epithelial sodium channel mutations. 
976

  57   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Spironolactone is not an effective treatment  as the increased activity of the

ENaC is not mediated by aldosterone (as reflected by the low plasma and 
urinary aldosterone levels).  
HIV: renal involvement 
Renal involvement in HIV patients may occur as a consequence of treatment or the vir us itself. 
Protease inhibitors such as indinavir can precipitate intratubular crystal obstruction 
 
HIV-associated nephropathy (HIVAN ) accounts for up to 10% of end-stage renal failure cases in

the United States. Antiretroviral therapy has been shown to alter the course of the d isease. There 
are five key features of HIVAN:  
 massive proteinuria 
 normal or large kidneys 
 focal segmental glomerulosclerosis with focal or global capillary collapse on renal biopsy.  
(collapsed appearance of glomeruli on light microscopy) is typical  
 elevated urea and creatinine 
Glomerulonephritides

Glomerulonephritides  
Knowing a few key facts is the best way to approach the difficult subject of glomerulone phritis: 
Membranous glomerulonephritis  
 presentation: proteinuria / nephrotic syndrome / chronic kidney disease 
 cause: infections, rheumatoid drugs, malignancy 
 1/3 resolve, 1/3 respond to cytotoxics, 1/3 develop chronic kidney disease 
IgA nephropathy - aka Berger's disease, mesangioproliferative GN 
 typically young adult with haematuria following an URTI

Diffuse proliferative glomerulonephritis  (DPGN) 
 
 classical post-streptococcal glomerulonephritis in child 
 presents as nephritic syndrome / acute kidney injury  
 The following features are supportive of diagnosis: 
 haematuria 
 proteinuria 
 oedema 
977

  58   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  most common form of renal disease in SLE 
 In DPGN, more than 50% of the glomeruli  (diffuse) show an increase in mesangial,

epithelial, endothelial (proliferative), and inflammatory cells (ie, glomerulonephritis). 
(Increased cellularity) 
 when < 50% of the glomeruli are involved, the condition is termed focal proliferative 
glomerulonephritis. However, this entity has the potential to progress to DPGN. 
Minimal change disease 
 typically a child with nephrotic syndrome (accounts for 80%) 
 causes: Hodgkin's, NSAIDs 
 good response to steroids 
Focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis 
 may be idiopathic or secondary to HIV, heroin 
Rapidly progressive glomerulonephritis - aka crescentic glomerulonephrit is 
 rapid onset, often presenting as acute kidney injury 
 causes include Goodpasture's, ANCA positive vasculitis 
Mesangiocapillary glomerulonephritis (membranoproliferative) 
 type 1: cryoglobulinaemia, hepatitis C  associated with low C4

 type 2: partial lipodystrophy  associated with low C3  
 C3 nephritic factor is an autoantibody specific for alternative pathway C3 convertase 
(C3NeF), found in mesangiocapillary GN type II and partial lipodystrophy. 
Diagnosis 
 Renal biopsy is the best investigation to diagnose Glomerulonephritis 
 RBC casts in urinary sediment suggest a diagnosis of acute glomerulonephritis 
(Acute nephritic syndrome)

(Acute nephritic syndrome) 
 
 Immune complex glomerulonephritides can be classified based on normal or decrease d C3. 
 Associated with reduced C3 and C4 
 Cryoglobolinaemia  
 Infective endocarditis 
 lupus nephritis  
 Associated with reduced C3. 
 membranoproliferative GN 
 post-streptococcal GN 
 
Glomerulonephritis and low complement  Disorders associated with 
glomerulonephritis and low serum complement levels:

1. post-streptococcal 
2. subacute bacterial endocarditis 3. systemic lupus erythematosus 
4. mesangiocapillary 
 
 978

  59   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
May 2014 exam : A patient of SLE present with pedal oedema , Ĺ BP . Dipstick urine shows protein

++, blood+++.What is the renal biopsy most likely to show? Diffuse proliferative glomerulonephritis 
(Diffuse proliferative glomerulonephritis is the most common and severe form of renal disease in SLE 
patients.)  
Minimal change disease   
 
 Minimal change disease nearly always presents as nephrotic syndrome, 
  accounting for 75% of cases in childrenand 25% in adults. 
 peak incidence 2-3 years of age  
Causes

Causes 
 The majority of cases are idiopathic, but in around 10-20% a cause is found: 
 drugs: NSAIDs, rifampicin  gold and lithium 
 Hodgkin's lymphoma , thymoma 
 infectious mononucleosis 
 The glomerular basement membrane is normal on electron microscopy   
 T-cell and cytokine mediated damage to the glomerular basement membrane ĺ polya nion 
loss

loss 
 the resultant reduction of electrostatic charge ĺ increased glomerular permeability to 
serum albumin 
Features 
 hypertension is rare ( only 10%) 
 highly selective proteinuria* (*only intermediate-sized proteins such as albumin and 
transferrin leak through the glomerulus) 
 A protein selectivity index of less than 10% is highly selective and is a ratio of serum 
and urine IgG and albumin.

and urine IgG and albumin. 
 High selectivity suggests minimal change disease but is less reliable in adults. 
 Renal biopsy: 
 light microscopy  are normal or small looking glomeruli 
  electron microscopy  shows fusion of podocytes  
(Effacement of the epithelial cell foot processes over the outer surface of the G BM) 
 renal biopsy is not indicated unless no response to steroids is seen within one 
month, there is hypertension, haematuria or renal impairment. 
979

  60   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  renal biopsy is usually only attempted when three or more episodes of 
oedema have occurred.

oedema have occurred. 
 
Podocyt es fusion is seen in minim al change glomerulonephrit is but m ay occasionally be a 
feature of focal segmental glomerulosclerosis as we ll. Minimal change however is f ar more 
comm on  
 
 majority of cases (80%) are steroid responsive 
 cyclophosphamide is the next step for steroid resistant cases 
 Immunosuppression treatment (cyclophosphamide) should be considered in patients

who are frequent relapsers  (two or more episodes in six months  of the initial 
response, or four relapses in any one year , children who are steroid dependent or 
steroid toxic).  
 
Prognosis  is overall good  
 Remission : Full renal recovery is the most likely outcome.  
 In Children : 
 30 – 40% of children achieve spontaneous remission  
 and 90% achieve remission following eight weeks treatment with high dose 
steroids. 
 In adults  only around 50% achieve remission.

 Relapse  is common. Roughly: 
 1/3 have just one episode 
 1/3 have infrequent relapses 
 1/3 have frequent relapses which stop before adulthood 
Membranous glomerulonephritis 
 
 Membranous glomerulonephritis is the commonest type of glomerulonephritis in  
adults  and is the third most common cause of end-stage renal failure (ESRF).  
 It usually presents with nephrotic syndrome or proteinuria.

 It is an antibody mediated disease in which the immune complexes localise to the 
subepithelial aspect of the capillary loop. That is, between the outer aspect o f the basement 
membrane and the podocyte (epithelial cell). 
 Males are twice as commonly affected as females 
 Typically seen in the over 40 age group ( Elderly patients )  
 
980

  61   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Causes 
 infections: hepatitis B , hepatitis C , malaria , syphilis , leprosy, HIV, schistosomiasis,

 malignancy : lung cancer,  non-Hodgkin's lymphomas lymphoma , leukaemia,  colon and 
gastric cancer  
 (30% of membranous nephropathy cases are secondary, of those around a third 
(10% of the total cases of membranous nephropathy) are diagnosed with an 
underlying malignancy) 
 (NOTE: In the case of Hodgkin ’s lymphoma,  the most common histological type of 
renal involvement is minimal change  glomerulonephritis followed by focal 
segmental glomerulosclerosis ).

segmental glomerulosclerosis ). 
 drugs: gold,  penicillamine , NSAIDs , captopril, and heavy metals: mercury and cadmium 
 autoimmune diseases: systemic lupus erythematosus (class V disease), thyroiditis, 
rheumatoid 
 Sickle cell disease.  
 Diabetes mellitus. 
 
Renal biopsy demonstrates: 
 electron microscopy: the basement membrane is thickened with subepithelial electron 
dense deposits ( Thickened capillary loops ). This creates a 'spike and dome' appearance

 Immune complex deposition with IgG and C3  
 Renal vein thrombosis is particularly likely to complicate membranous 
 As the left testicular vein drains into the left renal vein, a left-sided varicocele may 
develop in this condition.  
 
Prognosis   
 Rule of thirds 
 one-third: spontaneous remission 
 one-third: remain proteinuric 
 one-third: develop ESRF 
 Good prognostic features include:  
 female sex  
 young age at presentation and

 young age at presentation and  
 asymptomatic proteinuria of a modest degree at the time of presentation.  
Management:  aims are:  
1. induce a remission of the nephrotic syndrome, and 
2. prevent the development of end stage renal failure. 
 Immunosuppression: corticosteroids alone have not been shown to be effective. A 
combination of corticosteroid + another agent such as chlorambucil is often used 
 Cyclophosphamide plus methylprednisolone is the most appropriate

  62   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  blood pressure control: ACE inhibitors have been shown to reduce proteinuria

 Ramipril is proven to affect both proteinuria and hypertension in patients with 
a diagnosis of membranous nephropathy, and is therefore the most likely 
treatment to affect the patient's prognosis   
 consider anticoagulation 
  Approximately 30% of cases are secondary to other conditions, and in those cases 
treatment of the underlying cause may be curative. 
 
September 2011 exam: H/O colorectal cancer developed 'frothy' urine. The results

suggest nephrotic range proteinuria. Assuming the proteinuria is related to his colorectal 
cancer what is the renal histology most likely to show? Membranous glomerulonephritis  
 
May 2012 exam: H/O peripheral oedema with no past medical history of note. His urinary 
protein is 4.2g/24 hours. BP is 160/92 mmHg. A renal biopsy shows: thickened capillary 
walls& Subepithelial deposits.Given the likely diagnosis, which one of the following

drugs is most likely to be beneficial?  ACE inhibitor (∆ membranous glomerulonephritis)  
IgA nephropathy 
Basics 
 also called Berger's disease or mesangioproliferative glomerulonephritis 
 commonest cause of glomerulonephritis worldwide 
 thought to be caused by mesangial deposition of IgA immune complexes 
 there is considerable pathological overlap with Henoch-Schonlein purpura (HSP) 
 Has a male preponderance

 Has a male preponderance  
 commonly diagnosed in the age range of 20- 40. 
Differentiating between IgA nephropathy and post-streptococcal glomerulonephritis 
 
 post-streptococcal glomerulonephritis is associated with low complement levels 
 main symptom in post-streptococcal glomerulonephritis is proteinuria (although haematuria 
can occur) 
982

  63   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  there is typically an interval between URTI and the onset of renal problems in post-
streptococcal glomerulonephritis 
Presentations

Presentations 
 young male, recurrent episodes of macroscopic haematuria 
 Haematuria occurs within 12-24 hours of pharyngitis,  
 typically associated with mucosal infections e.g., URTI , or less commonly infection of othe r 
mucous membranes (e.g. GI, bladder, breast). 
 accompanied also by loin pain, muscle pain and fever.  
 nephrotic range proteinuria is rare 
 The majority of patients have normal renal function.  
 renal failure

 Alcoholic  cirrhosis ( Alcohol excess) (haematuria + alcohol excess  IgA 
nephropathy).  
 coeliac disease/dermatitis herpetiformis 
 Henoch-Schonlein purpura 
Diagnosis 
 Renal biopsy is the investigation of choice to confirm the diagnosis 
 histology: Mesangial hypercellularity,   
 positive immunofluorescence for IgA & C3 
 No specific treatment is available. Observation is the most appropriate management

 steroids/immunosuppressants not be shown to be useful .  
 Treatment with corticosteroids is usually reserved for those patients with 
hypertension and a rising creatinine.  
 When there is nephrotic range proteinuria (>3 g/day) an 8-12 week course of prednisolone 
should be prescribed.  
 If the proteinuria is <3 g/day an ACE inhibitor can be used.  
Prognosis 
 30% of children will have a spontaneous remission within 10 years 
 25% of patients develop ESRF within 20 years

 25% of patients develop ESRF within 20 years 
 markers of good prognosis: frank haematuria 
 markers of poor prognosis:  
 male gender,  
 proteinuria (especially > 2 g/day),  
 smoking,  
 hyperlipidaemia,  
 ACE genotype DD 
 
September 2011 exam: A 17-year-old man with several episodes of visible haematuria. 
occurs within a day or two of URTI . Urine dipstick is normal. What is the most likely 
diagnosis? IgA nephropathy  
 983

  64   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 January 2006 exam: A 10-year-old boy with past two days H/O sore throat associated with

blood in his urine. glomerulonephritis is suspected. What would a renal biopsy most 
likely show? Mesangial hypercellularity (∆ IgA nephropathy ) 
 
September 2007 exam: A 12-year-old boy with purpuric rash on the extensor surfaces of his lower 
legs + abdominal pain and an urticarial rash.  Urine dipstick reveals blood ++.What would be the 
likely finding on renal biopsy?  Mesangial hypercellularity (Henoch-Schonlein purpura is associated 
with IgA nephropathy)

with IgA nephropathy)  
 
January 2014 exam: A 19-year-old woman C/O painless visible haematuria, occur within a day or 
two of developing tonsillitis. BP is 148/90 mmHg. Given the likely diagnosis, which marker indicate 
poor prognosis? Hypertension (∆ IgA nephropathy ) 
 
September 2007 exam: Which one of the following is associated with a better prognosis in patients 
with IgA nephropathy? Frank haematuria  

Post-streptococcal glomerulonephritis 
 typically occurs 7-14 days following a group A beta-haemolytic Streptococcus  infection 
(usually Streptococcus pyogenes ).  
 caused by immune complex (IgG, IgM and C3) deposition in the glomeruli.  
 Young children most commonly affected. 
Features  
 general: headache, malaise 
 haematuria 
 nephritic syndrome 
 low C3 
 normal C4 level or only slightly reduced, indicating activation of the alternate complement 
pathway

pathway 
 Depressed CH 50 level 
 raised ASO titer 
Renal biopsy features 
 post-streptococcal glomerulonephritis causes acute, diffuse proliferative glomerulonephritis  
 endothelial proliferation with neutrophils 
 electron microscopy: subepithelial 'humps' caused by lumpy immune complex deposits.  
The hump-like appearance in subepithelial space is characteristic of post-
streptococcal glomerulonephritis . 
 'Lumpy-bumpy' appearance on immunofluorescence is characteristic.

 immunofluorescence: granular or 'starry sky' appearance 
 'wire-loop' lesions on light microscopy. 
 There is antibody and compliment deposition on immunostaining. 
 
Prognosis   
 Carries a good prognosis    984

  65   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Age is the most important prognostic factor  in post-streptococcal glomerulonephritis.

95% of affected children recover completely, compared with 25% of adults over 60 years 
old.   
Membrano-proliferative glomerulonephritis (MPGN). 
Overview 
 also known as mesangio-capillary  glomerulonephritis (MCGN),  
 may present as nephrotic syndrome, haematuria or proteinuria 
 It is associated with SLE, cryoglobulinaemia with or without hepatitis C , chronic infections

(SBE) , neoplasms. hepatitis B, schistosomiasis, malaria and leprosy,may also be 
associated 
 Circulating immune complexes are seen 
 Classically associated with decreased serum C3 (and a normal C4, indicating activation of 
the alternative pathway of complement).  
 Hypocomplementemia (Low C3 levels) is a characteristic finding with all types of (MPGN). 
 
Type 1 
 accounts for 90% of cases

Type 1 
 accounts for 90% of cases 
 histology: sub-endothelial immune deposits  of electron dense material,  Thickening 
and  splitting of the capillary basement membrane , resulting in a 'tram-track' 
appearance  
 causes: cryoglobulinaemia (  low C3 ), hepatitis C  (hepatitis C is endemic among the iv 
drug-users ). Hepatitis C is now considered the principal cause of 'idiopathic' 
mesangiocapillary glomerulonephritis (MCGN),  
Type 2  - 'dense deposit  disease'

Type 2  - 'dense deposit  disease' 
 causes: partial lipodystrophy, factor H deficiency , may be idiopathic or may occur after 
measles  
 reduced serum complement 
 C3b nephritic factor (an antibody against C3bBb) found in 70%  low C3  
 characterised by mesangial cell proliferation with electron-dense, linear intramembranous 
deposits that stain positive for C3 
 may be associated with: 
 Partial lipodystrophy  
 reduced plasma levels of C3, C4  
 hepatitis B or C  
Type 3

Type 3 
 Subepithelial and subendothelial deposits 
 causes: hepatitis B and C 
985

  66   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  steroids may be effective 
 September 2009 exam: patient of nephrotic syndrome is noted to have marked loss of

subcutaneous tissue from the face. What is the most likely underlying cause of her renal 
disease? Membranoproliferative glomerulonephritis type II (∆ partial lipodystrophy)  
 
September 2009 exam: A patient develops membranoproliferative glomerulonephritis 
secondary to partial lipodystrophy. Which type of complement is likely to be low? C3 
Rapidly progressive glomerulonephritis (RPGN)

Rapidly progressive glomerulonephritis (RPGN) 
 
 is a rapid loss of renal function associated with the formation of epithelial crescents  in the 
majority of glomeruli.   
 results in a rapid decrease in GFR of at least 50% over a short period (a few days to 3 
months).  
 The most aggressive GN, with potential to cause ESRF over days. 
 
Causes  
 Goodpasture's syndrome 
 Wegener's granulomatosis  others: SLE, microscopic Polyarthritis 
 secondary syphilis 
 
Types

Types  
Rapidly progressive glomerulonephritis (RPGN) is classified into three major groups: 
 Type I RPGN  (~3%): Serum anti-glomerular basement membrane (Anti-GBM) antibody is 
positive. Antibody deposits along the glomerular basement membrane in a linear fash ion. 
Example: Goodpasture syndrome. 
 Type II RPGN : Immune complex disease (~45% of cases): (Anti-GBM) antibody is 
negative, but irregular immune complex (antibody-antigen) deposits are found within the

glomeruli. Example: lupus nephritis and post-streptococcal glomerulonephritis. 
 Type III RPGN : (Pauci-immune  disease (~50% of cases, 80 –90% ANCA +ve): Serum anti-
neutrophil cytoplasmic (ANCA) antibodies are positive. Example: Wegener  granulomatosis 
and microscopic polyangiitis. 
 
Features 
 nephritic syndrome: haematuria with red cell casts, proteinuria, hypertension, oliguria  
 features specific to underlying cause (e.g. haemoptysis with Goodpasture's, vasculitic rash

or sinusitis with Wegener ’s 
 Immunofluorescence detects deposits of IgG and C3 in the glomerular BM 
986

  67   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  The main pathological finding is fibrinoid necrosis  ˃ 90% of biopsy specimens with

extensive crescent formation  in at least 50% of the glomeruli. These crescents are 
collections of epithelial cells and macrophages proliferation within the Bowman ’s space. 
Treatment   
 Aggressive immunosup pres sion with high-dose IV steroids and cyclophosphamide  
 +/- plasma exchange.  
 
Prognosis : 5-year survival 80%. 
 
January 2012 exam: H/O chronic sinusitis, haemoptysis and  microscopic haematuria.

cANCA (PR3)= Positive. Given the likely diagnosis, what findings would be expected on 
renal biopsy? Crescentic glomerulonephritis  
Focal segmental glomerulosclerosis (FSGS) 
 cause nephrotic syndrome and chronic kidney disease.  
 generally presents in young adults. 
 Incidence: 40% in adults.  20% in children of cases of nephrotic syndrome  
 have a high recurrence rate in renal transplants  
Causes  
 idiopathic   (in 80%)

Causes  
 idiopathic   (in 80%) 
 secondary to other renal pathology e.g. IgA nephropathy, reflux nephropathy  
 HIV 'collapsing glomerulopathy' 
 heroin 
 Alport's syndrome 
 sickle-cell 
 associated with severe obesity  
 
Histology 
 histology may appear normal and may be confused with minimal change 
nephropathy  
 deep glomeruli at the corticomedullary junction are affected first, these may be missed on

transcutaneous biopsy, leading to a mistaken diagnosis of a minimal change glomerular 
lesion 
 hyaline deposits consist of IgM, C3, IgA  
 fibrinogen are deposited in juxtamedullary capillaries 
 
Treatment  
 50% of (FSGS) do not respond to stero id 
  (ACE) inhibitors are a recognised strategy to slow the progression of renal disease. 
Prognosis 
 It leads to chronic renal failure in 50% of cases.  
 FSGS recurs in 40% of renal transplants

 FSGS recurs in 40% of renal transplants 
 
January 2011 exam:  A patient with H/O heroin abuse, his creatinine = 156, urine show = ++ protein. What is 
the most likely cause of his deteriorating renal function?  Focal segmental glomerulosclerosis  (Heroin is a 
known cause of focal segmental glomerulosclerosis)  987

  68   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Goodpasture's syndrome 
 
Goodpasture's syndrome is characterised by pulmonary haemorrhage and crescentic 
glomerulonephritis.

glomerulonephritis. 
 
 Goodpasture's syndrome is rare condition associated with both pulmonary haemorrhage 
and rapidly progressive glomerulonephritis.  
 more common in men (sex ratio 2:1)  
  has a bimodal age distribution (peaks in 20-30 and 60-70 age bracket).  
Genetics  
 associated with HLA DR2   
 p-ANCA  positive in 30% and is directed against myeloperoxidase. 

 It is a type II cytotoxic reaction  caused by anti-glomerular basement membrane (anti-GBM) 
antibodies against the α 3 chain of type IV collagen  (basement membrane of both the 
kidneys and lungs).   
  Goodpasture syndrome is due to IgG antibodies produced against the basement 
membrane causing damage via a type II hypersensitivity reaction .  
 
Features 
 pulmonary haemorrhage  
 respiratory symptoms can vary from minimal hemoptysis to massive alveolar

hemorrhage , leading to respiratory failure. In lungs, this is a type 2 
hypersensitivity  reaction. 
 Hemoptysis is a clinical feature of Goodpasture's syndrome due to cross 
reaction of anti-glomerular basement membrane antibodies  at the lungs. 
 cough 
 Fever 
 followed by rapidly progressive glomerulonephritis (RPGN) ( Renal impairment is caused by 
a crescentic glomerulonephritis )  
 proteinuria, and 
 red cell casts.

 red cell casts.    
Factors which increase likelihood of pulmonary haemorrhage 
988

  69   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  normally, the alveolar epithelium prevents contact of antibody with basement membran e

collagen, thus any condition that  increases permeability of alveoli  can cause triggering 
of this syndrome. Such susceptibility factors include: 
 smoking 
 lower respiratory tract infection 
 pulmonary oedema 
 inhalation of hydrocarbons and toxic gases 
 young males 
 
 serological testing  (for anti-GBM antibodies)  
 biopsy  from kidney rather than lung. 
 Renal biopsy: linear IgG deposits along basement membrane  (the most likely

finding on renal biopsy  Linear immunofluorescence)  
 raised transfer factor secondary to pulmonary haemorrhages.   
 Serial measurement of carbon monoxide (CO) diffusing capacity or transfer factor (Tlco) 
can be used to monitor progression, 
 
 ABC  
 If the patient is hypoxic   intubate  and mechanically ventilate the 
patient.  
 Patients should not smoke and should avoid hydrocarbon exposure.

 The most appropriate initial management  IV methylprednisolone and 
cyclophosphamide 
 plasma exchange (plasmapheresis) 
 Where there is severe haemoptysis, rapid removal of anti-GBM antibody is indicated, 
and the best way to do this is by plasmapheresis at a specialist centre.   
 This is usually accompanied by pulsed therapy with IV methylprednisolone and 
cyclophosphamide. 
 steroids 
 cyclophosphamide 
 Response is assessed by monitoring symptoms and anti-GBM antibody titres.

 Cyclophosphamide and prednisolone continued, typically for 6 - 9 months following 
remission.  
 
In the acute setting , treatment is focused on: 
1. managing life threatening complications of renal failure, such as hyperkalaemia   
haemodialysis.  
2. Removing the circulating auto-antibody responsible for disease  plasmapharesis 
(therapeutic plasma exchange), 
 the most important management step in the next few days after haemodialysis   
 
Prognosis:

 Despite treatment, the mortality  of Goodpasture's is 11% and it has a high morbidity  with 
60% of patients becoming dependent on dialysis. 989

  70   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  In practice, glomerulonephritis proves to be a much commoner threat to survival than lung 
haemorrhage,

haemorrhage, 
 
Other causes of raised anti-GBM antibody levels: 
 Some healthy individuals exposed to inhaled oils,hydrocarbons or solvents can hav e 
borderline raised anti-GBM antibody levels. 
 Anti-GBM antibodies have also been detected in HIV-negative patients with Pneumo cystis 
 
Nephrotic syndrome 
Triad of: 
 1. Proteinuria (> 3g/24hr) (The minimum proteinuria which is defined as 'nephrotic' is 
300 mg/mmol)  causing  
 2. Hypoalbuminaemia (< 30g/L) and

 2. Hypoalbuminaemia (< 30g/L) and 
 3. Oedema   
 Loss of antithrombin-III, proteins C and S and an associated rise in fibrinogen levels  
predispose to thrombosis.  
 Loss of thyroxine-binding globulin lowers the total, but not free, thyroxine levels. 
 Increased serum cholesterol 
 ↑(LDL)  
 LDL and VLDL are removed from serum by lipoprotein signals. If the 
lipoprotein is lost in the urine with nephrotic syndrome, then the lipid levels in 
the blood rise.

the blood rise. 
 HDL is usually normal 
 ↓↓ Ca & vit D (loss of  25-hydroxyvitamin D3 (25OHD3) in the urine  hypocalcaemia )  
 Serum C3 levels are decreased in immune complex-mediated glomerulonephritis 
 
 Nephrotic Nephritic 
Common primary causes Membranous 
Minimal change 
FSGS  
Mesangiocapillary GN IgA nephropathy 
Mesangiocapillary GN 
Common secondary 
causes Diabetes 
SLE (class V nephritis) 
Amyloid 
Hepatitis B/C Post streptococcal 
Vasculitis 
SLE (other classes of nephritis)

SLE (other classes of nephritis) 
Anti-GBM disease (Figs 1 & 2) 
Cryoglobulinaemia 
BP Normal –mild Ĺ Moderate –severe Ĺ 
Urine Proteinuria >3.5g/day Haematuria (mild –macro) 
GFR Normal –mild Ĺ  Moderate –severe Ļ 
 990

  71   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Causes  
Nephrotic syndrome - malignancies cause membranous glomerulonephritis 
 glomerulonephritis accounts for around 80% of cases

 minimal change glomerulonephritis (causes 80% in children, 30% in adults) 
 membranous glomerulonephritis 
 focal segmental glomerulosclerosis (FSGS). 
 Patients presenting with isolated heavy proteinuria without the other 
components of nephrotic syndrome  is more likely due to (FSGS).  
 membranoproliferative glomerulonephritis 
 Systemic disease (about 20%) 
 diabetes mellitus  
 (Diabetic nephropathy often presents as nephrotic syndrome but typically

develops at least 15 years after onset). 
 systemic lupus erythematosus 
 amyloidosis ( in patient with chronic inflammatory state , amyloidosis is the 
likely cause of NS)  
 Drugs 
 gold (sodium aurothiomalate), penicillamine 
 Others 
 congenital 
 neoplasia: carcinoma, lymphoma, leukaemia, myeloma 
 Chronic lymphocytic leukemia (CLL) and Non-Hodgkin's lymphoma (NHL) are 
the most common hematologic malignancies associated with glomerular 
diseases.

diseases. 
 Membranoproliferative glomerulonephritis (MPGN) are most common 
glomerular disease associated with CLL and NHL 
 the most common renal lesion associated with Hodgkin's disease is minimal 
change disease 
 infection: bacterial endocarditis, hepatitis B, malaria ( commonly plasmodium 
malariae)  
 
991

  72   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Investigations  
 Renal biopsy  
 Contraindications for renal biopsy:  
 Abnormal clotting  
 Hypertension >160/>90mmHg

 Hypertension >160/>90mmHg  
 Single kidney  (except for renal transplants)  
 Chronic kidney disease with small kidneys (<9cm)  
 Uncooperative patient  
 Horseshoe kidney  
 Renal neoplasms.  
 
Serum electrophoresis in nephrotic syndrome 
 ↑ serum α- and β -globulin  fractions. (The increase in globulin fractions is thought to occur 
due to increased synthesis in patients with urinary protein loss)

 A monoclonal paraprotein band will be present where myeloma is the underlying ca use, 
 there may be associated immune paresis with reduced concentrations of one or more o f the 
immunoglobulins IgG, IgA or IgM 
 
 increased risk of infection in particular pneumococcal infections due to  urinary 
immunoglobulin loss  and decreased splanchnic blood flow.  
 Increased risk of thromboembolism related to loss of antithrombin III  and

plasminogen in the urine ,  increased fibrinogen and increased factor VIIIc.  Renal vein 
thrombosis occurs in 15-20% of patients with nephrotic syndrome  
 Renal vein thrombosis   
 Occurs in 10-20%  
 Feature   (loin pain + haematuria) and acute renal injury  
 Initial investigation  US (swollen oedematous kidney) 
 Diagnosis Duplex US renal veins, CT or MRV 
 Treatment  long term anticoagulation. 
 hypocalcaemia (vitamin D and binding protein lost in urine)

 Intravascular volume depletion : Hypoalbuminaemia results in decreased intravascular 
oncotic pressure, leading to leakage of extracellular fluid from blood to the interstitium 
Treatment 
 
 In general, steroids are tried first and then second line agents such as cyclosporin and 
cyclophosphamide are introduced if needed.  
 Cyclophosphamide is the best treatment for steroid-dependent nephrotic syndrome

 No more than two courses of cyclophosphamide should be prescribed in children 
because of the risk of side effects, which include azoospermia 
 An alternative to cyclophosphamide is ciclosporin, which is effective but must be 
continued long-term to prevent relapse on stopping treatment. Ciclosporin is also 
potentially nephrotoxic  992

  73   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 January 2006 exam: What changes in patients with nephrotic syndrome predispose to the

development of venous thromboembolism? Loss of antithrombin III  
__________________________________________________________   
Contrast-induced nephropathy  
 Contrast media nephrotoxicity may be defined as a 25% increase in creatinine occurring 
within 3 days of the intravascular administration of contrast media. 
 Most likely to occur 48 to 72 hours after the administration of intravenous 
contrast   
 eg: intravascular contrast agent during angiography

 A continued enhancement of the kidneys  days after contrast injection suggests contrast-
induced nephropathy. 
Risk factors include  
 known renal impairment (especially diabetic nephropathy)  25% 
 In those patients with pre-existing renal disease & (creatinine > 400 mmol/l) without  
diabetes  60% 
 In those patients with pre-existing renal disease & (creatinine > 400 mmol/l) with 
diabetes  100% 
 In an unselected population the incidence  2% to 7% 
 age > 70 years 
 dehydration

 the use of nephrotoxic drugs such as NSAIDs 
 Metformin is usually withheld for 48 hours after the use of contrast  
 Adequate hydration is the most important step to prevent contrast media 
 the evidence base currently supports the use of intravenous 0.9% sodium chloride 
at a rate of 1 mL/kg/hour for 12 hours pre- and post- procedure.

 There is also evidence to support the use of isotonic sodium bicarbonate.   
 When patients are dialysis-dependent it would be potentially dangerous to "pre-
hydrate" the patient and potentially fluid overload them.  
 N-acetylcysteine (usually given orally) has been shown to reduce the incidence of contrast-
nephropathy in some studies but the evidence base is not as strong as for fluid the rapy   
 
 The magnetic resonance angiography with gadolinium

 According to the latest guidelines, the need for a gadolinium-based contrast stu dy 
should be avoided in any patient with chronic kidney disease stage 3 or greater.   
 The magnetic resonance angiography with gadolinium is not recommended 
because it carries a risk of nephrogenic systemic fibrosis  
 This toxicity of gadolinium cannot be circumvented by hydration or N-acetylcyste ine 
 Dialysis-dependent patients who receive contrast for a CT  scan may need haemodialysis

to remove the contrast.  
 MR contrast  tends not to be nephrotoxic and therefore haemodialysis is not usually 
necessary to remove MR contrast. 
 993

  74   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
January 2014 exam: Which one is the most important step in reducing the risk of contrast-induced

nephropathy? Intravenous 0.9% sodium chloride pre- and post-procedure  
Analgesic nephropathy 
 common in women , F : M = 2: 1 , and presents most often in middle age 
 caused by non-steroidal anti-inflammatory drugs (NSAIDs) for chronic pain or headache,  
 Characteristically, associated with phenacetin use, particularly in Australia and New 
Zealand

Zealand 
 features may include anaemia , chronic renal failure, symptoms of urinary tract  
infection , haematuria or hypertension. 
 Complications 
 Urinary tract malignancy  (8-10% of patients with analgesic nephropathy),  
 For example, in women under the age of 50 analgesic abuse is the most commo n 
cause of bladder cancer. 
Renal stones 
 
 The most common stones are calcium oxalate  stones followed by calcium phosphate.

 Calcium phosphate stones are seen in renal tubular acidosis (RTA).  
 
 hypercalciuria, hyperparathyroidism, hypercalcaemia 
 cystinuria  ( AR defect in dibasic amino acid transporter) 
 high dietary oxalate. hyperoxaluria (for example, XS intake, ileal disease and bypa ss) 
 renal tubular acidosis => (Calcium phosphate stones) 
 medullary sponge kidney, polycystic kidney disease 
 beryllium or cadmium exposure 
994

  75   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Chronic infection with urea splitting organisms: causes stones made of magnesium

ammonium phosphate and calcium phosphate (infection stones (5%) 
 Familial :  Idiopathic hypercalciuria  inherited as autosomal dominant whereas cystinuria, 
cystinosis, urate uropathy and hyperoxaluria are autosomal recessive conditions.  
 the most common cause being increased gastrointestinal (GI) absorption of calcium.  
 The most common stones are calcium oxalate stones.    
 there appears to be a male predominance with a 2:1 ratio.

Risk factors for oxalate stones  (Calcium oxalate) 
 foods high in oxalate, (such as spinach, rhubarb and tea)  
 In patients who have oxalate kidney stones, dietary restrictions are necessary. 
Foods that should be avoided include: spinach, nuts, chocolate, dry beans, rhubarb 
and strawberries. 
 calcium-restricted diet 
 gastrointestinal disease such as Crohn's which increase colonic oxalate absorption

 in malabsorption,  the calcium in the small bowel is bound by the unabsorbed e xcess 
fatty acids. Oxalates are left free and are excessively absorbed. Subsequently, they 
can deposit in the kidney to form stones.  
 enteric oxaluria may occur in a number of disorders in which malabsorption results in 
excessive colonic absorption of oxalate . These include:  
 Coeliac disease 
 Crohn's disease 
 Chronic pancreatitis, and 
 Short bowel syndrome.

 Short bowel syndrome. 
 Bile salts in the colon increase oxalate absorption. 
 Excess vitamin C can be converted to oxalic acid in the body. Subsequent 
hyperoxaluria can lead to the formation of a kidney stone.  
Risk factors for urate stones 
 gout 
 ileostomy:  
 loss of bicarbonate and fluid results in acidic urine, causing the precipitation of uric 
acid 
 high purine intake,  
 High cell turnover. (for example, haematological malignancy).

 Primary polycythaemia would predispose to uric acid stone formation, whereas 
secondary polycythaemia does not. 
 Thiazide diuretics  cause hyperuricaemia and can predispose to hyperuricosuria 
and uric acid stone formation . 
 
Stag-horn calculi  (Triple phosphate stones: magnesium ammonium phosphate):  
 
 involve the renal pelvis and extend into at least 2 calyces.  
 They develop in alkaline urine and are composed of struvite (ammonium magnesium

phosphate, triple phosphate).  
 Urea plasma urea lyticum and Proteus infections predispose to their formation 995

  76   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Proteus produces urease, which leads to hydrolysis of urea to produce ammonia,

this leads to precipitation of organic and inorganic salts, one of which is known as 
struvite, or magnesium ammonium phosphate 
 classically produced by urea splitting organisms such as Klebsiella  or Proteus . 
 
Drug causes 
 drugs that promote calcium stones: loop diuretics, steroids, acetazolamide, theophylline 
 topiramate (anti-epileptic) increase the propensity to form calcium phosphate stones.  
 thiazides can prevent calcium stones (increase distal tubular calcium resorption)

Renal conditions associated with recurrent urinary tract infections : 
 Reflux nephropathy . 
 Renal stone (but is less likely than reflux nephropathy)  
 
Hypercalcuria   
Thiazide diuretics reduce renal tubular calcium excretion, and therefore can prevent calcium stone  
formation. 
 
 high urine calcium that is not due to hypercalcemia (idiopathic hypercalciuria)  
 Idiopathic hypercalciuria is often familial, the most common cause being increased

gastrointestinal absorption of calcium. 
 predisposes to stone formation. 
 The 24-hour urine is an essential component of the initial evaluation and guides 
recommendations for prevention  
 Treatment including dietary calcium restriction and pharmacological management. 
 Both thiazide diuretics and potassium citrate can be used to reduce urinary excretion  of 
calcium. Potassium citrate is generally preferred as it has fewer side effects,  and is 
therefore better tolerated.

therefore better tolerated. 
 Thiazide diuretics are the drug treatment of choice as they act directly on the renal 
tubule to reduce urinary calcium excretion  ( there is a disagreement between 
onexamination and pastest in which drug is better for hypercalcuria? But after thorough 
review of sources and uptodate, thiazide is a better  choice than potassium citrate ) 
 Dietary calcium restriction alone has minimal effect on calciuria, given the large am ount of

calcium that can be mobilised from bone.. 
 Loop diuretics increase urinary excretion of calcium, and therefore would exa cerbate 
calcium renal stone formation. 
 Pencillamine is used in the management of hypercalcuria associated with Wilson 's disease 
 Idiopathic hypercalciuria  has a familial or sporadic pattern . In the familial pattern an 
autosomal dominant inheritance is present. The type of the disease is identical in affected

members of the same family and the typical presentation is of recurrent urinary calculi.  
 
Imaging   996

  77   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 The table below summarises the appearance of different types of renal stone on x-ray  
 
Type Frequency Radiograph appearance

Type Frequency Radiograph appearance 
Calcium oxalate 
(the most common)  40% Opaque 
Mixed calcium oxalate/phosphate 
stones 25% Opaque 
Triple phosphate stones 10% Opaque 
Calcium phosphate 10% Opaque 
Urate stones 5-10% Radio-lucent 
Cystine stones 1% Semi-opaque, 'ground-glass' 
Xanthine stones <1% Radio-lucent 
 
 patients presenting to the Emergency Department usually have a KUB x-ray (sho ws 60% of 
stones)

stones) 
 the imaging of choice is a non-contrast CT (NCCT). 99% of stones are identifiable on 
NCCT.  
 
Imaging  (European Association of Urology guidelines 2016)  
 Ultrasound (US) should be used as the primary diagnostic imaging tool.  
 US is safe (no risk of radiation), reproducible and inexpensive.  
 US has a sensitivity of 45% and specificity of 94% for ureteric stones and a 
sensitivity of 45% and specificity of 88% for renal stones.

 the preferred method of imaging in pregnant women. 
 KUB (kidney-ureter-bladder radiography) x-ray 
 The sensitivity: 44-77% and specificity: 80-87%.  
 should not be performed if NCCT is considered.  
 KUB is helpful in differentiating between radiolucent and radiopaque stones and be 
used for comparison during follow-up.  
 Non-contrast CT (NCCT)  
 The imaging of choice  is a non-contrast CT (NCCT).  
 become the standard  for diagnosing acute flank pain

 99% of stones are identifiable on NCCT. 
 Following initial ultrasound assessment, use non-contrast-CT to confirm stone 
 more accurate than intravenous urography (IVU), so has replaced it. 
 
 Imaging in pregnant women 997

  78   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  first-line  ultrasound as the preferred method of imaging 
 second-line  magnetic resonance imaging (MRI)

 second-line  magnetic resonance imaging (MRI) 
 last-line option  low-dose computed tomography (CT) 
 
Acute management of renal colic  
 
Medication   
 the British Association of Urological Surgeons (BAUS) recommend diclofenac 
(intramuscular/oral) as the analgesia of choice for renal colic* 
 *Diclofenac use is now less common following the MHRA warnings about 
cardiovascular risk. 
 It is therefore likely the guidelines will change soon to an alternative NSAID such as

naproxen 
 BAUS also endorse the widespread use of alpha-adrenergic blockers to aid ureteric stone 
passage 
 Stones < 5 mm will usually pass spontaneously.  
 Lithotripsy and nephrolithotomy may be for severe cases. 
Prevention of renal stones  
Calcium stones  may be due to hypercalciuria, which is found in up to 5-10% of the genera l 
population.  
 high fluid intake 
 the main initial treatment 
 should aim for a daily urinary output in excess of 2000 ml.

 low animal protein, low salt diet (a low calcium diet has not been shown to be superior to a 
normocalcaemic diet) 
 thiazides diuretics (increase distal tubular calcium resorption)  and hence lower 
calcium concentration in the urine.  
Oxalate stones 
 cholestyramine reduces urinary oxalate secretion 
 pyridoxine reduces urinary oxalate secretion 
 High fluid intake and calcium carbonate are mainstay of prevention. 
 Avoid foods high in oxalate such as chocolate, rhubarb and nuts .

  Increasing dietary calcium intake decreases urinary oxalate excretion by reducing 
absorption (as free oxalate is bound).  
 Other treatments which can help enteric hyperoxaluria include : 
 Calcium, cholestyramine and magnesium - bind strongly to free intestinal oxalate, 
preventing absorption. 
 Iron and aluminium - act as intestinal oxalate binding agents. 
 Potassium citrate - alkalinises the urine, which reduces urinary oxalate excretion.

  propensity to form stones is reduced when citrate intake is increased. 
 Uric acid ston es 
 allopurinol 
 urinary alkalinization e.g. oral bicarbonate 
 Reducing intake of offal is most helpful at reducing urate excretion 998

  79   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Contraindications to lithotripsy 
 absolute contraindication   uncorrected bleeding disorder

 relative contraindications  Ureteric stricture, UTI and cardiac pacemaker  
 
September 2008 exam: What is the most likely composition of a stag-horn calculus? Struvite  
 
September 2012 exam: What are stag-horn calculi normally composed of? Magnesium 
ammonium phosphate  
Cystinuria 
 The commonest inborn error of amino acid transport. 
 Amino acids excreted in urine are cystine, ornithine, arginine and lysine (mnemonic - 
COAL).

COAL). 
 The glomerulus is unable to resorb these amino acids, and they are therefore excreted into 
the urine . 
Genetics 
 autosomal recessive  condition. 
 The rBAT gene is responsible,  
 There are two genes identified: 
 SLC3A1 (Chromosome 2)and  
 SLC7A9(Chromosome 19) 
Features:   
 Cystinuria usually presents with recurrent nephrolithiasis  in the form of cystine stones 
(which are often bilateral, multiple, and can form staghorns).

 The renal stones are semi radio-opaque due to the presence of sulphur. (Semi-o paque, 
'ground-glass' appearance) 
 On plain film, which is not used as much in the UK any more, they are radio-lucent.  
 On CT, as with almost all stones, cysteine stones are radio-opaque. 
 
Diagnosis 
 Diagnosis of cystinuria can be made by stone analysis ; such stones are pale yellow and 
analysis reveals high cystine levels. It can then be confirmed by an amino acid

chromatogram and quantification of cystine excretion. 
 cystine may precipitate out as pathognomonic hexagonally-shaped crystals  
 
Management  includes :  
 conservative 999

  80   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  high fluid intake (>4 L/day); 
 alkalinisation  
 Urine pH should be regularly monitored (aiming for 7.5-8), with sodium bicarbonate

being used if necessary (not in hypertensive patients or those with renal failure). 
 The aim of such treatment is to reduce the urinary cystine concentration to below 
300 mg/L. 
 If this fails, d-penicillamine, alpha-mercaptopropionylglycine or captopril can be used . 
 Cystine stones are not easily broken by lithotripsy, and therefore percutaneous removal is 
most often used. 
 Cystinosis   
 autosomal recessive

Cystinosis   
 caused by mutations in the CTNS gene, which encodes a lysosomal transporter of the 
amino acid cystine. Without this transporter, cystine accumulates in the lysosomes of 
proximal tubule cells, eventually leading to cell toxicity.  
 the most common form of Fanconi syndrome in children. 
 occurs almost exclusively in whites.  
Feature  
 presents in the first year of life with  
 failure to thrive, and rickets

 failure to thrive, and rickets  
 progressive renal damage (Renal failure develops before the age of 10 years) 
 polyuria, polydipsia  
 Visual impairment (occurs as a result of cystine deposits in the retina and cornea)   
Renal tubular acidosis (RTA) 
 All three types of renal tubular acidosis (RTA) are associated with hyperchloraemic 
metabolic acidosis (normal anion gap)

metabolic acidosis (normal anion gap)  
Type 1 RTA (distal) (acid retention) 
 Inability to generate acid urine (secrete H+)  by a failure of the alpha intercalated cells of 
the distal tubule  to excrete hydrogen ions.  
 Causes 
 Idiopathic,  gene defects, 
 Autoimmune disease such as primary biliary cirrhosis, thyroiditis  RA, SLE, Sjogren's, 
 Drugs: amphotericin B toxicity , analgesic nephropathy ,  
 hypergammaglobulinaemic states, 
 Features

 Features  
 hypokalaemia,  (as K+ reabsorption is linked to H+ excretion).   
 acidosis 
 low urinary ammonium production 1000

  81   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  inability to lower the urinary pH below 5.3 after ammonium chloride administration  
despite systemic acidosis  
 low urinary citrate

 low urinary citrate  
 Hypercalciuria:  These predispose to renal stones, rickets or osteomalacia and 
nephrocalcinosis 
 nephrocalcinosis and renal stones (  Alkaline urine increases the risk of calcium 
deposition ) 
 Osteomalacia develops because of calcium loss and buffering of retained H+ in bone  
 Bicarbonate and potassium supplements should be given to maintain adequate 
plasma levels.

plasma levels.  
 
Abdominal x-ray showing nephrocalcinosis - a classical finding in type 1 RTA 
 
Type 2 RTA (proximal) (bicarbonate loss) 
 decreased HCO3- reabsorption in proximal tubule 
 very rare in adult practice  
 As the distal tubule functions normally, the acidosis is less severe than type 1 RTA, and 
they urine has a pH of less than 5.3.  
 Causes  include 
 idiopathic,  
 as part of Fanconi syndrome,  
 Wilson's disease ,  
 cystinosis,  
 outdated tetracyclines

 outdated tetracyclines 
 carbonic anhydrase inhibitors   
 Features  
 The cardinal features are acidosis, hypokalaemia and hypophosphataemia  
 increased risk for hypophosphatemic rickets. 
1001

  82   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Complications 
 osteomalacia ( Phosphate wasting results in marked bone demineralisation )

Type 4 RTA (hyperkalaemic) ( hypoaldosteronism) 
 
 the most common renal tubular disorders 
 Causes  include: 
 hypoaldosteronism ,  
 diabetes   
 Diabetic nephropathy is associated with decreased renin production.  
 Patients with diabetes may have impaired extrarenal potassium homeostasis, 
caused by a lack of insulin, and autonomic neuropathy with resulting impaired 
beta2 -mediated influx of potassium into cells. 
 chronic reflux nephropathy

 chronic reflux nephropathy  
 decreased aldosterone production, secondary to: 
 diabetic hyporeninism,  
 angiotensin-converting enzyme inhibitors, angiotensin receptor blockers,  
 non-steroidal anti-inflammatory drugs,  
 heparin,  
 cyclosporine, or  
 adrenal insufficiency.  
 Features:  
 hyperkalaemia  
 usually mild but may be exacerbated by drugs such as beta-blockers and 
ACE inhibitors. 
 low sodium 
 metabolic acidosis

 metabolic acidosis 
 reduction in  renin and aldosterone leads in turn to a reduction in proximal tubular 
ammonium excretion 
 Treatment:  
 Treatment is usually successful with conservative measures  such as:  
 stopping provocatory agents,  
 low potassium diet.  
 Small doses of fludrocortisone  could be considered for refractory cases.  
 
Type 3 RTA  (Juvenile RTA) is combined proximal & distal RTA. 

 Results from inherited carbonic anhydrase II deficiency.  
 70% of the reported cases are from the Magreb region of North Africa 
 rarely discussed 
  described as a failure to generate NH3 in the setting of a decreased glomerular filtrat ion 
rate,   
 normokalaemic hyperchloraemic metabolic acidosis. 
 Asyndrome of osteopetrosis  
 Renal tubular acidosis 1002

  83   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Cerebral calcification 
 Mental retardation. 
 
Type  Type 1  Type 2  Type 4  
Location  Distal tubules Proximal tubules Adrenal

Acidosis?  Yes (severe) Yes Mild when present 
Potassium  Hypokalemia Hypokalemia Hyperkalemia 
Pathophysiology  H+ secretion Bicarb reabsorption hypoaldosteronism/ 
pseudohypoaldosteronism 
 
January 2010 exam:  Which feature is most likely to be seen as a consequence of type 1 
renal tubular acidosis? Nephrocalcinosis  
Renal vascular disease (RAS)

Renal vascular disease (RAS) 
 
The presence of difficult to treat hypertension, renal impairment, evidence of other 
atherosclerotic disease (carotid bruit) and discrepent renal size makes 
renovascular disease a distinct possibility.  
 
 Renovascular disease is due to disease affecting the arterial supply of the kidney(s).  
 The resulting renal hypoperfusion leads to hyperactivation of the renin-angiote nsin-
aldosterone axis, causing hypertension.

aldosterone axis, causing hypertension. 
 In one third of cases the disease is bilateral; 40% may have peripheral vascular disease 
and there may be proteinuria.  
 
Suspicion for renal artery stenosis:  
Current UK guidelines with regard to chronic kidney disease recommend referral for further 
investigation of atherosclerotic renal artery stenosis when there is:  
 Refractory hypertension (BP >150/90 mmHg despite 3 antihypertensives);

 Recurrent episodes of pulmonary oedema despite normal left ventricular function; 
 Rise of >20% serum creatinine or fall of GFR >15% over 12 months  with high clinical 
suspicion of widespread atherosclerosis, or during the first 2 months after initiation with an 
ACE inhibitor or angiotensin receptor blocker. 
 
A rise in serum creatinine more than 20% above the baseline  after starting an angiotensin-

converting enzyme inhibitor (ACEI) should prompt the clinician to hold the drug,  monitor re nal 
function and investigate for renal artery stenosis. 
 
1003

  84   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Causes  
 Atherosclerosis is most common cause (> 95% of patients).

 Arteriosclerosis (renal artery sclerosis) is a more common cause of RAS than fibromuscular 
dysplasia.  
 40% may have peripheral vascular disease (PVD) with intermittent claudication 
  there may be proteinuria.  
 In younger patients however fibromuscular dysplasia (FMD) needs to be considered.  
 FMD is more common in young women   
 and characteristically has a 'string of beads' appearance  on angiography .  
 Patients respond well to balloon angioplasty

 Patients respond well to balloon angioplasty   
 renal artery narrowing is unlikely to progress  
 Takayasu's arteritis  
 Congenital RAS is extremely rare and may be associated with coarctation of the aorta 
Associated risk factors  
 Smoking and hypertension that cause atheroma elsewhere in the body.  
Presentation  It may present as: 
  Hypertension , which can be resistant to standard treatment. 
 chronic renal failure  
  'flash' pulmonary oedema.

  'flash' pulmonary oedema. 
 It can also lead to renal impairment when patients are started on ACE inhibitors or 
angiotensin-II receptor antagonists, hypokalaemia or flash pulmonary oedema . A rise 
in creatinine of 15% from baseline is expected with commencement of an ACE-
inhibitor.  
 
 MR angiography is now the investigation of choice and can be performed safely in 
patients with CKD stage 3 and 4

patients with CKD stage 3 and 4  
 CT angiography.  Commonly used, but can be complicated by radio-contrast nepropathy in 
patients with CKD. 
 conventional renal angiography is less commonly performed used nowadays, but may st ill 
have a role when planning surgery 
 Atherosclerotic renal artery stenosis (RAS) is suggested by the asymmetric reduction in 
renal size on U/S, with mild proteinuria quite common in the condition.  
 ↑↑ Aldosterone  
 ↑↑ Renin

 ↑↑ Renin  
 Serum renin can differentiate renal artery stenosis (↑↑ Renin +↑↑ Aldosterone) 
from primary hyperaldosteronism ( ↓↓ Renin +↑↑ Aldosterone)  
 ↑↑ Renin work as a mechanism to improve renal perfusion.  
 ĻĻ Renin in primary hyperaldosteronism is due to the resulting hypertension causing 
excessive renal perfusion, which results in decreased renin production (negative 
feedback mechanism).  
 
 1004

  85   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Flash pulmonary edema, U&E s worse on A CE inhibitor , asymmetrica l 
kidneys 
Ļ 
Rena l Artery Stenosis 
Ļ 
do MR angiography

Ļ 
Ļ 
do MR angiography  
 Optimize vascular risk factors,  
  cautious use of ACE inhibitors and angiotensin-II receptor antagonists and avoiding oth er 
nephrotoxics.  
 The current evidence favours medical therapy in these patients, that is, an 
antiplatelet agent (aspirin), lipid lowering therapy (simvastatin) and tight blood 
pressure control (amlodipine).  
 No benefit of vascular intervention such as stenting.

 The ASTRAL trial showed no significant difference between stenting and me dical 
therapy, it is often decided on an individual level.  
 Although patients with unilateral renal artery stenosis who have recurrent pulmona ry 
oedema may benefit from stenting, the optimal first step is control of hypertension.  Per 
se, better targeting of blood pressure is likely to reduce the number of episodes of heart 
failure.

failure.  
 Renal artery stenting to reduce further risk of pulmonary oedema is the next step 
following medical therapy to control blood pressure.  The subsequent reduction in renin 
production will reduce the incidence of heart failure.  
 Although surgical renal artery bypass is successful, it is invasive and associated with 
significant operative morbidity versus percutaneous stent insertion.  
  
Indication for stenting in renal artery stenosis:( mrcpass.com)

 hemodynamically significant renal artery stenosis 
 Flash pulmonary oedema 
 episodic pulmonary edema,  
 congestive cardiac failure, 
 unstable angina.   
 
Prognosis   
 poor prognosis ( 80% mortality at five years ) is related to concurrent coronary disease.  
SLE: renal complications 
 Lupus nephritis affects a third of patients  early in the disease it is frequently unrecognised

until nephritic and/or nephrotic syndrome with renal failure occur. 
 
WHO classification 
 class I: normal kidney 
 class II: mesangial glomerulonephritis 
 class III: focal (and segmental) proliferative glomerulonephritis 1005

  86   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  class IV: diffuse proliferative glomerulonephritis 
 class V: diffuse membranous glomerulonephritis

 class V: diffuse membranous glomerulonephritis 
 class VI : sclerosing  glomerulonephritis 
 end stage renal disease  
 irreversible 
 not respond to any immunosuppression 
Class IV (diffuse proliferative glomerulonephritis) 
 is the most common  
 the most severe form , affecting > 50% of glomeruli,  
 Renal biopsy  characteristically shows the following findings: 
 glomeruli shows endothelial and mesangial proliferation, 'wire-loop'  appearance

 the capillary wall may be thickened secondary to immune complex deposition 
 electron microscopy shows subendothelial immune complex deposits 
 granular appearance on immunofluorescence 
 
Class V (Membranous nephropathy in SLE) 
 Nephrotic syndrome without haematuria in a patient with (SLE) suggests 
membranous nephropathy (class V) 
 The lesion is differentiated from idiopathic (non-lupus) membranous nephropathy by :

 The presence of tubuloreticular structures on electron microscopy, immune deposits 
along the tubular basement membrane (in addition to the glomerular basement 
membrane)  
 and the presence of concurrent subendothelial and mesangial immune dep osits (in 
addition to the subepithelial deposits typical of membranous)   
 Class V lupus nephritis is the only form of renal disease in SLE where serological 
and clinical manifestations of the underlying disease may be absent. Compleme nt

levels may be normal and dsDNA antibodies may be absent 
 
 Hypertension is found at presentation in 20-50% 
 20-30% present with acute renal failure 
 Lupus nephritis typically occurs in SLE patients with extrarenal symptoms such as a 
rash, arthralgia, Raynaud's phenomenon, and pleuro-pericarditis  
 
Laboratory features 
 Proteinuria is found in all patients with lupus nephritis and in 50-60% of cases is he avy 
enough to lead to a nephrotic syndrome

enough to lead to a nephrotic syndrome 
 Microscopic haematuria (80% of patients) 
 In lupus nephritis a biopsy is indicated in those patients with abnormal urinalysis 
and/or reduced renal function , for  histological classification ,disease activity, 
chronicity and prognosis.  
 
Immunological features 
 the pathognomonic feature of lupus on renal biopsy is 'full house' immunology on 
immunostaining, ie mesangial deposition of IgA, IgG, IgM, C3 and C4  1006

  87   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  This differentiates the necrotising glomerulonephritis with crescent formation seen in

lupus from a similar pattern which is seen in systemic vasculitis, as the latter 
condition is 'pauci immune', ie no immunoglobulin deposition   
 Lupus nephritis is associated with activation of the classical pathway , and often 
associated with suppression of both C3 and C4.   
 
Prognosis 
 Features associated with a poorer prognosis , and increased risk of progression to end 
stage renal failure include:  
 young age (<23) 
 Increased serum creatinine

 Increased serum creatinine 
 Diffuse proliferative lesions (WHO classification class IV) and 
 high chronicity index on renal histologic analysis. 
 treat hypertension 
 corticosteroids if clinical evidence of disease 
 immunosuppressants e.g. azathiopine/cyclophosphamide 
 patients with type IV (and sometimes type III, where < 50% of glomeruli are involved) 
should be treated with a combination of cyclophosphamide and steroids,

Urinary incontinence 
 Urinary incontinence (UI) is a common problem, affecting around 4-5% of the population .  
 It is more common in elderly females.  
Causes  
 overactive bladder (OAB)/ urge incontinence : due to detrusor over activity   
 The most common cause of post-prostatectomy incontinence in the patient with  
Parkinson's disease is detrusor hyperreflexia

Parkinson's disease is detrusor hyperreflexia 
 associated with hereditary spastic paraplegia (HSP) 
 stress incontinence : leaking small amounts when coughing or laughing 
 Urethral hypermobility is one of the most common causes of stress incontinence, 
which is common in postmenopausal women.  
 mixed incontinence : both urge and stress 
 overflow incontinence : due to bladder outlet obstruction, e.g. due to prostate enlargement

 Impaired detrusor contractility is the underlying mechanism of overflow incontinen ce, 
 loss of sphincter function   Total incontinence 
  is likely to occur in patients with a history of spinal dysfunction (due to previous 
surgery, trauma, nerve damage, metastasis)  
Initial investigation 
 bladder diaries should be completed for a minimum of 3 days 
 vaginal examination to exclude cystocele 
 urine dipstick and culture

 urine dipstick and culture 
Management  depends on whether urge or stress UI is the predominant picture.  
If urge incontinence is predominant: 1007

  88   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  bladder retraining (lasts for a minimum of 6 weeks, the idea is to gradually increase the 
intervals between voiding)

intervals between voiding) 
 bladder stabilising drugs: (antimuscarinic) is first-line 
 Oxybutynin  is an effective treatment for detrusor instability and is a parasympathetic 
muscarinic antagonist.  
 Consequently dry mouth is a problem in up to 70% of cases.  
 surgical management: e.g. sacral nerve stimulation 
If stress incontinence is predominant: 
 pelvic floor muscle training (for a minimum of 3 months) 
 surgical procedures: e.g. retropubic mid-urethral tape procedures

March 2017 part 2: A 72-year-old woman with urinary incontinence. Urodynamic studies 
confirm detrusor overactivity and significant post-voiding residual volume. She is unable to 
tolerate oxybutynin for bladder control due to postural hypotension and GI symptoms. 
Which of the following is the most appropriate intervention for control of her bladder 
symptoms?  
 Sacral nerve stimulator  
 
Type of incontinence Pathophysiolog ical 
mechanism Key featu res Treatment

mechanism Key featu res Treatment 
Stress incontinence   Increase in intra-
abdominal pressure (e.g
., from laughing, 
sneezing, coughing , 
exercising) ѧ  Ѧ 
pressure within the 
bladder 
ѧ bladder pressure > 
urethral sphincter 
resistance to urinary 
flow   Urinary leakage on 
activities 
that increase intra-
abdominal pressure  General principles of treatment 
of urinary incontinence  
 Duloxetine , surgery (see 
“Treatment ” in stress 
incontinence ) 
Urge incontinence   Inflammatory

Urge incontinence   Inflammatory 
conditions or 
neurogenic disorders ѧ 
sphincter dysfunction, 
detrusor overactivity 
or overac tive 
bladder   ѧ autonomous 
contractions of the 
detrusor muscle and 
premature initiation of 
a normal micturition  Strong, sudden sense 
of urgency, followed by 
involuntary leakage  General principles of treatment 
 Anticholinergic medication, 
surgery (see “Treatment ” in urge 
incontinence ) 1008

  89   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Type of incontinence Pathophysiolog ical 
reflex 
Mixed incontinence  Combination of

reflex 
Mixed incontinence  Combination of 
mechanisms of stress 
and urge incontinence   May have any of the 
clinical features above  General principles of treatment 
 Anticholinergics to treat aspects 
of urge incontinence  
Total incontinence  Complete loss of 
sphincter function (due 
to previous surgery, 
nerve damage, 
metastasis) or abnormal 
anatomy (fistula 
between urinary tract 
and skin)  Urinary leakage occurs 
at all times, with no

at all times, with no 
associated preceding 
symptoms or specific 
trigger activity  Gener al principles of treatment 
 Usually requires surgery 
Overflow 
incontinence(overf lo
w bladder)   Impaired detrusor 
contractility  and/or bla
dder outlet 
obstruction  ѧ chronical
ly distended 
bladder with Ѧ 
bladder pressure 
ѧ dribbling of urine 
when 
intravesical pressure > 
outlet resistance  Frequent, involuntary 
intermittent/continuous 
dribbling of urine in

dribbling of urine in 
the absence of an 
urge to urinate 
 Occurs only when the 
bladder is full 
 Often occurs with 
changes in position  Acute 
settings: intermittent catheteriz
ation 
 Timed voiding for day to day 
management 
 Treatment of underlying 
condition (see also “Treatment ” 
in urinary retention ) 
Further causes of 
urinary incontinence  Commonly seen 
in multiple 
sclerosis  or spinal cord 
injury   
 Detrusor sphincter 
dyssynergia  ѧ simultan

eous contractions of the 
detrusor muscleand 
involuntary activation of 
the internal urethral 
sphincter ѧ blockage of 
bladder outlet ѧ small  Voiding and/or storage 
dysfunction, intermitten
t voiding, urinary 
retention 
 Irregular, small 
volume incontinence wit
hout an associated urge 
to void(sometimes 
referred to as reflex 
incontinence)  General principles of treatment 
 Injection of botulinum toxin into

 Injection of botulinum toxin into 
the detrusor muscle  
 Transurethral resection of 
external urinary sphincter 
(TURS) 
 Alpha-blockers and/or 
anticholinergics 1009

  90   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
amounts of urine are 
pressed through the 
contracted sphincter

contracted sphincter 
muscle ѧ  high 
intravesical pressure 
along with 
inappropriate 
contraction of the 
Urinary retention  
 Causes: Drugs  
 Amitriptyline has anticholinergic effects being associated with tachycardia, dry 
mouth and urinary retention. 
 These features are not typical of selective serotonin reuptake inhibitors (SSRIs) such as

fluoxetine or seratonin and noradrenaline reuptake inhibitors (SNRIs) such as venlafaxine 
with urinary retention and dry mouth rarely reported. 
 Diazepam, a benzodiazepine does not have anticholinergic effects. It has bee n associated 
with urinary retention, but this is much less common than with anticholinergics. 
Recovery from obstructive uropathy  
 Amelioration of urinary obstruction and subsequent recovery initially results in a large 
electrolyte and water loss.

electrolyte and water loss. 
 Osmotic cerebral changes precipitated by urinary sodium loss, the major 
intravascular cation, is the cause of drowsiness. 
 Hypocalcaemia and hypomagnesaemia may occur as tubular reabsorption is suboptimal in 
the early stages of recovery, but is unlikely to affect conscious level. Acid-base sta tus 
should improve after relief of the obstruction. 
 Hyperglycaemia is not a common complication of recovery from obstructive uropathy.

Benign prostatic hypertrophy (BPH) 
 Age: around 50% of 50-year-old men will have evidence of BPH and 30% w ill have 
symptoms. Around 80% of 80-year-old men have evidence of BPH 
 Ethnicity: Black > White > Asian 
Features 
BPH typically presents with lower urinary tract symptoms (LUTS), which may be categorized into: 1010

  91   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  Voiding symptoms (obstructive): weak or intermittent urinary flow, straining, hesitancy, 
terminal dribbling and incomplete emptying

terminal dribbling and incomplete emptying 
 Storage symptoms (irritative) urgency, frequency, urgency incontinence and nocturia 
 Post-micturition: dribbling 
 Complications: urinary tract infection, retention, obstructive uropathy 
 
 If the suspicion is of prostatic hypertrophy, then  post-void residual volume is the best 
way to estimate the degree of bladder obstruction. 
Management options 
 Watchful waiting 
 Medication:

 Medication:  
 α-blocker (e.g. tamsulosin, alfuzosin)  for rapid symptom relief 
 Considered first-line, improve symptoms in around 70% of men 
 α-Blockers relax the smooth muscle of the bladder neck and can 
improve urinary flow rates  
 Ļ smooth muscle tone (prostate and bladder)  
 Adverse effects: dizziness, postural hypotension, dry mouth, depression 
 5 α-reductase inhibitors ( e.g. finasteride and dutasteride)  to reduce 
prostate volume

prostate volume  
 Block the conversion of testosterone to dihydrotestosterone (DHT), which 
induces BPH 
 Unlike α -1 antagonists causes a reduction in prostate volume and hence 
may slow disease progression. This however takes time and symptoms may 
not improve for 6 months.  
 They may also Ļ PSA concentrations by up to 50%  
 Adverse effects: erectile dysfunction, Ļ libido, ejaculation problems, 
gynecomastia

gynecomastia   
 The use of combination  (α-1 antagonists, 5 α -reductase inhibitors) therapy was 
supported by the medical therapy of prostatic symptoms (MTOPS) trial 
 Surgery: transurethral resection of prostate (TURP) 
 
1011

  92   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Prostatic carcinoma 
A man of advanced age presenting with bony metastases is most likely to have 
metastatic prostate cancer.

metastatic prostate cancer. 
 
 These are  adenocarcinomas  and hormonal factors are thought to play a part in the 
aetiology 
 As a rule, prostate cancer is more aggressive in younger men.  
 Prostate cancer begins in the outer peripheral zone of the prostate, and grows outward , 
invading surrounding tissue. BPH begins in an area of the inner prostate called the 
transition zone, a ring of tissue that makes a natural circle around the urethra. In BPH, the

growth is inward  toward the prostate ’s core. 
 Prostate cancer is now the most common cancer in adult males in the UK and is the second 
most common cause of death due to cancer in men after lung cancer.  
 By 80 years of age some 80% of men appear to have malignant foci within the 
prostate gland  
 Prostatic carcinoma is found in 10-30% of patients with BPH. 
 
Risk factors ( BPH is not a risk factor ) 
 Ĺ age (the strongest risk) 
 obesity

 obesity 
 High intake of animal fats  low intake of selenium 
 Afro-Caribbean ethnicity 
 family history: 5-10% of cases have a strong 
family history 
 
Features  
 Localised prostate cancer is often asymptomatic. This is partly because cancers tend to 
develop in the periphery of the prostate and hence don't cause obstru ctive symptoms early 
on.  
 bladder outlet obstruction: hesitancy, urinary retention 
 haematuria, haematospermia

 haematuria, haematospermia 
 pain: back, perineal or testicular 
 digital rectal examination: asymmetrical, hard, nodular enlargement with loss of median 
sulcus 
Investigation (NICE 2015)  
 lower urinary tract 
symptoms  or 
 erectile dysfunction or 
 visible haematuria  
} assess for prostate cancer 
(PSA)  test and digital rectal 
examination   
↑ 
PSA     Refer for P. cancer 
      (within 2 weeks) 
 
 Prostate-specific antigen (PSA)  
 (PSA) may be elevated in: 
 Prostatitis

 Prostatitis 
 Benign prostatic hyperplasia, and 
 Prostate cancer. 
 Some prostatic carcinomas may not be associated with an elevated PSA.  
 False positives PSA associated with:  1012

  93   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  UTI & catheterisation thus should be measured at least two weeks after 
a treated UTI . 
 prostatic needle biopsy  
 PR examination

 PR examination 
 False negatives PSA: Finasteride  is the only factor likely to decrease the level 
of serum PSA.  
 Trans-rectal prostatic biopsy 
 The most commonly used pathological grading system is the Gleason score  
 The most well differentiated tumours have a Gleason score of 2, and the mos t poorly 
differentiated a Gleason score of 10.  
 Bone scan, CT abdomen and pelvis also indicated to assess both extent of bo ny

metastases and local spread. (metastases may mimic the appearance of Paget's) 
 
Management:  depends on histological grading of the tumour  
prostate cancer stage  Treatment options 
Localised (T1/T2) 
T1 - clinically unapparent disease 
T2 - palpable disease confined to 
prostate   conservative: active monitoring & watchful 
waiting 
 radical prostatectomy 
 radiotherapy: external beam and brachytherapy 
Localised advanced (T3/T4) 
T3 = beyond prostatic capsule

T3 = beyond prostatic capsule 
T4 = involves bladder neck or rectum 
Most men will have occult mets  hormonal therapy: see below 
Metastatic hormonal therapy  
 Synthetic GnRH agonist 
 e.g. Goserelin (Zoladex) 
 cover initially with anti-androgen to 
prevent rise in testosterone 
 Anti-androgen 
 cyproterone acetate prevents DHT 
binding from intracytoplasmic protein 
complexes 
Orchidectomy

complexes 
Orchidectomy 
 
 Buserelin (Synthetic GnRH agonist) 
 Decreased androgen production 
 gonadotrophin releasing hormone agonist that exerts its actions at the level of the 
pituitary gland.  
 Initially treatment causes increased gonadotrophin release; however, after a few 
weeks of continued therapy, gonadotrophin production is inhibited, and testosterone 
levels fall.  
 The initial increase in testosterone levels may be accompanied by a ‘flare’ in disease

symptoms in some patients. 
What histological grading system is used to grade prostate cancer? 
 Gleason grading  
 Gleason grading takes account of the most prevalent tumour pattern in the 
pathological system (1-5) and the second most prevalent tumour pattern (1-5). 1013

  94   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  It is presented as, for example, Gleason 3+4 = 7. This is important as a Gleason 4+3

= 7 obviously has a worse prognosis than a Gleason 3+4 = 7 even though they both 
have the same total score. 
Neurogenic bladder 
 Although BPH is the commonest cause of obstructive renal failure  in older men, the need 
to consider neurogenic bladder when risk factors for this are present is very important 
 Neurogenic bladder is seen in : 
 diabetes mellitus, 
  multiple sclerosis,  
 cerebrovascular disease,

 cerebrovascular disease,  
 advanced Parkinson's disease,  
 spinal injuries 
Renal cell cancer  (also known as hypernephroma)  
 accounts for 85% of primary renal neoplasms.  
 It arises from proximal renal tubular epithelium 
Associations*  
 more common in middle-aged men 
 smoking 
 von Hippel-Lindau syndrome ( the most likely inherited condition)

is an inherited syndrome in which cysts or tumours in the kidney, pancreas, adrenal gland, 
epididymis, cerebellum, and spinal cord may form.(30 - 50% develops renal cell tumors) 
 tuberous sclerosis 
 *incidence of renal cell cancer is only slightly increased in patients with autosomal domina nt 
polycystic kidney disease 
Features 
classical triad: haematuria, loin pain, abdominal mass 
 only a minority being diagnosed with the classical triad of:Haematuria,Loin pain, A pal pable 
mass.

mass. 
 Haematuria is the presenting feature in 50-60% of cases  
 pyrexia of unknown origin 
 Anaemia  Fatigue 
 left varicocele (due to occlusion of left testicular vein) 
 endocrine effects:  
 may secrete erythropoietin (polycythaemia) Increased plasma viscosity. 
 may secrete parathyroid hormone (hypercalcaemia), renin, ACTH 
 25% have metastases at presentation 
 Commonest sites of metastases are lung (50-60%) and bone (30-40%)

 Urinalysis may show sterile pyuria 
 Liver dysfunction 
 Myopathy. 1014

  95   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
 Ultrasound scan of the renal tract would be the first investigation of choice , as it is

able to pick up 95% of renal cell carcinomas greater than 1 cm in diameter. It would also 
exclude infective or inflammatory collections within the renal tract. 
 If required a computerised tomography (CT) +/- guided biopsy could be obtained to prove  
the diagnosis.  
 
 for confined disease a partial or total nephrectomy depending on the tumour size 
 alpha-interferon and interleukin-2 have been used to reduce tumour size an d also treat 
patients with metatases

patients with metatases 
 receptor tyrosine kinase inhibitors (e.g. sorafenib,  sunitinib ) have been shown to have 
superior efficacy compared to interferon-alpha  
 recommended by NICE as a treatment for advanced renal cell carcinoma. 
Prognosis 
 Prognosis is related to tumour staging:  
 the 5-year survival rate is around 80-100% in those with TNM stage-1 lesions, but 
this falls to 5-10% in those with stage-4 lesions 
 
Wilms' tumour

Wilms' tumour 
 Wilms' nephroblastoma is one of the most common childhood malignancies.  
 typically presents in children under 5 years of age, with a median age of 3 years old. 
 primarily composed of blastema,  which is primitive kidney mesenchyme.  
Features  
 abdominal mass (most common presenting feature) 
 painless haematuria 
 flank pain 
 other features: anorexia, fever 
 unilateral in 95% of cases

 unilateral in 95% of cases 
 metastases are found in 20% of patients (most commonly lung) 
 Histologic examination is characterized by blastemal, stromal, and epithelial cells 
(triphasic tumor). 
 Beckwith-Wiedemann syndrome 
 as part of WAGR  syndrome with Aniridia, Genitourinary malformations, mental Retardation 
 hemihypertrophy 
 around one-third of cases are associated with a mutation in the WT1 gene on short 
arm of chromosome 11 
 nephrectomy

 nephrectomy 
 radiotherapy if advanced disease 
prognosis: 1015

  96   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
   good, 80% cure rate 
Angiomyolipoma

Angiomyolipoma  
 the most common benign tumour of the kidney 
  is a benign hamartomatous tumor composed of blood vessels, smooth muscle cells an d fat 
cells. 
 caused by mutations in either the TSC1 or TSC2 genes, which govern cell growth and 
proliferation.  
 commonly seen among patients with tuberous sclerosis.  
 also commonly found in women with the rare lung disease 
lymphangioleiomyomatosis.  
 Presentation:  
 retroperitoneal hemorrhage (most frequent)

 retroperitoneal hemorrhage (most frequent) 
 unilateral flank mass.  
 There are three methods of scanning that detect angiomyolipoma: ultrasound, CT 
and MRI.  
 Ultrasound is standard and is particularly sensitive to the fat in angiomyolipoma but 
less so to the solid components. However it is hard to make accurate measurements 
with ultrasound.  
 Computed tomography (CT) is very detailed and fast and allows accurate

measurement. However, it exposes the patient to radiation and the dangers that a 
contrast dye used to aid the scanning may itself harm the kidneys.  
 Magnetic resonance imaging (MRI) is safer than CT but many patients (particularly 
those with the learning difficulties or behavioural problems found in tuberous 
sclerosis) require sedation or general anaesthesia and the scan cannot be 
performed quickly.

performed quickly. 
 Some other kidney tumours contain fat, so the presence of fat isn't diagnostic. It can  
be difficult to distinguish a fat-poor angiomyolipoma from a renal cell carcino ma and 
a lesion growing at greater than 5 mm per year may warrant a biopsy in order to 
distinguish it from this form of cancer. 
 Large angiomyolipoma can be treated with embolisation. 
 do not normally require surgery unless there is life-threatening bleeding

Bladder cancer 
 In the Western world  
 transitional-cell (TCC) => 93% of bladder cancers 
 squamous-cell carcinomas (SCCs)  6%  
 adenocarcinomas  less than 1% 
 male: female ratio  3:1 
 women generally have a worse prognosis than men. 1016

  97   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  At the time of diagnosis around 70% of carcinomas are still localised to the bladd er, 20%

extend to involve regional lymph nodes and 3% present with distant metastases 
 Risk factors for  transitional cell carcinoma of the bladder include:   
 Smoking 
 Exposure to aniline dyes in the printing and textile industry 
 Rubber manufacture (exposure to nitrosamines (used in the manufacture of some 
cosmetics, pesticides, and in most rubber products) ) 
 Cyclophosphamide 
 Risk factors for squamous  cell carcinoma of the bladder include: 
 Schistosomiasis

 Schistosomiasis 
 Calmette-Gurin (BCG) treatment 
 Smoking 
Diagnosis 
 Cystoscopy is the gold standard for diagnosing bladder cancer. 
Treatment 
 Treatment of choice for localised tumours is transurethral tumour resection, with the use of 
intravesical chemotherapy. 
 
Orthotopic bladder reconstruction for carcinoma of the bladder: 
 Hyperchloraemic metabolic acidosis is a documented complication of neobladder 
formation.

formation.  
 Neobladder formation following radical cystectomy or cystoprostatectomy is 
becoming increasingly more common 
 Severe and persistent metabolic acidosis may manifest when patients undergo  
further surgery for other reasons .  
 Associated electrolyte abnormalities may include hypokalemia, hypocalcaemia, and 
hypomagnesaemia. 
 it's usually improves with time and is mild.  
 treat metabolic acidosis with intravenous fluids and bicarbonate.

 Intravenous infusion of 1.26% sodium bicarbonate and potassium 
replacement  
___________________________________________________ ___________ 
Rhabdomyolysis 
 
 Rhabdomyolysis will typically feature in the exam as a patient who has had a fall o r 
prolonged epileptic seizure and is found to have acute renal failure on admission  
 muscle trauma or necrosis   myoglobin ( a muscle protein ), which may cause tubular

damage  or blockage, intense renovascular constriction, and local inflammation  Acute 
renal failure 
 Rhabdomyolysis is strongly suggested by the fact that urinalysis is strongly positive for 
blood, whereas urine microscopy is negative for red blood cells. The positive urinalysis is 
caused by myoglobin , a muscle protein released during muscle damage; this appears in 
the urine and can cause acute renal failure. 
1017

  98   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
Causes 
 seizure 
 collapse/coma (e.g. elderly patients collapses at home, found 8 hours later) 
 ecstasy

 ecstasy 
 Crush injury : electrical injury, compartment syndrome, prolonged limb or tourniquet 
anaesthesia, extensive surgical dissection and infectious or inflammatory myopathies.  
 McArdle's syndrome 
 Metabolic myopathy 
 should be suspected when myoglobinuria is recurrent, associated with exercise or 
fasting and occurring with muscle cramps or weakness  
 Carnitine palmitoyltransferase (CPT) deficiency is the commonest cause of

inherited metabolic myopathy resulting in recurrent myoglobinuria 
 The enzyme defect is diagnosed using ischaemic forearm testing and muscle biopsy, 
which demonstrates abnormal lipid or glycogen deposits 
 Drugs: statins ( should be stopped in any patient presenting with the syndrome.)  
 
Features 
The biochemical features of rhabdomyolysis are raised creatine kinase, hypocalcaemia (especially 
early after injury), hyperkalaemia and acute kidney injury.

 acute renal failure with disproportionately raised creatinine 
 elevated CK , detectable a few hours after injury and peaks at the 48-h stage 
 myoglobinuria , on urine dipstick (shows as haematuria),  
 Urine is dark due to myoglobin.  
 Dipstick will be positive for blood (a false positive). On microscopy no red cells are 
seen although there may be pigmented granular casts. 
 hypocalcaemia  (myoglobin binds calcium) 
 elevated phosphate (released from myocytes) 
 hyperuricaemia

 hyperuricaemia  
 hyperkalaemia  
 
 IV fluids to maintain good urine output 
 urinary alkalinization is sometimes used  
Loin pain-haematuria syndrome 
 characterised by severe, unrelenting loin or flank pain and haematuria with 
dysmorphic features suggesting a glomerular origin 
 A recent report suggested an important psychological component  (unexplained somatic

symptoms, an adverse psychological event preceding the onset of pain and a history  of 
greater analgesic ingestion) 
 One possible explanation for the haematuria in some patients is coexistent thin basem ent 
membrane disease.  1018

  99   Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad                 
                                                                                                                                                                                      
  It was proposed that bleeding into and obstruction of the renal tubules was responsible for 
the loin pain 

 difficult to treat 
 Dependency on narcotic analgesia is common 
 Some patients undergo autotransplantation of the affected kidney in an attemp t to 
relieve the pain 
Renal tuberculosis 
 The combination of sterile pyuria, haematuria, dysuria and renal tract calcification is 
highly suggestive of renal tuberculosis 
 Many patients have refractory hypertension, which is renin-mediated and presumably due 
to segmental renal ischaemia

to segmental renal ischaemia 
 Excretion urography is the most helpful diagnostic investigation ,  may show cavitating 
lesions in the renal papillary areas, commonly with calcification. There may also be 
evidence of ureteral obstruction with hydronephrosis 
Xantho-granulomatous pyelonephritis (XGP) 
 It develops as an abnormal macrophage response to infection, particularly in the pres ence

of urinary tract obstruction, and is pathologically related to malacoplakia 
 A flank mass is usually palpable, thereby distinguishing it from simple acute pyelonep hritis 
or renal abscess, and occasionally mimicking renal cancer 
 The disease is almost invariably unilateral 
 Patients with XGP often appear chronically ill 
 Symptoms include anorexia, fevers, weight loss and flank pain 
Diagnosis

Diagnosis 
 The relatively rapid history, leukocytosis, renal impairment and positive urine culture make 
XPN much more probable than cancer 
 Computed tomography is the investigation of choice to confirm the diagnosis , and it 
will show the replacement of renal parenchyma by rounded, low-density areas surrounded  
by a ring of enhancement; it will also establish the extent of the lesion (which ma y involve 
surrounding structures) 
Prognosis and complications

Prognosis and complications 
 The course may extending over months or years 
 AA amyloid may develop, resulting in the onset of nephrotic syndrome 
Vesico-ureteric reflux 
Vesico-ureteric reflux management: 
 in childhood: surgical intervention would be beneficial.  
 When picked up in adulthood, the mainstay of management would be  
 blood pressure control

 blood pressure control  
 Strict glycaemic control (reduce the frequency of recurrent infections and 
reduce the risk of progression to diabetic nephropathy.)  
 prompt treatment of UTI and careful surveillance during pregnancy. 
 1019

  100    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
  Vesicoureteric reflux refers to the retrograde flow of urine from the bladder to the upper 
urinary tract

urinary tract  
 It is the most common cause of recurrent urinary tract infections in children.  
 This may occur due to incompetence of the valve at the vesicoureteric junction 
 It is most commonly detected the earliest in newborn girls 
 Present with recurrent UTI 
 Micturating cystourethrography  is the most useful investigation  to check for 
vesicoureteric reflux during voiding in children. It is identified in approximately 40% of

patients. (not useful in adult women because by this time the reflux tends to disappear) 
 the single most appropriate management for grade-V vesicoureteric reflux in child 
less than 1 year  Antibiotic prophylaxis 
 
grade Age(year) scaring Initial treatment Follow up 
V < 1 No Antibiotic prophylaxis Surgery  
V 1-5 No If unilateral: antibiotic prophylaxis  Surgery  
V 1-5 No If bilateral: surgery   
V 1-5 Yes Surgery   
V > 5  Surgery   
 
Grading of vesicoureteric reflux

Grading of vesicoureteric reflux  
 
grade Description  
I Reflux into a non-dilated ureter  
II Reflux into the upper collecting system without dilatation  
III Reflux into a dilated ureter and/or blunting of calyceal fornices  
IV Reflux into a grossly dilated ureter  
V Gross dilatation of the ureter, renal pelvis and calyces; calyces show loss of papillary 
impression  
Chronic reflux nephropathy (Chronic pyelonephritis)

 Chronic pyelonephritis  is also known as 'reflux nephropathy':  
 starts in infancy or early childhood, 
 predisposes to recurrent infections and progressive renal fibrosis and 
loss of function 
 the kidneys are small, shrunken and scarred 
Renal scarring  
 is a serious complication of chronic pyelonephritis that occurs due to vesicoureteric reflux. 
  It is mediated by cytokines, chemokines and their receptors, complement, adhesion 
molecules and extracellular matrix proteins.

molecules and extracellular matrix proteins.  
 The cytokines which seem to play the largest role are: 
 interleukin (IL)-1beta,  
 IL-3 
 Transforming growth factor (TGF)-beta .  1020

  101    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
  TGF-beta in particular seems to be pro-fibrotic  by recruiting fibroblasts ,

 In a genotype where its production is limited has been shown to be less likely 
to develop renal scarring. 
 
 Chronic reflux nephropathy should be suspected in the presence of multiple urinary tract 
infections, including during childhood 
  may present with difficult- to-treat hypertension in young age 
 The investigation of choice is excretion urography (Micturating cystourethrogram) , 
which may show : 
 an irregular renal outline,  
 calyceal clubbing

 calyceal clubbing  
 and cortical scarring on the affected side 
 The best course of action is to recognise this condition in childhood and consider surgical 
management where demonstrable ureteric reflux exists, or early intervention with antibio tics 
where repeat infection exists 
 Chronic reflux nephropathy is a relatively common cause of end-stage renal failure in late 
childhood or early adult life if it goes unrecognized

Recommendations  for the diagnostic evaluation of uncomplicated pyelonephritis  
 Perform urinalysis (e.g. using a dipstick method), including the assessment of white and 
red blood cells and nitrite, for routine diagnosis. 
 Perform urine culture and antimicrobial susceptibility testing in patients with 
pyelonephritis. 
 Perform ultrasound of the upper urinary tract to exclude obstructive pyelonephritis.

 Additional imaging investigations, such as an unenhanced helical computed tomograph y 
should be done if the patient remains febrile after 72 hours of treatment or in patients w ith 
suspected complications e.g. sepsis. 
  (European association of urology)  
Phimosis 
 Phimosis is common in 2 year olds 
 Prognosis and management 
 Most will slowly dilate, thus Wait and watch is the most appropriate treatment

 In those who have persistent problems into teenage years, around 85% will respo nd 
to topical steroids, reducing the need for circumcision 
 Where there is obvious infection, a dorsal slit may be considered   
Urethral syndrome 
 The condition is common in elderly postmenopausal women due to dryness and  atrophy of 
the urethral tissue 
 Presented with dysuria ,  increased frequency of micturition and sterile urine .

 Treatment : Topical oestrogen cream often results in a dramatic response  
 1021

  102    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
Urinary tract infection (UTI) in adults

Urinary tract infection (UTI) in adults 
Staphylococcus saprophyticus is the second leading cause of UTI in sexually active 
women ( E. coli  is the first).  
 
Classification of UTI   (European association of urology guidelines)  
UTIs Acute, sporadic or recurrent lower (uncomplicated cystitis) and/or upper 
(uncomplicated pyelonephritis) UTI, limited to non-pregnant, pre-menopausal 
women with no known anatomical and functional abnormalities within the

urinary tract or comorbidities. 
Complicated UTIs All UTIs which are not defined as uncomplicated. Meaning in a narrower 
sense UTIs in a patient with an increased chance of a complicated course: i.e. 
all men, pregnant women, patients with anatomical or functional abnormalities 
of the urinary tract, indwelling urinary catheters, renal diseases, and/or with 
other concomitant immunocompromising diseases for example, diabetes.

Recurrent UTIs Recurrences of uncomplicated and/or complicated UTIs, with a frequency of at 
least three UTIs/year or two UTIs in the last six months. 
Catheter-
associated UTIs UTIs in a person currently  catheterised or has been catheterised within the 
past 48 hours . 
Urosepsis A systemic, deleterious host response to infection originating from the urinary 
tract and/or male genital organs. Urosepsis is accompanied by signs of

systemic inflammation, presence of symptoms of organ dysfunction and 
persistent hypotension associated with tissue anoxia. 
 
Features 
 classic symptoms of (UTI): dysuria, frequency of urination, suprapubic tenderness, 
urgency, polyuria, haematuria  
 upper urinary tract infection (UUTI):  evidence of UTI with symptoms suggestive of 
pyelonephritis (loin pain, flank tenderness, fever, rigors or other manifestations of systemic 
inflammatory response).

inflammatory response). 
 lower urinary tract infection (LUTI):  evidence of UTI with symptoms suggestive of cystitis 
(dysuria or frequency without fever, chills or back pain).  
 
Diagnosis 
 Diagnosis of UTI is primarily based on symptoms and signs. Bacteriuria or pyuria do  not 
establish the diagnosis of UTI. 
 The gold standard test  for diagnosis of bacteriuria is culture of bladder urine obtained by

needle aspiration of the bladder as it minimises the risk of contamination of the urine 
specimen. 
 All other techniques (urethral catheter and midstream specimens of urine) carry a 
higher risk of contamination and therefore produce some false positive results 
 nitrite test:   1022

  103    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
  Gram negative organisms test positive on the nitrite test as they convert nitrates to 
nitrites for energy.

nitrites for energy.  
 
 Gram positive organisms are unable to reduce nitrate to nitrite and therefore, 
test negative.  
 UTI is usually diagnosed by  a bacterial count of >100 000/ml at mid-stream urine (MSU) 
 Presentation with a first urinary tract infection associated with haematuria in elderly 
patient  Re-testing of urine with cytological examination after antibiotics 
 Persistent haematuria should be investigated with excretion urography and cystoscopy

Recommendations for the diagnostic evaluation of uncomplicated cystitis 
(European association of urology)  
Diagnose uncomplicated cystitis based on: 
 a focused history of lower urinary tract symptoms (dysuria, frequency and urgency); 
 the absence of vaginal discharge or irritation, in women who have no other risk factors for 
complicated urinary tract infections. 
Use urine dipstick testing, as an alternative to culture for diagnosis of acute uncomplicated cystitis.

Urine cultures should be done in the following situations: 
 suspected acute pyelonephritis; 
 symptoms that do not resolve or recur within two-four weeks after the completion of treatment; 
 women who present with atypical symptoms; 
 pregnant women. 
 
Management  (Sign.uk recommendations for UTI 2012) 
 Men  
 urine sample should be taken for culture. 
 empirical antibiotics with a quinolone in men with symptoms suggestive of 
prostatitis. 
 Non-pregnant women  
 LUTI

 LUTI  
 Symptomatic bacteriuria  three-day course of trimethoprim or 
nitrofurantoin. 
 Amoxicillin, ampicillin, nitrofurantoin and oral cephalosporins may be 
considered as alternatives 
 Routine urine culture is not required to manage  
 If not respond to trimethoprim or nitrofurantoin  urine for culture to guide 
change of antibiotic 
 asymptomatic bacteriuria   Do not treat with an antibiotic.

 Recurrent UTI   consider using cranberry products to reduce the frequency 
of recurrence. 
 UUTI  
 ciprofloxacin (7 days) or co-amoxiclav (14 days). 
 Acute pyelonephritis 
 hospital admission should be considered 
 the BNF currently recommends a broad-spectrum cephalosporin or a 
quinolone (for non-pregnant women) for 10-14 days 1023

  104    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
 Pregnant women: 
 Treat symptomatic and asymptomatic UTI

 Treat symptomatic and asymptomatic UTI  
 Urine culture before starting empiric antibiotic and 7 days after completion empiric 
antibiotic treatment. 
 First line agent  Nitrofurantoin  
 A dose of 50 mg QDS or 100 mg BD of modified release for 7 days is 
 Care for nitrofurantoin 
 elderly patients may be at increased risk of toxicity. 
 contraindicated in significant renal impairment. The BNF advises 
against its use in patients with GFR<60.

against its use in patients with GFR<60. 
 Advise women with LUTI, who are prescribed nitrofurantoin, not to take 
alkalinising agents (such as potassium citrate). 
 Second line Trimethoprim  
 contra indicated in established folate deficiency, low dietary folate intake, or 
women taking other folate antagonists. 
 Third line cephalosporins  
 There is 20% cross-over with respect to allergy to penicillin and 
cephalosporins.  
 Complications

 Complications 
 asymptomatic bacteriuria  is associated with premature delivery  and low 
birthweight . 
 routine screening for  asymptomatic bacteriuria at antenatal 
appointments is therefore recommended. 
 Infections in pregnancy should be treated, as 25% of patients will develop 
acute pyelonephritis 
 
UTI in diabetes 
 Data from the American Diabetes Association have shown that 9.4% of people 
diagnosed with type 2 diabetes had a UTI compared to only 5.7% of those

without.  
 The most common pathogens isolated from the urine of diabetic patients with 
UTI were E. coli  and other Enterobacteriaceae such 
as Klebsiella  spp., Proteus  spp., Enterobacter  spp. and Enterococci. 
 Infection with Extended spectrum beta-lactamase-producing coli (ESBL-
producing E. coli  ) is an increasingly recognised cause of infection in diabetes  
patients and is associated with poor outcomes. 
 Carba penem s are generally considered the drug of choice for the

treatment of ESBL/ E. coli (ESBL –EC) infections 
 With a half-life of 4 h, ertapenem is commonly used as it is 
administered only once daily.  
 Fosfomycin is an oral antibiotic agent that has broad activity against multi-
drug-resistant pathogen, including ESBL –EC.  
 Another oral antimicrobial agent that can be considered for the treatment of 
ESBL -EC cystitis is nitrofurantoin. 
 
Extended spectrum beta lactamase (ESBL) urine infection  Intravenous meropenem  
 1024

  105    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
Antibiotic guidelines for urinary tract:  
The following is based on current BNF guidelines: 
 
Condition Recommended treatment

Lower urinary tract infection Trimethoprim or nitrofurantoin.  
Alternative: amoxicillin or cephalosporin 
Acute pyelonephritis Broad-spectrum cephalosporin or quinolone 
Acute prostatitis Quinolone or trimethoprim 
 
___________________________________________________ ___________
Asymtomatic bacteriuria (ABU)  
 
Risk factors for asymptomatic bacteriuria  
 Female sex 
  Sexual activity 
  Comorbid diabetes  Age 
  Institutionalisation

  Institutionalisation  
 Presence of catheter 
 
Recommendations for the management of ABU (European association of urology)  
 Do not screen or treat asymtomatic bacteriuria in the following conditions: 
 women without risk factors; 
 patients with well-regulated diabetes mellitus; 
 post-menopausal women; 
 elderly institutionalised patients; 
 patients with dysfunctional and/or reconstructed lower urinary tracts; 
 patients with catheters in the urinary tract;

 patients with catheters in the urinary tract; 
 patients with renal transplants; 
 patients prior to arthoplasty surgeries; 
 patients with recurrent urinary tract infections. 
 Screen for and treat asymptomatic bacteriuria prior to urological procedures breaching the  
mucosa. 
 Screen for and treat asymptomatic bacteriuria in pregnant women with standard sh ort 
course treatment. 
 Take a urine culture following treatment of asymptomatic bacteriuria to secure treat ment 
effect.

  106    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
 ___________________________________________________ ___________  
UTI in childhood

UTI in childhood 
 In up to 75% cases of single infection, no abnormality can be found 
 Escherichia coli is the most common organism isolated (> 70% of cases) 
 Chronic diarrhoea or even acute diarrhoea can be a presenting feature  of childhood 
urinary tract infection 
 Trimethoprim is often the best initial antibiotic of choice 
 In children (particularly neonates and infants), UTI can be haematogenous and may b e part

of a septicaemic process, therefore, blood cultures and iv antibiotics are necessary 
Recurrent urinary tract infection (rUTI) 
  two episodes of infection in six months, or three episodes in one year 
Incidence  
 annual incidence of a single UTI is 30 per 1000 women, with 44% experiencing recurrence  
within 12 months 
Risk factor  
 
Age-related risk factors for rUTI in women

Age-related risk factors for rUTI in women  
Young and pre-menopausal women Post-menopausal and elderly women 
 Sexual intercourse 
 Use of spermicide 
 A new sexual partner 
 A mother with a history of UTI 
 History of UTI during childhood 
 Blood group antigen secretory 
status  History of UTI before menopause 
 Urinary incontinence 
 Atrophic vaginitis due to oestrogen deficiency 
 Cystocoele 
 Increased post-void urine volume 
 Blood group antigen secretory status

 Blood group antigen secretory status 
 Urine catheterisation and functional status 
deterioration in elderly institutionalised women 
 
Diagnosis of rUTI  
 should be confirmed by urine culture. 
 
Recommendations  for the diagnostic evaluation and treatment of rUTIs  
 Do not perform an extensive routine workup in women with recurrent UTI without risk 
factors. 
 Advise patients on behavioural modifications which might reduce the risk of recurrent U TI.

 Use vaginal oestrogen replacement in post-menopausal women to prevent recurrent U TI. 
 Use immunoactive prophylaxis to reduce recurrent UTI in all age groups. 
 When non-antimicrobial interventions have failed, continuous or post-coital a ntimicrobial 
prophylaxis should be used to prevent recurrent UTI, but patients should be counse lled 
regarding possible side effects. 
 For patients with good compliance, self-administrated short term antimicrobial therap y 1026

  107    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
 should be considered. 
(European association of urology) 
 
Treatment

Treatment 
 After treating the acute infection, low dose antibiotics for 6-12 months  are the most 
evidence based preventive measure for recurrent (UTI) in women, and are recommended 
by Scottish Intercollegiate Guidelines Network and the European Association of Urology 
guidelines as the standard of care. 
 
Ref: 
  http://www.bmj.com/content/359/bmj.j5193

  http://www.bmj.com/content/359/bmj.j5193  
Non-antibiotic options for recurrent urinary tract infections in women (Published 23 November 2017) 
 European association of urology  http://uroweb.org/guideline/urological-infections/#3  
 
Recurrent lower urinary tract infection 
 Sexual activity in young females 
 Recurrent cystitis may often accompany the onset of sexual activity in young 
females

females 
 The appropriate first-line management is to advise strict attention to personal 
hygiene,  and an increase in fluid intake  and subsequent urine flow around times 
of sexual activity 
 Vesicoureteric reflux 
 Chronic reflux nephropathy:   
 the best diagnostic investigation is   Micturating cystourethrogram 
 Posterior urethral valves   
 the chief complaint of children with this disorder is a poor urinary stream 
 Urinary tract obstruction in BPH:

 Urinary tract obstruction in BPH:   
 post-void residual volume is the best way to estimate the degree of bladder 
Catheter-Associated UTI 
 Once catheter is in place, the  
 risk of bacteriuria Once catheter is in place: 
 short-term catheterization (ie, 2-4 days)  10% - 30%  
 long-term catheterization  90% -100%  
 the most common source of gram-negative bacteremia in hospitalized patients  
 Causes

 Causes  
 Enteric pathogens (eg, Escherichiacoli ) are most commonly responsible  
 Proteus  and Pseudomonas  species are the organisms most commonly associated 
with biofilm growth on catheters . 
 Candida , especially Candida albicans , is the second-most-common organism  
that can cause catheter-associated urinary tract infection or asymptomatic 
colonization  
 diagnosis  of catheter-associated urinary tract infection can be made when the urine

culture  shows 100 or more  CFU per mL of urine from a catheterized patient. 
 Treatment   1027

  108    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
  Symptomatic bacteriuria   
 mild to moderate infections  :oral quinolones, usually for 10 to 14 days.

 The recommended duration of therapy for severe infections  is 14 to 21 
days .  
 asymptomatic bacteriuria  
 not recommended , with the following  exceptions :  
 patients who are immunosuppressed after organ transplantation,  
 patients at risk for bacterial endocarditis and  
 patients who are about to undergo urinary tract instrumentation 
Urinary tract obstruction in children (posterior urethral valves)

 A poor urinary stream suggests a urinary tract obstruction (usually infravesical) 
 The most common cause in a male child is posterior urethral valves 
 posterior urethral valves:  symmetrical folds of urothelium extending distally from the 
prostatic urethra to the external urinary sphincter 
 Renal dysplasia is usually associated with posterior urethral valves 
 The best diagnostic method is a micturating cystourethrography 
 The other option is endoscopy .

 The other option is endoscopy . 
 30% of patients experience end-stage renal disease  
 Vesicoureteric reflux occurs in half the patients 
Urinary incontinence (UI) 
  (UI) is a common problem, affecting around 4-5% of the population.  
 more common in elderly females.  
 
Mechanisms  
 urge  incontinence /overactive bladder (OAB): due to detrusor over activity

 stress  incontinence: leaking small amounts when coughing or laughing 
 coughing, sneezing, and laughing  Ĺ intra-abdominal pressure and overwhelm the 
strength of bladder sphincter muscles in those with weak pelvic floors. 
 mixed  incontinence: both urge and stress 
 overflow  incontinence: due to bladder outlet obstruction, e.g. due to prostate enlargement  
 Autonomous neurogenic bladder (detrusor areflexia)

 caused by damage to the conus, cauda equina, and sometimes S2-4 nerve roo ts.  
 characterized by absent bladder sensation, decreased tone, increased  capacity, 
hesitancy, and significant residual urine. 
 
Management depends on whether urge or stress UI is the predominant picture. 
 If urge incontinence is predominant:

 If urge incontinence is predominant: 
 bladder retraining (lasts for a minimum of 6 weeks, the idea is to gradually increase 
the intervals between voiding) 
 bladder stabilising drugs: antimuscarinic is first-line 1028

  109    Notes & Notes for MRCP                                                                                      By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                                        
  In older men, tolterodine  is preferred to oxybutynin as the latter has a greater 
risk of causing confusion.

risk of causing confusion. 
 If anticholinergics fail or are contraindicated, mirabegron may be trialled.  
 Its mechanism of action is via beta-adrenoreceptor-mediated relaxation 
of the bladder wall.  
 surgical management: e.g. sacral nerve stimulation 
 If stress incontinence is predominant: 
 pelvic floor muscle training:  
 NICE recommend at least 8 contractions performed 3 times per day for a 
minimum of 3 months 
 surgical procedures: e.g. retropubic mid-urethral tape procedures

Which pharmacotherapies represents the most appropriate initial management step for 
overactive bladder? Tolterodine 
 1029

Rheumatology 
 
Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  1 
  
By
 
Rheumatology
 
Updated 
 
2017
 
Contains: 
 
 1030

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  2 
 Hyaline cartilage 
 Hyaline cartilage forms the articular surface 
 It is avascular , relying on diffusion from synovial fluid for nutrients 
 It is rich in type II collagen  and forms a meshwork containing  proteoglycan  molecules that 
retain water

retain water 
 Intermittent pressure from joint loading is essential to maintain normal cartilage functio n 
 Chondrocytes secrete proteoglycans and collagen and are embedded in the cartilage 
 Chondrocytes migrate to the joint surface along with the matrix that they produce  
Bone markers  
 Markers are useful for: 
  prediction of prognosis,  
 prediction of fracture risk,  
 assessing suitability for therapy and

 assessing suitability for therapy and 
 monitoring the success of therapy. 
 
Markers of bone formation  
(measured in serum) Markers of bone resorption 
(measurable in serum or urine) 
 Bone-derived alkaline phosphatase ( ALP).  
 Osteocalcin  
 Procollagen type 1 propeptides.  Telopeptides 
 Pyridinium cross-linking molecules 
 Tartrate-resistant acid phosphatase 
(TRAP) 
 Hydroxyproline. 
 Alkaline phosphatase  is useful but not specific to bone.

 Osteocalcin   
 is the main non-collagenous protein in bone.  
 During bone formation, osteoblasts make osteocalcin and release some of it into the 
circulation.  
 Resorption may cause a smaller increase in serum osteocalcin.  
 Collagen is made from procollagen , with cleavage of N- and C-terminal peptides. These 
peptides can be measured but are not as sensitive or specific as bone alkaline phosphat ase. 
Markers of bone resorption

Markers of bone resorption 
 Telopeptides and the pyridinium cross-linking molecules are formed during the hydrolysis of type 
1 collagen.  
 TRAP is released by osteoclasts directly but the serum also contains TRAP from other sources, 
making interpretation difficult.  
 Hydroxyproline is mainly found in collagens and is excreted in the urine when collag en is broken 
down: this is also non-specific.  
_____________________________________________________________________

Rheumatoid factor  
 
 Rheumatoid factor (RF) is a circulating antibody (usually IgM) which reacts with the Fc portion of 
the patients own IgG. 
 Rheumatoid factor is an antibody with reactivity to the heavy chain of IgG.   
 The rheumatoid factor may be of IgM, IgG or IgA class. 
 The conventional (agglutination) test, detects only IgM RF. 
1031

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  3 
  high titre levels are associated with severe progressive disease (but NOT a marker of disease 
 
RF can be detected by either:  
 Rose-Waaler test: sheep red cell agglutination 
 Latex agglutination test (less specific) 
 
A positive rheumatoid factor is associated with:  
 More severe erosive disease

 More severe erosive disease  
 Extra-articular manifestations including subcutaneous nodules and  
 Increased mortality.  
 
Conditions associated with a positive RF include:  
 Sjogren's syndrome (around 100%) 
 Felty's syndrome (around 100%) 
 Mixed cryoglobulinemia (types II and III) - 40 to 100% 
 rheumatoid arthritis (70-80%) 
 Mixed connective tissue disease - 50 to 60% 
 infective endocarditis (= 50%) 
 SLE (= 20-30%) 
 systemic sclerosis (= 30%)

 systemic sclerosis (= 30%) 
 Polymyositis/dermatomyositis - 5 to 10% 
 general population (= 5%) 
Rheumatoid arthritis 
 
Around 70% of patients with rheumatoid arthritis are HLA-DR4. Patients with Felty's syndrome  
(a triad of rheumatoid arthritis, splenomegaly and neutropaenia) are even more strongly 
associated with 90% being HLA- DR4 
 
 Prevalence = 1%  
 F:M ratio = 3:1

 F:M ratio = 3:1 
 there is a slight female preponderance.  In younger patients, females have a 2:1 predominance 
but as age increases this becomes closer to 1:1. 
 It appears to be milder in less developed countries, raising the possibility of some new 
environmental agent that may be more common in industrialised nations. 
 peak onset = 30-50 years, although occurs in all age groups 
 some ethnic differences e.g. high in Native Americans 
Aetiology 
 unknown.

Aetiology 
 unknown. 
 Genetics: (HLA), DRw4, is more common in patients with RA. 
 A number of studies have suggested a link between Proteus mirabilis  infection and the 
development of RA, and this may contribute to the increased incidence of RA in wo men, who are 
more susceptible to UTI.  
 Proteus mirabilis  is a bacterium in fecal flora. 
 Proteus mirabilis  is a Gram-negative, anaerobic, rod  
 molecular structure of Proteus mirabilis is very similar to cells in joints. 
1032

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  4 
  When the immune system develops antibodies to combat the bacteria, the an tibodies 
inadvertently attack the similarly structured joint tissues. 
Rheumatoid arthritis - TNF is key in pathophysiology 
 
 Cytokines affect all phases of the inflammatory process and tumour necrosis factor (TNF) ,

interleukin 1 , and interleukin 6 seem to be the most abundant in the joint. 
 TNF is an important in the pathogenesis of rheumatoid arthritis.   
 TNF is secreted mainly by macrophages  
 TNF blockers (e.g. infliximab, etanercept) are now licensed for treatment of severe RA. 
 See topic about TNF in immunology part 
 Rheumatoid arthritis involves pannus  formation , which leads to cartilage destruction and 
joint ankylosis.

joint ankylosis. 
 Pannus  is an abnormal layer of fibrovascular tissue or granulation tissue.  
 Common sites for pannus formation include over the cornea, over a joint surface 
(as seen in rheumatoid arthritis), or on a prosthetic heart valve.  
 Pannus may grow in a tumor-like fashion, as in joints where it may erode articular 
cartilage and bone. 
 
Diagnosis 
 
NICE have stated that clinical diagnosis is more important than criteria such as those defined b y the

American College of Rheumatology. 
 
2010 American College of Rheumatology criteria  
Target population. Patients who 
 1) have at least 1 joint with definite clinical synovitis 
 2) with the synovitis not better explained by another disease 
Classification criteria for rheumatoid arthritis (add score of categories A- D; 
a score of 6/10 is needed definite rheumatoid arthritis ) 
 
Factor Scoring 
A. Joint involvement  
 
 1 large joint 0 
 2 - 10 large joints 1

1 large joint 0 
 2 - 10 large joints 1 
 1 - 3 small joints (with or without 
involvement of large joints) 2 
 4 - 10 small joints (with or without 
involvement of large joints) 3 
 10 joints (at least 1 small joint) 5 
B. Serology (at least 1 test result is needed for 
classification)    
 Negative RF and negative ACPA 0 
 Low-positive RF or low-positive ACPA 2 
1033

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  5 
 Factor Scoring 
 High-positive RF or high-positive ACPA 3 
C. Acute-phase reactants (at least 1 test result is 
needed for classification)    
 Normal CRP and normal ESR 0 
 Abnormal CRP or abnormal ESR 1 
D. Duration of symptoms    
 < 6 weeks 0 
 > 6 weeks 1 
 Key 
 RF = rheumatoid factor

> 6 weeks 1 
 Key 
 RF = rheumatoid factor 
 ACPA = anti-cyclic citrullinated peptide antibody 
 
Differential diagnosis: 
 Rheumatoid arthritis typically affects the metacarpophalangeal and proximal 
interphalangeal joints symmetrically.  Psoriatic arthritis affects the distal interphalangeal 
joints and tends to be asymmetrical.  
 Rheumatoid arthritis vs osteoarthritis  
 Rheumatoid arthritis  Osteoarthritis

Rheumatoid arthritis  Osteoarthritis  
pathophysiology autoimmune (inflammatory) degenerative due to ↑ wear and tear on 
joints  loss of cartilage (non-
inflammatory) 
 
Age of starting  At any age  Usually later in life  
 
Speed of onset  Rapid, over weeks to months  Slow, over yeas   
  
Pain improves with movement  worse with movement and better with 
rest 
Primary joint 
affected Proximal interphalangeal  Distal  interphalangeal  
 
Metacarpophalangeal Carpometacarpal

Metacarpophalangeal Carpometacarpal  
Heberdens nodes  Absent  Present  
Joint 
characteristics  Soft, warm and tender Hard and bony (little or no swelling)  
 
Stiffness  Worse after resting (morning stiffness) If present, worse after effort, may be 
described as evening stiffness  
Usually  > 1 hour  Usually < 1 hour  
Systemic 
symptoms  Present (eg: fatigue ) Absent  
 
RF and anti-CCP  Positive  Negative  
ESR and C-
reactive protein  Elevated  Normal

reactive protein  Elevated  Normal  
 
x-ray  Osteophytes absent  Osteophytes may be present  
 1034

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  6 
  
Features 
 The most common form, inflammatory arthritis, is characterised by symmetric arthritis of the 
small joints of the hands and feet  that has lasted for >6 weeks. 
 typically affects the proximal interphalangeal, metacarpophalangeal and wrists join ts.

 The sacroiliac joint is spared in rheumatoid arthritis. 
 Morning stiffness lasting >1hour 
 Extra-articular features, such as: 
 rheumatoid nodules over the extensor surfaces of tendons  
 vasculitic skin involvement 
 Joint deformity:  (in advanced RA with damage to the ligaments and joints). 
 Swan neck deformity : DIP hyperflexion with PIP hyperextension.  
 Boutonniere's deformity : PIP flexion with DIP hyperextension.

 Ulnar deviation : due to inflammation of the MCP joints, which leads to dislocation of 
these joints with the pull of the tendons on the dislocated joints.  
 
 Lab 
 Analysis of synovial fluid  
 abundant neutrophils . 
 High protein levels. 
Referral  
Indications for urgent referral for specialist opinion: 
 any person with suspected persistent synovitis of undetermined cause. Refer urgently  if any of the 
following apply: 
 the small joints of the hands or feet are affected 
1035

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  7 
  more than one joint is affected 
 there has been a delay of 3 months or longer between onset of symptoms and seeking  medical 
advice. 
 
Anti-cyclic citrullinated peptide antibodies are associated with rheumatoid arthritis 
 
 Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)

 up to 40% of patients with RA may have normal levels 
 In the early stages of an insidious onset of the RA disease, the acute phase m arkers CRP 
and ESR are often normal, particularly when small joints are involved. 
  A normal C-reactive protein can help to exclude the diagnosis of an inflammatory arthritis, 
but an elevated value is never a specific finding. 
 Rheumatoid factor (RF) is positive in about 60% to 70%  
 anti-cyclic citrullinated peptide (CCP) antibodies

 Anti-CCP positivity is a prognostic marker. 
 Anti-cyclic citrullinated peptide antibody may be detectable up to 10 years befo re the 
development of rheumatoid arthritis. 
 It may therefore play a key role in the future of rheumatoid arthritis, allowing early 
detection of patients suitable for aggressive anti-TNF therapy. 
 It has sensitivity similar to rheumatoid factor (70-80%) with a much higher specificity of 9 0-
95%.

95%. 
 NICE recommends that patients with suspected RA with RF negative should be tested for 
Anti-CCP Abs.  
 NICE state that: Consider measuring anti-cyclic citrullinated peptide (CCP) antibodies in 
people with suspected RA if: 
 they are negative for rheumatoid factor, and 
 there is a need to inform decision-making about starting combination therapy 
 ANA: present in 20-30% of patients with rheumatoid arthritis. 
 x-ray

 x-ray  
 at the early stage, the most likely investigation that will help with a diagnosis are   
the X-rays.   
 At the stage of early RA  the diagnostically most informative test is hand and feet 
X-ray  periarticular osteopenia and marginal erosions at affected joints. 
 Foot joints are often radiologically affected before hand  joints. 
 Periarticular osteopenia and osteoporosis would point towards a diagnosis of (RA).

 Loss of joint space is common in both RA and OA also in Pseudogout. 
 
The radiographic features of rheumatoid arthritis can be remembered by the mnemonic  LESS : 
Loss of joint space, Erosions, Soft tissue swelling, and Soft bones (osteopenia) 
 
Early x-ray findings Late x-ray findings 
 loss of joint space 
 juxta-articular osteoporosis 
 soft-tissue swelling  periarticular erosions 
 subluxation 
 
Prognostic features  
 Poor prognostic features:

Poor prognostic features:   
 Anti-CCP antibodies (The poorest prognostic factor) 
 Rheumatoid factor positive  
 HLA DR4  
 Insidious onset  
 Acute or Sudden onset is not a poor prognosis.  
 Poor functional status at presentation  
 X-ray: early articular erosions (e.g. within the first 6 months of presentation and in less than < 2 
years). 
 Extra articular features e.g. nodules  
 Female sex.  
 1036

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  8 
  
Extra-articular complications  
 Ocular: common, with 25% of patients having eye problems  
 keratoconjunctivitis sicca (most common)  
 characterised by dry, burning and gritty eyes caused by decreased tear production 
 Other associated symptoms include irritation, redness, discharge, and easily

fatigued eyes. Blurred vision may also occur. Scarring of the cornea may occur in 
some cases without treatment 
 do Tear-film integrity 
 A reflex response to irritation of the corneal surface is epiphora, or watering. 
 Symptoms will be worse when tear-film evaporation is greater, 
 episcleritis (erythema)  
 scleritis (erythema and pain) 
 corneal ulceration,  
 keratitis,  
 Iatrogenic 
 steroid-induced cataracts,

 steroid-induced cataracts,  
 'steroid cataract' is typically posterior subcapsular , and causes constant 
and gradually progressive blur.  
 (Steroids  raised intraocular pressure) 
 Steroids can cause raised blood glucose levels. Fluctuating blood sugar 
levels can cause osmotic swelling of the lens in the eye, resulting in 
fluctuations in vision. However, diabetic retinopathy will not affect vision 
unless maculopathy occurs or vitreous haemorrhage occurs.

 chloroquine retinopathy 
 
 Cardiac: 
 Constrictive pericarditis is the commonest cardiac complication of rheumatoid 
arthritis 
 ischaemic heart disease: RA carries a similar risk to type 2 diabetes mellitus.  
 Respiratory:  
 pulmonary fibrosis,  
 pleural effusion (  rheumatoid pleural effusion: characterised by  low glucose level)  
 pulmonary nodules,  
 bronchiolitis obliterans,  
 methotrexate pneumonitis,  
 pleurisy 
 cricoarytenoid arthritis:

 pleurisy 
 cricoarytenoid arthritis: 
 seen in up to 75% of patients with rheumatoid arthritis.  
 It can cause sore throat, hoarse voice and stridor , but is often asymptomatic.  
 symptoms can rapidly worsen in the post-operative period .  
 It is unrelated to any lung fibrosis.  
  the most helpful diagnostic test  Spirometry with flow–volume loop  
 Also: direct laryngoscopy and high-resolution computed tomography of the larynx .

 Patients can need urgent tracheostomy and steroids, both orally and via joint 
injection. 
 Osteoporosis 
 cord compression 
 The recent limb weakness and the presence of pyramidal signs in the legs in a patient 
with rheumatoid arthritis are highly suggestive of spinal cord lesion at the cervical or 
thoracic region.  
1037

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  9 
  Although plain radiography of the cervical spine is the initial imaging assessment tool for 
neck pain in patient with rheumatoid arthritis, those with symptoms or signs of cord 
compression should undergo immediate MRI and be sent for surgical consultation. 
 Increased risk of infections

 Increased risk of infections 
 Which micro-organisms may be associated with the development of rheumatoid 
arthritis in susceptible patients?  Proteus mirabilis  
 Depression 
 
Less common   
 Felty's syndrome (RA + splenomegaly + low white cell count) 
 Amyloidosis 
 Poorly controlled rheumatoid arthritis + proteinuria and hypoalbuminaemia raises 
the possibility of systemic amyloidosis  Rectal biopsy

 Secondary amyloid A (AA) amyloidosis is an important complication of rheumatoid arthritis 
(RA)  (~20%). 
 It is caused by extracellular accumulation of AA fibrils, derived from the acute-pha se-
reactant serum amyloid A protein, within various tissues and organs. 
 Any patient with longstanding RA who develops proteinuria, or intractable diarrhoea, 
should be investigated for AA amyloidosis.   
 Normocytic, normochromic anemia of chronic disease is very characteristic of RA.

Atlanto-axial subluxation 
Rheumatoid arthritis is the most common inflammatory disease involving the spine. It has a  predilection 
for the craniocervical spine. 
The three different patterns of instability which can result are: 
 Atlantoaxial subluxation 
 Atlantoaxial impaction, and 
 Subaxial subluxation. 
Atlantoaxial subluxation  (distance between the arch of atlas and odontoid peg >2.5 mm)

 may occur due to erosion of the odontoid process or due to laxity of the transverse liga ment from 
rheumatoid pannus resulting in posterior subluxation of the odontoid. 
 can lead to cervical cord compression 
 Although radiographic changes are seen in up to 86% of patients, the prevalence o f neurological 
deficit is relatively low.  
 Radiographs should be taken laterally with the neck held in flexion. 
 Only a minority of patients require surgical management.

 Non-surgical treatment options include patient education, lifestyle modification and regular 
radiographic follow up. 
 
Management (Nice guidelines  2015 ) 
 Patients with evidence of joint inflammation should start a combination of disease-modi fying 
drugs (DMARD) as soon as possible.  
 Other important treatment options include analgesia, physiotherapy and surgery. 
Pharmacological management   
DMARDS 
 first-line for newly diagnosed active RA  combination of DMARDs (including

methotrexate and at least one other DMARD, plus short-term glucocorticoids)  as soon as 
possible, ideally within 3 months of the onset of persistent symptoms. 
 
 Consider offering short-term treatment with glucocorticoids (oral, intramuscular or intra-articular) 
to rapidly improve symptoms in newly diagnosed RA if they are not already receiving 
glucocorticoids as part of DMARD combination therapy.

 If DMARD therapy induce disease control  reduce drug doses to levels that still maintain 
disease control. 
 
 DMARDs: ( Drug-specific Recommendations (BSR guidelines February 2017)  
1. Methotrexate ( MTX ) (the most widely used DMARD).  
 All patients should be co-prescribed folic acid  supplementation at a minimal dose 
of 5 mg once weekly. 1038

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  10 
  Monitoring of FBC & LFTs is essential due to the risk of myelosuppression and liver 
 Other important side-effects include pneumonitis 
2. Sulfasalazine  
3. Azathioprine (AZA) 
 Patients should have baseline thiopurine methyltransferase (TPMT) status 
assessed  
4. Leflunomide  
5. Hydroxychloroquine ( HCQ )

5. Hydroxychloroquine ( HCQ ) 
 Patients should have baseline formal ophthalmic examination , ideally includin g 
objective retinal assessment for example using optical coherence tomography, 
within 1 year of commencing an antimalarial drug   
 
Recommended DMARD Blood Monitoring Schedule when Starting or Adding a New DMARD  (BSR 
guidelines February 2017)  
 Check FBC, creatinine/calculated GFR, ALT and/or AST and albumin 
 every 2 weeks  until on stable dose for 6 weeks;

 then once on stable dose, monthly  for 3 months;  
 thereafter, at least every 12 weeks . 
 Contact rheumatology team urgently and consider interruption in treatment  if any of the 
following develop:  
 white cell count <3.5 × 109/l;  
 mean cell volume >105 fL;  
 neutrophils <1.6 × 109/l;  
 creatinine increase >30% over 12 months and/or calculated GFR <60 ml/min;  
 unexplained eosinophilia >0.5 × 109/l;  
 ALT and/or AST >100 U/l;  
 platelet count <140 × 109/l;

 platelet count <140 × 109/l;  
 unexplained reduction in albumin <30 g/l 
 In the setting of acute infection, most DMARDs (except hydroxychloroquine) should be 
discontinued until the infectious process has resolved.   
Monitoring rheumatoid arthritis 
 Measure CRP and key components of disease activity (using a composite score such as DAS28) 
regularly ( monthly until treatment has controlled the disease)  to inform decision-making 
about: 
 increasing treatment to control disease

 increasing treatment to control disease 
 cautiously decreasing treatment when disease is controlled. 
 
 Offer people with RA an annual review to: 
 assess disease activity  and damage, and measure functional ability (using, for example, 
the Health Assessment Questionnaire [HAQ]) 
 check for the development of comorbidities , such as hypertension, ischaemic heart 
disease, osteoporosis and depression 
 assess symptoms that suggest complications , such as vasculitis and disease of the

cervical spine, lung or eyes 
TNF-inhibitor 
 The current indication for a TNF-inhibitor is an inadequate response to at least two DMARDs 
including methotrexate 
 Examples of anti-TNF alpha agents: 
 Etanercept 
 SC administration twice weekly 
 Infliximab 
 IV administration 
 Adalimumab 
 SC administration 
 Adverse effects of TNF blockers include: 
  reactivation of latent tuberculosis and demyelination.

 The risk of TB reactivation is most pronounced in the first 3 months of treatment. 
 BTS guidelines therefore recommend a clinical examination, and chest radiograph to 
check for TB. 
 In the UK, patients have a baseline CXR and assessment of risk of infection with 
Mycobacterium tuberculosis prior to starting treatment with anti- TNF α.  1039

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  11 
  Any patient with active TB ,  
 should receive standard chemotherapy. 
 They must complete two months full treatment before starting an ti-TNF alpha 
 Patients with  past TB ,  
 who have received previous adequate therapy  can be started on anti-TNF alpha 
therapy but need to be monitored regularly.

therapy but need to be monitored regularly. 
 TB not previously adequately treated,  chemoprophylaxis should be given before 
commencing anti-TNF alpha treatment. 
 What is the optimal TB screening test in patient with previous TB? 
 Interferon gamma release assay 
 The test is not altered by previous TB or previous BCG vaccination. 
 Positive testing indicates a need for anti-tuberculous treatment alongside 
golimumab, for example isoniazid.

golimumab, for example isoniazid. 
 Mantoux testing is less indicative of prior infection because it is  likely to 
evoke a positive reaction in patients with previous TB or who have received 
BCG vaccination. 
  Patients with a normal chest radiograph  who have not started immunosuppressive  
threrapy,   a tuberculin test is helpful. 
 Patients with a normal chest radiograph + already on immunosuppressive treatment ,

 the result of the tuberculin test is dampened and it is therefore not useful. 
  An individual risk assessment should be made: if the annual risk of TB is greater than 
that of drug-induced hepatitis then chemoprophylaxis should be given . If not, the 
patient should be monitored and investigated early if symptoms consistent with TB  
develop. 
 Chemoprophylaxis is generally with isoniazid for 6 months.

 Patients who test positive with either of Quantiferon Gold test and Elispot tests sho uld be treated 
with chemoprophylaxis (either isoniazid for 6 months, or dual therapy Rifampicin + INH for 2 
months) at the same time as being started on anti-TNF alpha treatment. 
 TNF-inhibitors should be stopped 2-4 wks before any major operation. 
 
Rituximab  
 Anti-CD20 monoclonal antibody, results in B-cell depletion.  
 Two doses of 1g intravenous infusions are given two weeks apart.

 Nice guidelines of RA   Rituximab in combination with methotrexate is recommended as 
an option for treatment of rheumatoid arthritis who have had an inadequa te response to or 
intolerance of other disease-modifying anti-rheumatic drugs (DMARDs), including treatment w ith 
at least one tumour necrosis factor α (TNF -α) inhibitor therapy.  
 
 Treatment with rituximab plus methotrexate should be continued only if: 
 There is an adequate response following initiation of therapy.

 An adequate response is defined as an improvement in disease activity score (DAS28) of 
1.2 points or more.  
 Repeat courses of treatment with rituximab plus methotrexate should be given no more 
frequently than every 6 months.  
Tocilizumab   
 anti-IL 6 receptor monoclonal antibody.  
 It is licensed for the treatment of moderate to severe rheumatoid arthritis (RA) which has 
responded inadequately to DMARDs or TNF antagonists.  
 
Rheumatoid arthritis: pregnancy  
 
Key points

Key points  
 patients with early or poorly controlled RA should be advised to defer conception until their 
disease is more stable 
 RA symptoms tend to improve in pregnancy but only resolve in a small minority. Patients te nd to 
have a flare following delivery 
 patients should be referred to an obstetric anaesthetist due to the risk of atlanto- axial subluxation 
 
Medications in pregnancy and breast  feeding  1040

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  12 
  Methotrexate (teratogenic) and NSAIDs (1st trimester, risk of abortion) so they are 
absolutely contraindicated. 
 methotrexate is not safe in pregnancy and needs to be stopped at least 3 months be fore 
conception 
 NSAIDs may be used until 32 weeks but after this time should be withdrawn due to the risk of

early close of the ductus arteriosus 
 leflunomide is not safe in pregnancy 
 Prednisolone, Sulfasalazine and hydroxychloroquine are safe in pregnancy  
 Corticosteroids   
 relatively safe in pregnancy when used in low dose ˂ 20 mg daily.   
 low-dose corticosteroids may be used in pregnancy to control symptoms 
 The routine use of oral calcium and Vit D is recommended.  
 Stress doses of steroids should be used during labour and delivery if the mother re ceived

steroids (even low dose) for more than 2-3 weeks during pregnancy, and the neonate 
should be monitored for evidence of adrenal insufficiency and infection. 
 Sulfasalazine  can be safely used during all stages of pregnancy, it is compatible with breast 
feeding, although should be advised with cautions because of the rare possibility tha t the mother 
is a slow acylator. 
 Azathioprine  can be used in pregnancy if Sulfasalazine and hydroxychloroquine are not 
controlling.

controlling. 
  During pregnancy  continue current dose of azathioprine and add folic acid  
 Breast feeding is not recommended with azathioprine. 
 Prednisolone and hydroxychloroquine may be taken whilst breast-feeding.  
 Azathioprine, cyclophosphamide, methotrexate and cyclosporine are contraindicated in breast -
feeding mothers. 
 
 A piano player in a local hotel c/o morning stiffness, and pain affecting his hips, knees and e lbows.

On examination he has nodules over his elbows and pain over the PIP joints of his fingers.  
 
What is the most appropriate initial therapy in this man with respect to his long term abil ity to play the 
piano?  Splinting of his fingers for a period  
 
September 2009 exam: A 25-year-old woman presents with a symmetrical arthropathy affecting her 
hands. On examination she has synovitis of the 2nd and 3rd metacarpophalangeal joints. What type of

HLA allele is most associated with this condition? HLA DR4  
 
A patient of RA on etanercept, scheduled for elective surgery. What advice regarding his 
medication should be given prior to surgery?  Stop etanercept 2 –4 weeks prior to surgery   
 
Updated British Society for Rheumatology (BSR) guidelines (January 2005) for prescribing tu mour 
necrosis factor (TNF- α) blockers in adults with RA recommend:  
 withholding etanercept and other TNF- blockers (infliximab and adalimumab) for 2 –4

weeks prior to a major surgical procedure.  
 restarted postoperatively if there is no evidence of infection and once wound he aling is 
satisfactory.   
 
Felty ’s syndrome 
 defined as the triad of rheumatoid arthritis, splenomegaly and leukopenia 1041

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  13 
  It is considered an extra-articular manifestation of rheumatoid arthritis,  
 occurs more frequently in patients suffering from other extra-articular manifestations such as 
Sjogren syndrome 
 occur in less than 1% of patients with rheumatoid arthritis. 
 usually occurs in patients with long-standing seropositive RA.

 There is a female preponderance (60-70%).Two-thirds of the patients are females. 
 Cases are usually recognised from the fifth decade of life, patients having suffered f rom 
rheumatoid arthritis for around 10 years 
Feature 
 RA, leucopenia, lymphadenopathy and splenomegaly. 
 Leg ulcers, recurrent infections and episcleritis may be present.  
 ANA is positive in more than 90% of patients  
Treatment 
  most appropriate initially  Pulsed corticosteroid therapy

 Pulsed corticosteroid and/or cyclophosphamide therapy may be effective in raising neutrophil 
counts, as may appropriate switching / intensification of DMARD therapy for the rheumatoid. 
 disease-modifying anti-rheumatic drugs (DMARDs) including in severe disease use of 
cyclophosphamide  
 colony stimulating factor to stimulate production of granulocytes.  
 A few studies have suggested that the short-term use of lithium may be useful in 
stimulating granulopoiesis

stimulating granulopoiesis  
 Splenectomy : usually reserved for patients with severe neutropenia and recurrent infectio ns who 
fail to respond to medical intervention. 
 
Torn rotator cuff 
 torn rotator cuff can occur spontaneously in elderly patients with rheumatoid arthritis.  
 The patient is able to abduct the arm, but the pain worsens during the middle of the range of 
abduction . 
 Differential diagnosis

 Rotator cuff tendonitis: 
 usually insidious in onset with pain from 0-90 degrees. 
Seronegative spondyloarthropathies 
Common features 
 associated with HLA-B27 
 rheumatoid factor negative - hence 'seronegative' 
 peripheral arthritis, usually asymmetrical 
 sacroiliitis 
 enthesopathy: e.g. Achilles tendonitis, plantar fasciitis

 extra-articular manifestations: uveitis, pulmonary fibrosis (upper zone), amyloidosis, aortic 
regurgitation 
Spondyloarthropathies 
 ankylosing spondylitis 
 psoriatic arthritis 
 Reiter's syndrome (including reactive arthritis) 
 enteropathic arthritis (associated with IBD) 
Adhesive capsulitis See endocrinology (diabetes)  
Ankle injury: Ottawa rules

Ankle injury: Ottawa rules 
 The Ottawa Rules for ankle x-rays have a sensitivity approaching 100%  
 An ankle x-ray is required only if there is any pain in the malleolar zone  and any one of the 
following findings: 
1. bony tenderness at the lateral malleolar zone (from the tip of the lateral malleolus to 
include the lower 6 cm of posterior border of the fibular) 
2. bony tenderness at the medial malleolar zone  (from the tip of the medial malleolus to

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  14 
 3. inability to walk four weight bearing steps immediately after the injury and in the 
emergency department 
 There are also Ottawa rules available for both foot and knee injuries 
Ankylosing spondylitis 
 
 seronegative spondyloarthropathy that involves chronic inflammatory disease of the spine 
and sacroiliac joints.  
  autoimmune disorder;  
 Ankylosing spondylitis is a HLA-B27 associated spondyloarthropathy.  
 It has a polygenic inheritance .  
 Typically presents in males (sex ratio 3:1)  
 Age: 20 – 40 years  
Features  
Typically a young man who presents with lower back pain and stiffness of insidious onset

 Stiffness  
 Early morning stiffness of more than 30 minutes 
 usually worse in the morning and improves with exercise 
 Back pain  
 the hallmark clinical feature  
 Key features of the pain include:  
 insidious onset  
 Alternating buttock pain 
 Waking in the second half of the night 
 Pain easing with non-steroidal anti-inflammatory drugs (NSAIDs) 
 Pain which is worse with rest and eases with exercise 
 Tenderness over the sacroiliac joints (positive Mennell's sign)

Clinical examination 
 reduced lateral flexion  
 reduced forward flexion ( Positive Schober ’s test ):  
 While the patient is in a standing position the examiner makes a mark approximately  at 
the level of L5.  
 Two points are marked: 5 cm below and 10 cm above this point (for a total of 15 cm  
distance).  
 Then the patient is asked to touch his/her toes while keeping the knees straight.  
 If the distance of the two points do not increase by at least 5 cm (with the total distan ce

greater than 20 cm), then this is a sign of restriction in the lumbar flexion. 
 reduced chest expansion 
 accentuated  thoracic kyphosis  
 loss of  lumbar lordosis  
1043

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  15 
 Associations - the 'A's: 
 Anterior uveitis  
 The most common  extra-articular manifestations  (in around 40% of patients)  
 Usually acute, unilateral anterior uveitis  
 more common in B27 positive than B27 negative patients. 
 Apical fibrosis 
 Achilles tendonitis 
 AV node block

 AV node block 
 cauda equina syndrome 
 peripheral arthritis (25%, more common if female) 
 features of inflammatory bowel disease (diarrhea with blood) (seen in around 5% )  
 IgA-nephropathy  
 Dactylitis 
 An inflammation of the fingers and/or toes  
 seen also in rheumatoid arthritis, sarcoidosis, and sickle-cell disease. 
 
 the best option to confirm a diagnosis of ankylosing spondylitis  Sacroiliac joints x ray

 Inflammatory markers (ESR, CRP) are typically raised  although normal levels do not exclude 
ankylosing spondylitis. 
 HLA-B27 is of little use in making the diagnosis because  
  it is positive in 90% of patients with ankylosing spondylitis and 10% of normal patients 
 The likelihood of a positive test depends on the racial and ethnic background of the 
patient 
 The commonest subtype HLA associations  are  
 HLA B*2705  (Caucasians),  
 B*2704  (Chinese, Japanese) and

 B*2704  (Chinese, Japanese) and  
 B*2702  (Mediterranean).  
 The B*2706 subtype is weakly associated and commonly found in normal 
south east Asian individuals.  
 Radiographs   
 Plain x-ray of the sacroiliac joints is the most useful investigation in establishing 
the diagnosis .  
 Radiographs may be normal early in disease , later changes include: 
 sacroilitis: subchondral erosions, sclerosis 
 squaring of lumbar vertebrae

 squaring of lumbar vertebrae 
 'bamboo spine' (  vertebral fusion) (late & uncommon) 
1044

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  16 
  syndesmophytes: due to ossification of outer fibers of annulus fibrosus (The 
tramline appearance  is due to syndesmophyte growth between the margins of the 
vertebrae)  
 Syndesmophytes grow vertically, as opposed to spondylophytes, which grow 
horizontally 
 chest x-ray: apical fibrosis

 chest x-ray: apical fibrosis 
 
40-year-old male. There is typical appearance of bamboo spine with a single central radio dense line related to ossification of 
supraspinous and interspinous ligaments which is called dagger sign. Ankylosing  is detectable in both sacroiliac joints 
 
Lateral cervical spine. Complete fusion of anterior and posterior elements in ankylosing spondylitis, so 
called bamboo spine 
1045

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  17 
  
Fusion of bilateral sacroiliac joints. Sacroiliitis may present as sclerosis of joint margins which can be 
asymmetrical at early stage of disease, but is bilateral and symmetrical in late disease 
 
Syndesmophytes and squaring of vertebral bodies. Squaring of anterior vertebral m argins is due to

osteitis of anterior corners. Syndesmophytes are due to ossification of outer fibers of ann ulus fibrosus 
 
 MRI: 
 More sensitive than x-ray 
 Best method for early detection  
 Shows: 
 bone marrow edema   (The earliest change  visible on MRI)  
 squaring of the vertebrae ,  
 erosion of apophyseal joint  
 obliteration of sacroiliac joint  
1046

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  18 
  Spirometry  may show a restrictive defect  due to a combination of pulmonary fibrosis , 
kyphosis and ankylosis of the costovertebral joints. 
 
New York criteria  
 Current British Society for Rheumatology recommendations state that the modified New York 
criteria should be used to diagnose ankylosing spondylitis:

 Clinical criteria: 
 Low back pain, present for more than three months, improved by exercise b ut not 
relieved by rest 
 Limitation of lumbar spine motion in both the sagittal and frontal planes 
 Limitation of chest expansion relative to normal values for age and sex. 
 Radiological criteria : 
 Sacroilitis on x ray. 
 Diagnosis: 
 Definite AS if the radiological criterion is present plus at least one clinical criterion

 Probable AS if three clinical criteria are present alone or if the radiological criterion 
is present but no clinical criteria are present. 
Management  (2010 EULAR guidelines) 
 Non-pharmacological: 
 encourage regular exercise such as swimming 
 Pharmacological   
 NSAIDs  
 NSAIDs are the first-line treatment 
 Anti-TNF therapy  
 The second line  
 the 2010 EULAR guidelines suggest: 'Anti-TNF therapy should be given to

patients with persistently high disease activity despite conventional treatments'  
 The anti-TNF drugs are currently only used for patients with severe ankylosing 
spondylitis which has failed to respond to NSAIDs. 
 research is ongoing to see whether anti-TNF therapies such as etanercept and 
adalimumab should be used earlier in the course of the disease 
 Disease-modifying drugs  
 the disease-modifying drugs which are used to treat rheumatoid arthritis (such as

sulphasalazine) are only really useful if there is peripheral joint involvement  
 where there is proved inflammatory bowel disease , many patients are started on 
sulfasalazine, as this may be a useful disease-modifying agent for both bowel an d 
joint disease. 
Avascular necrosis 
Avascular necrosis (AVN) may be defined as death of bone tissue secondary to loss of the blood

supply. This leads to bone destruction and loss of joint function. It most commonly affects th e epiphysis 
of long bones such as the femur. 
Causes 
 long-term steroid use 
 alcohol excess 
 trauma 
Features 
 initially asymptomatic 
 pain in the affected joint 
 plain x-ray findings may be normal initially 
 MRI is the investigation of choice.  It is more sensitive than radionuclide bone scanning 
 treated with lifelong warfarin with target INR 2-3

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  19 
Behcet's syndrome 
 
Overview 
 Behcet's syndrome is a complex multisystem disorder associated with presumed autoimmune 
mediated inflammation of the arteries and veins. 
 affects small and large vessels (venous and arterial) .

 The pathogenesis of Behcet disease involves mainly the T helper cells. 
 associated with HLA B5* ( More than 60% ) and MICA6 allele 
 *more specifically HLA B51, a split antigen of HLA B5 
 HLA B5 is associated with ocular disease;  
 HLA B12 is associated with recurrent oral ulcers.  
 more common in the eastern Mediterranean (e.g. Turkey) 
 more common and more severe in men 
 tends to affect young adults (e.g. 20 - 40 years old)

 around 30% of patients have a positive family history 
Features 
 The classic triad of symptoms are: 1) oral ulcers 2) genital ulcers 3) anterior uveitis (iritis) 
 thrombophlebitis 
 Seronegative arthritis 
 Usually  asymmetric arthritis. 
 neurological involvement (e.g. aseptic meningitis) 
 GI: abdominal pain, diarrhoea, colitis 
 erythema nodosum, DVT 
 pathergy (development of pustules at venepuncture sites). 
 Fever 
Diagnosis 
 no definitive test

 Fever 
Diagnosis 
 no definitive test 
 diagnosis based on clinical findings 
 positive pathergy test  is suggestive (puncture site following needle prick becomes inflamed with 
small pustule forming) 
 Pathergy  is the non-specific hyper-reactivity of the skin following minor trauma, and is specific 
to Behcet's disease . It involves intradermal injection of skin with a 20-gauge needle under 
sterile conditions. It is considered positive if an erythematous sterile papule develops within

48 hours.  
 The International Study Group criteria  for classification of Behcet's disease requires the 
presence of recurrent oral ulceration  (minor aphthous, major aphthous or herpetiform 
ulceration observed by physician or patient, which have recurred at least three times in a 12  
month period), and two of the following:  
 Recurrent genital ulceration: aphthous ulceration or scarring, observed by physician or 
patient

patient 
 Eye lesions : anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; 
or retinal vasculitis observed by ophthalmologist 
 Skin lesions : erythema nodosum observed by physician or patient, pseudofolliculitis or 
papulopustular lesions; or acneiform nodules observed by the physician in post-
adolescent patients not on corticosteroid treatment 
 Positive pathergy test:  read by physician at 24- 48 hours. 
 
Treatment

Treatment 
 Colchicine is the first line treatment. 
 Anterior uveitis associated with Behcet disease is treated with topical corticosteroids. 
Charcot joint  (Charcot ’s arthropathy) See endocrinology (diabetes)  
 
1048

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  20 
  
Chronic fatigue syndrome 
 Diagnosed after at least 4 months  of disabling fatigue  affecting mental and physical 
function  more than 50% of the time  in the absence of other disease  which may explain 
symptoms .  

symptoms .  
 past psychiatric history has NOT  been shown to be a risk factor 
Fatigue is the central feature, other recognised features include 
 sleep problems, such as insomnia, hypersomnia, unrefreshing sleep, a disturbed sleep-wake  
cycle 
 muscle and/or joint pains 
 headaches 
 painful lymph nodes without enlargement 
 Recurrent sore throat

 Recurrent sore throat  
 cognitive dysfunction, such as difficulty thinking, inability to concentrate, impairment of sho rt-term 
memory, and difficulties with word-finding 
 physical or mental exertion makes symptoms worse 
 general malaise or 'flu-like' symptoms 
 dizziness 
 nausea 
To confirm a diagnosis of fatigue the following main features need to be present: 
 must be new in onset, persistent or recurrent and unexplained by other condition s.

 should be characterised by post-exertional malaise. 
 should result in a substantial reduction in activity level. 
Red flag symptoms which suggest another diagnosis include:  
 Significant weight loss 
 Inflammatory arthropathy or connective tissue disease 
 Localising or focal neurological signs. 
 NICE guidelines suggest carrying out a large number of screening blood tests to exclude o ther

pathology e.g. FBC, U&E, LFT, glucose, TFT, ESR, CRP, calcium, CK, ferritin* ( *children and 
young people only ), coeliac screening and also urinalysis 
 treatment of choice: graded exercise therapy  
 a formal supervised program,  
 not advice to go to the gym 
 'pacing' - organising activities to avoid tiring 
 cognitive behaviour therapy - very effective, 
 low-dose amitriptyline may be useful for poor sleep

 referral to a pain management clinic if pain is a predominant feature  
 
Prognosis 
 Better prognosis in children 
Compartment syndrome  
 
 Pain with passive stretching of the muscles, is the earliest clinical indicator of compartment 
syndrome. 
 
 Patients with compartment syndrome typically present with pain whose severity appears out of 
proportion to the injury  
 The pain of compartment syndrome is often:

 The pain of compartment syndrome is often: 
 described as burning, deep and aching in nature  
 worsened by passive stretching of the involved muscles .  
 The patient may describe a tense feeling in the extremity. 
 The most important diagnostic physical finding is a firm, wooden feeling on dee p palpation. 1049

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  21 
  Decreased 2-point discrimination is the most consistent early finding 
 in acute anterior lower leg compartment syndrome, the first sign to develop may be nu mbness 
between the first 2 toes (superficial peroneal nerve). 
 A Creatine phosphokinase (CPK)  concentration of 1000-5000 U/mL or greater or the presence

of myoglobinuria can suggest compartment syndrome. 
 Measurement of intracompartmental pressures  remains the standard for diagnosis  of 
compartment syndrome.  
 
 Trauma 
 Anticoagulation therapy and bleeding disorders (eg, hemophilia) significantly increase th e 
likelihood of compartment syndrome. 
 Vigorous exertion may lead to compartment syndrome. Compartment syndrome has b een found 
in soldiers and athletes without any trauma.

in soldiers and athletes without any trauma. 
 If compartment syndrome is suspected, check intracompartmental pressure, even in the a bsence 
of any trauma history. 
structures at risk  
Forearm compartments and structures at risk: 
 ventral compartment - median and ulnar nerves; radial and ulnar arteries 
 dorsal compartment - posterior interosseous nerve; no major vessels 
Lower limb and structures at risk: 
 anterior tibial compartment - deep peroneal nerve; anterior tibial artery

 superfical posterior compartment - no major nerves or vessels 
 deep posterior compartment - posterior tibial nerves and vessels; peroneal artery 
 peroneal compartment - deep and superfical peroneal nerves 
 Loss of peripheral pulses is a late sign indicating that the pressure within the compartment h as 
exceeded arterial blood pressure. 
 Compartment syndrome can occur in the absence of a fracture, for example, crush injuries .

 Pain is the earliest and most reliable symptom of the onset of compartment syndrome.  
 Passive stretch of the muscles traversing the compartment increases pain. 
 Treatment involves decompression of the affected compartment(s) including the skin. 
Feature 
High risk injuries are fractures of the forearm and lower leg, especially those that have b een internally 
fixed or infected.  
Early features of an evolving compartment syndrome are: 
 increasing pain despite immobilisation

 increasing pain despite immobilisation 
 Passive stretch of affected muscles exacerbates pain  
 sensory deficit in the distribution of the peripheral nerve(s) passing through that co mpartment 
 swelling and tenderness of the muscle compartment 
 pain on passive stretching of muscles within the compartment - for example, passive extensi on of 
the toes or fingers causing increased pain in the calf or the forearm

Late features  are those of tissue ischaemia with additionally, pallor, pulselessness, paralysis, coolne ss 
and loss of capillary return 
 
Treatment 
  Early orthopaedic referral and continuous instrumented pressure monitoring is necessary.  
 Urgent decompression is required to prevent severe ischaemia. 
 All potentially constricting dressings, casts and splints must be removed  
 The compartment pressure should be measured. Open fasciotomy is indicated if it is above

40 mm Hg . Otherwise, the limb should be closely observed until improvement is apparent 
clinically. 
 If no improvement occurs, perform a fasciotomy, which in the leg, may mean ope ning all four 
compartments.  
Complex regional pain syndrome  (CRPS)   
 characterized by severe pain out of proportion to the original injury and is often 
accompanied by sensitivity, swelling, and changes in the skin

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  22 
  It may initially affect one limb and then spread throughout the body; 35% of affect ed people 
report symptoms throughout their whole body 
 Precipitating factors 
 injury and  
 surgery 
 CRPS type I caused by event, such as a crush or soft tissue injury; or by immobilization, such a s 
a tight cast or frozen shoulder.

a tight cast or frozen shoulder.  
 CRPS type II caused defined nerve injury.  
 Type II, formerly known as causalgia 
 Electromyography (EMG) and Nerve Conduction Studies (NCS) are the most reliable methods o f 
detecting nerve injury. They can be used as one of the primary methods to distinguish b etween 
CRPS I & II, which differ based on whether there is evidence of actual nerve damage.  
  The most common symptoms are pain sensations, including burning, stabbing, grinding, and

throbbing. Moving or touching the limb is often intolerable.  
 Both types demonstrate continuing pain, allodynia, or hyperalgesia that is usually 
disproportionate to the inciting event.  
 allodynia  (pain resulting from a stimulus which would not normally provoke pain, such as 
a light touch of the skin)  (perception of pain from a nonpainful stimulus) 
 hyperalgesia  (an exaggerated sense of pain) disproportionate to the inciting event

 At some point during the syndrome's development, both show evidence of ed ema, changes in 
skin blood flow revealed by color changes and skin temperature changes greater than 1.1°C 
from the homologous body part, or abnormal sudomotor activity in the painful reg ion.  
 
A repeat X-ray is the most appropriate next investigation  looking for patchy osteoporosis   in 
patient developed clinical features consistent with complex regional pain syndrome type 1 (CRPS1)

consumption of C4 + strongly positive rheumatoid factor  cryoglobulinaemia.  
 Cryoglobulins are abnormal immunoglobulins which precipitate when cooled below 37°C 
(maximum precipitate formation takes place at +4°C) and redissolve in plasma when wa rmed 
back to 37°C ( reversible precipitation at low temperatures ) 
 The precipitated clump can block blood vessels and cause toes and fingers to become

gangrenous.  
 Cryoglobulins usually consist of IgM directed against the Fc region of IgG. 
 Common causes: 
 hepatitis C, 
 multiple myeloma,  
 SLE, rheumatoid arthritis,  
 Idiopathic (one third of cases) 
 Immune deposition  on the wall of small vessels result in generalized vasculitis , which presents 
with a reticulated skin pattern of micro-thrombosis  and areas of gangrene.

 cryoglobulins  form an immune complexes  activate the complement system, resulting in 
Ļcomplement levels ( Hypocomplementemia )  
 
Three types  
 Type I  (25%):  
 monoclonal ( IgG or IgM) 
 associated with haematological diseases such as myeloma and Waldenstrom's. 
 Type II  (25%):  
 mixed  monoclonal and polyclonal: usually with RF 
 composed of a monoclonal IgM  rheumatoid factor plus polyclonal IgG  
 associations: hepatitis C , RA, Sjogren's, lymphoma

 most importantly, hepatitis C infection which should always be excluded.  
 If serological testing is negative, then the cryoprecipitate should be checked 
for HCV RNA by PCR.  1051

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  23 
  For hepatitis C associated mixed cryoglobulinaemia, interferon alpha is the 
treatment of choice , although rapidly progressive disease may require 
immunosuppressive therapy. 
 
 Type III  (50%):  
 polyclonal: usually with RF 
 composed of a polyclonal IgM  rheumatoid factor plus polyclonal IgG .

 associations: RA, Sjogren's 
 
Mixed cryoglobulinemia 
 Types II and III  cryoglobulinemia 
 both type II and III cryoglobulinaemia have rheumatoid factor reactivity  
 represent 80% of all cryoglobulins. 
 contain rheumatoid factors (RFs)  which are usually IgM  
  closely associated with hepatitis C  virus (HCV)  
 
Symptoms  (if present in high concentrations) 
Meltzer's triad (seen in cryoglobulinaemia (types II/III) palpable purpura, arthralgia and 
myalgia

myalgia  
 Raynaud's only seen in type I 
 cutaneous: vascular purpura, distal ulceration 
 arthralgia 
 renal involvement (diffuse glomerulonephritis) 
 axonal peripheral neuropathy   
 cryoglobulins  small-vessel vasculitis  axonal peripheral neuropathy   
 may be sensorimotor, or purely sensory. 
 Pulmonary embolism, arterial and venous thrombosis are common. 
 
A vasculitic rash and neuropathy in a patient with hepatitis C is suggestive of 
cryoglobulinaemia. 
 
Tests

Tests 
 low complement (esp. C4) 
 A markedly low C4 occurs in about 90% of patients with mixed cryoglobulinaemia (Type II) 
as a result of classic pathway activation. 
 Since they precipitate at low temperatures, cryoglobulins should always be transported to t he lab 
at 37°C. Failure to do this will result in a false negative result as the cryos will precipitate and b e 
removed with the clot. 
 high ESR 
Treatment

 high ESR 
Treatment 
 immunosuppression ( high dose steroids and cyclophosphamide).  
 Plasmapheresis 
 
Hypocomplementemia  is seen in many conditions, including: 
 lupus,  
 mixed cryoglobulinemia ,  
 membranoproliferative glomerulonephritis, and  
 hereditary angioedema.  
 
Dactylitis 
 Dactylitis describes the inflammation of a digit (finger or toe).

 A 'sausage-shaped' digit is a classical description of dactylitis  
 Causes include : 
 spondyloarthritis: e.g.  Psoriatic  and reactive arthritis  
 sickle-cell disease 
 other rare causes include tuberculosis, sarcoidosis and syphilis 
 1052

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  24 
  
De Quervain's tenosynovitis 
 De Quervain's tenosynovitis is a common condition in which the sheath containing the extensor 
pollicis brevis and abductor pollicis longus tendons is inflamed.  
 It typically affects females aged 30 - 50 years old 
Causes

Causes 
 commonly caused by occupational  or avocational repetitive movement of the thumb 
  also associated with RA, psoriatic arthritis, direct trauma, pregnancy, and the post-partum 
period. 
Features  
 pain on the radial side of the wrist 
 tenderness over the radial styloid process 
 abduction of the thumb against resistance is painful 
 Finkelstein's test:   
 Used to confirm the diagnosis

 Used to confirm the diagnosis  
 the patient is asked to bring the thumb across the palm and clasp the f ingers around it. 
The examiner then pulls it in the ulnar direction, which elicits a sharp pain. 
 analgesia 
 steroid injection 
 immobilisation with a thumb splint (spica) may be effective 
 surgical treatment is sometimes required 
Diffuse idiopathic skeletal hyperostosis

Diffuse idiopathic skeletal hyperostosis  
 Diffuse idiopathic skeletal hyperostosis (DISH) describes the relatively common finding of 
ossification at sites of tendinous and ligamentous insertion of the spine. It tend s to be seen in 
elderly patients.  
 DISH is generally asymptomatic.  
Drug -induced lupus  
 In drug-induced lupus not all the typical features of systemic lupus erythematosus are  seen, with

renal and nervous system involvement being unusual.  
 It usually resolves on stopping the drug. 
 symptoms are said to appear some 3 weeks to 2 years after the onset of therapy  
 affect the 50-70 year age group most commonly,  
 has a male:female ratio of 1:1  
 affects Caucasians more commonly than other populations.  
 
Features  
 joint pains, myalgia  and malaise are more common  
 skin (e.g. malar rash) (seen in 25%)  
 pulmonary involvement (e.g. pleurisy) are common

 Raynaud ’s is seen in around 25%  
 ANA positive in 100%, dsDNA negative 
 anti-histone antibodies are found in 80-90% 
 anti-Ro, anti-Smith positive in around 5% 
1053

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  25 
  C3/C4 levels are usually normal.  
 
                                                 A woman with drug-induced lupus 
Most common causes 
 hydralazine 
Less common causes 
 simvastatin   
 captopril,  
 minocycline 
 phenytoin   
 valproate,  
 penicillamine, 
  methyldopa

  methyldopa 
 griseofulvin 
 withdrawal of the offending medication, with rapid clinical resolution normally apparent. 
 low-dose corticosteroids may speed recovery in patients who are slow to improve.  
Extractable nuclear antigens  
Overview 
 specific nuclear antigens 
 usually associated with being ANA positive 
Examples

Examples 
 anti-Ro: Sjogren's syndrome, SLE, congenital heart block 
 anti-La: Sjogren's syndrome 
 anti-Jo 1: polymyositis 
 anti-scl-70: diffuse cutaneous systemic sclerosis 
 anti-centromere: limited cutaneous systemic sclerosis 
Gout 
 
 Gout is the most prevalent form of inflammatory arthropathy.  
 Primary gout has no obvious mode of inheritance , but familial juvenile gouty nephropathy

is an autosomal dominantly inherited disorder.  
 Gout is a form of microcrystal synovitis caused by the deposition of monosodium urate  
monohydrate in the synovium. 
 It is caused by chronic hyperuricaemia (uric acid > 0.45 mmol/l) 
 Serum urate concentrations exceeding 7 mg/dl are associated with increased risk of gout.  
 gout appears to be an independent risk factor for cardiovascular mortality and morb idity 
1054

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  26 
  Hyperuricaemia may be associated with both hyperlipidaemia and hypertension. It ma y also be 
seen in conjunction with the metabolic syndrome   
 Hyperuricaemia may be found in asymptomatic patients who have not experienc ed attacks of 
gout 
 Gout attacks may occur when the serum uric acid is normal.

 The aetiology of gout can broadly be divided into:  
1. Underexcretion of uric acid via the kidney (90%) or 
 Uric acid is the end product of purine metabolism.  
 in normal circumstances, uric acid excretion is two thirds renal and one third via 
intestinal bacterial uricolysis.  
 Where renal elimination is impaired, the amount of extra-renal excretion can be  
increased. 
2. Endogenous overproduction of uric acid (10%) 
Predisposing factors   
Increased synthesis Decreased excretion

Increased synthesis Decreased excretion  
 Lesch-Nyhan disease 
 myeloproliferative disorders (eg: 
ALL)  
 diet rich in purines 
 exercise 
 psoriasis 
 cytotoxics  drugs: low-dose aspirin*, diuretics, pyrazinamide 
 pre-eclampsia 
 alcohol 
 lead 
 Down's syndrome. 
 
*aspirin in a dose of 75-150mg is not thought to have a significant effect on plasma urate levels. the British

Society for Rheumatology recommend it should be continued if required for cardiovascul ar prophylaxis  
 
Lesch-Nyhan syndrome 
 hypoxanthine-guanine phosphoribosyl transferase (HGPRTase) deficiency 
 x-linked recessive therefore only seen in boys 
 features:  
 gout,  
 renal failure,  
 neurological deficits,  
 learning difficulties, 
  aggressiveness    
 self-mutilation (for example, biting of finger tips and/or lips).  
Other rare causes

Other rare causes 
 Starvation leads to an increase in lactic acid, which impairs the kidneys' ability to excrete  uric 
acid and therefore increases the risk of developing gout. .  
 
Gout: drug causes 
Drug causes  
 thiazides, furosemide 
 If diuretics are being used to treat hypertension an alternative antihypertensive should be 
considered, but they should not be stopped in the presence of heart failure 
 alcohol 
 cytotoxic agents 
 pyrazinamide

 alcohol 
 pyrazinamide 
 Aspirin in a dose of 75-150mg is not thought to have a significant effect on plasma urate 
levels 
  joint aspiration  Presence of long needle-shaped Crystals (uric acid crystal )  
 Serum urate may reduce during an acute attack; (normal urate concentration does not rule out a 
diagnosis of gout).  
Gout: management 
Acute management  
 NSAIDs   are first line in conjunction with gastro-protective medication

 NSAIDs should be avoided in elderly patients taking warfarin due to the risk of a life-
threatening gastrointestinal haemorrhage. 1055

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  27 
  NSAIDs  should be avoided in impaired renal function.  
 The first line treatment for acute gout is (NSAID) or colchicine. In renal impairment, 
a NSAID would be contraindicated.  Colchicine is safe to use in renal 
impairment.   
 NSAIDs are relatively  contraindicated in congestive cardiac failure 
 Corticosteroids

Corticosteroids are highly effective, and can be used where NSAIDs are not tolerated, or in 
refractory disease (intra-articular, oral, intramuscular, intravenous). 
 intra-articular steroid injection:  Potential local side effects  of corticosteroid injections 
include:  
 increased pain for the first couple of days,  
 septic arthritis,  
 subcutaneous atrophy (causing skin dimpling), 
  skin depigmentation,  
 accidental nerve injury and tendon rupture.

 accidental nerve injury and tendon rupture.  
 Oral steroids  may be considered if NSAIDs and colchicine are contraindicated . A 
dose of prednisolone 15mg/day is usually used 
 Avoided in diabetics because it would adversely affect diabetic control. 
 A recent trials found that oral prednisolone (30 mg/day for 5 days) had analgesic 
effectiveness equivalent to that of indomethacin and naproxen. 
 Colchicine:  has a slower onset of action.

 Colchicine:  has a slower onset of action.  
 Colchicine may be given to patients with acute gout, even if there is renal failure 
 effective when given within 12 hours of symptoms onset  at a loading dose of 1 mg 
followed 1 hour later by 0.5 mg on day 1  
 inhibits microtubule polymerization by binding to tubulin, interfering with mitosis. Also 
inhibits neutrophil motility and activity   
 useful in patients with renal impairment who develop gout as NSAIDs are relatively

contraindicated. should be avoided in patients with severe renal impairment.  
 The BNF advises to reduce the dose by up to 50% if creatinine clearance is less than 50  
ml/min and to avoid if creatinine clearance is less than 10 ml/min. 
 the most appropriate management for patient on colchicine 600mcg daily presented 
with acute gout and mild renal impairment Increase his colchicine to cope with 
the exacerbation

the exacerbation   
 may be increased up to a dose of 3mg, divided in 600mcg portions to cope with the  acute 
attack. 
 useful in patients taking warfarin as combined NSAID is harmful to GIT  
 Until recently it was thought that colchicine had little or no interaction with warfarin 
therapy, but a case series was recently published that suggested INR is increased in 
some patients prescribed colchicine . 
 The main side-effect is diarrhea

 The main side-effect is diarrhea 
 increased risk of myopathy if co-prescribed a statin.  
 Colchicine should not be given to patients receiving strong P-glycoprotein and/or CYP3A4 
inhibitors such as cyclosporin or clarithromycin. (2016 updated EULAR evidence-based 
recommendations for the management of gout . 
(http://ard.bmj.com.proxy1.athensams.net/content/76/1/29 ) 
 
 strong P-glycoprotein and/or CYP3A4 inhibitors such as cyclosporin, clarithromycin,

verapamil and ketoconazole when prescribed with colchicine increased colchicine 
plasma concentration, thereby exposing patients to risk of serious side effects. 
  IL-1 blockers:    
 European Medicines Agency approved anti- IL-1ȕ monoclonal antibody canakinumab  
(150 mg subcutaneously, one dose) for patients with contraindication to colchicine, 
NSAIDs and steroids  
 Current infection is a contraindication to the use of IL-1 blockers.  
  
 Rasburicase  
 recombinant urate oxidase

 recombinant urate oxidase 
 may be given during the acute attack of gout , to allow allopurinol therapy to be 
commenced without the initial worsening of symptoms. 
 But it is not currently licensed for the treatment of acute gout  associated with other 
conditions. 
 the best choice for warfarinsed patient  
 if the patient is already taking allopurinol it should be continued 1056

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  28 
  Rest the affected joints 
 Acute gout pain with congestive cardiac failure and renal impairment, developed severe 
diarrhoea with colchicine. The treatment of choice    Prednisolone  
 
Allopurinol prophylaxis   
Allopurinol 
 
Allopurinol action

Allopurinol action 
 Allopurinol is used in the prevention of gout. It works by inhibiting xanthine oxidase  
Allopurinol is an isomer of hypoxanthine and as such is a purine analogue. It a cts by inhibiting 
xanthine oxidase thereby blocking the oxidation of hypoxathine and xanthine. This reduc es the 
production of uric acid. 
 In addition, the build up of hypoxanthine and xanthine results in their conversion  to adenosine

and guanosine. This causes feedback inhibition of amidophosphoribosyl transferase, which is th e 
rate-limiting enzyme of purine biosynthesis. 
 Allopurinol therefore reduces both purine breakdown and synthesis.  
 
Allopurinol prescription  
 allopurinol should not be started until 2 weeks after an acute attack has settled a s it may 
precipitate a further attack if started too early 
 initial dose of 100 mg od, with the dose titrated every few weeks to aim for a serum u ric acid of <

300 µmol l/l 
 can be used even in moderate –severe renal failure as long as dose reduction is employed 
 NSAID or colchicine cover should be used when starting allopurinol 
 allopurinol is recommended for first-line ULT, starting at a low dose (100 mg/day ) and increasing 
by 100 mg increments every 2 –4 weeks if required, to reach the uricaemic target.  
 If the SUA target cannot be reached by an appropriate dose of allopurinol, or if allopurinol cannot

be tolerated   switch to febuxostat  or a uricosuric , or combined with a uricosuric.  
 Febuxostat  is a xanthine oxidase inhibitor that is recommended as second-line 
treatment to prevent gout when allopurinol has not been tolerated. 
 In refractory gout not responding  to above  3rd line drug (  pegloticase )  
Indications for allopurinol 
 recurrent attacks - the British Society for Rheumatology recommend 'In uncomplicated g out uric

acid lowering drug therapy should be started if a second attack, or further attacks occur with in 1 
year' 
 tophi 
 renal disease 
 uric acid renal stones 
 The incidence of renal stones is increased in patients with gout; 80% of these are uri c acid 
stones. 
 prophylaxis if on cytotoxics or diuretics 
 patients with Lesch-Nyhan syndrome often take allopurinol for life 
Allopurinol interactions  
 Azathioprine  
 metabolised to active compound 6-mercaptopurine

 xanthine oxidase is responsible for the oxidation of 6-mercaptopurine to 6-thiouric acid  
 allopurinol can therefore lead to high levels of 6-mercaptopurine 
 a much reduced dose (e.g. 25%) must therefore be used if the combination cannot  be 
avoided 
 allopurinol Increases toxicity and effects of azathioprine and 6-mercaptopurine. So 
 Reduce dose of azathioprine and 6-mercaptopurine to one quarter of usual dose. 
 Cyclophosphamide

 Cyclophosphamide 
 allopurinol reduces renal clearance, therefore may cause marrow toxicity 
 Warfarin  
 Allopurinol can interact with warfarin to enhance the anticoagulant effect of wa rfarin. 
 Allopurinol increase INR by inhibiting the metabolism of warfarin.  
1057

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  29 
  
Lifestyle modifications 
 reduce alcohol intake and avoid during an acute attack 
 lose weight if obese 
 avoid food high in purines e.g. Liver, kidneys, seafood, oily fish (mackerel, sardines)  and 
yeast products 
 avoid sugar-sweetened drinks , foods rich in fructose and orange or apple juice

 foods negatively associated with gout ( should be encouraged)  
 Low-fat dairy products   (skimmed milk and low-calorie yoghurt. This likely results from the 
uricosuric property of milk)  
  Coffee 
 Cherries..الك 
 
Prophylactic treatment 
Prophylaxis against flares : 
 Prophylaxis is recommended during the first 6 months of urate-lowering therapy  (ULT). 
 Recommended prophylactic treatment is colchicine , 0.5–1 mg/day, a dose that should be

reduced in patients with renal impairment.  
 In cases of renal impairment or statin treatment, patients and physicians should be a ware of 
potential neurotoxicity and/or muscular toxicity with prophylactic colchicine.  
 Co-prescription of colchicine with strong P-glycoprotein and/or CYP3A4 inhibitors should be 
avoided.  
 If colchicine is not tolerated or is contraindicated, prophylaxis with NSAIDs  at a low dosage, if not 
contraindicated, should be considered.

contraindicated, should be considered. 
 
Target of serum uric acid (SUA) in long term  
 For patients on ULT, SUA level should be monitored and maintained to <6 mg/dL (360 µmol/L).  
 A lower SUA target (<5 mg/dL; 300 µmol/L) to facilitate faster dissolution of crystals is 
recommended for patients with severe gout (tophi, chronic arthropathy, frequent attacks) until 
total crystal dissolution and resolution of gout.  
 SUA level <3 mg/dL is not recommended in the long term.

 SUA <6 mg/dL (360 µmol/L) should be maintained lifelong.  
 
Other points 
Antihypertensive drugs either increase serum uric acid levels  (e.g., diuretics, ȕ -blockers ) or 
decrease  serum uric acid levels  (e.g., calcium -channel blockers , losartan). 
 
 losartan has a specific uricosuric action ( ↑excretion of uric acid in the urine, thus reducing the 
serum uric acid) and may be particularly suitable for the many patients who have coe xistant 
hypertension

hypertension 
 Uricosuric agents should be avoided in those with renal stones 
 calcium channel blockers also decrease serum uric acid levels, possibly by a renal vasodilatory 
effect 
 increased vitamin C intake (either supplements or through normal diet) may also decrease serum 
uric acid levels 
 When gout occurs in a patient receiving loop or thiazide diuretics, substitute the diuretic if 
possible;  
 for hypertension, consider losartan or calcium channel blockers;

 for hyperlipidaemia, consider a statin or fenofibrate. (have uricosuric property ) 1058

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  30 
  
Recurrent arthritis  
 Crystal arthritis (gout or Pseudo-gout) are the most common cause of recurrent arthritis. 
 Patient with recurrent arthritis but now is free  ask the patient to report to the clinic 
during the next attack  Crystal arthritis for aspiration during the attack

Hip pain in adults 
The table below provides a brief summary of the potential causes of hip pain in adults  
 
Condition Features 
Osteoarthritis  Pain exacerbated by exercise and relieved by rest 
Reduction in internal rotation is often the first sign 
Age, obesity and previous joint problems are risk factors 
Inflammatory arthritis  Pain in the morning 
Systemic features 
Raised inflammatory markers 
Referred lumbar spine

Referred lumbar spine 
pain  Femoral nerve compression may cause referred pain in the hip 
Femoral nerve stretch test may be positive - lie the patient prone. Extend the hip 
joint with a straight leg then bend the knee. This stretches the femoral nerve and 
will cause pain if it is trapped 
Greater trochanteric 
pain syndrome 
(Trochanteric bursitis)  Due to repeated movement of the fibroelastic iliotibial band 
Pain and tenderness over the lateral side of thigh

Most common in women aged 50-70 years 
Meralgia paraesthetica  Caused by compression of lateral cutaneous nerve of thigh 
Typically burning sensation over antero-lateral aspect of thigh 
Avascular necrosis  Symptoms may be of gradual or sudden onset 
May follow high dose steroid therapy or previous hip fracture of dislocation 
Pubic symphysis 
dysfunction  Common in pregnancy 
Ligament laxity increases in response to hormonal changes of pregnancy

Pain over the pubic symphysis with radiation to the groins and the medial 
aspects of the thighs. A waddling gait may be seen 
Transient idiopathic 
osteoporosis  An uncommon condition sometimes seen in the third trimester of pregnancy 
Groin pain associated with a limited range of movement in the hip 
Patients may be unable to weight bear 
ESR may be elevated 
1059

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  31 
Hip problems in children  
The table below provides a brief summary of the potential causes of hip problems in chil dren 
 
Condition Notes 
Development 
dysplasia of the 
hip Often picked up on newborn examination 
Barlow's test, Ortolani's test are positive

Barlow's test, Ortolani's test are positive 
Unequal skin folds/leg length 
Transient 
synovitis 
(irritable hip)  Typical age group = 2-10 years 
Acute hip pain associated with viral infection 
Commonest cause of hip pain in children 
Perthes disease  Perthes disease is a degenerative condition affecting the hip joints of children, typically 
between the ages of 4-8 years. It is due to avascular necrosis of the femoral head

Perthes disease is 5 times more common in boys. Around 10% of cases are bilateral 
Features 
 hip pain: develops progressively over a few weeks 
 limp 
 stiffness and reduced range of hip movement 
 x-ray: early changes include widening of joint space, later changes include 
decreased femoral head size/flattening 
Slipped upper 
femoral 
epiphysis  Typical age group = 10-15 years  
More common in obese children and boys 
Displacement of the femoral head epiphysis postero-inferiorly

Bilateral slip in 20% of cases 
May present acutely following trauma or more commonly with chronic, persistent 
symptoms  
Features 
 knee or distal thigh pain is common 
 loss of internal rotation of the leg in flexion 
Juvenile 
idiopathic 
arthritis (JIA)  Preferred to the older term juvenile chronic arthritis, describes arthritis occurring in 
someone who is less than 16 years old that lasts for more than three months.

Pauciarticular JIA refers to cases where 4 or less joints are affected. It accounts for 
around 60% of cases of JIA 
Features of pauciarticular JIA 
 joint pain and swelling: usually medium sized joints e.g. knees, ankles, elbows 
 limp 
 ANA may be positive in JIA - associated with anterior uveitis  
Septic arthritis  Acute hip pain associated with systemic upset e.g. pyrexia. Inability/severe limitation of 
affected joint 
 
 1060

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  32 
 Image gallery  
 
Perthes disease - both femoral epiphyses show extensive destruction, the acetabul a are deformed 
Perthes disease - bilateral disease  
 
Slipped upper femoral epiphysis - left side 
 
1061

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  33 
  
Lateral epicondylitis 
 
Lateral epicondylitis typically follows unaccustomed activity such as house painting or playing t ennis

('tennis elbow'). It is most common in people aged 45-55 years and typically affects th e dominant arm. 
 
Features  
 pain and tenderness localised to the lateral epicondyle 
 pain worse on wrist extension against resistance with the elbow extended or supination of t he 
forearm with the elbow extended 
 episodes typically last between 6 months and 2 years. Patients tend to have acute pain for 6- 12 
weeks 
 advice on avoiding muscle overload 
 simple analgesia

 simple analgesia 
 physiotherapy 
 Lower back pain (LBP) is one of the most common presentations seen in practice.  
 Whilst the majority of presentations will be of a non-specific muscular nature  it is worth 
keeping in mind possible causes which may need specific treatment.  
 musculogenic (strain) etiology is the most common cause of low back pain. 
 
Red flags  for lower back pain

Red flags  for lower back pain 
 
1062

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  34 
  
The table below indicates some specific causes of LBP : 
Facet joint  May be acute or chronic 
 Pain worse in the morning and on standing 
 On examination there may be pain over the facets.  
 The pain is typically worse on extension of the back 
Spinal stenosis   Usually gradual onset

Spinal stenosis   Usually gradual onset 
 Unilateral or bilateral leg pain (with or without back pain), numbness, and 
weakness which is worse on walking. Resolves when sits down.  
 Pain may be described as 'aching', 'crawling'. 
 Relieved by sitting down, leaning forwards and crouching down 
 Clinical examination is often normal 
 Requires MRI to confirm diagnosis 
spondylitis   Typically a young man who presents with lower back pain and stiffness

 Stiffness is usually worse in morning and improves with activity 
 Peripheral arthritis (25%, more common if female) 
arterial disease   Pain on walking, relieved by rest 
 Absent or weak foot pulses and other signs of limb ischaemia 
 Past history may include smoking and other vascular diseases 
 
   (also known as zygapophyseal, 
apophyseal, or Z-joint)  
 are synovial joints between the spinal 
vertebrae  
 Function: guide and limit movement of the

 Function: guide and limit movement of the 
spinal motion segment.  
 
Assessment 
 Do risk stratification for new cases 
 such as the STarT Back risk assessment tool  
 do not request imaging unless serious underlying pathology is suspected. 
 
STarT Back Screening Tool  
1. My back pain has spread down my leg(s) at some time in the last 2 weeks  
2. I have had pain in the shoulder or neck at some time in the last 2 weeks  
3. I have only walked short distances because of my back pain

4. In the last 2 weeks, I have dressed more slowly than usual because of back pa in  
5. It’s not really safe for a person with a condition like mine to be physically active  
6. Worrying thoughts have been going through my mind a lot of the time  
7. I feel that my back pain is terrible and it ’s never going to get any better  
8. In general I have not enjoyed all the things I used to enjoy

9. Overall, how bothersome has your back pain been in the last 2 weeks? Not at all (0), Sligh tly, (0), 
Moderately (0), Very much (1), Extremely (1)  
 STarT Back scoring:  
 For questions 1-8, score 1 for agreement, 0 for disagreement  
 Low risk = total score 0-3;  
 high risk = score 4-5 of questions 5-9 only;  
 the rest are medium risk.  
 
Management (NICE: November 2016) 
1063

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  35 
  Non-pharmacological  
 Self-management 
 encouragement to continue with normal activities. 
 Exercise 
 Manual therapies (spinal manipulation, mobilisation or soft tissue techniques such as 
massage) 
 Traction is NOT recommended 
 Psychological therapy (cognitive behavioural)

 Psychological therapy (cognitive behavioural) 
 Acupuncture and Electrotherapies are NOT recommended 
 Pharmacological  
 NSAIDs 
 Do not offer paracetamol alone for managing low back pain. 
 Consider weak opioids (with or without paracetamol) for managing acute low back pain 
only if an NSAID is contraindicated, not tolerated or has been ineffective. 
 Do not offer opioids for managing chronic  low back pain. 
 Antidepressants and anticonvulsants are not recommended

 Invasive n on-surgical treatments  
 Spinal injections are not recommended for treatment. 
 except for 'radiofrequency denervation'.  
 To determine whether these people will benefit from this procedure, they 
may be offered a diagnostic block of the nerves that supply the joints 
between the vertebrae.  
 If they experience significant pain relief they may then be offered 
radiofrequency denervation in an attempt to achieve longer-term 
relief. 
 Radiofrequency denervation

relief. 
 Radiofrequency denervation  
 for chronic low back pain if : 
1) non-surgical treatment has not worked and 
2) the main source of pain is thought to come from structures supplied by the  
medial branch nerve and  
3) they have moderate or severe pain  
 Only performed after a positive response to a diagnostic medial branch block. 
 epidural injections  of local anaesthetic and steroid in people with acute and severe 
sciatica.  
 Invasive surgical treatments:

sciatica.  
 Invasive surgical treatments: 
  spinal decompression  
 for sciatica when non-surgical treatment has not improved pain  
 Spinal fusion and  disc replacement are NOT recommended in  treatment of low back 
pain. 
 (NICE - Low back pain and sciatica in over 16s Quality standard: July 2017) 
Mixed connective tissue disease (MCTD)

Mixed connective tissue disease (MCTD) 
 
 MCTD is an overlap syndrome characterised by combinations of clinical features of SLE, 
systemic scleroderma and polymyositis  (e.g. arthralgia, myositis and Raynaud's ).  
 The presenting symptoms of MCTD are most often: 
 Raynaud's phenomenon 
 puffy hands 
 arthralgias 
 myalgias 
 fatigue. 
 Diagnosis Anti-RNP positive 
 A defining feature of MCTD is the presence of antibodies against the U1 ribonucleoprotein

(U1 RNP) complex, and hence the presence of high titre anti-U1 RNP will confirm the 
clinical diagnosis of MCTD. 
1064

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  36 
  
Osteoarthritis 
The trapezio-metacarpal joint (base of thumb) is the most common site of hand o steoarthritis 
 
 Pathogenesis involves the localised loss of cartilage, with remodelling of adjacent b one. 
 Osteoarthritis characteristically affects the distal interphalangeal  as well as the proximal

interphalangeal and first metacarpophalangeal joints. 
 The carpometacarpal (CMC) joint is classically involved 
 Joint swelling is bony in nature , unlike the boggy swelling which occurs in inflammatory 
arthritis.  
 Thenar wasting occurs in OA of the first CMC joint due to disuse. 
 pain is exacerbated by exercise and relieved by rest, although in advanced dise ase rest and 
night pain can develop. 
 Obesity is one of the commonest causes for the early appearance of osteoarthritis

 Osteoarthritis may be secondary to haemochromatosis  do  Ferritin 
 
Osteoarthritis: x-ray changes 
 
X-ray changes of osteoarthritis 
 decrease of joint space 
 subchondral sclerosis 
 subchondral cysts 
1065

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  37 
  osteophytes forming at joint margins 
 
Osteoarthritis: management 
 
NICE published guidelines on the management of osteoarthritis (OA) in 2014 
 all patients should be offered help with weight loss, given advice about local muscle 
strengthening exercises and general aerobic fitness

 paracetamol and topical NSAIDs are first-line analgesics.  Topical NSAIDs are indicated only 
for OA of the knee or hand  
 second-line treatment is oral NSAIDs/COX-2 inhibitors, opioids, capsaicin cream and intra-
articular corticosteroids. A proton pump inhibitor should be co-prescribed with NSAIDs and COX-
2 inhibitors. These drugs should be avoided if the patient takes aspirin 
 non-pharmacological treatment options include supports and braces, Transcutaneous

Electrical Nerve Stimulation (TENS) and shock absorbing insoles or shoes 
 if conservative methods fail then refer for consideration of joint replacement 
 
What is the role of glucosamine? 
 normal constituent of glycosaminoglycans in cartilage and synovial fluid 
 a systematic review of several double blind RCTs of glucosamine in knee osteoarthritis reported 
significant short-term symptomatic benefits including significantly reduced joint space narrowing  
and improved pain scores

and improved pain scores 
 more recent studies have however been mixed 
 the 2008 NICE guidelines suggest it is not recommended 
 a 2008 Drug and Therapeutics Bulletin review advised that whilst glucosamine provides modest  
pain relief in knee osteoarthritis it should not be prescribed on the NHS due to limited eviden ce of 
cost-effectiveness 
Studies have shown that paracetamol 1 g combined  with codeine at dose of 60 mg  have the best 
analgesic outcomes. 
 
1066

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  38 
  
Osteogenesis imperfecta 
Osteogenesis imperfecta (more commonly known as brittle bone disease) is a group of disorde rs of 
collagen metabolism resulting in bone fragility and fractures. The most common, and  milder, form of 
osteogenesis imperfecta is type 1

osteogenesis imperfecta is type 1 
 
Overview  
 abnormality in type 1 collagen due to decreased synthesis of pro-alpha 1 o r pro-alpha 2 collagen 
polypeptides 
Features 
 presents in childhood 
 fractures following minor trauma 
 blue sclera 
 deafness secondary to otosclerosis 
 dental imperfections are common 
Osteomyelitis

Osteomyelitis 
 
Patients with sickle cell disease have a predisposition to develop osteomyelitis due 
to Salmonella  species. 
 
 Osteomyelitis: infection of bone marrow and bone 
 Acute form: develops within days or weeks 
 Chronic form: develops slowly (over months or years) and is associated with avascular bone  
necrosis and sequestrum formation within the bone 
Causes  
 Staph. aureus  is the most common cause followed by Pseudomonas

  Pseudomonas aeruginosa  is more common in intravenous drug users.  
 Salmonella  species is the commonest cause in patients with sickle- cell anaemia. 
 Pasteurella multocida 
 seen in cases caused by cat and dog bites  
 Haematogenous osteomyelitis:  
 most commonly involves the vertebrae, but infection may also occur in the metaphysis  of 
the long bones ,  pelvis, and clavicle.  
 The lumbar spine is most commonly affected, followed by the thoracic and cervical 
regions.

regions. 
 the location is usually metaphyseal  
 The metaphysis is commonest site of osteomyelitis, because: 
 Is highly vascular 
 Has a hair pin like arrangement of capillaries 
1067

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  39 
  Has sluggish blood flow 
 has relatively fewer phagocytic cells than the physis or diaphysis, allowing 
infection to occur more easily in this area 
 thin cortex 
 Posttraumatic osteomyelitis  
 typically found in the tibia. 
 Contiguous-focus osteomyelitis 
  direct inoculation of bacteria via trauma

  direct inoculation of bacteria via trauma  
 Infection usually results approximately one month after inoculation.  
Predisposing conditions  
 sickle cell anaemia 
 intravenous drug user 
 immunosuppression due to either medication or HIV 
 MRI is the imaging modality of choice , with a sensitivity of 90-100% 
 show  cortical destruction, bone marrow inflammation, soft tissue involvement

 Bone scintigraphy (Gallium bone scan) if MRI is contraindicated (metal foreign body implants) ĺ 
detects sites of infection 
  X-ray shows: 
 still provide the best  initial screening  test for acute and chronic osteomyelitis.  
 Early stages (< 2 weeks of symptoms onset): typically no pathological findings 
 Later stages: bone destruction, sequestrum formation, periosteal reactions  
 lytic lesion with sclerotic margins ( Brodie ’s abscess ) 
 a form of chronic osteomyelitis

 a form of chronic osteomyelitis   
 thickened bone with irregular and patchy sclerosis that gives a honeycombed 
appearance.  
 Sequestra are seen as dense loose fragments lying within a cavity in the bone. 
 insidious onset  (eg: 6-month history of gradually progressive swelling and pain) 
 often near the site of the metaphysis, 
 Deep ‘boring ’ pain is often the predominant symptom.  
 Osteomyelitis can cause a raised periosteum which is part of the radiographic sign known

as the Codman triangle .  
 Bone biopsy 
 Detects both osteonecrosis and the pathogen ĺ confirms the diagnosis and helps gu ide 
more specific therapy 
 Septic arthritis 
 Infection of the joint; in contrast to osteomyelitis, involvement of the metaphysis is rare  
 Ewing sarcoma 
 x-ray: lytic bone lesions,  onion skin appearance of the periosteum  
 
 flucloxacillin for 6 weeks 
 clindamycin if penicillin-allergic

 clindamycin if penicillin-allergic 
 Beta-lactams and vancomycin are commonly used as initial empiric therapy. 
 Osteomyelitis from contiguous spread of infection 
  Piperacillin-tazobactam  
 Patients with penicillin allergy    Clindamycin  or metronidazole plus   ciprofloxacin  
 If MRSA is suspected:  Add vancomycin   (or linezolid if allergic to vancomycin)  
Osteomalacia

Osteomalacia 
The symptoms of proximal bone pain with hypocalcaemia and low phosphate suggest a 
diagnosis of osteomalacia 
 
↓↓ Ca ↓↓ P ↓↓ vit D + ↑↑ ALP  osteomalacia 
Basics 1068

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  40 
  normal bony tissue but decreased mineral content 
 rickets if when growing 
 osteomalacia if after epiphysis fusion 
 occurs more commonly in patients of South Asian origin , particularly those who have a cultural 
tendency to spend more time inside.

tendency to spend more time inside.  
 more common in ethnic groups who are dark-skinned, or cover themselves up so that cholesterol 
cannot be converted to vitamin D in the skin.  
 Asians who eat chapattis are also at risk, as the phytic acid in the chapattis chelates vitamin D 
and calcium 
 Europid ethnic origin is associated with a reduced risk of osteomalacia versus populations with 
increased skin pigmentation. 
Causes

Causes 
 vitamin D deficiency e.g. malabsorption, lack of sunlight, diet  
 vitamin D resistant; inherited 
 liver disease, e.g. cirrhosis 
 drug induced e.g. anticonvulsants 
 Mercury poisoning  or any heavy metal poisoning causes an acquired Fanconi syndrome with 
proximal (type 2) renal tubular acidosis. 
Features 
 rickets: knock-knee, bow leg, features of hypocalcaemia 
 osteomalacia:

 osteomalacia:  
 bone pain, particularly around the hips and lower back,  
 fractures,  
 muscle tenderness,  
 proximal myopathy 
 low calcium, phosphate, 25(OH) vitamin D 
 raised alkaline phosphatase  as it is released from bone reflecting osteoblastic activity. 
 Serum PTH is also usually elevated and normalises gradually on response to treatment.  
  There is also acidosis which is caused by the inhibition of phosphate, bicarbonate, and sodium

reabsorption by PTH.  
 x-ray:  
 children - cupped, ragged metaphyseal surfaces;  
 adults - translucent bands ( Looser's zones ( Linear areas of low density ) 
(pseudofractures)  
 Looser ’s zones  characterised by low-density bands extending from the  cortex 
inwards in the shafts of long bones. 
Treatment 
 calcium with vitamin D tablets 
May 2013 exam: A 58-year-old woman C/O aches and pains in her bones. Generally weak and

lethargic. low calcium, phosphate and vitamin D levels combined with a raised alka line phosphatase 
and parathyroid hormone level .What is the most appropriate management? Start vitamin D3 
supplementation (∆  osteomalacia)  
 
Oncogenic osteomalacia 
 Certain tumours, including mesenchymal tumours, adenocarcinomas (e.g. prostatic carcinoma) 
and haematological malignancies such as myeloma and chronic lymphocytic leukaemia, ap pear 
to produce a phosphaturic substance.  
 Features

 Features 
 bone pain and/or fracture, profound proximal myopathy and severe hypopho sphataemia,  
 usually accompanied by a marked reduction in concentration of 1,25-OH vitamin D.  
 Other abnormalities of renal function such as glycosuria and aminoaciduria may also be 
present.  
 vitamin D metabolites and phosphate supplements may result in some resolution of 
skeletal symptoms.  
 In the case of solid tumours, removal of the primary tumour also results in improvement of

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  41 
Osteopetrosis 
Overview 
 also known as marble bone disease 
 rare disorder of defective osteoclast function  resulting in failure of normal bone resorption 
 results in dense, thick bones that are prone to fracture 
 bone pains and neuropathies are common.

 bone pains and neuropathies are common. 
 calcium, phosphate and ALP are normal 
 stem cell transplant and interferon-gamma have been used for treatment 
Osteoporosis  
In osteoporosis, there is decreased bone mass , but mineralization is normal. 
causes 
 unknown (95%)   
 Advancing age and female sex .  
 Prevalence increases from 2% at 50 years to more than 25% at 80 years in women.

Risk factors: the most 'important' ones are risk factors that are used by major risk assessment tools 
such as FRAX:  
 history of glucocorticoid use 
 history of parental hip fracture ( family history of osteoporotic fracture ) 
 low body mass index 
 current smoking 
Other risk factors 
 sedentary lifestyle 
 premature menopause 
 Early menarche and late menopause are associated with reduced risk of fracture. 
 Caucasians and Asians

 Caucasians and Asians 
 endocrine disorders: hyperthyroidism, hypogonadism (e.g. Turner's, testosterone deficiency), 
growth hormone deficiency, hyperparathyroidism, diabetes mellitus 
 multiple myeloma, lymphoma 
 gastrointestinal disorders: inflammatory bowel disease, malabsorption (e.g. Coeliac's), 
gastrectomy, liver disease 
 osteogenesis imperfecta, homocystinuria 
Risk factors for post-menopausal osteoporosis, include 
 Early onset (<45 years) menopause

 Early onset (<45 years) menopause 
 Absence of hormone replacement therapy, calcium and vitamin D supplemention  and 
 Low body weight. 
 
Medications that may worsen osteoporosis (other than glucocorticoids): 
 SSRIs 
 antiepileptics 
 proton pump inhibitors 
 glitazones 
 long term heparin therapy 
 aromatase inhibitors e.g. anastrozole (used for breast cancer in postmenopausal women

and gynecomastia in men.  aromatase, which converts androgens into estrogens by a process called aromatization.)  
feature 
 Classically, osteoporosis in the absence of fracture, does not cause pain . Many patients with 
osteoporosis have concomitant disorders such as osteomalacia and osteoarthritis which cause 
bone pain.  
 Patients with osteoporosis may have no warning signs until the first fracture  occurs.

 Gradual height loss and dorsal kyphosis may result from microfractures or complete fractures of 
vertebral bodies. 
Investigations for secondary causes  
If a patient is diagnosed with osteoporosis or has a fragility fracture further investigations may be 
warranted. NOGG recommend testing for the following reasons: 
 exclude diseases that mimic osteoporosis (e.g. osteomalacia, myeloma); 1070

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  42 
  identify the cause of osteoporosis and contributory factors; 
 assess the risk of subsequent fractures; 
 select the most appropriate form of treatment 
The following investigations are recommended by NOGG: 
 History and physical examination

 History and physical examination 
 Blood cell count, sedimentation rate or C-reactive protein, serum calcium,albumin, creatinine, 
phosphate, alkaline phosphatase and liver transaminases 
 Thyroid function tests 
 Bone densitometry ( DXA) 
Other procedures, if indicated 
 Lateral radiographs of lumbar and thoracic spine/DXA-based vertebral imaging 
 Protein immunoelectrophoresis and urinary Bence-Jones proteins 
 25OHD 
 PTH 
 Serum testosterone, SHBG, FSH, LH (in men),

 Serum testosterone, SHBG, FSH, LH (in men), 
 Serum prolactin 
 24 hour urinary cortisol/dexamethasone suppression test 
 Endomysial and/or tissue transglutaminase antibodies (coeliac disease) 
 Isotope bone scan 
 Markers of bone turnover, when available 
 Urinary calcium excretion 
So from the first list we should order the following bloods as a minimum fo r all patients: 
 full blood count 
 urea and electrolytes 
 liver function tests 
 bone profile 
 CRP

 CRP  
DEXA scan 
Basics 
 T score: based on bone mass of young reference population  (compare the patient's bone mineral 
density (BMD) with that of a healthy young adult) 
 T score of -1.0 means bone mass of one standard deviation below that of young re ference 
population 
 Z score is adjusted for age, gender and ethnic factors (Z-scores compare the individual's BMD 
with that of a population of peers)

with that of a population of peers) 
 The Z-score is not routinely used in the diagnosis of osteoporosis 
 It can be used to investigate the possibility of osteoporosis in premenopausal women, 
men under the age of 50 and children. 
 It is most useful when the bone mineral density is less than 2 standard deviations below 
the normal. 
T score 
 > -1.0 = normal  
 -1.0 to -2.5 = osteopaenia 
 < -2.5 = osteoporosis

 < -2.5 = osteoporosis  
Osteoporosis diagnosis according to the WHO and International Osteoporosis Foundation 
criteria:  
diagnosis T score  definition 
normal  ( ≥ −1) hip BMD greater than the 1 SD below the young 
adult reference mean  
osteopaenia    (−1 to −2.5)  hip BMD between 1 and 2.5 DS below the young 
osteoporosis  (≤ −2.5) hip BMD 2.5 SD or more below the young adult 
reference mean

reference mean  
Severe osteoporosis  (≤ −2.5 PLUS fracture)  hip BMD 2.5 SD or more below the young adult 
reference mean + one or more fragility fractures  
 
 1071

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  43 
  
May 
2016   
  
 5% of young adults lie outside the boundaries of T score – 2.0 to +2.0  
 2.5% of young adults have a T score above + 2.0 & 2.5% of young adults have a T score below -2.0 
 99.7% of young adults have a T score between – 3.0 to +3.0 
 68% of young adults have a T score between – 1.0 to +1.0

Osteoporosis: glucocorticoid-induced 
 Steroids cause a decrease in calcium absorption from the gut, increased urinary calciu m 
excretion, and also causes bone resorption, resulting in osteoporosis.  
 The risk ↑↑ with prednisolone 7.5mg a day for 3 or more months.  
 patients should be managed in an anticipatory, i.e. if it likely that the patient will have to take 
steroids for at least 3 months then we should start bone protection straight away, rather th an

waiting until 3 months has elapsed.  
 A good example is a patient with newly diagnosed polymyalgia rheumatica. As it is ve ry likely 
they will be on a significant dose of prednisolone for greater than 3 months bone p rotection 
should be commenced immediately. 
Management of patients at risk of corticosteroid-induced osteoporosis  
The RCP guidelines divide patients into two groups. 
1. age > 65 years or H/O previously fragility fracture  give bone protection.

 Fragility fracture - defined by The WHO as resulting from a mechanical force equiv alent to 
a fall from standing height or less which should not ordinarily cause a fracture. 
2. age < 65 years  bone density scan 
 
T score Management 
Greater than 0 Reassure 
Between 0 and -1.5 Repeat bone density scan in 1-3 years 
Less than -1.5 Offer bone protection 
 
The first-line treatment is alendronate. Patients should also be calcium and vitam in D replete.

Osteoporosis: Assessing patients following a fragility fracture 
 The management of patients following a fragility fracture depends on ag e. 
Patients ≥ 75 years of age  
 Patients ≥ 75 years + fragility fracture  start first-line therapy (an oral bisphosphonate), without 
DEXA scan . 
 For example, a 79-year-old woman falls over on to an outstretched hand and sust ains a Colles' 
fracture (fracture of the distal radius). Given her age she is presumed to have osteoporosis and

therefore started on oral alendronate 70mg once weekly. No DEXA scan is arranged. 
 the 2014 NOGG guidelines have a different threshold, suggesting treatment is started in all 
women > 50 years who've had a fragility fracture - 'although BMD measurement may sometimes 
be appropriate, particularly in younger postmenopausal women.'  
Patients < 75 years of age  
 patient < 75 years + fragility fracture  DEXA scan should be arranged.

 These results can then be entered into a FRAX tool to assess ongoing fracture risk. 
 
1072

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  44 
 Osteoporosis: assessing risk NICE guidelines (2012)  
 
Who should be assessed for fragility fracture? 
 all women aged ≥ 65 years and all men aged ≥ 75 years.  
 Younger patients + presence of risk factors, such as: 
 previous fragility fracture 
 current use or frequent recent use of oral or systemic glucocorticoid

 history of falls 
 family history of hip fracture 
 other causes of secondary osteoporosis 
 low body mass index (BMI) (< 18.5 kg/m) 
 smoking 
 alcohol (> 14 units/week for women and > 21 units/week for men). 
Methods of risk assessment  
 NICE recommend using a clinical prediction tool such as FRAX or Q Fracture to assess a 
patient's 10-year risk of developing a fracture. This is analogous to the cardiovascular risk tools 
such as QRISK. 
FRAX

FRAX  
 estimates the 10-year risk of fragility fracture 
 valid for patients aged 40-90 years 
 based on international data so use not limited to UK patients 
 assesses the following factors:  
1. age,  
2. sex,  
3. weight,  
4. height,  
5. previous fracture,  
6. parental fracture,  
7. current smoking,  
8. glucocorticoids,  
9. rheumatoid arthritis,  
10. secondary osteoporosis,  
11. alcohol intake

11. alcohol intake 
 bone mineral density (BMD) is optional, but clearly improves the accuracy of the results.  
 NICE recommend arranging a DEXA scan if FRAX (without BMD) shows an intermediate result 
Q Fracture 
 developed in 2009 based on UK primary care dataset 
 can be used for patients aged 30-99 years (this is stated on the Q Fracture website, bu t other 
sources give a figure of 30-85 years)

sources give a figure of 30-85 years) 
 includes a larger group of risk factors e.g. cardiovascular disease, history of falls, chronic liver 
disease, rheumatoid arthritis, type 2 diabetes and tricyclic antidepressants 
DEXA scan  
 There are some situations where NICE recommend arranging BMD assessment (i.e. a DEXA 
scan) rather than using one of the clinical prediction tools: 
 before starting treatments that may have a rapid adverse effect on bone density ( for

example, sex hormone deprivation for treatment for breast or prostate cancer). 
 in people aged under 40 years who have a major risk factor, such as history of multiple 
fragility fracture, major osteoporotic fracture, or current or recent use of high-dose o ral or 
high-dose systemic glucocorticoids (more than 7.5 mg prednisolone or equivalent per day 
for 3 months or longer). 
 Indicators of low BMD are: 
  low body mass index (defined as less than 22 kg/m2),

 medical conditions such as ankylosing spondylitis, Crohn's disease,  
 conditions that result in prolonged immobility, and  
 untreated premature menopause 
 
Interpreting the results of FRAX  
1073

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  45 
  If the FRAX assessment was done without a bone mineral density (BMD) measurement the 
results (10-year risk of a fragility fracture) will be given and categorised automatically in to one of 
the following: 
 low risk: reassure and give lifestyle advice 
 intermediate risk: offer BMD test

 intermediate risk: offer BMD test 
 high risk: offer bone protection treatment 
 If the FRAX assessment was done with a bone mineral density (BMD) measurement the 
 reassure 
 consider treatment 
 strongly recommend treatment 
 If you use Q Fracture instead patients are not automatically categorised into low, inte rmediate or

high risk. Instead the 'raw data' relating to the 10-year risk of any sustaining an osteoporotic 
fracture. This data then needs to be interpreted alongside either local or national guidelines, 
considering certain factors such as the patient's age. 
When should we reassess a patient's risk (i.e. repeat the FRAX/Q Fracture) ?  
 if the original calculated risk was in the region of the intervention threshold for a proposed 
treatment and only after a minimum of 2 years, or

 when there has been a change in the person's risk factors 
 
Osteoporosis: management  
 secondary prevention of osteoporotic fractures in postmenopausal women  (NICE 
guidelines 2008). Key points include  
 osteoporotic fragility fractures in postmenopausal women + confirmed osteoporosis (a T-
score of - 2.5 SD or below)  treatment .  
 In women aged ≥ 75 years, a DEXA scan may not be required 
 vitamin D and calcium supplementation should be offered to all women unless the clinicia n

is confident they have adequate calcium intake and are vitamin D replete 
 If osteoporosis is established, the treatment includes 1500 mg/day of calcium 
and 400-800 pg  /day of vitamin D  
 Dietary intake of calcium should be: 
 800-1000 mg/day in childhood through early adulthood 
 1000-1200 mg/day in the middle years 
 1500 mg/day in the elderly 
 alendronate is first-line 
 around 25% of patients cannot tolerate alendronate, usually due to upper gastroin testinal

problems. These patients should be offered risedronate or etidronate (see treatm ent 
criteria below) 
 strontium ranelate and raloxifene are recommended if patients cannot tolerate 
bisphosphonates (see treatment criteria below) 
 Treatment criteria for patients not taking alendronate : for patients who do not tolerate 
alendronate, the most important thing to remember is: 
 the T-score criteria for risedronate or etidronate are less than the others implying that

these are the second line drugs 
 if alendronate, risedronate or etidronate cannot be taken then strontium ranelate o r 
raloxifene may be given based on quite strict T-scores (e.g. a 60-year-old woman wo uld 
need a T-score < -3.5) 
 the strictest criteria are for denosumab 
 
Supplementary notes on treatment  
 Bisphosphonates  
 Oral bisphosphonates  (alendronic acid, ibandronic acid and risedronate sodium) are 
recommended for treating osteoporosis only if:

recommended for treating osteoporosis only if: 
 the 10 ‑year probability of osteoporotic fragility fracture is at least 1%.  
 Intravenous  bisphosphonates  (ibandronic acid and zoledronic acid) are recommended 
for treating osteoporosis only if: 
 the 10 ‑year probability of osteoporotic fragility fracture is at least 10%  or 
 the 10 ‑year probability of osteoporotic fragility fracture is at least 1% and the

person has difficulty taking oral bisphosphonates (alendronic acid, ibandronic acid 
or risedronate sodium) or these drugs are contraindicated or not tolerated. 1074

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  46 
  alendronate, risedronate and etidronate are all licensed for the prevention and treatme nt 
of post-menopausal and glucocorticoid-induced osteoporosis 
 reduce the risk of both vertebral and non-vertebral fractures  
 alendronate, risedronate may be superior to etidronate in preventing hip fractures 
 Alendronic acid

 Alendronic acid  
 tablets, 10 mg once a day 
 tablets, 70 mg once a week 
 Risedronate sodium  
 tablets, 5 mg once a day 
  tablets, 35 mg once a week 
 Etidronate is an oral bisphosphonate 
 administered in 90-day cycles, with each cycle consisting of etidronate 
(400 mg/day) for 14 days followed by calcium carbonate (1.25 g/day) for the 
remaining 76 days.  
 Zoledronic acid 
 intravenous infusion, 50 micrograms/ml once a year 
 ibandronate is a once-monthly oral bisphosphonate

 Ibandronic acid:  
 tablets, 150 mg once a month 
 injection, 3 mg/ml once every 3 months 
  Instructions for administration  
 Alendronate and risedronate must be taken with 200 ml and 120 ml of water, 
 Before and immediately after administration patients should not eat or drink, and 
must remain upright for stipulated time periods.  
 Etidronate should be taken with water at the midpoint of a 4-hour fast (that is,

2 hours after and 2 hours before food, vitamins with mineral supplements such as 
iron, calcium supplements, laxatives containing magnesium, or antacids containing 
calcium or aluminium). 
 contraindicated in patients with a GFR less than 35 ml/min  
 Data from randomised controlled trials supports use of bisphosphonates down to 
GFRs as low as 30-35 ml/min. Below this level RCT evidence is unavailable, and 
the risk of adynamic bone disease associated with renal impairment is significantly

elevated.  
 Bisphosphonate induce osteonecrosis of the jaw  (associated with dental extraction 
surgery and increased with underlying malignancy, especially multiple myeloma) 
 Most cases have been associated with zoledronic acid  and pamidronate given 
intravenously for metastatic bone disease.  
 The reported incidence in patients with malignancy treated with these drugs is 
between 1.3-4.0%. 
 Dental disease is a recognised predisposing factor.

 The lesions usually heal with minimal surgical debridement, chlorhexidine 
mouthwashes, antibiotics and analgesia. 
(Ref: NICE guidelines : Bisphosphonates for treating osteoporosis. Published date:  09 August 2017) 
 
 Vitamin D and calcium  
 poor evidence base to suggest reduced fracture rates in the general population at risk of 
osteoporotic fractures - may reduce rates in frail, housebound patients 
 Raloxifene - selective oestrogen receptor modulator (SERM)

 (SERMs) are drugs with selective activity in various organ systems, acting as weak 
oestrogen-receptor agonists in some systems and as oestrogen antagonists in others.  
 prevent bone loss  
 reduce risk of vertebral fractures, but has not yet been shown to reduce the risk of non-
vertebral fractures 
 increase bone density in the spine and proximal femur 
 less effective in preventing loss of bone mineral density versus bisphosphonates or 
denosumab. 
 disadvantages

 disadvantages 
 may worsen menopausal symptoms 
 increased risk of thromboembolic events 
 contraindicated in: 
 history of venous thromboembolism (VTE),  
 hepatic impairment,  1075

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  47 
  cholestasis,  
 severe renal impairment,  
 unexplained uterine bleeding or endometrial cancer.  
 Raloxifene should not be co-administered with systemic oestrogens,  
 in patients with breast cancer it should not be used for osteoporosis treatment or

prevention until treatment of the breast cancer, including adjuvant treatment, ha s 
been completed.  
 advantage:  
 may decrease risk of breast cancer 
 Strontium ranelate  
 Action 
 'dual action bone agent' - increases deposition of new bone by osteoblasts 
(promotes differentiation of pre-osteoblast to osteoblast) and reduces the resorption 
of bone by inhibiting osteoclasts 
 Indication 
 secondary prevention of osteoporotic fragility fractures in postmenopausal women 
who are:

who are: 
 unable to take alendronate and risedronate  due to contraindication, 
intolerance or unable comply with the special instructions for the 
administration. And 
  have a combination of T-score, age and number of independent clinical risk 
factors for fracture (see denosumab indications below).  
 Dose and administration  
 The dose is 2 g once daily in water, preferably at bedtime. 
 Advice is to avoid food for 2 hours before and after taking granules ,

particularly calcium-containing products e.g. milk; also preferably avoid concomitant 
antacids containing aluminium and magnesium hydroxides for 2 hours after taking 
granules. 
 Treatment with strontium ranelate should be discontinued during treatment with oral 
tetracycline or quinolone antibiotics. 
 it is not recommended in patients with severe renal impairment  
 should be used with caution in patients at increased risk of VTE. 
 Disadvantages

 Disadvantages 
 concerns regarding the safety profile of strontium have been raised recently. It 
should only be prescribed by a specialist in secondary care 
 due to these concerns the European Medicines Agency in 2014 said it should only 
be used by people for whom there are no other treatments for osteoporosis 
 increased risk of cardiovascular events : any history of cardiovascular disease or 
significant risk of cardiovascular disease is a contraindication

 increased risk of thromboembolic events:  a Drug Safety Update in 2012 
recommended it is not used in patients with a history of venous thromboembolism 
 may cause serious skin reactions such as Stevens Johnson syndrome 
 Denosumab 
 human monoclonal antibody that inhibits RANK ligand , which in turn inhibits the 
maturation of osteoclasts  
 RANK occurs on the surface of osteoclast precursors and osteoclasts. Inhibiting it

leads to reduced osteoclast formation, function and survival. This leads to reduced 
bone reabsorption in both cortical and trabecular bone. 
 given as a single subcutaneous injection every 6 months  
 initial trial data suggests that it is effective and well tolerated 
 (NICE guidelines 2010) state that : it is recommended only in postmenopausal women a t 
increased risk of fractures:  
 who are unable to comply with alendronate and either risedronate or etidronate, or

have an intolerance of, or a contraindication to, those treatments and 
 who have a combination of T-score, age and number of independent clin ical 
risk factors for fracture  
 independent clinical risk factors for fracture are : 
 parental history of hip fracture,  
 alcohol intake of 4 or more units per day, and  
 rheumatoid arthritis. 1076

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  48 
  
 The recommended dosage is 60 mg subcutaneous injection once every 6 months . 
 Side effects: 
 Like bisphosphonates it is associated with osteonecrosis of the jaw , but not other 
adverse events such as reflux oesophagitis.  
 The risk of a dynamic bone disease may be less for denosumab versus

bisphosphonates because it does not accumulate in bone. 
 
 Teriparatide  
 is a recombinant fragment of human parathyroid hormone and, as an anaboli c agent, it 
stimulates new formation of bone and increases resistance to fracture. 
 Action 
 Increased osteoblast activity (the main effect )  
 increased calcium absorption from the gut and  
 reduced calcium excretion from the kidney.  
 Indications

 an alternative treatment option for the secondary prevention of osteoporotic fragility 
fractures in postmenopausal women who are: 
 unable to take alendronate and risedronate, or strontium ranelate due to 
contraindication , intolerance or unsatisfactory response and 
 age ≥ 65 years and have a T-score of  ≤ –4.0 SD, or a T-score of ≤ –3.5 SD 
plus more than two fractures, or  
 age 55–64 years and have a T-score of ≤ –4 SD plus more than two 
fractures.  
 Dose

 Dose 
 The recommended dose is 20 micrograms administered once daily by 
subcutaneous injection in the thigh or abdomen.  
 the maximum total duration of treatment was restricted, by the marketing 
authorisation, to 18 months.  
 Contraindications include: 
 pre-existing hypercalcaemia,  
 metabolic bone diseases other than primary osteoporosis (including 
hyperparathyroidism and Paget's disease of bone),

 unexplained elevations of alkaline phosphatase, and  
 previous radiation treatment to the skeleton.  
 Hormone replacement therapy  
 has been shown to reduce the incidence of vertebral fracture and non-vertebral fractures 
 due to concerns about increased rates of cardiovascular disease and breast cancer it is 
no longer recommended for primary or secondary prevention of osteoporosis unless the  
woman is suffering from vasomotor symptoms 
 Hip protectors

 Hip protectors 
 evidence to suggest significantly reduce hip fractures in nursing home patients 
 compliance is a problem 
 Falls risk assessment 
 no evidence to suggest reduced fracture rates  
 however, do reduce rate of falls and should be considered in management of hig h risk 
patients 
 
Raloxifene and teriparatide are second line treatments if bisphosphonates are n ot tolerated, 
ineffective or unsuitable for the patient.

ineffective or unsuitable for the patient. 
 
(Ref: NICE  guidelines . Last updated: 09 August 2017) 
 
Pathophysiology of bone diseases  
 Osteoporosis  decreased bone mass, but mineralization is normal. 
 Osteomalacia  Decreased bone mineralization (due to vitamin D deficiency) 
 Paget's disease  Disorder of bone remodeling (excessive bone resorption, followed by disorganized 
bone formation occurs, producing thickened but weak bone.)

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  49 
 Paget's disease of the bone 
 
The constellation of bony pain, unilateral hearing loss, and an isolated raised ALP sho uld point you 
in the direction of Paget's disease of the bone.  
 
Disease localization 
 most commonly involves the axial skeleton, the pelvis being the most common , but it can 
affect any area.

affect any area. 
 In the majority of patients, the disease affects at least two bones , but in one third of patients 
only one bone is affected. 
 Second most prevalent skeletal disease after osteoporosis  
 (UK prevalence 5%) but symptomatic in only 1 in 20 patients  
 more common in men (sex ratio 3:2 men: women).  
 Age of onset: > 55 years 
 increased but uncontrolled bone turnover

 increased but uncontrolled bone turnover  
 It is thought to be primarily a disorder of osteoclasts, with excessive osteoclastic 
resorption followed by increased osteoblastic activity.  
 it is a focal disorder of bone remodelling characterized by an increase in the number and size of 
osteoclasts in affected skeletal sites while the rest of the skeleton is spared. 
 ↑↑osteoclasts   ↑↑bone resorption  subsequent increase in new bone formation and altered 
bone architecture.

bone architecture.  
 The structure of the new bone is disorganised and mechanically weaker and therefore liable to 
pathological fracture and deformity.  
 
 male sex 
 northern latitude 
 family history 
Clinical features  - only 5% of patients are symptomatic 
 most commonly  no symptoms .  
 The diagnosis is typically found incidentally on radiographs and laboratory investigations.

 Paget disease should be considered in an asymptomatic patient who presents with 
isolated ALP elevation that cannot be explained by any other means 
(e.g., cholestasis or bone metastases) 
 bone pain (e.g. pelvis, lumbar spine, femur) 
 Bone pain is typically increased with rest and on weight bearing. 
 Unlike osteoarthritis, pagetic bone pain usually increases with rest, on weight bearing, 
when the limbs are warmed, and at night.

when the limbs are warmed, and at night. 
 classical, untreated features: bowing of tibia, bossing of skull 
 deafness (cranial nerve entrapment) 
 In the skull, the 8th nerve can be compressed, resulting in hearing loss. This is one of the 
more common complaints, being present in 37% of respondents in a recent survey of 
2000 patients with Paget's disease .  
 bone sarcoma  (1% if affected for > 10 years)

 bone sarcoma  (1% if affected for > 10 years) 
 Although the risk of osteogenic sarcoma is 30 times that of patients without Paget ’s, the 
risk of sarcoma development is still small  Less than 1%  
 Symptoms of osteogenic sarcoma include increased pain localised to one particular area 
and pathological fracture. 
 tumor arising from mesenchymal stem cells (osteoblasts) 
 Most common primary bone malignancy 
 x-ray

 x-ray 
 Sunburst appearance of lytic bone lesions  and/or codman triangles (a ridge of 
sub-periosteal new bone is raised by an underlying tumor) 
1078

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  50 
  Surgery (definitive resection)  with adjuvant polychemotherapy 
 usually resistant to radiation therapy 
 Pathological fractures  
 Spinal cord compression  
 skull thickening  
 (A classic symptom: a hat which no longer fits) 
 high-output cardiac failure 
  (due to AV shunts in bone) 
 
Diagnosis

Diagnosis 
 Raised alkaline phosphatase (ALP) - calcium* and phosphate are typically normal  
 the Best initial test 
 * calcium  is usually normal but hypercalcaemia may occur with prolonged immobilisation 
 X-ray:  
 eg: (skull x-ray) thickened vault, osteoporosis circumscripta 
 Osteolysis and new bone formation typical of the disease. 
 Radiographic features  in the mixed lytic and sclerotic phase of Paget's disease include: 
 bone expansion,

 bone expansion,  
 cortical thickening and  
 trabecular bone thickening .  
 the best investigation to confirm the diagnosis  Skeletal survey  
 Recent evidence has suggested that limited skeletal survey is superior to bone scan  
for the assessment of the disease because, when there is significant osteoclastic 
resorption of bone, bone scanning underestimates the extent of disease activity and 
still requires plain radiography for confirmation.  
 Bone biopsy

 Bone biopsy  
 abnormal " mosaic " pattern in woven and lamellar bone. 
 
Treatment 
 Indications for treatment include:  
 bone pain,  
 skull or long bone deformity,  
 fracture,  
 periarticular Paget's  
 The mainstay of treatment for Paget ’s disease is bisphosphonate therapy,  which is proven 
to relieve symptoms of pain  and has been shown to reduce the risk of pathological  fracture 
in long bones and complications of Paget ’s such as deafness .

 bisphosphonate (either oral risedronate or IV zoledronate) 
 Unless contraindicated, all patients on bisphosphonates should be given 
supplements of calcium and Vitamin D to avoid symptomatic hypocalcaemia. 
 In patients who cannot tolerate these, calcitonin is second-line therapy. 
 calcitonin is less commonly used now 
 the most appropriate way to monitor disease activity is  6-monthly alkaline phosphatase 
levels  
 
1079

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  51 
 The radiograph demonstrates marked thickening of the calvarium. There are also ill-defi ned sclerotic 
and lucent areas throughout. These features are consistent with Paget's disease. 
 
Penicillamine 
 largely unknown

 largely unknown 
 thought to reduce IL-1 synthesis and prevent the maturation of newly synthesiz ed collagen 
Uses 
 rashes 
 disturbance of taste 
Perthes disease 
 Perthes disease is a degenerative condition affecting the hip joints of children, typically betwe en 
the ages of 4-8 years.  
 It is due to avascular necrosis of the femoral head

 Perthes disease is 5 times more common in boys.  
 Around 10% of cases are bilateral 
Features  
 limp 
 x-ray: early changes include widening of joint space, later changes include decreased femoral 
head size/flattening 
 osteoarthritis 
 premature fusion of the growth plates 
 
1080

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  52 
  
Perthes disease - bilateral disease 
Pseudogout  
 
Chondrocalcinosis  in a question is most likely to indicate  Pseudogout  
 
 Pseudogout is a form of microcrystal synovitis caused by the deposition of calcium 
pyrophosphate dihydrate in the synovium  
 low magnesium, low phosphate 
Features 
 knee, wrist and shoulders most commonly affected 
1081

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  53 
  joint aspiration:  
 Polar light microscopy:  
 weakly-positively birefringent rhomboid shaped crystals  
 Synovial fluid findings:  
 10,000- 50,000 WBCs/μL with > 90% neutrophils  
 x-ray:  
 chondrocalcinosis  
 (cartilage called  due to deposition of calcium pyrophosphate dihydrate crystals  in

the large joints, particularly the knees.) 
 
 aspiration of joint fluid, to exclude septic arthritis 
 NSAIDs or intra-articular, intra-muscular or oral steroids as for gout 
Psoriatic arthropathy 
If first-degree relatives of patients with psoriasis have joint problems, psoriatic arthritis should 
 
 Chronic progressive seronegative inflammatory arthritis occurring in patients with underlying

psoriasis.  
 most commonly a seronegative oligoarthritis  found in patients with psoriasis  
 Oligoarthritis  (most common, accounting for 70% of cases)  
 autoimmune disease , associated with an increased frequency of HLA-B7 and HLA-B27.  
 affects men and women equally  
 the range of age of onset between 35 –55 years.  
 Around 10-20% percent of patients with skin lesions develop an arthropathy   
 
Types

Types  
 Five subsets of psoriatic arthritis have been described based on the pattern of joint invo lvement, 
with an increased prevalence of the spondylitic form in males  and the rheumatoid form in 
females.   
1.  asymmetric oligoarthritis  (most common) ( 43%).  
2. symmetric polyarthritis  ( 33%)  
 proximal interphalyngeal joint involvement. 
3. sacroilitis 
4. DIP joint disease  
  associated with nail pitting, and onycholysis (separation of nail from nail bed)

5. arthritis mutilans (severe deformity fingers/hand, 'telescoping fingers') (rare) 
 
The relation between skin lesion and Psoariatic arthritis  
 Psoriatic arthropathy correlates poorly with cutaneous psoriasis and often precedes the 
development of skin lesions.  
 Psoriasis precede psoriatic arthritis in 60-80% of patients (usually by less than 10 years) 
 In 15-20% of patients, arthritis appears before the psoriasis 
 Small plaques should be looked for on the elbows and scalp.

Feature 
 Psoariatic arthritis tends to affect the distal interphalangeal joints (DIP) . 
 can present with or without associated psoriatic skin lesions or only with nail malformations.  
 If no obvious skin lesions are visible, the clinician must look for psoriasis in hidden sites such as 
the scalp, intergluteal cleft and umbilicus.  
 Nail involvement includes onycholysis, transverse ridging and nail pitting.

 vertebrae may be asymmetrically affected and there may be involvement of the atlantoaxial jo int 
with erosion of the odontoid and consequent subluxation. 
 Dactylitis with sausage digits is seen in 35% of patients 
 Extra-articular features include: 
 Ocular involvement may occur in 30% of patients, including: 
 conjunctivitis (in 20%)  
 acute anterior uveitis (in 7%) ;  1082

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  54 
  in patients with uveitis, 43% have sacroiliitis 
 Synovitis affecting flexor tendon sheaths,  (with sparing of the extensor tendon sheath)  
 
 Ĺ (ESR) and C-reactive protein level 
 Negative rheumatoid factor 
 Low levels of circulating immune complexes ( in 56% of patients)

 High Serum immunoglobulin A levels ( in two thirds of patients) 
 Radiography   
 asymmetric “pencil- in-cup ” deformity  in the distal interphalangeal joints of the fingers. 
 
Diagnositic criteria  
 established inflammatory articular disease with at least 3 points from the following features:  
1. Current psoriasis (assigned a score of 2) 
2. history of psoriasis (in the absence of current psoriasis; assigned a score of 1)

3. family history of psoriasis  (in the absence of current psoriasis and history of psoriasis; 
assigned a score of 1) 
4. Dactylitis (assigned a score of 1) 
5. Juxta-articular new-bone formation (assigned a score of 1) 
6. RF negativity (assigned a score of 1) 
7. Nail dystrophy (assigned a score of 1) 
  
 The condition can be distinguished from the sacroilitis seen in ankylosing spondylitis by t he

presence of the other clinical signs in the nails and the skin and by differences in the patterns of 
vertebral involvement.  
 Polyarticular psoriatic arthritis distinguished from rheumatoid arthritis by: 
1. presence of dactylitis and  
2. absence of anticyclic citrullinated peptide antibodies. 
 
 treat as rheumatoid arthritis but better prognosis 
 limited disease   NSAIDs usually sufficient  
 do not prevent progressive joint damage

 do not prevent progressive joint damage  
 Patients with progressive peripheral arthritis (polyarthritis, joint erosions) or oligoarthritis 
refractory to NSAIDs and/or intra-articular corticosteroids require disease-modifying 
antirheumatic disease therapy (e.g., methotrexate) early in the disease course. 
 methotrexate will improve both the joint and skin problems 
 Sulfasalazine is safe to use in pregnancy and there is no need to stop it.

 Sulphasalazine tends to only improve joint symptoms and not improve the 
 Tumour necrosis factor (TNF)-alpha inhibitors may be considered as second-line  therapy for 
most disease manifestations. 
 If not respond to an adequate trial of two DMARDs (for example, leflunomide, 
methotrexate, sulfasalazine)   anti-TNF agents  
 Apremilast  (Nice guidelines February 2017)  
 phosphodiesterase 4 (PDE4)  inhibitor.

 phosphodiesterase 4 (PDE4)  inhibitor.  
 ↓anti-inflammatory cytokines and mediators associated with psoriatic arthritis (including 
[TNF]-alpha and interleukin [IL]-23). 
 Apremilast, alone or in combination with (DMARDs), is recommended for psoriatic arthritis 
only if: 
 they have peripheral arthritis with 3 or more tender joints and 3 or more swollen 
joints and 
 not responded to adequate trials of at least 2 standard DMARDs. 
 Adverse   effects

 Adverse   effects 
 (GI) disorders (most commonly diarrhoea and nausea);  
 upper respiratory tract infections;  
 headache; and tension headache. 
 Stop apremilast at 16 weeks if the psoriatic arthritis has not shown an adequate res ponse  
 
 Hydroxychloroquine  exacerbate psoriatic skin lesions 1083

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  55 
  In patients with cutaneous psoriasis, systemic corticosteroids predispose to pustular psoriasis, 
and may result in a flare of skin psoriasis when they are stopped. 
 
Notice the nail changes on this image as well  
 X-ray showing some of changes in seen 
in psoriatic arthropathy. Note that the

in psoriatic arthropathy. Note that the 
DIPs are predominately affected, rather 
than the MCPs and PIPs as would be 
seen with rheumatoid. Extensive juxta-
articular periostitis is seen in the DIPs but 
the changes have not yet progressed to 
the classic 'pencil- in-cup' changes that 
are often seen. 
 
1084

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  56 
  
This x-ray shows changes affecting both the PIPs and DIPs. The close-up images sho w extensive 
changes including large eccentric erosions, tuft resorption and progresion towards a 'pencil- in-cup' 
changes. 
 
Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  57 
  
 Reactive arthritis is defined as an arthritis that develops following an infection where the 
organism cannot be recovered from the joint. 
 the presence of bacterial infection on joint aspiration would count against it.  
 Reactive arthritis is one of the HLA-B27 associated seronegative spondyloarthropathies.

 It encompasses Reiter's syndrome , a term which described a classic triad of urethritis, 
conjunctivitis  and arthritis following a dysenteric illness during the Second World War.  
 Later studies identified patients who developed symptoms following a sexually transmitte d 
infection (post-STI, now sometimes referred to as sexually acquired reactive arthritis, SARA). 
 
Eye diseases in Reiter's syndrome: 
 Most common  conjunctivitis (50%) 
 Less common  iritis (12%) 
 
 post-STI form much more common in men (e.g. 10:1) 
 post-dysenteric form equal sex incidence 
 
The table below shows the organisms that are most commonly associated with reactive arthritis : 
Post-dysenteric form Post-STI form 
Shigella  flexneri 
Salmonella typhi murium 
Salmonella  enteritidis 
Yersinia enterocolitica  
Campylobacter  Chlamydia trachomatis  
 
Features  
 typically develops within 4 weeks of initial infection

 symptoms generally last around 4-6 months 
 arthritis is typically an asymmetrical oligoarthritis of lower limbs 
 mainly affecting the large weight-bearing joints (usually knee and ankle). 
 dactylitis 
 symptoms of urethritis 
 eye:  
 conjunctivitis (seen in 50%),   
 anterior uveitis 
 skin:  
 circinate balanitis (painless vesicles on the coronal margin of the prepuce),  
 keratoderma blenorrhagica  (waxy yellow /brown papules on palms and soles) 
 
 usually self-limiting 
 symptomatic: analgesia, NSAIDS, intra-articular steroids 
 sulfasalazine and methotrexate are sometimes used for persistent disease  
 
 Antibiotics given at the time of the non-gonococcal venereal infection will reduce the likelihood 
of that person developing reactive arthritis.  
 Appropriate treatment during the acute stage would be doxycycline 100 mg bd if 
Chlamydia infection is confirmed.  
 
Prognosis

Prognosis  
 Prognosis with respect to long-term complications is better when dysenteric  infection is the 
precipitant factor rather than Chlamydial  infection. 
 arthritis usually resolves in 3 months  
 In general, symptoms last from a few weeks to around 6 months in total. 
 symptoms rarely last more than 12 months 
 Around 25% of patients have recurrent episodes  
 10% of patients develop chronic disease  1086

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  58 
  In HLA-B27-positive  patients, ankylosing spondylitis  may develop in up to 50% of patients 
who have suffered an episode of reactive arthritis . 
 HIV infection is associated with a higher risk of reactive arthritis 
 HLA-B27  is found in 80 –90 % of Caucasians with HIV-associated reactive arthritis,

 while studies of Africans with HIV-associated reactive arthritis have found nearly all to be 
HLA-B27-negative  
 Rarer long-term complications  include: 
 urethral stricture,  
 cataracts, and  
 aortic root necrosis.  
 
Keratoderma blenorrhagica 
___________________________________________________ _________________________  
Amyloidosis 
 
Amyloidosis should always be considered in a patient with a long-standing inflammatory

and/or infectious disease who presents with kidney, liver, or GI involvement. 
Overview  
 amyloidosis is describes the extracellular deposition of an insoluble fibrillar protein  termed 
amyloid 
 amyloid also contains a non-fibrillary protein  called: 
  amyloid-P component, derived from the acute phase protein serum amyloid P 
 apolipoprotein E  
 heparan sulphate proteoglycans 
 the accumulation of amyloid fibrils leads to tissue/organ dysfunction 
Causes

Causes 
 Amyloidosis may be inherited or acquired; acquired form is associated with long standing  chronic 
illnesses (DM, Rheumatoid Arthritis). 
Feature 
 unexplained weight loss,  
 fatigue,  
 oedema resistant to diuretic therapy. 
 joint pains and stiffness, usually upper limbs more than lower limbs.  
Types: 
 Light-chain amyloidosis ( AL-amyloidosis) 
 Most common form of amyloidosis in developed nations 
 Etiology:  
 primary disease caused by plasma cell dyscrasias e.g., :

 multiple myeloma,  
 Waldenström's macroglobulinemia,  
 non-Hodgkin lymphoma 
 Pathophysiology:  
 increased production of the light chains of immunoglobulins ĺ deposition of AL 
(amyloid light chain) protein in various organs 
 Features: rapidly progressive clinical course  
 Heart:  
1087

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  59 
  restrictive cardiomyopathy,  
 atrioventricular block 
 An ECG is required in all patients to look for conduction 
 Kidney:  
 nephrotic syndrome,  
 type II renal tubular acidosis,  
 nephrogenic diabetes insipidus 
 Tongue:  
 macroglossia ĺ obstructive sleep apnea  
 Nervous system:

 Nervous system:  
 Amyloid peripheral neuropathy 
 carpal tunnel syndrome 
 only seen in AL, never seen in AA 
 autonomic neuropathy 
 Gastrointestinal tract:  
 malabsorption 
 periorbital ecchymoses  
 Enlargement of the submandibular salivary glands 
 shoulder pad sign due to periarticular infiltration with amyloid and 
pseudohypertrophy is specific for AL 
 Bleeding disorders 
 Reactive amyloidosis (AA-amyloidosis) 
 Etiology: secondary disease

 Etiology: secondary disease 
 Chronic inflammatory conditions (e.g., IBD, rheumatoid arthritis , SLE, vasculitis) 
 Chronic infectious diseases (e.g., tuberculosis, bronchiectasis, leprosy, 
osteomyelitis) 
 Certain tumors (e.g., renal cell carcinoma, lymphomas) 
 chronic inflammatory process ĺ increased production of acute phase reactant SAA 
(serum amyloid- associated protein) ĺ deposition of AA (amyloid- associated) 
protein in various organs 
 Clinical features

 Clinical features  
 Kidney: most common feature  renal involvement   
 Adrenal glands:  
 primary adrenal insufficiency 
 Liver and spleen:  
 hepatomegaly, splenomegaly 
 malabsorption  
 β-2 microglobulin amyloidosis 
 Precursor protein is ȕ -2 microglobulin, part of the major histocompatibility complex

 Associated with patients on renal dialysis 
 neurological impairment in patients on longstanding dialysis. 
 
Diagnosis  
 Biopsy  
 Biopsy of abdominal wall fat, the  rectum  or a salivary gland can be examined  
 The tissue is treated with Congo red stain   the amyloid proteins appear apple-green  
birefringence on  Light microscopy.  
 Tests to diagnose the underlying disease 
 Light chain amyloidosis 
 Serum electrophoresis:  monoclonal gammopathy

 Serum electrophoresis:  monoclonal gammopathy 
 Urine test for Bence-Jones proteins  multiple myeloma 
 Reactive amyloidosis:  ESR, CRP, chest x-ray 
 1088

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  60 
  
Renal amyloid with congo red staining - apple-green birefringence 
 
Congo red staining. Amyloid deposits are seen in both the arteries/arterioles and within the glomerulus .

The deposit of amyloid within the mesangium is not dissimilar to the nodular lesions seen  in diabetic 
Pathological feature of amyloidosis 
1. Electron micrography - fibrillar appearance 
2. x Ray diffraction pattern - beta pleated sheet structure 
3. Haematoxylin and eosin staining - amorphous eosinophilic appearance 
1089

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  61 
 4. Congo red histological staining - apple-green birefringence 
5. Solubility in water and buffers of low ionic strength. 
 
Treatment 
 The only treatment is renal transplantation.  
 It can be reduced by using high flux dialysis membranes in patients who are likely to be on 
dialysis for a prolonged period.

dialysis for a prolonged period. 
 
Amyloidosis: cardiac 
 Cardiac amyloidosis most commonly presents as restrictive cardiomyopathy, associated with AL 
Presentation: Typical presentation of right heart failure:  
 Jugular venous distension 
 Peripheral oedema 
 Orthopnoea and paroxysmal nocturnal dyspnea are typically absent 
Diagnosis 
 Combination of low-voltage ECG and thickened ventricular walls is one of the characteristic 
features of cardiac amyloidosis.

features of cardiac amyloidosis. 
 Echocardiographic abnormalities  include: 
  dilatation of atria, thickened interatrial septum, diastolic dysfunction and small-volum e 
 The most distinctive feature of cardiac amyloidosis is a sparkling, granular appearance of 
myocardium, but this is a relatively insensitive feature occurring only in about 25% of 
cases. 
 Cardiac amyloidosis is associated with a 'global speckled' pattern on echo.

The ECG typically shows low-voltage complexes with poor R wave progression i n the chest leads (a pseudoinfarction 
pattern). 
Management of AL 
 The most effective treatment is autologous bone marrow transplants with stem cell rescue s. 
However many patients are too weak to tolerate this approach 
 Other treatments can involve application of chemotherapy similar to that used in m ultiple 
myeloma. A combination of bortezomib and dexamethasone has been propose d, as has

melphalan and dexamethasone. 
 Digoxin is contraindicated in cardiac amyloidosis (restrictive cardiomyopathy) 
Septic arthritis 
 
Causes 
 most common organism overall is Staphylococcus aureus  
 The most likely organisms are staphlococci (70%) and beta-haemolytic streptococci 
(20%). 
 in young adults who are sexually active Neisseria gonorrhoeae  should also be considered

 The most likely organism to have been aspirated from the infected hip joint replacement  
prosthesis  Propionibacterium acnes  (PA):  
1090

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  62 
  Gram positive bacilli,  
 it is poorly virulent,  
 symptoms of PA infection may occur many years after original arthropathy,  
 it is sensitive to penicillins, clindamycin and carbapenems. 
Feature 
 Fifty percent of cases will have an associated bacteraemia.  
 Early x-rays are almost always normal.

 Early x-rays are almost always normal. 
 after original arthroplasty  Propionibacterium acnes 
 gram positive bacterium which is poorly virulent.  
 Symptoms may occur many years after original arthroplasty and the bacteria are only 
identified at the time of joint revision.  
 Prolonged intravenous antibiotics given at the time of revision arthroplasty are said to 
resolve infection in around 90% of cases.  
 known to be sensitive to penicillins, clindamycin and carbapenems .

 synovial fluid should be obtained before starting treatment 
 intravenous antibiotics which cover Gram-positive cocci are indicated. The BNF currently 
recommends flucloxacillin or clindamycin if penicillin allergic 
 antibiotic treatment is normally be given for several weeks (BNF states 6-12 weeks) 
 ideally these should be intravenous for 2 weeks and then oral for 4 weeks. 
 needle aspiration should be used to decompress the joint

 surgical drainage may be needed if frequent needle aspiration is required 
 if patient on warfarin, What is the most appropriate management of anticoa gulation before joint 
aspiration and injection? 
 If INR is within the therapeutic range  no need to stop the warfarin or change the 
dose.  
 The risk of a thrombotic episode if anticoagulation is changed outweighs any risk 
associated with injecting joint while taking anticoagulation.

Sjogren's syndrome 
 Sjogren's syndrome is an autoimmune disorder affecting exocrine glands resulting in dry 
mucosal surfaces.  
 It may be primary (PSS) or secondary to rheumatoid arthritis or other connective tissue 
disorders, where it usually develops around 10 years after the initial onset.  
 primary Sjögren's syndrome occurs alone and more likely to have positive anti Ro SSA

antibodies than secondary Sjögren's). 
 Hypergammaglobulinaemia is present in 80% of individuals. 
 Typically secondary Sjögren's has pre-existent rheumatoid or systemic lupus erythematosus 
before the development of Sjögren's symptoms. 
 more common in females (ratio 9:1).  
 There is a marked increased risk of lymphoid malignancy (40-60 fold) 
Features  
 dry eyes: keratoconjunctivitis sicca 
 dry mouth 
 vaginal dryness 
 Raynaud's,  
 myalgia

 myalgia 
 sensory polyneuropathy 
 renal tubular acidosis (usually subclinical) 
 Plasma cell infiltration of salivary and lacrimal glands: Parotid swelling. 
 
1091

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  63 
  higher risk of developing lymphoma  
 These lymphomas are primarily of B cell origin.  
 High risk factors for lymphoma development in Sjogren's syndrome patients include: 
 persistent unilateral or bilateral parotid gland enlargement,  
 splenomegaly and lymphadenopathy,  
 low C4 complement levels,

 low C4 complement levels,  
 type 2 mixed cryoglobulinaemia 
 
 rheumatoid factor (RF) positive in nearly 100% of patients 
 ANA positive in 70% 
 anti-Ro (SSA) antibodies in 70% of patients with PSS 
  Anti-Ro antibody is associated with:  
 congenital complete heart block  
  neonatal lupus 
 The mother is usually positive for anti-Ro or anti-La antibodies but may not 
have overt lupus erythematosus. 
 anti-La (SSB) antibodies in 30% of patients with PSS

 Hypergammaglobulinaemia (Ĺ IgG) in 80%  
 low C4 
 Schirmer's test: filter paper near conjunctival sac to measure tear formation 
 placement of a standard strip of filter paper on the inside of the lower eyelid.  
 Wetting of less than 5 mm in 5 min indicates defective tear production. 
 Rose Bengal staining of the eyes  commonly shows punctuate or filamentary keratitis .   
 histology: focal lymphocytic infiltration

 histology: focal lymphocytic infiltration 
 the most definitive test for Sjögren ’s syndrome  Labial gland biopsy 
 artificial saliva and tears 
 pilocarpine may stimulate saliva production 
 
Other causes of dry eyes, and/or dry mouth include: 
 past head and neck radiation 
 hepatitis C infection 
 acquired immunodeficiency disease 
 pre-existing lymphoma 
 graft versus host disease, or 
 the use of an anticholinergic drugs.

 the use of an anticholinergic drugs. 
Systemic lupus erythematosus (SLE)  
  
 Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disorder.  
 much more common in females (F:M = 9:1) 
 more common in Afro-Caribbeans* and Asian communities 
 *It is said the incidence in black Africans is much lower than in black Americans - the 
reasons for this are unclear

reasons for this are unclear 
 onset is usually 20-40 years 
 incidence has risen substantially during the past 50 years (3 fold using American Colleg e of 
Rheumatology criteria) 
 autoimmune disease 
 associated with HLA B8, DR2, DR3 
 thought to be caused by immune system dysregulation leading to immune complex  formation 
 immune complex deposition can affect any organ including the skin, joints, kidneys and brain 
Features  
1092

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  64 
 The triad of fever, arthralgia and rash in a woman of childbearing age should suggest the diagnosis 
of systemic lupus erythematosus (SLE). 
 
The multisystem presentation of fever, arthralgia, pericarditis and nephritis associated

with the epidemiological clues (a young black female) suggest a diagnosis of (SLE).  
 
 fatigue 
 fever                                                      
 mouth ulcers 
Skin 
 
 malar (butterfly) rash: spares nasolabial folds 
 discoid rash: scaly, erythematous, well demarcated rash in sun-exposed areas. Lesions may 
progress to become pigmented and hyperkeratotic before becoming atrophic 
 photosensitivity 
 Raynaud's phenomenon 
 livedo reticularis

 non-scarring alopecia 
Musculoskeletal 
 arthralgia typically affecting the small joints of the hands, wrists and knees.  
 non-erosive arthritis 
   Jaccoud's arthropathy    gross 
deformities of the hands without joint 
damage or erosions  
 caused by recurrent episodes of synovitis 
that damage tendon sheaths and slings 
resulting in joint deformity  
 seen in: 
 SLE 
 Parkinson's disease, and

 Parkinson's disease, and 
 Hypocomplementaemic urticarial 
vasculitis.  
Cardiovascular 
 myocarditis 
Respiratory 
 pleurisy 
 fibrosing alveolitis 
 Direct pulmonary involvement in (SLE) occurs in 30% (pleuropericarditis, atelectasis, 
pneumonitis, raised hemidiaphragms and pulmonary fibrosis ).  
Renal 
 glomerulonephritis (diffuse proliferative glomerulonephritis is the most common type)  
Neuropsychiatric 
 anxiety and depression 
 psychosis

 psychosis 
 seizures 
 
1093

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  65 
 Immunology 
 
SLE - antibodies associated with congenital heart block = anti- Ro 
 
 99% are  ANA positive ( the best screening  test for SLE) 
 Almost all patients with SLE have a positive ANA test result.  
 ANA test is sensitive but not specific for SLE.

 A negative result argues strongly against a diagnosis of active SLE, but does not exclude 
the possibility of other autoimmune diseases. 
 Negative ANA has the highest negative predicted value  (The highest negative 
predicted value implies the test with the greatest sensitivity.) 
 
 20% are rheumatoid factor positive 
 anti-dsDNA: highly specific  (> 99%), but less sensitive (70%) 
 anti-Smith: most specific (> 99%), sensitivity (30%)

 Therefore, absence of anti-DNA or anti-Sm antibodies should not exclude SLE as a 
diagnosis 
 also: anti-U1 RNP, SS-A (anti-Ro) and SS-B (anti- La) 
 Anti-Rho and -La antibodies are associated with the development of neonatal l upus. 
 Anti-Ro/SS-A antibodies are found in 30% of patients with SLE.  
 Anti-Ro antibodies can cross the placenta to cause transient cutaneous lupus in the 
neonate (5-25% of babies) or permanent congenital heart block (1-3% of babies).

Markers of SLE disease activity 
 Early markers of SLE disease activity include: 
  falling  C4 levels,  
 although congenital C 4 deficiency is itself a predisposing factor for SLE 
development, so these tests must be interpreted with caution.  
 rising immunoglobulins,  
 falling haemoglobin (Hb), white cell count (WCC), platelets and albumin. 
Monitoring 
 ESR: during active disease the CRP is characteristically normal - a raised CRP may indicate 
underlying infection

underlying infection 
 complement levels (C3, C4) are low during active disease (formation of complexes lea ds to 
consumption of complement) 
 anti-dsDNA titres can be used for disease  monitoring  (but note not present in all patients) 
 
 Basics 
 NSAIDs 
 sun-block 
 Hydroxychloroquine 
 useful for skin disease 
 If internal organ involvement e.g. renal, neuro, eye then consider prednisolone, 
 
Complication

Complication   
 Lupus patients are more prone to infection . 
 Up to two-thirds of lupus patients will have some lung involvement during the cou rse of 
their disease. The most common manifestations are pleuritis and pleural effusions. 
SLE: pregnancy 
Overview 
 Unlike many autoimmune diseases (SLE) often becomes worse during pregnancy and the 
puerperium  
 risk of maternal autoantibodies crossing placenta 
 leads to condition termed neonatal lupus erythematous

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  66 
  strongly associated with anti-Ro (SSA) antibodies 
treatment  
 azathioprine  
 A large body of evidence from the use of azathioprine in pregnancy for the treat ment of 
both rheumatological conditions and inflammatory bowel disease, supports it's use.

 Although it is less effective in the management of SLE with renal disease versus other 
options, balance of benefit risk makes it the preferred intervention.  
 Ciclosporin   
 appears to be associated with premature delivery and low birth weight,  
 although it does not seem to be associated with malformations, this drives it's use  as an 
alternative to azathioprine  in patients who fail to gain control of their disease.

 Cyclophosphamide, methotrexate and mycophenolate are all contraindicated for use in 
_____________________________________________________________________  
Drug-induced lupus erythematosus  
 The pathogenesis of drug-induced lupus is unclear.  
 Factors that influence drug metabolism, such as acetylator status, have been  implicated. 
  In addition, lupus-inducing drugs have been shown to generate a variety of cy totoxic products on

exposure to  MPO  released from activated neutrophils. 
Causes 
The most commonly associated drugs  
 procainamide  
 hydralazine 2,  
 quinidine. 
 Isoniazid (INH) - low risk 
 Sulfasalazine - low risk. 
 anti-TNF alpha agents,  
 Statins 
 minocycline . 
 Minocycline associated with the development of long term immunological memory, and  
therefore exacerbation of symptoms within 12-24 hours of rechallenge. 
 strongly positive ANA

 strongly positive ANA  
 HLA-DR4 phenotype (hydralazine-induced disease) 
 slow  acetylator status 
 Slow acetylators have increased risk of isoniazid-induced peripheral neuropathy, and 
hydralazine or procainamide-induced systemic lupus erythematosus (SLE). 
 large total daily doses of precipitating drugs 
Features 
Classically, drug-induced lupus erythematosus is characterised by  
 Systemic disease with a lower incidence of nephritis 
 Lack of cutaneous involvement and

 Lack of cutaneous involvement and 
 The presence of antihistone antibodies . 
 Characteristically, the erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) are 
both markedly elevated,  
 the ANA is strongly positive  
 and there is a hypergammaglobulinaemia. 
 Anti-dsDNA antibodies are usually negative;  
 antihistone antibodies are positive in 95% of drug-induced lupus (but also 50-8 0% of idiopathic 1095

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  67 
 SLE3). 
There are several features which distinguish drug-induced lupus from idiopathic SLE : 
 Males and females are equally affected in drug-induced lupus, whereas idiopat hic SLE affects 
females nine times more frequently. 
 Caucasians are affected by drug-induced lupus more commonly than Afro-Caribbeans ,

whereas the inverse is true of idiopathic SLE. 
 the age of onset is typically older in drug-induced lupus, but this depends on the age a t drug 
exposure. 
 Fever, arthralgia, serositis and ANA occur at least as frequently in drug-induced lupus as 
idiopathic SLE. 
 Haematological, renal and central nervous system (CNS) involvement, and double-stranded DNA 
autoantibodies are rare. 
Treatment 
 Typically, no further treatment is required after Withdrawal of the precipitating drug

 However, there are situations where corticosteroids or disease modifying antirheumatic drugs 
(DMARDs) are required to aid resolution. 
 The time taken for symptoms to resolve after stopping minocycline is highly varia ble, from a few 
days to two years. 
Prognosis 
 Spontaneous recovery usually occurs promptly 
 Juvenile idiopathic arthritis (JIA)  (Still ’s disease)  

 The ACR criteria define juvenile rheumatoid arthritis (JRA) by age limit (< 16 y)  and the duration 
of disease (> 6 weeks ).  
 the most common form of arthritis in children and adolescents.   
 Prevalence: 1/1000 children 
 Sex: ♀ > ♂   
Types 
 Oligoarticular  JIA 
 Most  common form (accounts for 50% of all JIA cases) 
 affects four joints or fewer  during the first 6 months , 
 has the highest risk of developing Chronic anterior uveitis (up to 25%)

 Bilateral eye involvement is common 
 RF negative 
 ANA positive ( ∼ 70% of cases) 
 NSAIDs 
 Possibly intra-articular steroid injections 
 Possibly methotrexate 
 Polyarticular JIA  
 40% of cases 
 characterised by inflammatory arthritis affecting five or more joints  during the first 6 
months of the disease. 
 ANA positive ( ∼ 40% of cases) 
 Treatment: Standard therapy with methotrexate and NSAID 
 Systemic-onset JIA  (Still's disease )

 Systemic-onset JIA  (Still's disease ) 
 < 10% of cases 
 presents with  fever , arthritis and at least one of the following : 
 erythematous rash,  
 generalised lymphadenopathy,  
 Hepatosplenomegaly  
 serositis (including pleural and pericardial effusions) 1096

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  68 
  RF negative 
 ↑ Acute phase reactants (e.g., CRP, ferritin) 
 Treatment: Poor response to methotrexate and TNF inhibitors  (etanercept, adalimumab)  
 
 Exposure to antibiotics during childhood may increase the risk of JIA. 
Features

Features 
Joint pain, daily spiking fevers, and a 'salmon-pink' rash are classic symptoms. 
 
 persistent  non-tender joint swelling  (The cardinal feature) 
 The first manifestation of JIA is often limping , especially in young children. 
  The persistent swelling most often occurs in the large joints. 
 Damage to joints is associated with a T H1 response.  
 Up to 25% of patients have a positive anti-nuclear antibody .

 microcytic anaemia which tends to be resistant to iron replacement  
 pericarditis is often found.  
 hepatosplenomegaly,  
 JIA can decrease bone mass and increase the risk of osteoporosis.  
 ↑ ESR  (usually seen with all forms of JIA). 
 Rheumatoid nodules and rheumatoid factor are usually  absent  
 Rheumatoid factor (RF) is absent in most cases of JIA except seropositive polyarticular 
JIA. 
 anterior uveitis

JIA. 
 anterior uveitis   
 What eye condition is most commonly associated with this presentation?  anterior 
uveitis.  
 about 30 –50% of children with JIA have uveitis at diagnosis, especially those who 
are antinuclear antibody (ANA) positive. 
 The uveitis is typically asymptomatic at onset and must be screened  for with an 
ophthalmologic slit lamp examination . 
 Untreated uveitis can be associated with cataracts, glaucoma and macular oedema

  about 50 –70% of people with severe uveitis develop visual impairment.  
 If a patient with (JIA) developed new-onset anterior uveitis despite treatment 
with subcutaneous methotrexate  adalimumab (as adalimumab is more 
effective in treating uveitis than etanercept)  
 
Treatment 
 Options for pharmacotherapy include NSAIDs, corticosteroids, methotrexate, and anti-TNF 
biologicals. 
 Treatment with a IL-6 receptor antibody  has proved to be successful.

 As per NICE guidance, if patient had not responded to methotrexate and should be 
considered for biologic therapy with either adalimumab, etanercept or tocilizumab.   
Prognosis 
 Anti-CCP  antibodies indicate a poor prognosis. 
 Early disease onset is associated with a greater degree of growth impairment and deformity. 
Adult onset Still's disease (AOSD)  (Adult Still's disease)

Adult-onset  Still's disease   triad of  persistent high spiking fevers , joint pain , and a distinctive 
salmon-colored bumpy rash . 
 
 typically affects 16-35 year olds 
 
Features 
 rash: salmon-pink, maculopapular ( most prominent with fever) 
  occurs in approximately 90% of patients  
 often seen only when the patient is febrile and is easily missed. 
 pyrexia (> 39oC)  especially in the afternoon and evening

 described as quotidian or diquotidian returning to 37°C or below between episodes. 1097

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  69 
  lymphadenopathy 
 Hepatosplenomegaly,  
 There is often an accompanying sore throat and myalgia. 
Rarely  there may be: 
 Aseptic meningitis 
 Cranial nerve palsies 
 Iritis , and 
 Peripheral neuropathy. 
  neutrophilic leukocytosis, thrombocytosis,  
 ↑  serum ferritin

 ↑  serum ferritin 
 High serum ferritin, with low glycosylated fraction, are characteristic and can be used as 
disease activity markers.  
 ↑ ESR and C-reactive protein. 
 Interleukin (IL)-1, IL-6, IL-18, macrophage colony stimulating factor, interfe ron gamma and TNF-
alpha are all elevated. 
 rheumatoid factor (RF) and anti-nuclear antibody (ANA) negative 
Diagnosis 
 Diagnosis is clinical, and should include exclusion of infectious disease, neoplasms and other 
autoimmune disease.

autoimmune disease. 
Treatment 
 non-steroidal anti-inflammatory drugs (NSAIDs),  
 corticosteroids,  
 disease-modifying anti-rheumatic drugs  
 biological agents.  
 Intravenous immunoglobulin may have a role. 
Prognosis  
 tends to be better when systemic symptoms predominate. 
 
Adult onset Still's disease is typically rheumatoid factor negative  
Raynaud's 
 
Raynaud's 
 
 Raynaud phenomenon manifests as recurrent vasospasm of the fingers and toes and  usually 
occurs in response to stress or cold exposure. 
Types 
 Primary Raynaud phenomenon (Raynaud disease).  
 Raynaud disease is characterized by the occurrence of the vasospasm alone, with n o 
association with another illness.  
 Raynaud's disease typically presents in young women  (e.g. 30 years old) with 
symmetrical attacks

symmetrical attacks 
 Around 2% of women and 6% of men with Raynaud's phenomenon develop system ic 
sclerosis. 
 Diagnosis : Primary Raynaud's can be diagnosed if all the following are present : 
 Attacks triggered by exposure to cold and/or stress 
 No suspicion of underlying disease 
 Symmetrical episodes affecting both hands, but not necessarily all fingers 
 No tissue necrosis, ulceration, gangrene or severe ischaemia 
 Normal nail-fold capillaries (Normal capillaroscopy findings)

 Normal ESR and negative anti-nuclear antibodies. 
 Secondary Raynaud phenomenon  
 Secondary causes  
 connective tissue disorders: 
 scleroderma (most common) (90%)  
 mixed connective-tissue disease (85%)  
1098

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  70 
  rheumatoid arthritis  
 SLE 
 leukaemia 
 Hyperviscosity: polycythemia, paraproteinemias (plasmacytoma, Waldenstrom's 
disease), cryoglobulinemia, cold agglutinin disease 
 use of vibrating tools 
 Vasculitides: e.g., Buerger's disease 
 cervical rib 
 drugs:  
 oral contraceptive pill,  
 ergot

 drugs:  
 ergot 
 methysergide (for intermittent migraine) 
 beta-blockers 
 vinblastine  
 bleomycin 
 
 Factors suggesting underlying connective tissue disease  
 onset after 40 years 
 Episodes lasting in excess of one hour 
 episodes of secondary Raynaud's are longer  
 Episodes of primary disease typically terminate within 15 minutes  
following warming in, but can often be prolonged in secondary disease.  
 unilateral symptoms 
 rashes

 rashes 
 presence of autoantibodies 
 features which may suggest rheumatoid arthritis or SLE, for example arthritis or 
recurrent miscarriages 
 digital ulcers,  
 calcinosis 
 very rarely: chilblains 
 
Which investigation would be most useful in determining whether the Raynaud ’s is related to 
vasculitis?  Nail fold capillaroscopy  
 The most useful initial assessment  must include nail fold capillary loop examination ,

 ideally by  capillaroscope  or, if not available, by ophthalmoscope  using magnification. 
 method 
 Nailfold capillaroscopy is performed by applying a drop of oil onto the 
periungual region of the nail and using an ophthalmoscope set to 40 d iopter 
to examine. 
 interpretation 
1099

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  71 
  Patients with connective tissue disorder such as systemic sclerosis most 
often will show  dilated, distorted, paucity or missed nail fold capillary 
loops. 
 
 For primary Raynaud phenomenon:  
 First line  lifestyle measures.  
 The best initial  line

 The best initial  line   
 Advise on lifestyle changes to reduce the frequency of the attacks, such as 
heated gloves, stopping smoking and avoiding the cold environments 
 Second line  pharmacologic treatment.  
 First pharmacologic line: calcium channel blockers e.g. nifedipine 
 IV prostacyclin infusions:  
 effects may last several weeks/months  
 indications  
 if the patient does not respond to nifedipine Retard or  
 has developed digital ulceration or ischaemia

 has developed digital ulceration or ischaemia  
 iloprost  is a synthetic analogue of prostacyclin  
 The urgent treatment of severe Raynaud ’s with threatened or 
established gangrene is with intravenous iloprost. 
 Third line  non-pharmacologic treatment.  
 Digital sympathectomy  should be considered as a last resort when drug therapy 
has failed or has not been tolerated. 
 For secondary Raynaud phenomenon:  
  Treatment of underlying disorder

  Treatment of underlying disorder  
 ACE inhibitors  also have the best evidence for reno-protection  where there is 
underlying  autoimmune pathology . 
 If there is NO underlying autoimmune pathology  ACEi has NO benefit  
 ACE inhibitors and anti-platelet agents have been trialled in small case 
series, although no definitive benefit has yet been shown. 
Chilblains (pernio )

Chilblains (pernio )  
 Chilblains (pernio) are itchy, painful purple swellings which occur on the fingers and toes 
after exposure to the cold.  
 They are occasionally associated with underlying connective tissue disease but this is rare 
Systemic sclerosis ( SSc) 
 Systemic sclerosis is a chronic autoimmune disease characterised by increased fibroblast 
activity and fibrosis in a number of different organ systems.

 characterised by hardened, sclerotic skin and other connective tissues.  
  It is four times more common in females ( ♀ > ♂ ) 
 Higher incidence in African Americans 
 Peak incidence: 30 –50 years 
 
Types: There are three patterns of disease:  
 
1. Limited cutaneous  systemic sclerosis  
 
 The more common type of SSc. 
 Raynaud's may be first sign 
 seen in 90-95% of patients with systemic sclerosis.  
 scleroderma affects face  and distal limbs predominately

 Areas of skin affected include only the face, forearms and lower legs up to the knee. 
 It does not affect the upper arms, upper legs, or trunk. 
 associated with anti-centromere antibodies 
1100

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  72 
  Previously known as CREST syndrome ( Calcinosis, Raynaud's phenomenon, Esophageal 
dysmotility, Sclerodactyly, Telangiectasia) 
 the most likely cause of this patient's dysphagia?  Esophageal smooth muscle atrophy 
and fibrosis 
 Pulmonary hypertension is one of the more common late complications seen in CREST 
syndrome

syndrome 
 The most common cause of death   
 Malabsorption is most likely to develop as a further complication  
 Involvement of GIT can occur from mouth to anus  
 can present with both diffuse and limited cutaneous forms.  
 Most GIT manifestations result from dysmotility  secondary to infiltration of the 
intestinal wall with fibrous tissue , 
 can cause life-threatening malabsorption and malnutrition. 
 Gastric emptying is delayed in 10- 75% of patients and causes symptoms of early

satiety, bloating and emesis.  
 Treatments include metoclopramide and erythromycin.  
 small bowel is also involved in 20-60% of patients, due to reduced or absent 
migrating motor complexes  predisposing to bacterial overgrowth.  
 The contributes to malabsorption, as does associated pancreatic insufficiency.  
 In the colon there is often development of diverticuli involving all layers of the 
intestinal wall, or constipation due to reduced motility.

2. Diffuse cutaneous  systemic sclerosis 
 less common. 
 scleroderma affects trunk and proximal limbs predominately  (although face may be involved 
in either type)  
 Skin areas involved include also the upper arms , thighs or trunk. 
 associated with scl-70 antibodies 
 hypertension, lung fibrosis  and renal involvement seen 
 Pulmonary involvement is the second commonest organ involvement after oeso phageal 
disease and is the leading cause of death.

disease and is the leading cause of death. 
 Pulmonary fibrosis is associated with anti-Scl-70 antibodies in up to 70% of cases.  
 scl-70 antibodies associated with a higher risk of severe interstitial lung disease  
 Reduced DLCO is the earliest sign of pulmonary disease in systemic sclerosis, 
often before fibrotic changes manifest clinically. 
3. Scleroderma  (without internal organ involvement ) 
 tightening and fibrosis of skin

 tightening and fibrosis of skin 
 may be manifest as plaques (morphoea) or linear 
 
1101

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  73 
  
Antibodies 
 ANA positive in 90% 
 therefore  in a negative test  consider an alternative diagnosis  
 RF positive in 30% 
 Anti-centromere  antibodies associated with limited cutaneous  systemic sclerosis 
 Anti- scl-70 antibodies associated with diffuse cutaneous  systemic sclerosis

  (anti-Scl- 70) also known as Anti-topoisomerase I antibodies   
 associated with a higher risk of severe interstitial lung disease 
1102

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  74 
  Anti-RNA polymerase III  antibodies  
 found in patients with diffuse disease   
 associated with: 
 rapidly progressive skin involvement  
 increased risk for scleroderma renal crisis. 
 increased risk for cancer 
 Serum protein electrophoresis: Ĺ Ȗ-globulins 
 
Treatment

Treatment 
 Immunosuppressive therapy:  e.g., methotrexate  
 Organ-specific therapy:  
 gastroesophageal reflux disease  PPIs 
 Renal crisis  ACE inhibitors  
 Renal crises result from an acute renal vasculopathy  with associated hyper-
reninaemia, not glomerulonephritis.  
 ACE inhibitors in the acute setting improves long term survival , end organ 
damage due to hypertension, and can lead to an improvement in renal functio n 
even up to 2 years after crisis.

even up to 2 years after crisis. 
 Interstitial lung disease  secondary to underlying diffuse systemic sclerosis: 
 The most appropriate treatment is cyclophosphamide  
 Azathioprine is normally used as maintenance therapy following 
 
Prognosis 
 U&Es  have a crucial role with respect to determining prognosis and appropriate therapeutic 
intervention. 
 the most important initial investigation with respect to determining  patient outlook ?  
Urea and electrolytes

Urea and electrolytes 
 Sclerodema renal crisis 
 A major complication of systemic sclerosis 
 Severe and life threatening renal disease develops in approximately 10-15% of patients.  
 Features 
 severe hypertension, with diastolic BP over 100 mmHg , usually with grade III or IV 
hypertension retinopathy, together with rapid deterioration of renal function and heart 
failure; 
 symptoms of malignant hypertension, with headaches, blurred vision, fits and h eart 
failure.

failure. 
 haematological tests often demonstrate a thrombocytopenia and/or microangiopathic 
haemolysis. 
 Hypertension  ACE inhibitor (calcium channel blockers can be added). 
  While ACE inhibitors are generally avoided in most patients with acute 
renal failure, scleroderma renal crisis is an exception to the rule  as long as 
renal function is closely monitored.  
 Renal dialysis may be required.

 Renal dialysis may be required.  
 An excessive reduction in BP or hypovolemia (should be avoided) ↓ renal perfusion 
 acute tubular necrosis. Thus, parenteral antihypertensive agents (such as 
intravenous nitroprusside or labetalol) should be avoided.  
 
 1103

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  75 
Morphea (localised scleroderma)  
 
 idiopathic inflammatory skin condition which causes excessive collagen deposition and fibrosis. 
Types 
 Morphea is classified into subtypes according to the clinical presentation and depth of tissu e

involvement: 
 circumscribed morphea ,  
 the commonest form, "circumscribed/plaque" morphea.  
 This is a well-defined oval to round plaque that fails to meet the criteria for 
generalised morphea.  
 generalized morphea ,  
 linear morphea 
 pansclerotic morphea  
 autoimmune component is suggested by enhanced T helper 2  (Th2) dependent interleukin 4  
(IL-4) activity, which in turn upregulates transforming growth factor beta ( TGF -beta ).

 TGF-beta  stimulates fibroblast production of collagen and other extracellular matrix proteins. 
Features 
 Unlike systemic sclerosis, morphea lacks features such as sclerodactyly, Raynaud phenomenon, 
nailfold capillary changes, telangiectasias, and progressive internal organ involvement.  
 Morphea can present with extracutaneous manifestations, including fever, lymphade nopathy, 
arthralgias, fatigue, central nervous system involvement,  

 Hypergammaglobulinaemia (↑↑IgM , IgG)  
 peripheral eosinophilia  
 ↑↑ ESR and CRP 
 Anti-Cu/Zn superoxide dismutase  antibodies have been found in up to 90% 
Treatment  
 Superficial circumscribed morphea 
 Tacrolimus 0.1% ointment applied twice daily for 12 weeks may be a useful first-line   
 Generalized, linear, or deep morphea 
 combination therapy with oral prednisone and methotrexate

 To minimize the risk of relapse, the recommended treatment duration of MTX is at least 2 
years. 
 Systemic corticosteroids can be helpful in the inflammatory phases of morphea, but they 
are not recommended for long-term monotherapy 
 Mycophenolate mofetil is a second-line 
Prognosis 
1104

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  76 
  generally resolves within 3 –5 years, although sometimes a patch may persist for over 25 years.  
Polymyalgia rheumatica ( PMR ) 
 overlaps with temporal arteritis   30% of patients also have giant cell arteritis.

 histology shows vasculitis with giant cells, characteristically 'skips' certain sections of affected 
artery whilst damaging others 
 muscle bed arteries affected most in polymyalgia rheumatica 
 
 occurring in patients age 50 years or older. 
 More common in women 
Features 
 
 typically patient > 60 years old 
 very rarely seen in the under 50s. 
 usually rapid onset (e.g. < 1 month)

 usually rapid onset (e.g. < 1 month) 
 typically presents with pain and stiffness of the shoulder and pelvic girdle muscles.  
 aching, morning stiffness in proximal limb muscles (not weakness) 
 Pain and muscle stiffness worst in the mornings 
 mild polyarthralgia, lethargy,  
 depression,  
 low-grade fever , anorexia, night sweats 
 ESR > 40 mm/hr 
 the next best investigation 
 a high ESR would prompt immediate treatment with steroids.

 Raised C reactive protein (CRP) 
 Alkaline phosphatase is an acute-phase reactant and is raised in approximately a thir d of 
patients with polymyalgia rheumatica. 
 note CK and EMG normal 
 reduced CD8+ T cells 
 Normochromic / normocytic anaemia  
 Giant cell arteritis (GCA) 
 GCA and PMR frequently co-exist,  
 cranial symptoms including headache , jaw claudication , and vision symptoms  are 
typically absent in patients with PMR .

typically absent in patients with PMR .  
 PMR typically has less prominent symptoms than GCA. 
 
Treatment 
 prednisolone e.g. 15mg/od - dramatic response 
 Response to a moderate dose of steroids can be useful in confirming the diagnosis of 
PMR.  
1105

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  77 
  The maximum dose of prednisolone should not exceed 20 mg once daily.  
 Patients should report 70% improvement in symptoms within three to four weeks, an d 
inflammatory markers should have normalised by this point. 
 Calcium and vitamin D supplementation should be initiated for all patients with PMR wh o

are starting corticosteroid therapy. Bisphosphonates should be added for long term steroid 
therapy. 
 The usual starting dose is 15 mg prednisolone per day.  
 Patients should expect relief of symptoms within 24-72 hours.  
 One of the best ‘tests ’ for Polymyalgia Rheumatica (PMR) is how patients respond 
to corticosteroid therapy.  
 Tapering  
 Tapering should be guided by clinical response. 
 The dose should be increased if symptoms are not well controlled within one week.

 The effective starting dose should be maintained for two to four weeks after the 
patient becomes asymptomatic. 
 Generally, the daily dose can be lowered by 1.0-2.5 mg every two to four weeks t o 
find the minimum dose needed to maintain symptom suppression. Once the patient 
is reduced to 10 mg per day, the daily dose can be tapered by 1 mg every four 
weeks. 
 Approximately 50-75% of patients can discontinue corticosteroid therapy after two 
years of treatment.

years of treatment. 
 Methotrexate and azathioprine   
 If symptoms relapsed when the dose of prednisolone has been reduced  
below the current dose,  Continue the current dose of prednisolone and 
start methotrexate   
 used in patients with corticosteroid intolerance or as corticosteroid-sparing agents.  
 These are generally reserved for patients in whom it has been difficult to redu ce the 
prednisolone after prolonged high dosages (for example, 10 mg or more per day for

more than a year). 
 These agents should be added to the prednisolone initially, but with a view to 
slowly reduce and withdraw prednisolone. 
 As with steroid therapy, azathioprine or methotrexate can be discontinued if there 
has been sufficient response. 
Prognosis 
 Rapid improvement often occurs within 24 to 72 hours with low-dose  prednisolone. 
Temporal arteritis (Giant cell arteritis (GCA).

Temporal arteritis (Giant cell arteritis (GCA). 
Giant cell arteritis  should always be considered in elderly patients with headaches, 
ocular symptoms, systemic symptoms and high ESR.  
In elderly people giant cell arteritis is a common presentation of acute 
monocular visual loss. 
 
 also known as giant cell arteritis (GCA).  
 Temporal arteritis is large vessel vasculitis  
  overlaps with polymyalgia rheumatica (PMR).

  overlaps with polymyalgia rheumatica (PMR).  
  Histology shows changes which characteristically 'skips' certain sections of affected artery whilst 
damaging others.   
 It is a clinical emergency.  
 Sex: ♀ > ♂  
 Peak incidence: 70 –79 years; rarely seen in patients < 50 years 
Diagnosis 
1106

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  78 
  The American College of Rheumatology 1990 criteria requires 3 of the follow ing for GCA 
diagnosis: 
 
1. Age >50 y/o 
2. New onset localised headache 
3. Temporal artery tenderness or decreased pulsation 
4. ESR >50mm/hr 
5. Temporal artery biopsy positive 
 
Features  
 typically patient > 60 years old

Features  
 headache (found in 85%) 
 jaw claudication (65%)  is a very specific sign for temporal arteritis. 
 visual disturbances secondary to anterior ischemic optic neuropathy 
 15-20% of patients develop permanent visual loss.  
 tender, palpable temporal artery 
 features of PMR: aching, morning stiffness in proximal limb muscles (not weakness)

 also lethargy, depression, low-grade fever, anorexia, night sweats 
 raised inflammatory markers: ESR > 50 mm/hr (note ESR < 30 in 10% of patients). CRP may 
also be elevated 
 ESR can be within normal range in 5-10% of GCA cases.  
 temporal artery biopsy: skip lesions  may be present (certain sections of affected artery whilst 
damaging others)  
 An adequate length of temporal artery (3 to 5 cm) should be obtained because

inflammatory lesions may be present in a segmental fashion.  
 A negative temporal artery biopsy can occur in up to 50 percent of patients, often b ecause 
the sampled region was not involved in the pathologic process. Therefore, it is not 
sensitive enough to rule out temporal arteritis .  
 Treatment should not be delayed while waiting for the biopsy to be performed.  
 note creatine kinase and EMG normal 
Treatment

Treatment 
 high-dose prednisolone  - there should be a dramatic response, if not the diagnosis should be 
reconsidered 
 urgent ophthalmology review. Patients with visual symptoms should be seen the  same-day by an 
ophthalmologist. Visual damage is often irreversible  
 As GCA requires long-term steroid therapy bone sparing agents (a  bisphosphonate and 
vitamin D)  and a gastroprotective drug (e.g omeprazole ) should be prescribed.

 Also, low dose aspirin  should be considered as it has been shown to reduce the rate of visual 
loss and cerebrovascular accidents in GCA. 
Current BSR guidelines recommend : 
1. Uncomplicated GCA (no jaw or tongue claudication, or visual symptoms) 
 prednisolone 40-60 mg daily 
2. Complicated GCA: (  with visual involvement and/or jaw/tongue claudication ) 
 Evolving visual loss or history of amaurosis fugax : IV methylprednisolone

500 mg-1 g  daily for three days, followed by oral corticosteroids 
 Established visual loss: at least 60 mg prednisolone daily 
Polyarthritis  
 SLE 
 seronegative spondyloarthropathies 
 pseudogout 
 viral infection: EBV, HIV, hepatitis, mumps, rubella 
____________________________________________________________ 1107

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  79 
 Polyarteritis nodosa (PAN) 
 systemic vasculitis of the medium -sized vessels, with necrotizing inflammation leading to 
aneurysm formation and tissue ischemia;  
 most commonly involving skin, peripheral nerves, muscles, joints, gastrointestinal tract, and 
kidneys .

kidneys .  
 any organ with the exception of the lung  can be affected,  
 Peak incidence: ∼ 45–65 years 
 Sex: ♂ > ♀  
 more common in middle-aged men  
 diffuse vascular inflammation and ischaemia of the affected organs.  
 PAN is a medium-vessel vasculitis that is a type III hypersensitivity reaction. 
 
 hepatitis B infection  
Features  
 Nonspecific symptoms: (found in 65% to 80% of patients) 
 fever, malaise, arthralgia , weight loss

 fever, malaise, arthralgia , weight loss 
 Neurological involvement: (in 55% of patients) 
 polyneuropathy ( mononeuritis multiplex ),  
 cerebral ischemia (stroke) 
 Skin involvement: (in 44%) 
 skin rash ,  
 Skin ulcers, nodules 
 Renal involvement : (in 11%) 
 Hypertension is a manifestation of renal ischaemia via activation of the renin-
angiotensin system. 
 haematuria

 but red cell casts are absent because glomerular inflammation is not a feature. 
 renal impairment 
 Coronary artery involvement ;  
 increased risk of myocardial infarction 
 GI involvement:  
 abdominal pain, nausea, vomiting 
 can present with abdominal pain and melena due to involvement of  the mesenteric 
arteries. 
 Testicular pain 
 testicular pain from ischaemic orchitis is a characteristic feature 
 uncommon presentation

 uncommon presentation 
 Usually spares the lungs 
 
PAN should be considered in young adults presenting with stroke or myocardial infarction 
 The diagnosis may be confirmed with a biopsy of involved tissue  
 
 1108

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  80 
  
Livedo reticularis 
 
Angiogram from a patient with polyarteritis nodosa. Both kidneys demonstrate beading a nd numerous 
microaneurysms affecting the intrarenal vessels. Similar changes are seen affecting the int rahepatic 
1109

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  81 
 vessels with a few small microaneurysms noted. The proximal branches of the SMA appears normal; 
however there are no normal straight arteries from the jejunal arteries and lack of normal anastom otic 
arcades and loops. This is associated with multiple microaneurysms. 
 
Diagnosis

Diagnosis 
 The American College of Rheumatology (ACR) 1990 criteria  
 Three of the following 10 criteria are required:  
1. Weight loss ≥4 kg   
2. Livedo reticularis 
3. Testicular pain or tenderness  
4. Myalgias, weakness, or leg tenderness 
5. Mononeuropathy or polyneuropathy 
6. Diastolic blood pressure >90 mmHg 
7. Elevated urea or creatinine 
8. Positivity for hepatitis B virus (HBV) infection 
9. Arteriographic abnormality

9. Arteriographic abnormality 
10. Biopsy of small- or medium-sized artery containing polymorphonuclear leukocytes. 
 
 Hepatitis B surface antigen is positive in 30%,  
  p-ANCA is positive only in 20% .  
 ANCA is classically negative in PAN.  
 Angiography :  
 Conventional angiography is the imaging modality of choice , and should be performed 
if there is a clinical suspicion of PAN.  
 typically demonstrates: 
 microaneurysms and

 microaneurysms and  
 focal narrowing in medium-sized blood vessels.  
 Biopsy 
 should be performed if angiography is not available or does not conclusively show a 
medium-vessel vasculitis.  
  Shows:  
 focal and segmental transmural necrotising inflammation with fibrinoid 
necrosis  in medium-sized vessels.  
 pleomorphic cellular infiltrate  of lymphocytes, neutrophils, macrophages, and 
 granulomas are absent.  

 PAN are differentiated from the other small- and medium-vessel vasculitide s by: 
  absence of anti-neutrophil cytoplasmic antibodies,  
 Glomerulonephritis is not a feature of PAN , but it is common in anti-neutrophil 
cytoplasmic antibodies (ANCA) vasculitis. Making this distinction early by way of urinalysis 
for protein, blood, and casts  is a simple first-line test  that can guide further investigation 
and treatment. 
 Red cell casts are absent in PAN

 Red cell casts are absent in PAN 
 If there is evidence of glomerular inflammation such as urinary casts, then an 
alternative diagnosis such as microscopic polyangiitis (MPA) or granulomatosis 
with polyangiitis (Wegener's) (GPA),must be considered. 
 lung involvement is not seen in PAN, and abnormal respiratory findings should sug gest an 
alternative diagnosis  
 and by confirmation that small vessels (i.e., arterioles, capillaries, venules) are not 
involved. 
Treatment

involved. 
Treatment  
 idiopathic PAN  corticosteroids and cyclophosphamide 
 hepatitis B related disease   plasmapheresis and antiviral agents.  
 Azathioprine can be used as maintenance therapy, and typically has fewer side e ffects than 
 
Cyclophosphamide  causes premature ovarian failure and infertility in both m en and women. 1110

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  82 
Granulomatosis with polyangiitis (Wegener's granulomatosis) 
 
 Granulomatosis with polyangiitis is now the preferred term for Wegener's granulomatosis.  
 It is an autoimmune condition associated with a necrotizing granulomatous vasculitis, affecting

both the upper and lower respiratory tract as well as the kidneys. 
 the classical triad  consists of  
1. necrotising granulomatous inflammation of the respiratory tract,  
2. glomerulonephritis  
3. small-vessel vasculitis.  
 
Features  
 upper respiratory tract: epistaxis, sinusitis, nasal crusting 
 saddle-shape nose deformity 
 lower respiratory tract: dyspnoea, haemoptysis 
 migrating alveolar shadowing 
 rapidly progressive glomerulonephritis ('pauci-immune', 80% of patients)

 It usually presents with rapidly progressing renal failure (within three months), proteinuria 
and microscopic haematuria.  
 also:  
 vasculitis (causing carotid artery tenderness) 
 vasculitic rash,  
 eye involvement (e.g. proptosis),  
 cranial nerve lesions 
 
 c-ANCA ( PR3-ANCA (targeting peroxidise-3 ) positive in > 90%, p-ANCA  (MPO-ANCA (targeting 
myeloperoxidase)  positive in 25% 
 cANCA directed against proteinase-3

 cANCA directed against proteinase-3  
 cANCA  is highly specific, but is found in only 50% of patients with disease localised to the 
respiratory tract and 95% with generalised Wegener's. 
 chest x-ray: wide variety of presentations, including cavitating lesions 
 renal biopsy: epithelial crescents in Bowman's capsu le 
 
 steroids 
 Prednisolone  is given in doses of around 1 mg/kg per day initially, after which the

dose is reduced rapidly, typically at weekly intervals.  
 In case of renal failure with indications for dialysis, the initial management 
Methylprednisolone   
1111

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  83 
  Methylprednisolone should be given immediately , followed by haemodialysis 
and then cyclophosphamide. 
 cyclophosphamide (90% response) 
 The combination of prednisolone and cyclophosphamide is now established as 
the standard therapy and the treatment of choice for induction of remission in 
Wegener's granulomatosis

Wegener's granulomatosis  
 Cyclophosphamide : Traditionally, oral dose (2 mg/kg per day), but latterly 
intravenous boluses have proved increasingly popular, given in doses of 0.5-0.75 
g/m2 body surface ar ea at intervals of 2 weeks (at least for short periods) to 2 
months. 
 If a patient had a vasculitic neuropathy. Current practice is to use 
cyclophosphamide for induction therapy.  
 Both rituximab and methotrexate have also been used for induction therapy in  ANCA-associated

vasculitis, although they would not be first-line treatment.  
 Azathioprine is used as maintenance treatment following cyclophosphamide  
 ciclosporin is rarely used in the management of ANCA-associated vasculitis. 
 Evidence from controlled trials suggests that once remission is achieved azathioprine or 
methotrexate may be reasonable alternatives to cyclophosphamide.  
 In refractory Wegener's, both infliximab and rituximab have shown some degree  of promise. 

 in case of decreased conscious level with acute renal failure  (with indication for dialysis ) 
and respiratory function is failing . The first immediate step   Endotracheal intubation and 
positive pressure ventilation , transfer the patient to a critical care setting  (especially to 
protect airway with a GCS 8/15). 
 
Prognosis 
 median survival = 8-9 years  
 
Extra notes:

Extra notes: 
 Alveolar proteinosis is a rare diffuse lung condition, characterised by alveolar and interstitial 
accumulation of phospholipid protein derived from surfactant. It can be conge nital, secondary or 
acquired, and patients often present with recurrent respiratory infections. Transfer factor (KCO) is 
typically reduced. 
 Microscopic polyangiitis is a small vessel vasculitis which classically spares the upper respiratory 
tract.

tract. 
Microscopic Polyangiitis 
Usually the PR3 antibody is associated with Wegener's  granulomatosis, whereas the MPO  
antibody is associated with microscopic polyangiitis , which is closely linked. 
 
 Microscopic polyangiitis is similar to wegener ’s granulomatosis except in 3 things: 
1. it only affects small blood vessels in the lungs or kidneys. 
 No nasopharyngeal damage like wegener's

 No nasopharyngeal damage like wegener's  
2. Associated with p-ANCA antibodies .  
 anti-MPO (pANCA, 45%) antibody is strongly positive than anti-PR3 (cANCA, 30%) 
3. No granuloma on biopsy  
Henoch-Schonlein purpura 
 Henoch-Schonlein purpura (HSP) is an IgA mediated  small vessel vasculitis  
  involving mainly the blood vessels of the skin, GI tract, the kidneys and the joints.

 90% of cases of HSP occur in children aged 2-10 years but can occur in any age group.  
 In children, (HSP) is the most common cause of vasculitis affecting the kidneys.  
 typically commoner in males,  
 may follow an infectious agent.  
 It can present one to three days following infection of an IgA secreting mucous membrane 
(commonly following pharyngitis, but can occur following infection of the gastrointestinal tra ct, 
bladder or breast).  1112

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  84 
  An important risk factor in adults  chronic alcohol intake.  
  associated with: Helicobacter pylori , hepatitis B and malignancy.   
Features 
HSP is characterised by the tetrad of : 
 purpura 
 arthritis, and 
 renal involvement (haematuria and proteinuria).

 Patients with proteinuria have a worse prognosis than patients with haematuria alone. 
 palpable purpuric rash (with localized oedema) over buttocks and extensor surfaces of arms  and 
legs (due to a cutaneous vasculitis) 
 abdominal pain (due to gut vasculitis, which may be severe in some cases, leading to bloo dy 
diarrhoea) 
 polyarthritis (common symptom) 
 features of IgA nephropathy may occur e.g. haematuria, renal failure

 HSP nephritis becomes clinically manifest in only 20-30%.  
 It usually presents as macroscopic haematuria and proteinuria  
 Of those patients with renal involvement, as many as 10% may develop chronic renal 
failure and end-stage renal disease. However, fewer than 1% of all patients with HSP 
suffer this poor prognosis. 
 Skin biopsy and immunofluorescence demonstrate leukocytoclastic vasculitis with IgA

deposition, ( meaning lots of white blood cells in the skin around small blood vessels)  which is 
pathognomonic  for HSP.  
 Immunofluorescence studies will reveal  IgA deposits within blood vessel walls  
Treatment 
 analgesia for arthralgia 
 treatment of nephropathy is generally supportive.  
 All patients with hypertension and proteinuria (greater than 1 g/day) should be 
started on an angiotensin-converting enzyme (ACE) inhibitor , which may control the 
BP and proteinuria.

BP and proteinuria. 
 Once the BP has been controlled, patient should have a renal biopsy, and if th is showed 
changes of a crescentic glomerulonephritis (GN), then an immunosuppression regime 
similar to that used in renal vasculitis should be started (probably with high dose steroids 
in the first instance +/- cyclophosphamide). 
 There is inconsistent evidence for the use of steroids and immunosuppressants

 Management of HSP in adults often involves the use of immunomodulatory or imm une-
suppressive regiments (in contrast to children where the majority of cases resolve 
spontaneously).  
Prognosis 
 usually excellent, HSP is a self-limiting condition, especially in children without renal involvem ent 
 There is often a more complicated course in adults, and 50% of patients who presen t with renal 
involvement develop renal insufficiency. 
 around 1/3rd of patients have a relapse 
 
 1113

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  85 
  
September 2011 exam: What is the most likely renal outcome in Henoch-Schonlein 
purpura? Full renal recovery  
 
Kawasaki disease 
 Kawasaki disease is a type of vasculitis which is predominately seen in children.

 Whilst Kawasaki disease is uncommon it is important to recognise as it may cause potentia lly 
serious complications, including coronary artery aneurysms  
 
Features  
 high-grade fever which lasts for > 5 days. Fever is characteristically resistant to antipyretics 
1114

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  86 
  conjunctival injection 
 bright red, cracked lips 
 strawberry tongue 
 cervical lymphadenopathy 
 red palms of the hands and the soles of the feet which later peel 
Diagnosis 
 Kawasaki disease is a clinical diagnosis as there is no specific diagnostic test 
 high-dose aspirin*

 high-dose aspirin* 
 *Kawasaki disease is one of the few indications for the use of aspirin in children. Due to 
the risk of Reye's syndrome aspirin is normally contraindicated in children. 
 intravenous immunoglobulin 
 Combination therapy with intravenous immunoglobulin (IVIG) and aspirin during 
the acute phase of Kawasaki disease produces a more marked anti-inflammatory 
effect and reduction in coronary artery abnormalities  than does aspirin alone.

 echocardiogram (rather than angiography) is used as the initial screening test for coronary artery 
aneurysms 
 
 coronary artery aneurysm (25% of cases)  
 lakayasu1s arter1 t1s  
 
Takayasu ’s disease (TD)  
 Takayasu's arteritis is a large vessel vasculitis.  
 chronic inflammatory granulomatous pan-arteritis of the major arteries  Affected vessels

 It typically causes occlusion of the aorta (the ascending arch of the aorta) 
 The subclavian artery is commonly affected, and subclavian steal syndrome may occur  
 The brachial, radial and ulnar arteries can also be involved.  
Pathology 
 continuous or patchy granulomatous inflammatory process involving macrophages, lymph ocytes, 
and multinucleated giant cells which causes progressive occlusive disease of the aorta and its 
branches.  

branches.  
 most commonly affects women (the ratio of women to men is 8:1).  
 typical age onset of 25-30 years.  
 most common in Asia. 
 It is very rare in the Western world with an annual incidence of between 2 and 3 per milli on.  
Features  
 questions commonly refer to an absent limb pulse .  
 systemic features of a vasculitis e.g. malaise, headache 
 unequal blood pressure in the upper limbs 
 carotid bruit

 carotid bruit 
 vascular symptoms such as claudication.  (intermittent claudication)  
1115

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  87 
  systemic symptoms of fever, arthralgia and weight loss. 
 neurological symptoms such as transient ischaemic attacks. 
 Cardiac features include angina, heart failure, and aortic regurgitation.  
 Renal manifestations may include mesangial proliferative glomerulonephritis.  
 aortic regurgitation (around 20%)

 aortic regurgitation (around 20%) 
 ESR and CRP are usually elevated,  
 levels of pentraxin 3 may be a useful marker of disease activity.  
 
Treatment 
 Corticosteroids with the addition of steroid sparing second agents such as methotrexate or 
azathioprine are the mainstay of therapy.  
Prognosis 
 With good care, 15-year survival rates approach 90%. 
 
 Subclavian steal syndrome  (SSS)

Subclavian steal syndrome  (SSS) 
The proximal part of left subclavian is blocked on left side so 
no flow in vertebral and to left arm. Blood from right vertebral 
enters left vertebral and flows back to supply left arm   
Etiology 
 Atherosclerosis 
 Cervical rib 
 Takayasu's arteritis   
Features 
 Presyncope (sensation that one is about to faint) 
 Syncope (fainting) 
 Neurologic deficits 
 Blood pressure differential between the arms 
 severe memory problems

 severe memory problems 
 hands showing circulation problems (hands can have 
blotchy patches of red and white) (associated with other 
stigma to vascular disease (e.g. vascular 
insufficiency ulcers of the foot). 
 
Buerger ’s disease  
Overview  
 Thromboangiitis obliterans (Buerger ’s disease) is a disease of small and medium-sized

arteries  and veins  resulting in inflammation and ulceration ,  in which the distal vessels become 
blocked in the hands and feet .  
 There is no excessive atheroma and it does not involve the coronary arteries like atherosclerosis.  
 The disease occurs mainly in cigarette smokers; it has not been documented in non-
smokers . 
 Prevalence is higher in men and people of Far Eastern origin. 
Feature 
 symptoms of arterial ischaemia  resulting in gangrene of the digits.

 claudication with diminished or absent pulses.  
 The feet or legs may be cyanosed or dusky; the skin is thin and without hair.  
 Ulcerations occur and necrosis follows 
 Migratory phlebitis in the superficial vein  is present in 40% of cases.  
Diagnosis  
 usually clinical.  
 Arteriogram will show occlusion of distal arteries of the hands and feet.  
 Histopathology  
 examination of affected arteries reveals fresh inflammatory thrombus within both small

and medium-sized arteries and veins, with giant cells surrounding the thrombus. 
Treatment   
 Supportive 1116

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  88 
  stop smoking.  
Prognosis 
 can be excellent (i.e. complete resolution of symptoms) with smoking cessation 
 in some cases, however, amputation is unavoidable 
___________________________________________________ _____________________________   
IBD-associated arthropathy

IBD-associated arthropathy  
 The history of weight loss, diarrhoea and a mono/oligo-arthropathy suggests a  diagnosis of 
inflammatory bowel disease (IBD). 
 IBD-associated arthropathy is considered a subtype of seronegative spondyloarthropathy .  
 A variety of joint involvement has been described, from large joint pauciarticular arthropat hy to a 
rheumatoid pattern polyarthropathy. 
 Peripheral arthritis is generally non-erosive and the oligoarticular variant particularly may

correlate with intestinal disease activity. 
 Axial arthritis may include inflammatory back pain, sacroilitis, or ankylosing spondylitis and is less 
likely to correlate with gastrointestinal symptoms.  
 mechanisms remain unclear.  
 Treatment of the gastrointestinal disease is not always sufficient for control of arthritis, an d 
biologic agents may be indicated. 
 
The description of weight loss, diarrhoea and a mono/oligo-arthropathy suggests a diagnosis

of inflammatory bowel disease. (IBD). 
Differential diagnoses of arthropathies associated with iron deposition in t he 
joints:  brown-stained synovial fluid. 
 Haemophilia 
 Haemosiderosis from recurrent haemarthrosis 
 Haemochromatosis, and 
 Pigmented villonodular synovitis (PVNS). 
SAPHO syndrome

SAPHO syndrome 
 SAPHO is an acronym for synovitis, acne, pustulosis, hyperostosis, and osteitis. It is characterise d by 
osteosclerotic bone lesions, sterile osteomyelitis, and a variety of skin lesions. 
 Synovitis - may be present rarely, and associates with erosions. 
 Acne -  may be severe (conglobate or fulminans) and recur with new bony involvement. 
 Pustulosis  - palmo-plantar pustulosis occurs in approximately 50% of patients, other skin

lesions may include psoriasis, hidradenitis suppurativa, acne, and rarely Sweet's syndrome. 
 Hyperostosis  (increase in bone substance) and osteitis (inflammation of the bones) - the  bony 
lesions typically involve the acromioclavicular, and sternoclavicular joints. Other sites include 
anterior chest wall, sternum, clavicle, pubic symphysis, spine, and mandible. These le sions are 
visualised on 99m technetium bone scan or MRI. 
The cause of the SAPHO syndrome is unknown.  

 skin lesions are characterised by neutrophilic pseudoabscesses. 
 Bone biopsy can reveal sterile osteomyelitis. 
Diagnosis should be suspected when there is an association of rheumatic pain with a pustular 
skin disease. 
treatment  
 no specific treatment, 
 some cases remit spontaneously 
 Typical treatment can be used for the arthritic symptoms (i.e. non-steroidal anti-infla mmatories 
and disease modifying anti-rheumatic agents).

and disease modifying anti-rheumatic agents).  
 Isotretinoin and aciretin can be used to treat the skin disease.  
 In the more severe cases corticosteroids, calcitonin, bisphosphonates and TNF-inhibitors can be  
used. 
 
 1117

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  89 
Elbow pain 
The table below details some of the characteristic features of conditions causing elbow pain: 
Lateral 
epicondylitis (tennis 
elbow) Features 
 pain and tenderness localised to the lateral epicondyle

 pain worse on resisted wrist extension with the elbow extended or 
supination of the forearm with the elbow extended 
 episodes typically last between 6 months and 2 years. Patients tend to 
have acute pain for 6-12 weeks 
 most appropriate to gain short term relief for the patient?  Local 
steroid/anaesthetic injection  
Medial 
epicondylitis 
(golfer's elbow)  Features 
 pain and tenderness localised to the medial epicondyle 
 pain is aggravated by wrist flexion  and pronation

 symptoms may be accompanied by numbness / tingling in the 4th and 5th 
finger due to ulnar nerve involvement 
Radial tunnel 
syndrome   Most commonly due to compression of the posterior interosseous branch of 
the radial nerve.  
 It is thought to be a result of overuse. 
Features  
 symptoms are similar to lateral epicondylitis making it difficult to diagnose 
 however, the pain tends to be around 4-5 cm distal to the lateral epicondyle

 symptoms may be worsened by extending the elbow and pronating the 
forearm 
Cubital tunnel 
syndrome  Due to the compression of the ulnar nerve.  
Features  
 initially intermittent tingling in the  4th and 5th finger 
 may be worse when the elbow is resting on a firm surface or flexed for 
extended periods 
 later numbness in the 4th and 5th finger with associated weakness 
Olecranon bursitis  Swelling over the posterior aspect of the elbow. There may be associated pain,

warmth and erythema. It typically affects middle-aged male patients. 
 
Shoulder problems 
The table below summarises the key features of common shoulder problems: 
 
Adhesive capsulitis 
(frozen shoulder)  Common in middle-age and diabetics 
Characterised by painful, stiff movement 
Limited movement in all directions, with loss of external rotation and abduction 
in about 50% of patients

in about 50% of patients 
Supraspinatus 
tendonitis 
(Subacromial 
impingement, 
painful arc)  Rotator cuff injury 
Painful arc of abduction between 60 and 120 degrees 
Tenderness over anterior acromion 
____________________________________________________________ 1118

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  90 
  
Prepatellar  bursitis  
 The most useful in initial diagnosis of prepatellar bursitis  
Crepitation of the knee 
Polymyositis 
Polymyositis is the commonest cause of inflammatory muscle disease in people under 50-

years-old ( inclusion body myositis is the commonest in those over 50-years-old ). 
 
Overview 
 inflammatory disorder causing symmetrical , proximal , painless  muscle weakness 
 thought to be a T-cell mediated cytotoxic process directed against muscle fibres 
 dermatomyositis is a variant of the disease where skin manifestations are prominent, for ex ample 
a purple (heliotrope) rash on the cheeks and eyelids 
 typically affects middle-aged,  
 female: male 3:1 

 idiopathic  
 connective tissue disorders 
 Adenocarcinomas  of the cervix, lung, ovaries, pancreas, bladder, and stomach account 
for approximately 70% of the cancers associated with inflammatory myopathies. 
Features 
 proximal muscle weakness  +/- tenderness 
 Raynaud's 
 respiratory muscle weakness 
 interstitial lung disease: e.g. fibrosing alveolitis or organising pneumonia 
 dysphagia , dysphonia

 dysphagia , dysphonia 
 Dysphagia is common but the ocular muscles are very rarely involved unlike myasthenia 
gravis where this is a predominant feature. 
 
 elevated creatine kinase    (the initial investigation)  
 Electromyography (EMG) 
 EMG are abnormal in almost all patients (90%). 
 Triad of: 
1. Short, small polyphasia motor units 
2. Fibrillation and sharp waves  
3. Bizarre, repetitive discharges   
 muscle biopsy

 muscle biopsy 
 muscle biopsy is the definitive investigation to establish the diagnosis 
 Histopathology  endomysial  mononuclear inflammatory infiltrate  and muscle fiber 
necrosis . 
  endomysial inflammation with CD8 T cells ( MHC class I ). 
 anti-Jo-1 antibodies are seen in pattern of disease associated with lung involveme nt, Raynaud's 
and fever 
 Positive rheumatoid factor - Found in more than 50%  
 Myoglobinuria

 Myoglobinuria 
 CBC - May show leukocytosis (in more than 50%) or thrombocytosis.  
 ESR or CRP: elevated in 50%  
 Antinuclear antibody -  Positive in one third  
Treatment 
 Prednisolone is the mainstay of treatment, at an initial dose of 1 mg/kg/d.  
 In patients who fail to show improvement, disease-modifying steroid-sparing age nts may be 
added.  
 A high-protein diet and supervised exercise may further improve symptoms.  
1119

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  91 
 Prognosis 
 Most patients have a favourable response to corticosteroid therapy, and 5-year surv ival rates 
approach 80%. 
Dermatomyositis 
proximal weakness with normal reflexes and sensation and absence of 
fasciculations : 
 without skin lesion  polymyositis

 without skin lesion  polymyositis 
 with skin lesion  dermatomyositis 
Overview 
 inflammatory disorder causing symmetrical, proximal muscle weakness and characteristic 
skin lesions 
 may be idiopathic or associated with connective tissue disorders or underlying 
malignancy (typically lung cancer, found in 20-25% - more if patient older) 
 polymyositis  is a variant of the disease where skin manifestations are not prominent 

 Autoantibodies binding to the vasculature , muscle atrophy, and lymphocytic 
 caused by CD4 T cells that cause perimysial inflammation and atrophy. 
Skin features 
 photosensitive 
 Pruritus of skin lesions, sometimes intense enough to disturb sleep  
 ‘shawl sign ’: macular rash over back and shoulder  
 “V-neck sign ”: Violaceous erythema or poikiloderma involving the anterior chest  
 heliotrope rash  in the periorbital region

 heliotrope rash  in the periorbital region 
 The characteristic heliotrope rash consists of a violaceous or erythematous rash 
(sometimes with oedema) in a symmetrical distribution involving periorbital skin. 
This is frequently subtle and may involve only a mild discolouration along the eyelid 
margin. 
 Since a heliotrope rash is rarely observed in other disorders, its presence is highly 
suggestive of dermatomyositis .

suggestive of dermatomyositis . 
 Gottron's papules  - roughened red papules over extensor surfaces of fingers 
 "mechanic's hands" (rough, cracked skin),  
 fingers telangiectasia - nail fold capillary dilatation. 
 Gottron ’s papules (rough papules on extensor 
surfaces of the phalanges are pathognomonic  if 
there is a history of weakness and elevated 
creatine kinase (CK)). 
 
Gottron's papules are found over bony prominences, 
particularly the metacarpophalangeal joints, the

particularly the metacarpophalangeal joints, the 
proximal interphalangeal joints, and/or the distal 
interphalangeal joints. Papules may also be found 
overlying the elbows, knees, and/or feet. 
 proximal muscle weakness +/- tenderness 
 respiratory muscle weakness  ↓ Vital capacity (VC)  
 Commonly, there is muscle wasting and reduced reflexes  
 interstitial lung disease: e.g. Fibrosing alveolitis or organising pneumonia  
1120

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  92 
  dysphagia, dysphonia 
 Ocular symptoms are rare and if present should alert you to consider a different diagnosis  
 elevated creatine kinase 
  the most helpful test in the diagnosis  
 EMG 
 high levels of the complement component C5b-9 around the capillary  vessels .

 Perimysial inflammation with lymphocytic infiltrate  
 ANA positive in 60% 
 anti- Mi-2 antibodies are highly specific  for dermatomyositis, but are only seen in 
around 25% of patients 
 anti-Jo-1 antibodies are not commonly seen in dermatomyositis - they are more common 
in polymyositis where they are seen in a pattern of disease associated with lung 
involvement, Raynaud's and fever 
 Screen for malignancy  
 prednisolone

 prednisolone 
Inclusion body myositis (IBM) 
Painless weakness and wasting with selective involvement of long finger flexors and 
quadriceps is characteristic of inclusion body myositis.  
Overview 
 a syndrome of diffuse, progressive, asymmetric , proximal, and distal weakness that is generally 
refractory to immunosuppressive treatment .  
 cause of myopathy associated with cytoplasmic inclusions on muscle biopsy

pathology 
 the pathologic findings involve both inflammatory and degenerative characteristics  
 Like in polymyositis, inclusion body myositis presents with and increased sarcolemmal 
expression of MHC class I  antigens.  
 IBM occurs more frequently in men than women . 
 More common in older Caucasian males. 
 the most common acquired myopathy in patients older than 50 years   
 and accounts for 16-28% of inflammatory myopathies in the United States and  Canada. 
Features

Features 
 muscle weakness can affect both proximal and distal muscles  
 unlike polymyositis and dermatomyositis, asymmetry is common. 
 characteristically affects quadriceps and finger/wrist flexors are usually more severely 
affected than extensor counterparts 
 The onset of muscle weakness in IBM is generally gradual (over months or years). 
 Dysphagia is common, occurring in 40-66% of patients  

 Dysphagia due to weakness of the cricopharyngeal musculature may predispose to aspira tion 
pneumonia 
 The most common cause of death is respiratory system disorders. 
Diagnosis 
 anti-cN1A autoantibodies   
 Muscle biopsy shows intranuclear or cytoplasmic  tubofilaments  on electron microscopy. 
 Poor response to immunosuppressive or immunomodulatory therapies 
 Polymyositis and dermatomyositis show a much better response to steroids than IBM.

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  93 
  
 Polymyositis  Dermatomyositis  IBM 
Onset  Subacute  Subacute  Slow   
 age  Commonest < 50 
years Commonest < 50 years commonest > 50 years  
Affected muscles  Proximal  Proximal Proximal and distal  
symmetry symmetrical symmetrical Asymmetrical  
Common incidence  Female  Female  Male

Common incidence  Female  Female  Male   
Skin lesion NO Characteristic rash  NO 
CK  Highly elevated (up to 
50 fold) Highly elevated (up to 50 
fold) Mild elevated (up to 10 
fold) or normal 
 
antibodies anti-Jo-1 are more 
common anti- Mi-2 are highly 
specific  anti-cN1A autoantibodies  
Muscle biopsy endomysial 
inflammatory 
infiltrate  and muscle 
fiber necrosis . 
 
 perivascular and 
interfascicular 
inflammatory infiltrates 
with adjoining groups of 
muscle fiber

muscle fiber 
degeneration/regeneration intranuclear or 
cytoplasmic 
tubofilaments  
T cell  CD8 T cell 
 CD4 T cell  
Response to steroids good Good  Poor  
 
Fibromyalgia (FM) 
 Fibromyalgia is a syndrome characterised by widespread pain throughout the body with  tender 
points at specific anatomical sites .

points at specific anatomical sites .  
 The cause of fibromyalgia is unknown. but may involve hyperexcitability within the spinal cord or 
brainstem, altered pain perception and somatisation.  
 occur in between 1 and 2% of the general population   
 women are 10 times more  likely to be affected 
 typically presents between 30-50 years old 
Features 
 chronic pain: at multiple site, sometimes 'pain all over' 
 lethargy

 lethargy 
 sleep disturbance, headaches, dizziness are common 
 50% of patients with fibromyalgia complain of diarrhoea and constipation , often associated 
with abdominal bloating. 
 Morning fatigue  
 patients often look unwell, and may appear depressed and anxious. 
 Other features include tissue swelling, morning stiffness  
 
Diagnosis 
 is clinical  pain in all four quadrants of the body , as well as tenderness  in 11 of 18 
anatomically defined trigger areas.

anatomically defined trigger areas.  
 The normal ESR  in patients with FM contrasts with the high ESR in elderly patients with 
polymyalgia rheumatica. 
 ESR and CRP can assist in identifying/excluding an underlying inflammatory disorder. 
 explanation 
 aerobic exercise: has the strongest evidence base 
 cognitive behavioural therapy 1122

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  94 
  medication: pregabalin, duloxetine, amitriptyline 
 Tricyclic anti-depressants such as amitriptyline are first line agents used for 
treatment. (medical-masterclass.com 2017 mrcp part 2)  
 
Key facts: 
 How to diagnose? 
 A female, presented with a feature of pain and tenderness  over multiple area + normal

ESR  and CRP. 
 What is the best management? 
 aerobic exercise 
Cervical spondylosis  
 Cervical spondylosis is the most common progressive disorder of the spine, associated with 
normal aging.  
  degeneration of the intervertebral discus and facet joints in the cervical spine. 
 rugby, horse-riding and flying, all of which increase loads on the head. 
Symptoms

Symptoms  
 Asymptomatic  In the majority of cases  
 myelopathy and radiculopathy   
 Radiculopathy  is due to compression, stretching or angulation of the cervical nerve roots. 
 Myelopathy  is due to compression, ischaemia or recurring minor trauma to the cord.  
 Cervical spondylitic myelopathy is the most common cause of myelopathy in adults.  
 There is a mixture of upper and lower motor neurone signs. These may or may not b e

accompanied by pain in the neck and/or upper limb, orbits or temporal regions. In ad dition there 
is often cervical stiffness, and poor balance. On examination there is limited range of moveme nt 
of the cervical spine and poorly localised tenderness. 
 Radiculopathy causes dermatomal pain, often with accompanying changes in sensation or 
weakness in related muscles. The most commonly affected nerve roots are C5-7, and senso ry

symptoms (shooting pain, numbness, hyperaesthesia) are more common than weakness. Du ral 
irritation can be demonstrated with the Spurling test in which radicular pain is reproduced with  
lateral flexion and rotation of the neck, with pressure on top of the patient's head. Reflex es are 
usually reduced. 
 differential diagnosis  is broad, and includes acute neck strain, osteomyelitis, fibromyalgia, 
inflammatory arthritis and osteoporosis.  
 MRI and electrophysiology.  
investigation

investigation  
 The investigation of choice is (MRI)  
 High signal-intensity lesions on MRI indicate a poor prognosis. 
 nerve conduction studies to assess the degree of nerve damage .  
 Initially conservative measures such as regular activity, physiotherapy and addressing risk 
factors should be instigated.  
 cervical collar should not be used.  
 Analgesia, anti-inflammatories and tricyclic antidepressants can be helpful.

 Indications for surgery include progressive neurological defects, compression of the cervical 
nerve root and/or spinal cord and intractable pain.  
 Decompression improves neurologic function in some patients and prevents worsening in 
others, but there are significant risks.  
 Epidural injection can be considered where surgical intervention is not an option. 
 Patients will usually improve with time, and surgical intervention is needed in less than 5 % of 
patients.

patients. 
 In general, progression of cervical spondylosis is slow, although 10% develop chronic neck pain. 
Dupuytren ’s contracture.  
  progressive painless contracture of the palmar facial bands, causing flexion deformities of the 
fingers.  
  autosomal-dominant  condition with variable penetrance.  1123

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  95 
 Prevalence 
 has a male : female predominance of 10:1.  
 prevalence rates approaching 25% in elderly Scandinavians.  
 most commonly observed in persons of Northern European descent and affects 4-6% of 
Caucasians worldwide.  

 fibroblast proliferation , and collagen deposition leading to contractures of the palmar fascia. 
 Interleukin 1  (IL-1) is the most abundant cytokine  
 Normal palmar fascia is primarily composed of type I collagen; Dupuytren disease is a ssociated 
with an increase in type III collagen . 
Risk factor: 
 Alcoholism (10%) ,  
 diabetes mellitus  ( 8%).  
 previous myocardial infarction,  
 hand trauma,  
 HIV infection,  
 cigarette smoking.

 cigarette smoking.  
Features 
 bilateral in 45% ;  
 in unilateral cases, the right side is more often affected.  
 The ring finger is most commonly involved, followed by the fifth digit an d then the middle finger. 
The index finger and the thumb are typically spared. 
 Penile fibromatosis (Peyronie's disease) is seen in about 7-10% of patients. 
 
Rheumatoid arthritis seems to protect against the development of Dupuytren disease. 
 
 Surgery followed by physiotherapy to improve finger function is the recommen ded course of 
action.  
 Collagenase therapy may be an alternative to surgery in some cases. 
 
Ledderhose disease  is involvement of the plantar fascia by a similar process of nodule and cord 
formation leading to contraction of the toes .  
Costochondritis  
 has a higher prevalence in women 
 commoner over the age of 40 years.

 commoner over the age of 40 years.  
 It is associated with tenderness over the costochondral junctions and/or sternum , pain on 
coughing and deep breathing, and equal involvement with both sides of the che st.  
 Non-steroidals would be an appropriate first line intervention for pain relief.  
1124

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  96 
Multicentric reticulohistiocytosis  
 Multicentric reticulohistiocytosis is a rare non-Langherhan ’s cell histiocytosis with skin and joint 
 Nearly all organs can be involved.  
 Association with cancer occurs in about 25% of cases.

 Association with autoimmune diseases has also been recorded.  
 The characteristic nail fold nodules  of multicentric reticulohistiocytosis have the appearance of 
‘coral beads ’. Nodules may be numerous, may grow to as large as 2 cm, and may involve 
 Hand radiograph shows erosive changes in multiple joints . Distal interphalangeal erosions are 
characteristic and may lead to pseudo-widening of the joint spaces.

 Microscopic examination shows a histiocytic nodular infiltrate made of giant cells with ground-
glass appearance and periodic acid-schiff (PAS) positive cytoplasm.  
 
 characteristic nail fold nodules of multicentric 
reticulohistiocytosis 
Relapsing polychondritis (RP)  
 inflammatory condition that involves cartilaginous structures, predominantly those of the 
pinna, nasal septum and larynx.

pinna, nasal septum and larynx.  
 most common in the fifth decade.  
Feature 
 General symptoms include : intermittent fever and weight loss  
 other more specific symptoms include:  
 sudden onset of ear pain  with an inability to sleep on the affected side, diminished hearing,  
 monoarthritis or polyarthritis, back pain, myalgias,  
 mild epistaxis, saddle-shaped nose,  
 redness of the eyes indicative of conjunctivitis, episcleritis and/or scleritis,

 hoarseness of the voice  and recurrent respiratory infections.  
 patient may presents with symptoms suggestive of tracheal involvement and is at risk of 
developing tracheomalacia. 
 The most appropriate next investigation is a flow–volume loop , which might 
show a truncated expiratory limb that is characteristic of tracheomalacia, as well as 
provide information on the severity of the disease.  
 no specific diagnostic laboratory findings

 no specific diagnostic laboratory findings  
 the non-specific indicators of inflammation (ESR, CRP) are often elevated. 
  It is important in these patients to investigate for the presence of other concurrent 
autoimmune diseases. 
Treatment 
 systemic corticosteroids. 
 
1125

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  97 
Baker cyst  
 
Look for a patient with osteoarthritis or rheumatoid arthritis with a swollen calf. A ruptured Baker ’s 
cyst is a “pseudophlebitis. ” Unruptured cysts can be palpated.

 A Baker ’s cyst (popliteal cyst) is a posterior herniation of the synovium of the knee. 
 A Baker cyst is the most common mass in the popliteal fossa.  
 Since the cyst is an extension from the knee joint, it is lined by synovium.  
Causes 
 the most common cause  osteoarthritis 
 Gout 
 Reiter's syndrome 
 Psoriasis 
 Systemic lupus erythematosus 
 Internal derangement (meniscal tears, anterior cruciate ligamaent (ACL) tears, osteochondr al 
fractures)

fractures) 
 Infection (septic arthritis, tuberculosis) 
 Chronic dialysis 
 Hypothryroidism 
 Pigmented villonodular synovitis 
 Sarcoidosis 
 Ultrasonography  is the imaging technique of choice in the evaluation of a popliteal mass, but 
using this technique it may be difficult to show a true connection with the joint space to est ablish 
a definitive diagnosis of popliteal cyst.  
complication

complication   
 The most common complication  is rupture or dissection of fluid into the adjacent proximal 
gastrocnemius muscle belly which results in a syndrome mimicking the symptoms of a dee p vein 
thrombosis.  
 Doppler ultrasonography will, however, show the vascular lumen to be compressible (the lu men 
is not compressible in deep vein thrombosis due to the presence of the thrombus).  

Familial Mediterranean Fever (FMF) also known as recurrent polyserositis)  
 FMF is an autoinflammatory disease  
 caused by  mutations in  Mediterranean fever (MEFV)  gene, which encodes  a protein 
called pyrin .  
 The MEFV  gene  is located on  the short arm of chromosome 16  
 typically presents by the second decade.  
 more common in people of Turkish, Armenian and Arabic descent  
Features  - attacks typically last 1-3 days

Features  - attacks typically last 1-3 days  
 pyrexia 
 abdominal pain(95%) (due to peritonitis) 
 pleurisy  pericarditis 
 arthritis 
 erysipeloid rash on lower limbs 
Diagnosis 
 ↑acute phase response, ↑C-reactive protein, ↑WBCC and other markers of inflammation.  
 In patients with a long history of attacks, monitoring the kidney function is of importa nce in 
predicting chronic kidney failure. 
 genetic test to detect mutations in the MEFV gene.

 A specific and highly sensitive test for FMF is the "Metaraminol Provocative Test (MPT)," 
whereby a single 10 mg infusion of Metaraminol is administered to the patient. A positive  
diagnosis is made if the patient presents with a typical, albeit milder, FMF attack within 48 ho urs.  
 Attacks are self-limiting, and require analgesia (NSAIDs)   1126

Notes & Notes  for  MRCP                                                                                               By Dr. Yousif  Abdallah Hamad  98 
  Colchicine is most effective in preventing attacks of and preventing the development of 
amyloidosis in FMF.  
 anakinra is indicated in those who do not respond to colchicine. 
 Anakinra  is a drug used to treat rheumatoid arthritis. It is an interleukin 1 (IL1) receptor 
antagonist. 
 1127

Haematology & Oncology 
 
Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   1 
  
By
 
Haematology
 
&
 
Oncology
 
Updated
 
2017
 
Cont ains:  
1/ Passmedicine 2017    
2/ on examination 2017  
3/ pastest 2017 
4/Red fonts: previous exams 
5/ Other updated UK sources  
 
 1128

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   2 
  
Haematological changes during pregnancy  
 Platelet  
 Isolated thrombocytopenia 
 occur in 8%  
 Usually mild with platelet above 70  
 Occur due to presence IgG antibodies , which are reactive to platelet 
 No intervention  , recover after delivery   
_______________________________________________________

Hyposplenism 
Causes 
 splenectomy 
 coeliac disease, dermatitis herpetiformis 
 Graves' disease 
 amyloid 
Features 
 Howell-Jolly bodies 
 siderocytes 
Eosinophilia 
Causes of eosinophilia may be divided into pulmonary, infective and other 
Pulmonary causes  
 asthma 
 allergic bronchopulmonary aspergillosis 
 Loffler's syndrome

Infective causes 
 schistosomiasis 
 nematodes: Toxocara, Ascaris, Strongyloides 
 cestodes: Echinococcus 
 drugs: sulfasalazine, nitrofurantoin 
 psoriasis/eczema 
 eosinophilic leukaemia (very rare) 
Lymphopenia 
Causes 
 common finding in elderly patients.

Causes 
 common finding in elderly patients.  
 If greater than 0.5 * 109/l no action is normally needed 
 immunosuppresive drugs e.g. methotrexate 
 viral infections e.g. HIV 
 non-viral infections e.g. tuberculosis, malaria 
 autoimmune disorders e.g. rheumatoid 
 
 1129

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   3 
 Blood films: pathological cell forms 
Pathological red cell forms  
 
Abnormality Associated condition(s) Appearance 
Target cells Sickle-cell/thalassaemia 
Hyposplenism  
Liver disease 
 
'Tear-drop' 
(Dacrocyte) 
poikilocytes Myelofibrosis 
(The morphology results 
because RBCs are

because RBCs are 
mechanically  squeezed out 
of the bone marrow.) 
 
Spherocytes Hereditary spherocytosis 
Autoimmune hemolytic 
anaemia 
 
Basophilic 
stippling Lead poisoning  
Thalassaemia 
Sideroblastic anemia 
Myelodysplasia 
 
Howell-Jolly 
bodies Hyposplenism 
 
(Howell-Jolly bodies are the 
basophilic remnants of the 
RBC nucleus .) 
 
1130

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   4 
 Abnormality Associated condition(s) Appearance 
Heinz bodies G6PD deficiency 
Alpha-thalassaemia 
 
Schistocytes 
('helmet cells') Intravascular haemolysis 
Mechanical heart valve 
Disseminated intravascular 
coagulation 
 
'Pencil' 
poikilocytes Iron defiency anaemia 
 
Burr cells 
(echinocytes) Uraemia

Burr cells 
(echinocytes) Uraemia  
Pyruvate kinase deficiency 
liver disease 
 
Acanthocytes  Abetalipoproteinemia  
 
 (irregularly distributed spicule in 
1131

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   5 
red blood cells).  
Bite cell 
(Degmacyte) G6PD 
(when spleen removes heinz 
bodies from RBCs ) 
 
Blood films: typical pictures 
Hyposplenism e.g. post-splenectomy 
 target cells 
 Howell-Jolly bodies

 These are spherical bluish inclusions within erythrocytes 
 They  are nuclear fragments of condensed DNA which are normally removed by the 
spleen. 
 They are seen in severe haemolytic anaemias or in hyposplenic/asplenic patients. 
 Pappenheimer bodies 
 siderotic granules 
 acanthocytes 
 'pencil' poikilocytes 
 if combined with B12/folate deficiency a 'dimorphic' film occurs with mixed microcytic an d

macrocytic cells 
Myelofibrosis 
 'tear-drop' poikilocytes 
Intravascular haemolysis 
 schistocytes 
Megaloblastic anaemia 
 hypersegmented neutrophils 
 
Congenital Pelger –Huet anomaly  
 is a laminopathy associated with mutations in the lamin B receptor.  
 This leads to bilobed nuclei in neutrophils  and in homozygotes,  
 can also be associated with: 
  skeletal abnormalities which include shortened limbs.

 Like this patient, heterozygotes usually suffer no symptoms and the neutrophil  anomaly is 
picked up as an incidental finding.   
 
MRCP part- 1 – jan 2017 
A 23-year-old man with tiredness and was noted to have a neutrophil abnormality on his blood film 
with bilobed nuclei . His father has a skeletal anomaly with a short right arm, Examination reveals no 
lymphadenopathy, and abdominal examination is entirely normal. What is t he most likely diagnosis?   1132

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   6 
  Congenital Pelger –Huet anomaly  
 
Leucocyte alkaline phosphatase 
Raised in Low in 
 myelofibrosis 
 leukaemoid reactions 
 infections 
 steroids, Cushing's syndrome 
 pregnancy, oral contraceptive pill  chronic myeloid leukaemia 
 pernicious anaemia

 pernicious anaemia 
 paroxysmal nocturnal haemoglobinuria 
 
Leukaemoid reaction 
 The leukaemoid reaction describes the presence of immature cells such as myeloblasts, 
promyelocytes and nucleated red cells in the peripheral blood. This may be due to inf iltration of 
the bone marrow causing the immature cells to be 'pushed out' or sudden dema nd for new cells 
 
Causes  
 severe infection 
 severe haemolysis 
 massive haemorrhage

 massive haemorrhage 
 metastatic cancer with bone marrow infiltration 
 
Differentiating chronic myeloid leukaemia from a leukaemoid reaction:  
Chronic myeloid leukaemia Leukaemoid reaction  
low leucocyte alkaline phosphatase score 
  high leucocyte alkaline phosphatase score 
 toxic granulation (Dohle bodies) in the white cells 
 'left shift' of neutrophils i.e. three or less 
segments of the nucleus 
 
Coagulation study 
Prothrombin time (PT)

Prothrombin time (PT) 
 Prothrombin time (PT) is a measure of the time it takes for the extrinsic pathway to create a fibrin  
clot.   
 tests function of factors (I, II, V, VII, X) 
 defect in any of these ĺ Ĺ PT  
 e.g. vitamin K deficiency  
 best test to follow warfarin therapy  
 normalized as an INR (international normalized ratio) 
 note also increases PTT time

 note also increases PTT time 
 also used to measure hepatic function as most of the factors are synthesized in the  liver Used to 
monitor the extrinsic pathway 
 Factors make up the extrinsic pathway: 
 Damaged endothelium ĺ tissue factor release ĺ Factor VII activation ĺ common 
pathway activation 
 In patients with vitamin K deficiency, the PT is typically prolonged while the partial 
thromboplastin time (PTT) is usually normal.

thromboplastin time (PTT) is usually normal.  
 Long -term use of antibiotics  changes in the gut flora  vitamin K deficiency   ↑PT   
 Long -term use of antibiotics (particularly cephalosporins like cefepime) would cause 
changes in the gut flora that result in vitamin K deficiency (due to decreased populat ions 
of the bacteria that synthesize it).  
 vitamin K deficiency would impair the gamma-carboxylation of factors II, VII, IX, and 
proteins C and S.

proteins C and S.  
 As a result, the  PT, which measures the clotting time of the extrinsic pathway  (starting 
with tissue factor and factor VII), would increase , just as it would in a patient on warfarin. 
Partial Thromboplastin Time (PTT) (sometimes also called Activated Partial Thromboplastin Time)   
 tests function of all factors EXCEPT (VII, XIII) 1133

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   7 
  defect in any of theseĺ Ĺ PTT  
 when prolonged indicating hemophilia or (sometimes) von Willebrand ’s Disease.  
 best test to follow heparin therapy  
 note also increases PT time  
 Used to monitor the intrinsic pathway  
 Factors make up the intrinsic pathway: 
 Factors XII, XI, IX, VIII.

 Factors XII, XI, IX, VIII. 
 elevated APTT could be due to: 
 treatment with heparin 
 haemophilia 
 von Willebrand's disease, or 
 antiphospholipid syndrome. 
 
The commonest cause of reduced  APTT  is  in-vitro clotting cascade activation , but tests 
should be repeated to exclude pathological causes of hypercoagulability. 
 
DIC vs TTP  
 DIC is distinguished from thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic 
syndrome (HUS) based on coagulation studies.

syndrome (HUS) based on coagulation studies.  
 Although TTP and HUS are also microangiopathic hemolytic anemias, patients with these 
conditions do not have derangement or consumption of clotting factors.  
 DIC  Increased PT, PTT, decreased platelets  
 TTP & HUS     normal PT, normal PTT, and decreased platelets.  
Isolated factor deficiency 
 Normal PT, increased PTT , and normal platelets suggests an isolated factor deficiency such as

hemophilia A and B, in which there is a deficiency of factors VIII and IX, respectively.  
 An isolated elevated PTT may also suggest von Willebrand's disease. 
 
1134

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   8 
  
Giant platelet syndrome (Bernard-Soulier syndrome; BSS) 
 is a defect in platelet adhesion.  
 The genetic defect is in glycoprotein 1b (GP1b).  
 characterized by increased megakaryocytes and abnormally large platelets on peripheral 
smear, hence its name.

smear, hence its name.  
 thrombocytopenia and an elevated bleeding time but a normal prothrombin time (PT) 
and partial thromboplastin time (PTT). 
 BSS can be distinguished from a deficiency in von Willebrand factor (vWF) b y a ristocetin 
test.  
 Ristocetin is an antibiotic that causes vWF to bind to GP1b, causing agglutination in 
normal blood.  
 In patients with either defective vWF or GP1b (BSS), platelets do not aggregate in the 
presence of ristocetin.

presence of ristocetin.  
 The addition of normal plasma corrects this defect in von Willebrand's disease, bu t not 
in BSS (because the platelet receptor remains defective). 
 
Bone marrow sampling 
 There are two types of sample that are typically taken: an aspirate and a treph ine biopsy. The 
aspirate just looks at the cells whereas a trephine biopsy shows the structure of the bone 
marrow.

marrow. 
 It is typically performed to investigate the possiblity of bone marrow involvement in leu kaemia, 
lymphoma and myeloma.   
 
Assessment of anaemia  
 
From BMJ best practice   
 
Iron metabolism  
  
Absorption:  
 Upper small intestine.  
 About 10% of dietary iron absorbed.  
 Fe2+ (ferrous iron) much better absorbed than Fe3+ (ferric iron).  
 Absorption is regulated according to body's need.  
 Increased by vitamin C (ascorbic acid ) and gastric acid.  
1135

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   9 
  vitamin C aids iron absorption  by reducing iron from the ferric to the ferrous form, and 
by chelating it into a complex which enhances absorption. 
 Decreased by PPIs, tetracycline, gastric achlorhydia, tannin (in tea).  
 From an intake of approximately 6 mg/1000 kcal of dietary iron only 15% is bioavailable.

Distribution in body 
 Total body iron = 4g (2500 mg in the RBCs, 500 mg in liver, 500 mg in macrophages a nd about 
500 mg in muscle).  
 Haemoglobin = 70%  
 Ferritin and hemosiderin = 25%  
 Myoglobin = 4%  
 Plasma iron = 0.1%  
 Approximately 4 mg of iron circulate within the plasma. So approximately 0.1% of body 
iron circulates in the plasma.  
Transport  
 Carried in plasma as Fe3+ bound to transferrin.  
Storage   
 Stored as ferritin in tissues.

Storage   
 Stored as ferritin in tissues.  
 It is the plasma protein responsible for binding iron,  
 is an acute phase reactant protein which is increased in inflammatory conditions. 
Excretion  
 The majority of iron contained within the RBCs is metabolised and re-utilised but 1 mg  per day is 
lost through the gut. 
 
Transferrin  
 serum transferrin is the bus that carry absorbed iron to storage places & stored as ferritin.

transferrin saturation is the % of people [iron] carried by that bus [transferrin]. 
 TIBC is the no. of empty chairs in that bus. 
 
 Transferrin is a glycoprotein responsible for internal iron exchange 
 Iron (Fe 3+)  is carried in the blood bound to transferrin .   
 Fe2+ (ferrous iron) is oxidised to Fe3+ (ferric iron) by caeruloplasmin to bind to 
transferrin  
 Transferrin is the binding protein of iron. So when the levels of ferritin are low, the bod y signals

the liver to synthesize more of Transferrin to maintain the levels of iron  
 Pregnancy and oral contraceptive pill (OCP) both increase transferrin.  
 Transferrin saturation %  
1136

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   10 
  The transferrin saturation % (plasma iron /TIBC x 100) is used as a measure of iron 
stores.  
 In absence of anaemia, transferrin is about 33% saturated with iron (about one th ird 
saturated with iron) .  
 A value below 16% is indicative of iron deficiency.

 iron deficiency  low serum Fe, rise TIBC, rise the transferrin level.  
 iron overload   fall in both TIBC and transferrin   
 haemochromatosis   increased in Transferrin saturation%  
 the content within mucosal cells is naturally high in haemochromatosis with high iron store 
saturation.  
  in haemochromatosis TIBC is low because transferrin is FULL of iron and no more e mpty 
space, hence LOW TIBC and for the same reason transferrin saturation is high [ FULL] 
 
Iron studies

Iron studies  
 Serum iron  
 Total iron binding capacity (TIBC)  
 Transferrin 
 raised in iron deficiency anaemia (IDA) 
 raised in pregnancy and by oestrogen 
 Transferrin saturation 
 calculated by serum iron / TIBC 
 Ferritin 
 raised in inflammatory disorders 
 low in IDA 
 Rarer tests 
 transferrin receptors  increased in IDA 
 Anaemia of chronic disease 
 normochromic/hypochromic, normocytic anaemia 
 reduced serum and TIBC 
 normal or raised ferritin

 normal or raised ferritin 
Iron deficiency anaemia (IDA) 
 iron deficiency is the most common cause of anemia worldwide.  
Causes 
 the commonest cause of iron-deficiency anaemia worldwide being hookworm inf ection ( Necator 
americanus  and Ancylostoma duodenale ), which affects 25% of the global population. 
 microcytic anaemia in a female should raise the possibility of either gastrointestinal blood loss or 
menorrhagia. 
Features

Features 
 Koilonychia (spoon-shaped nails) 
 atrophic glossitis 
 post-cricoid webs 
 Plummer-Vinson syndrome (dysphagia, esophageal webs and iron deficiency)  
 other cutaneous manifestations of iron deficiency include: 
 pruritus,  
 dry and brittle hair  
 the hair, skin, nail and mucous membrane changes are often visible before the  
patient is clinically anemic. 
 angular stomatitis 
 Blood film 
 target cells 
 'pencil' poikilocytes

 'pencil' poikilocytes 
 if combined with B12/folate deficiency a 'dimorphic' film occurs with mixed microcytic and 
 Serum ferritin 
 Hypoferritinaemia confirms IDA and is the preferred screening test . 
 the most sensitive marker for iron deficiency 1137

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   11 
  Ferritin is an acute phase reactant and may be grossly elevated in the context of 
acute inflammation (when it does not accurately reflect iron stores) and to a lesser 
degree in chronic inflammation. 
 British Society Guidelines on the diagnosis and management or iron 
deficiency anaemia suggest that:

deficiency anaemia suggest that: 
 a cut-off of 12-15 mg/L reflects iron deficiency in the absence of 
inflammation.  
 Where inflammation is present a ferritin of 50 mg/L or more may still 
be compatible with iron deficiency. 
Treatment of IDA 
Iron tablet preparations 
 Among the tablet preparations, there are: 
1. non-enteric coated pills  
 most commonly used as initial treatment due to their lower cost. 
2. enteric-coated  
3. prolonged-release formulations.

3. prolonged-release formulations. 
 Delayed release and enteric-coated iron are better tolerated than the non-enteric 
coated tablets.  
 less effective since they may contain less iron and their iron may not be released in 
the duodenum, where iron is absorbed. 
 patients who have been treated unsuccessfully with enteric-coated and prolon ged-
release iron preparations may respond well to the administration of nonenteric-
coated ferrous salts

coated ferrous salts   
 Ferrous sulphate  has more elemental iron by mass than the same dose of ferrous gluconate 
 Sustained release preparations  may improve tolerance of oral iron but do not aid absorption. 
 
Iron prescription 
 Ideally, patients should not take iron supplements within 1-2 hours of antacids  alkaline 
environment reduces absorption (acidity required  for iron solubility) 
 Iron tablets are recommended between meals or at bedtime  to avoid the alkalinizing effect of

food and to take advantage of the peak gastric acid production late at night. 
 calcium, phosphorus and magnesium salts contained in iron-containing multivitamin pil ls impair 
absorption of elemental iron. For this reason, multivitamin preparations should never be 
recommended as a sole therapy for iron deficient anemia.  
 Iron absorption is also delayed with tetracyclines, milk, and phosphate-containing, carbona ted 
beverages such as soft drinks.

beverages such as soft drinks. 
 Iron replacement in chronic renal failure  
 In chronic renal failure, Erythropoeitin (EPO) therapy is only considered in pateints where 
the ferritin is >l00 mg/1.  
 If ferritin < 100  iron replacement is the initial intervention of choice.  
 
 IV iron  
 Parenteral iron acts no faster than oral iron. It is indicated when oral iron cannot be 
tolerated or is not absorbed. 
 Indications for IV iron include:  
 unable to tolerate orally,

 unable to tolerate orally,  
 Patients who fail to comply with prescriptions for oral iron supplementation.  
 A history of exertional angina  with anaemia  strongest indication for 
transfusion 
 GIT disorders, such as IBD (ulcerative colitis and Crohn's disease), in which 
symptoms may be aggravated by oral iron therapy 
 Iron is poorly absorbed from the GI tract in patients with renal failure, as 
such  IV replacement is the modality of choice .

such  IV replacement is the modality of choice . 
 It is considered best practice to administer 1000 mg of low molecular weight iron dextran 
in 250 mL of normal saline in 1 hour without premedication;  
 a test dose of 10 to 25 mg is infused over 3 to 5 minutes prior to the first infusion.    
 If no acute reaction is observed, the remaining solution is infused over the balance of 1  
hour.   
 For those with a history of drug allergies or hypersensitivity, 125 mg of methylprednisolone

is infused prior to the test dose. 
British society of gastroenterology (BSG) guidelines 2011: 1138

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   12 
  correct anaemia and replenish body stores achieved most simply and cheaply with ferrous 
sulphate 200 mg twice daily. 
 Lower doses may be as effective and better tolerated and should be considered in p atients not 
tolerating traditional doses.

tolerating traditional doses. 
 Other iron compounds (eg, ferrous fumarate, ferrous gluconate) or formulations (iron 
suspensions) may also be tolerated better than ferrous sulphate .  
 Oral iron should be continued for 3 months after the iron deficiency has been corre cted so that 
stores are replenished.   
 Ascorbic acid (250e500 mg twice daily with the iron preparation) may enhance iron abs orption 
 Iron treatment should follow transfusion to replenish stores.

Anemia of Chronic Disease  
 decreased RBC production due to any longstanding  inflammatory, infectious, or m alignant 
disease (includes rheumatoid arthritis, severe trauma, heart disease, diabetes mellitus, and 
inflammatory bowel disease) 
Mechanism of Anemia of Chronic Disease 
 there is primarily a decreased availability of iron, relatively decreased levels of erythrop oietin,

and a mild decrease in the lifespan of RBCs to 70-80 days (normally 120 days) 
 in anemia of chronic kidney disease, ↓erythropoietin production by the interstitial 
fibroblasts, (also known as type I interstitial cells) ,  anemia.  
 The kidneys are responsible for approximately 90% of erythropoietin production. 
 Increase in hepcidin  level in the course of inflammatory disease Ļrelease of iron from 
macrophages + ↓dietary iron absorption.

macrophages + ↓dietary iron absorption. 
 hepcidin is an acute-phase reactant that is increased in states of inflammation 
 cytokines, such as interleukins (IL-1 and IL-6), and tumor necrosis factor (TNF-alpha),  
destruction of RBC precursors and decrease the number of erythropoietin receptors on 
progenitor cells. 
 RBCs morphology 
 normochromic, normocytic anemia. 
 Reticulocyte count

 Reticulocyte count 
 ↓reticulocyte count points to ĻRBC production as the primary mechanism responsible for 
anemia,  
 Ĺ ferritin  
 Ļ serum iron 
 Ļ TIBC, transferrin saturation, and MCV 
Treatment 
 treatment of the underlying disease.  
 If underlying disease is unknown or treatment of underlying disease does not improve 
symptomatic anemia 
 measure EPO 
 if low, administer EPO or erythropoiesis-stimulating agents (ESAs) 
 make sure iron stores are sufficient

 make sure iron stores are sufficient  
 if insufficient, patients may be resistant to EPO 
 if normal, give packed RBCs 
_______________________________________________________  
Hepcidin  
 Hepcidin, a peptide hormone synthesized in the liver .  
 reduces extracellular iron in the body by several mechanisms: 
1. lowers dietary iron absorption by reducing iron transport across gut mucosal cells 
(enterocytes); 
2. reduces iron exit from macrophages, the main site of iron storage;

3. reduces iron exit from the liver. In all three instances this is accomplished by reducing the 
transmembrane iron transporter ferroportin. 
 inflammation Ĺhepcidin  Ļserum iron due to: 
 iron trapping within macrophages and liver cells  1139

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   13 
  decreased gut iron absorption.  
 inadequate amount of serum iron being available for developing red cells anemia 
 hemochromatosis Ļhepcidin level  iron overload due to: 
 increased ferroportin  mediated iron efflux from storage and increased gut iron 

 Hepcidin inhibits iron transport by binding to the iron export channel ferroportin  which is located 
on the basolateral surface of gut enterocytes and the plasma membrane of macr ophages. 
  Inhibiting ferroportin leads to: 
 Ļ iron release from macrophages  
 Ļ dietary iron absorption. 
Thalassaemias  
Alpha is located on 16, beta on 11chromosome .

Alpha is located on 16, beta on 11chromosome . 
 
 The thalassaemias are a group of genetic disorders characterised by a reduced production rate 
of either alpha or beta chains. 
 It is a haemoglobinopathy resulting from defective synthesis of globin chains required for Hb 
synthesis.  
 Each copy of chromosome 16  has two genes for the alpha globin  subunit ( four in total ).  
 And each copy of chromosome 11  has one genes for the beta globin  subunit ( two in total ).

Types of haemoglobin 
Haemoglobin  Chains  % Hb in normal adult  
Hb A α2ȕ2 ( (two alpha and two beta chains)  97% 
Hb A 2 α2δ2 (two alpha and two delta chains)  < 3.5% 
Hb F α2Ȗ2 (two alpha and two gamma chains) <1% 
 
 Alpha-thalassaemia is due to a deficiency of alpha chains in haemoglobin 
 Alpha-thalassaemia is found in malarial regions of the world (Mediterranean, So uth-east Asia,

Indian sub-continent, Middle East, Sub-Saharan Africa) and should be suspe cted in patients with 
these ethnic backgrounds and with microcytosis and/or anaemia. 
 Acquired Hb H disease is rare and occurs most commonly in male patients with myelodysplastic 
syndrome. 
 
Overview  
 2 separate alpha-globulin genes (four in total) are located on each chromosome 16  
 There are 4 different alpha-thalassaemias:  
1. silent carrier  (1 affected alpha-globin gene),

2. alpha-thalassaemia trait  (2 affected alpha-globin genes),  
3. Hb H disease  (typically 3 affected alpha-globin genes) 
4. Hb Bart hydrops fetalis syndrome  (typically deletion of all 4 alpha-globin genes).  
 Clinical severity depends on the number of alpha chains present 
 If 1 or 2 alpha chains are absent  then the blood picture would be hypochromic  and 
microcytic , but the Hb level would be typically normal  
 Loss of 3 alpha chains results in a hypochromic microcytic anaemia with

splenomegaly and HbH in red cells . This is known as Hb H disease  
 If all 4 alpha chains absent (i.e. homozygote) then death in utero (hydrops fetalis, Bart's 
hydrops) 
  Persistence of HbF has survival advantages in severely affected subjects.  
 Co-inheritance of alpha-gene mutations, and persistence of fetal haemoglob in production, may 
restore the globin balance and result in a milder syndrome.  
 Features 
 most are asymptomatic.

 Features 
 most are asymptomatic.  
 Many patients with Hb H are also clinically well, but are at risk for:  
 acute haemolytic episodes 
 aplastic crises 
 iron overload, even in the absence of chronic transfusions 
 hypersplenism; and  
 endocrine disease. 1140

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   14 
  Hemoglobin gel-electrophoresis 
 α-thalassemia trait  normal 
 3 gene deletion α -thalassemia  HbH (ȕ,ȕ,ȕ,ȕ)  
 4 gene deletion α-thalassemia  Hb Barts (Ȗ,Ȗ,Ȗ,Ȗ)  
Beta-thalassaemia

Beta-thalassaemia 
 
If a person has MCV > 80  and MCH > 27 , in the absence of symptoms , thalassemia can be 
reasonably excluded.  
 
 Beta-thalassaemias are due to mutations in the HbB gene on chromosome 11  
 autosomal recessive   
 β thalassaemia minor / trait   protects against malaria  
 Ĺ(Hb F)   inhibits the development of the malarial parasite. 
Types 
 ȕ thalassaemia major  (ȕ 0):  
 prevent any formation of ȕ chains,  
 the most severe form of ȕ thalassemia.

 the most severe form of ȕ thalassemia.  
 2 gene depletion (ȕ0ȕ0)  (α,α,α,α hemoglobin  present) 
 HbF tries to convert to HbA during first year of life,  
 extramedullary haemopoiesis with hepatosplenomegaly and bone marrow e xpansion, 
“hair on end ” appearance of bone.  
 Features 
 anaemia  
 splenomegaly  
 occurs secondary to extramedullary hematopoiesis. 
 bone deformities  
  bone marrow expansion can cause "chipmunk facies" or "crew cut sign" on 
a skull X-ray.

a skull X-ray. 
 early death if not treated appropriately. 
 Treatment :  
 The recommended treatment for thalassaemia major involves lifelong regular blood 
transfusions, usually administered every two to five weeks , to maintain the 
pretransfusion haemoglobin level above 9 –10.5 g/dl . 
 transfusion programme with iron chelation is the best initial approach. 
 Indications for transfusion 
 Hb < 7g/dl on 2 occasions, > 2 weeks apart (excluding all other contributory

causes such as infections) or 
 Hb > 7g/dl with: Facial changes , Poor growth , Fractures, and 
Extramedullary haematopoiesis 
 The transfusional iron overload  can be managed with iron chelation, both IV/S C 
(desferrioxamine) and/or oral (deferasirox). 
 Desferrioxamine binds iron but needs to be given for 8-12 hours a day for 5-
7 days per week, so is a major undertaking for the patient.  
 SE: high frequency deafness, retinopathy and Yersinia infection.

 Stem cell transplantation options offer cure. 
  parents and other siblings should be screened by genetic testing. 
 
 ȕ thalassaemia intermedia  (ȕ+): 
 caused by a mutation in the Kozak consensus sequence of the Beta globin gene on 
chromosome 11.  
 they allow some ȕ chain formation to occur.  
 In either case there is relative excess of α chains, but these don’ t form tetramers.  
 ȕ thalassaemia minor / trait:   
 1 gene deletion 
 Features  
 usually asymptomatic  
1141

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   15 
  mild hypochromic, microcytic anaemia  - microcytosis is characteristically 
disproportionate to the anaemia  (marked microcytosis (very low MCV) (i.e. the 
Microcytosis is disproportionately with very low MCV for the near normal Hb level 
>9).   
 HbA2 raised (> 3.5%)

>9).   
 HbA2 raised (> 3.5%) 
 HbA2 levels above 3.5% are screening criteria for the ȕ -thalassemia 
carrier state.  
 Note that in cases of severe iron deficiency anaemia the HbA2 may be 
normal in thalassemia minor. 
 
 Thalassemia can co-exist with other haemoglobinopathies. The most common of the se are:  
 HbE/thalassaemia:   
 common in Cambodia, Thailand, and parts of India 
 clinically similar to ȕ thalassaemia major or thalassaemia intermedia. 
 HbS/thalassaemia:

 HbS/thalassaemia:   
 common in African and Mediterranean populations  
 clinically similar to sickle cell anaemia with additional feature of splenomegaly.  
 HbC/thalassaemia:  common in African and Mediterranean populations:  
 HbC/ȕ0 thal assaemia:  causes moderate to severe haemolytic anaemia with 
splenomegaly. 
 HbC/ȕ+ thalassaemia:  produce a milder disease. 
 
Delta thalassaemia

Delta thalassaemia 
 about 3% of adult Hb is made of alpha and delta chains.  
 mutations can occur which affect the ability of this gene to produce delta chains.  
Aplastic anaemia  
 Characterised by pancytopaenia and a hypoplastic bone marrow 
 Peak incidence of acquired = 30 years old 
Features  
 Assessment of bone marrow cellularity is best made on trephine biopsy , which often shows

replacement of the normal cellular marrow by fatty marrow.  
 normochromic, normocytic anaemia 
 leukopenia, with lymphocytes relatively spared 
 thrombocytopenia 
 may be the presenting feature acute lymphoblastic or myeloid leukaemia 
 a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelody splasia 
 In patients with aplastic anemia, the bone marrow is markedly hypocellular . 
Causes 
 congenital: Fanconi anaemia, dyskeratosis congenita

 drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold 
 toxins: benzene  
 infections: parvovirus, hepatitis 
Supportive 
 blood products 
 prevention and treatment of infection 
Anti-thymocyte globulin (ATG) and anti-lymphocyte globulin (ALG) 
 prepared in animals (e.g. rabbits or horses) by injecting human lymphocytes 
 is highly allergenic and may cause serum sickness (fever, rash, arthralgia), therefore steroid 
cover usually given

cover usually given 
 immunosuppression using agents such as ciclosporin may also be given 
Stem cell transplantation 
 allogeneic transplants have a success rate of up to 80% 
 
 1142

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   16 
 _______________________________________________________
Pure Red Cell Aplasia (PRCA)  
Overview 
 uncommon disorder  
 maturation arrest occurs in the formation of erythrocytes. Erythroblasts are virtually absent in 
bone marrow; however, white blood cell and platelet production are normal.

 The anemia due to PRCA is usually normocytic but can be macrocytic.   
Diagnosis  
 characteristics of PRCA include   
1. Severe unexplained anemia 
2. ĻReticulocyte count <1% 
3. The presence of less than 0.5% mature erythroblasts in the bone marrow 
4. Normocellular bone marrow in most cases 
Causes 
  most cases of chronic PRCA are idiopathic (acquired primary).   
 Secondary PRCA  associated with:

 Secondary PRCA  associated with:  
 Autoimmune disorders  (eg, type 1 diabetes, thyroiditis, rheumatoid arthritis, Sjögren 
syndrome)  
 Thymomas 
 Systemic lupus erythematosus 
 Hematologic malignancies 
 Solid tumors 
  Erythropoietin-induced pure red cell aplasia in treatment of CKD anaemia  
 
Treatment  
 can be transient and reversible (PRCA due to medications and infections are often re versible.)  
 symptomatic anaemia  transfusion  
 Treatment of underlying conditions

 Treatment of underlying conditions  
 parvovirus B19 infections  High-dose intravenous immunoglobin 
 PRCA due to drugs  disappear when the drug is stopped. 
 thymoma  thymectomy or gamma irradiation of the thymus 
 Immunosuppressive:  
 Corticosteroids are the mainstay of therapy (45% respond )   the first choice  
 cyclosporine,  azathioprine, Cyclophosphamide and rituximab are used 

Fanconi ’s Anaemia  
 Autosomal recessive  
 Aplastic anaemia  
 Ĺ risk of AML  
 Neurological manifestation  
 Skeletal abnormalities  
 Skin pigmentation (café; au lait spots) 
Macrocytic anaemia 
Macrocytic anaemia can be divided into causes associated with a megaloblastic bone marrow a nd 
those with a normoblastic bone marrow 
Megaloblastic causes Non-megaloblastic causes 
 folate deficiency

 folate deficiency 
  alcohol 
 reticulocytosis 
 myelodysplasia 
 drugs: cytotoxics 
 If serum folate levels are low, serum vitamin B12 and methylmalonic acid levels should be 
measured to exclude concurrent vitamin B12 deficiency before folate levels are correct ed.  
 Normal serum homocysteine levels make folate deficiency unlikely.

 RBC folate is a more accurate indicator of folate deficiency than serum folate level.  1143

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   17 
Vitamin B12 ( cobalamin ) deficiency  
Function of vitamin B12 deficiency 
 Red blood cell development 
 Maintenance of the nervous system.  
 B12 is necessary for normal folate metabolism, and therefore when there is a prim ary B12

deficiency, one can see a low red cell folate as a consequence. 
Sources 
 Vit B12 is only found in foods of animal origin e.g. meat, fish and eggs.  
 It is absorbed after binding to intrinsic factor (IF) (secreted from parietal cells in the stomach) and 
is actively absorbed in the terminal ileum.    
 A small amount of Vit. B12 is passively absorbed without being bound to IF.  
 Hepatic stores of vitamin B12 can last for up to 5 years , so it is not uncommon for vegans to

display vitamin B12 deficiency years after starting their diet  
Causes  
 Dietary deficiency of Vit B12: like vegetarians 
 An MCV of >115 fL is typically seen in nutritional deficiency. 
 very rare 
 Folate deficiency due to dietary problems is common, particularly in the elderly, but 
it does take many years to become B12 deficient  as a result of dietary 
 Pernicious anaemia  
 Post gastrectomy

 Post gastrectomy 
  A patient with  combined iron deficiency and B 12 deficiency ,  Which operation is he 
most likely to have had?  Partial gastrectomy  
 Disorders of terminal ileum (site of absorption): Crohn's, blind-loop,  Malabsorption of vitamin B-
12 secondary to small bowel bacterial overgrowth, tapeworm, etc. 
  Bacterial overgrowth syndrome 
 characterized by diarrhea, steatorrhea, and macrocytic anemia.

 The common feature is proliferation of colonic bacteria in the small bowel. In normal 
individuals, the small bowel is relatively sterile. 
 Common bacteria involved are E.coli or bacteroides.  
 Macrocytic anemia results from increased utilization of vitamin B12 by the colonized 
bacteria.  
 Steatorrhea is caused by reduced concentration of conjugated bile acids. Bacteroides  can 
convert conjugated bile acids to unconjugated bile acids, which result in impaired micelle 

 Diarrhea is due to steatorrhea. 
Features of vitamin B12 deficiency 
 Macrocytic anaemia  
 mild jaundice  is typical of megaloblastic anaemia (vitamin B 12 or folate deficiency) because of 
increased destruction of red cell precursors in the bone marrow. 
 Sore tongue and mouth  
 Neuropsychiatric symptoms: e.g. Ataxia, Mood disturbances  
 Neurological involvement can be present in B12 deficiency even in the absence of

anaemia, especially in patients over the age of 60 .  
 The peripheral nerves are most commonly involved, followed by subacute dege neration of 
the spinal cord.  
 Early signs are loss of peripheral vibration and joint position  sense , which is usually 
followed by loss of reflexes and weakness.  
 The legs and feet are usually more involved than the hands.  
 In the late stages there may be spasticity, upgoing plantars and ataxia but thankfully t his is 
rare in the UK.

rare in the UK. 
 Serum  methylmalonic acid  levels are elevated  in vitamin B12 deficiency.  
 more sensitive Serum vitamin B12 levels, and should be used to definitively exclude 
vitamin B12 deficiency. 
 elevated homocysteine  and methylmalonic acid levels. 
 Blood smear will show hypersegmented neutrophils. 
Treatment 
 even in case of profound  anaemia, if the patient is not haemodynamically compromised 
 no need for blood transfusion. 1144

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   18 
  intramuscular vitamin B 12 and oral folic acid.  
 Patient need to continue on treatment with ferrous sulphate as iron stores are likely to  be 
depleted rapidly once the marrow starts functioning. 
 Giving oral folic acid without vitamin B 12 would be hazardous and could precipitate subacute

combined degeneration of the spinal cord. 
Pernicious anaemia 
 more common in females (F:M = 1.6:1) 
 typically develops in middle to old age 
 more common if blood group A 
 autoimmune disease caused by antibodies to gastric parietal cells or intrinsic factor 
 results in vitamin B12 deficiency 
 associated with thyroid disease,  
 diabetes 
 Addison's 
 rheumatoid   
 vitiligo

 vitiligo 
 predisposes to gastric carcinoma 
Features 
 lethargy, weakness 
 dyspnoea 
 paraesthesia 
 mild jaundice  
 sore tongue 
 possible signs:  
 retinal haemorrhages, 
 mild splenomegaly,  
 retrobulbar neuritis 
 
Normal serum gastrin excludes  pernicious anaemia 
 
 anti-gastric parietal cell antibodies in 90% ( most common , but low specificity)

 anti-intrinsic factor antibodies in 50% ( specific  for pernicious anaemia) 
 macrocytic anaemia  
 pancytopenia  ( with low WCC and platelets) 
 LDH may be raised due to ineffective erythropoiesis 
 also low serum B12,  
 hypersegmented polymorphs on film, megaloblasts in marrow 
 Schilling test  
 radiolabelled B12 given on two occasions 
 first on its own 
 second with oral IF 
 urine B12 levels measured

 urine B12 levels measured 
 
 macrocytic anaemia and isolated B12 deficiency (folate is normal) suggest an isolated 
problem with B12 absorption  pernicious anaemia 
 If no neurological involvement: 1 mg of IM Hydroxocobalamin 3 times each week for 2 
weeks, then once every 3 months.   
 If a patient has deficient in both vitamin B12 and folic acid then it is important to treat the B12 
deficiency first to avoid precipitating subacute combined degeneration (SCD) of the cord.

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   19 
Sickle cell disease 
Overview 
 Sickle cell disease is a haemoglobinopathy caused by  the substitution of glutamic acid by 
valine at position 6 (from the N-terminal) of the beta chain. (In sickle cell anaemia, valine

replaces glutamic acid at the sixth amino acid of the beta globin) 
 HbS is caused by a single base mutation on the beta-chain  
 The β globin gene is found on the short arm of chromosome 11.  
HbS has the following properties:  
 contains two α -like globins and two β -like globins and four haem molecules.  
 less negatively charged, due to the loss of glutamate for valine.  
 has a life span of only 30 days compared to the normal 120 days. 
 less soluble than HbA.

 less soluble than HbA.  
 has lower affinity for oxygen than HbA (right-shift of the oxygendissociation curve), wh ich 
increases the risk of desaturation, but improves the yield of oxygen to the tissues. 
Types 
 Sickle cell trait: heterozygous (HbAS) 
  occurs when a child inherits a sickle gene from one parent and a normal gene from th e 
other parent.  
 Sickle cell disease: homozygous (HbSS) 
  occurs when a child inherits a sickle gene from each parent.

 Other, rarer forms of sickle cell disease in which the person has only one copy of the mutation  
that causes Hb S and one copy of another abnormal Hb allele. Examples: 
 “HbSC ”: (sickle –haemoglobin C disease). 
 “HbS/β+” : (sickle-beta-plus-thalassemia). 
 “HbS/β0”  : (sickle-beta-zero-thalassemia) 
Sickling of the erythrocyte 
 A low partial pressure of oxygen (PO 2) causes HbS to polymerise and precipitate resulting in 
sickling of the erythrocyte.

sickling of the erythrocyte.   
 HbSS patients sickle at PO 2 of 5-6 kPa  
 HbAS patients sickle at PO 2 of 2.5-4 kPa.  
 HbSC Sickling occurs at around 4 kPa . 
Sickle cell disease and malaria 
 Sickle cell trait (HbAS) is known to protect against falciparum malaria. As a result, the 
frequencies of sickle cell carriers are high in malaria-endemic areas. 
 Patients with HbSS are at higher risk of severe malaria with complications and have a h igher 
 
Feature

Feature 
 Black pigment gallstones occur in 50 %  of patients with sickle cell disease   
 due to an increase in bilirubin excretion.  
 Their small size allows migration into the common bile duct causing low-grade obstructio n.  
 Typically leading to hyperbilirubinaemia rather than bile duct dilatation.  
  cholecystectomy is suggested for patients with sickle cell disease if abdominal surgery is 
being performed for other reasons.

being performed for other reasons.  
 Due to decreased life span of the erythrocyte, average 17 days (normal 120 day s), there 
is also a chronic circulating unconjugated hyperbilirubinaemia. 1146

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   20 
  There is often an inability to concentrate urine  
 The inner medulla is hypoxic, hypertonic and acidotic and therefore predisposes to 
sickling of red blood cells, which results in vasoocclusion and reduction in renal medullary 
blood flow. 
 proximal tubule dysfunction   impairs  urinary concentration

 distal tubular dysfunction  impairs potassium excretion. 
 Functional hyposplenism in SCD also renders sufferers susceptible to infection with 
encapsulated bacteria (pneumococci, meningococci). 
 Patients with sickle cell disease have a predisposition to develop osteomyelitis due to 
Salmonella species. 
Sickle-cell crises: Four main types of crises  are recognised:  
 thrombotic crises , also known as painful crises or vaso-occlusive crises

 precipitated by infection, dehydration, deoxygenation ,acidosis , cold temperatures, 
extreme exercise and stress. 
 infarcts occur in various organs including the bones (e.g. avascular necrosis of hip, hand-
foot syndrome in children, lungs, spleen and brain 
 sequestration crises  
 sickling within organs such as the spleen or lungs causes pooling of blood with worsening 
of the anaemia 
 acute chest syndrome: dyspnoea, chest pain, pulmonary infiltrates, low pO2 - the most

common cause of death after childhood 
 stroke  
 5-10% of sickle cell patients will suffer a stroke, usually during childhood.  
 The risk can be predicted by transcranial Doppler measurement of middle cerebral 
artery (MCA) flow rate,  
 prompt institution of a prophylactic transfusion program to reduce the HbS % can 
prevent further strokes.  
 treatment once occurred  Exchange transfusion programme  
 aplastic crises  
 caused by infection with parvovirus

 caused by infection with parvovirus 
 sudden fall in haemoglobin  without an appropriate  ↑ reticulocytosis. 
 The condition is self-limited, with bone marrow recovery occurring in 7-10 days, foll owed 
by brisk reticulocytosis. 
 haemolytic crises  
 rare 
 fall in haemoglobin due an increased rate of haemolysis 
 The anaemia associated with sickle cell disease is usually only symptomatic below 70 g/L, 
as oxygen is released more readily from erythrocytes.

 (remember, patients with sickle cell tend to run with a Hb between 70-90 g/L norma lly) 
 The anemia of SC is usually a chronic, reasonably well-compensated hemolytic anemia  
with an appropriate reticulocytosis. For example, the mean hemoglobin and hematocrit 
concentrations on average may be 79 g/L and 22.9% respectively, with a  reticulocyte 
count of between 3-15%.  
 
Diagnosis  of sickle cell disease requires the detection of HbS.

 Sickledex test : addition of reagent to blood  turbidity confirming the presence of HbS, but it 
gives no information on other haemoglobins. 
 Haemoglobin electrophoresis  is the only investigation that determines the nature of the 
haemoglobinopathy 
 
 Treatment 
 analgesia e.g. opiates 
 rehydrate 1147

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   21 
  oxygen 
 consider antibiotics if evidence of infection 
 blood transfusion 
 exchange transfusion: e.g. if neurological complications 
 Avoid 
 iron therapy: There is a tendency to iron overload and therefore iron the rapy is not usually 
indicated.

indicated.  
 Intra-articular steroids have been associated with a sickle cell crisis, the mechanism of 
which is not fully understood, but they should be avoided. 
 pharmaceutical interventions to prevent sickle cell crisis and other acute complications  
 Hydroxyurea 
 acts by inhibiting ribonucleotide reductase , which inhibits both purine and 
pyrimidine synthesis. 
 Action: ↑fetal haemoglobin (Hb F) which protects against sickling.

 reduces the incidence of acute chest syndrome and the need for blood transfusion 
 The major side effect is severe myelosuppression. 
 Malaria chemoprophylaxis in endemic area 
 
 Acute chest syndrome   
 defines  as 'an acute illness characterized by fever and/or respiratory symptoms, 
accompanied by a new pulmonary infiltrate on chest X-ray'.  
 management:  
 Oxygen therapy to maintain saturations > 95% 
 Intravenous fluids to ensure euvolaemia 
 Adequate pain relief

 Adequate pain relief 
 Incentive spirometry in all patients presenting with rib or chest pain 
 Antibiotics with cover for atypical organisms 
 Early consultation with the critical care team and haematology 
 Blood transfusi on: 
 A senior haematologist will make a decision as to whether a simple or 
exchange transfusion is necessary. 
 guidelines suggest Hb target of 100-110g/L in either instance.  
 All adults who have hyposplenism, including patients with SCD, need:

 Yearly influenza vaccine.  
 Pneumococcal C vaccine, (adults and children over 2 years) repeated every five years.  
 Haemophilus influenzae type b; if not already given as part of childhood  immunisation.  
 Conjugated meningococcal C vaccine; if not already given as part of childhood 
immunisation.  
 Meningococcal ACWY vaccine; if travelling to areas with high risk of meningitis. 
 Patients with sickle cell disease are prone to infections within encapsulated organisms

because of their asplenic state.  
 These include: 
 Streptococcus pneumoniae ,  
 Haemophilus influenzae  and  
 Neisseria meningitidis .  
 To combat these infections, patients with homozygous sickle cell disease should be on 
lifelong penicillin  and be vaccinated against these organisms . 
 
Salmonella  osteomyelitis is seen in patients with sickle cell anaemia  
 
screening for sickle cell disease in a pregnant women: 
 She will first be screened for sickle cell carrier status.

 If that test is positive, her partner will be screened,  
 If both are found to be carriers this is confirmed by genetic testing before offerin g chorionic 
villus sampling (CVS) (8-10 weeks) or amniocentesis (14-16 weeks). 
 
 1148

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   22 
  
Priapism  
 Priapism is most often due to idiopathic thrombosis of the prostatic venous plexus. 
 Other causes include: 
  leukaemia,  
 sickle-cell anaemia  and 
  carcinomatosis. 
 Priapism occurs fairly frequently which may lead to permanent impotence if it is not 
relieved.

relieved. 
 
Sideroblastic anaemia 
 Sideroblastic anaemia is a condition where red cells fail to completely form haem, whose 
biosynthesis takes place partly in the mitochondrion. This leads to deposits of iron in the 
mitochondria that form a ring around the nucleus called a ring sideroblast.  
Causes: It may be congenital or acquired  
 Congenital cause: delta-aminolevulinate synthase-2 deficiency

 The enzyme delta aminolevulinic acid (ALA) is essential in the biosynthesis of heme.  
 Delta ALA requires pyridoxine (vitamin B6) and copper as cofactors. 
 Hereditary sideroblastic anemia follows a  X-linked  genetic inheritance pattern. 
 Acquired causes  
 myelodysplasia (seen in older age groups) 
 alcohol 
 the most common reversible cause 
 lead 
 drugs: anti-TB medications, chloramphenicol. 
 Pyridoxine (vitamin B6) deficiency, caused by isoniazid and oral contraceptives, is

a reversible cause of sideroblastic anemia. 
 hypochromic microcytic anaemia (more so in congenital) 
 Basophilic stippling: 
 visualization of ribosomes on the surface of red blood cells  
 can be seen on a peripheral blood smear of patients with sideroblastic anemia. 
 Ferritin levels are  increased 
 bone marrow:  
 sideroblasts and increased iron stores 
 Sideroblasts are red cell precursors with iron-laden mitochondria and are detected 
via Prussian blue  staining.

via Prussian blue  staining. 
 Ringed sideroblasts are pathognomonic  for sideroblastic anemia. 
 treat any underlying cause 
 removal of toxic agents such as zinc and lead, and drugs such  as penicillamine and 
isoniazid.  
 pyridoxine  may help 
 1149

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   23 
   The figure illustrates sideroblasts, which 
are nucleated (immature) erythrocytes with 
granules of iron in their cytoplasm.  
 
Haemolytic anaemias: by site

Haemolytic anaemias: by site 
The combination of anaemia and jaundice should always suggest haemolytic anaemia until 
proved otherwise  
 In intravascular haemolysis free haemoglobin is released which binds to haptoglobin.  
 The benefit of this  process ( Haptoglobin binds with free plasma hemoglobin ): 
 permits degradative enzymes access to the hemoglobin,  
 preventing the loss of iron via the kidneys,  
 shielding the kidneys from damage by hemoglobin.

 As haptoglobin becomes saturated haemoglobin binds to albumin forming methaema lbumin 
(detected by Schumm's test).  
 Free haemoglobin is excreted in the urine as haemoglobinuria, haemosiderinuria  
 
Intravascular haemolysis  Extravascular haemolysis 
 mismatched blood transfusion 
 G6PD deficiency* 
 red cell fragmentation: heart valves, TTP, 
DIC, HUS 
 cold autoimmune haemolytic anaemia  haemoglobinopathies: sickle cell, 
thalassaemia

thalassaemia 
 hereditary spherocytosis 
 haemolytic disease of newborn 
 warm autoimmune haemolytic anaemia 
 
*strictly speaking there is an element of extravascular haemolysis in G6PD as well, although it is usuall y 
classified as a intravascular cause 
 
1150

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   24 
 Haemolytic anaemias: by cause 
 
Hereditary causes  
 can be subdivided into membrane, metabolism or haemoglobin defects  
 membrane: hereditary spherocytosis/elliptocytosis 
 metabolism: G6PD deficiency 
 haemoglobinopathies: sickle cell, thalassaemia 
Acquired causes

Acquired causes  
 can be subdivided into immune and non-immune causes 
 Acquired: immune causes 
 autoimmune: warm/cold antibody type 
 alloimmune: transfusion reaction, haemolytic disease newborn 
 drug: methyldopa, penicillin 
 methyldopa  Anti-RBC antibodies  
 penicillin  reaction between penicillin-like drugs and their antibodies 
 Acquired: non-immune causes 
 microangiopathic haemolytic anaemia (MAHA): TTP/HUS, DIC, malignancy, pre-
eclampsia 
 prosthetic cardiac valves

eclampsia 
 prosthetic cardiac valves 
 paroxysmal nocturnal haemoglobinuria 
 infections: malaria 
laboratory tests  
 Hemoglobin: decreased 
 MCV: normocytic 
 Reticulocyte count and reticulocyte production index: increased 
 Unconjugated bilirubin: increased 
 LDH: increased (esp. in intravascular hemolysis) 
 Haptoglobin: reduced 
 
Microangiopathic anemia   
 The patient ’s newly diagnosed heart murmur along with new anemia and schistocytes

indicate aortic stenosis as the underlying cause .  
 
 Aortic stenosis  mechanical destruction of RBCs (as they travel through the narrowed 
aortic opening)   microangiopathic anemia  
 
 Schistocytes  are fragmented RBCs. Also called helmet cells, they are pathognomic of 
microagiopathic hemolytic anemias.  
 
Zieve syndrome   
 triad of jaundice, hemolytic anemia, and hyperlipidemia.  
 Hepatic dysfunction is usually evident in all cases.  
 Hemolytic anemia is reversible.

 Hemolytic anemia is reversible.  
 Hyperlipidemia due to excess alcohol intake causes metabolic and osmotic abnormalities i n 
(RBCs), making them very susceptible to hemolysis.  
 Peripheral blood smear reveals: 
 normocytic normochromic anemia 
 acanthocytes 
 Acanthocytes are also called spur cells.  
 They have multiple projections on their surface caused by hyperlipidemia. 
 Definitive treatment  alcohol cessation.

 Definitive treatment  alcohol cessation. 
 
 Zieve's syndrome should be suspected whenever there is anemia and elevation of unc onjugated 
bilirubin in the setting of acute alcohol intake with no obvious sign of gastrointestinal blee ding. 
 
 1151

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   25 
Autoimmune haemolytic anaemia (AIHA)   
 Autoimmune haemolytic anaemia (AIHA) may be divided in to 'warm' and 'cold' types, acco rding 
to at what temperature the antibodies best cause haemolysis.

 It is most commonly idiopathic but may be secondary to a lymphoproliferative disorder, infectio n 
or drugs.  
 AIHA is characterised by a positive direct antiglobulin test (Coombs' test)  
 
Warm AIHA  
 In warm AIHA the antibody (usually  IgG ) causes haemolysis best at body temperature and 
haemolysis tends to occur in extravascular  sites, for example the spleen . Management 
options include steroids, immunosuppression and splenectomy .  
 Causes of warm AIHA

 Causes of warm AIHA  
 autoimmune disease : e.g. systemic lupus erythematosus* 
 SLE can rarely be associated with a mixed-type AIHA 
 neoplasia: e.g. lymphoma, CLL 
 drugs: e.g. methyldopa, Penicillins, Cephalosporins, levodopa, NSAIDs and Quinidine 
 treated by  stopping the drug ± short course of oral prednisolone. 
 The bone marrow respond by increasing RBCs production, which will be evident in periphe ral

blood by increase in the reticulocytes, immature RBCs, which will have high MCV.   
 Management  options include steroids, immunosuppression and splenectomy.  
 Blood transfusion can be life-saving until immunosuppression can take effect.  
 All patients with active haemolysis are at risk of acquiring folate deficiency due to increased  
metabolic demands and all should receive folic acid  replacement therapy. 
 
Cold AIHA

Cold AIHA  
 The antibody in cold AIHA is usually IgM and causes haemolysis best at 4 deg C.  
 Haemolysis is mediated by complement and is more commonly  intravascular .  
 Causes of cold AIHA  
 neoplasia: e.g. lymphoma 
 infections:  e.g. mycoplasma, EBV 
 Secondary cold agglutinin disease typically presents with anaemia and 
haemoglobinuria due to intravascular haemolysis two to three weeks following 
infection  such as with:  
 Mycoplasma pneumoniae  
 Viruses (EBV, CMV, etc)

 Viruses (EBV, CMV, etc) 
 Legionnaires' disease 
 Malaria  The best diagnostic test  Cold agglutinin titre  
 Cold agglutinins occur normally but at very low titres. 
 Features may include symptoms of Raynaud's and acrocyanosis 
 Patients respond less well to steroids 
 
 Warm AIHA  Cold AIHA  
Definition haemolysis best at body temperature haemolysis best at 4 deg C 
antibody IgG IgM 
Site of haemolysis extravascular  (e.g :spleen)  intravascular

Causes   autoimmune disease : e.g. systemic 
 neoplasia: e.g. lymphoma, CLL 
 drugs: e.g. methyldopa  neoplasia: e.g. lymphoma 
 infections : e.g. 
mycoplasma, EBV 
treatment steroids, immunosuppression and 
splenectomy. respond less well to steroids 
 
 1152

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   26 
  
Paroxysmal cold haemoglobinuria (PCH)   
 a rare type of autoimmune haemolytic anaemia (AIHA) occurring primarily in 
children/adolescent.  
 The classic symptom is a sudden onset of haemoglobinuria following exposure to co ld, even 
for a few minutes.

for a few minutes.   
 Symptoms may occur minutes to hours following exposure to cold.  
 Haemoglobinuria is not always present because in some persons with PCH the autoantibody 
level is not high enough to cause intravascular haemolysis.  
 The direct agglutination test (DAT) (Coomb ’s test) is usually negative.  
 
Cold agglutinin disease  
 caused by autoantibodies that react at temperatures < 37 °C,  
 typical causes are:  
 lymphoproliferative disorders,

 lymphoproliferative disorders, 
  infections such as mycoplasma or Epstein –Barr virus.  
 Around 50% of cases are idiopathic.  
 Non-Hodgkin ’s lymphoma is more typically associated with cold agglutinins than 
Hodgkin ’s. 
 
Hook effect 
 Also called or the prozone effect    
 In agglutination test, a person's serum (which contains antibodies) is added to a test tube,  
which contains a particular antigen.

which contains a particular antigen.  
 If the antibodies agglutinate with the antigen to form immune complexes, then the  test is 
interpreted as positive.  
 However, if too many antibodies are present that can bind to the antigen, then  the antigenic 
sites are coated by antibodies, and few or no antibodies directed toward the pathog en are able 
to bind more than one antigenic particle. Since the antibodies do not bridge betwe en antigens,

no agglutination occurs. Because no agglutination occurs, the test is interpreted as negative. In 
this case, the result is a false negative.  
 The range of relatively high antibody concentrations within which no reaction occurs is called  
the prozone. 
 The effect can also occur because of antigen excess, when both the capture and detection 
antibodies become saturated by the high analyte concentration. In this case, no sandwich can

be formed by the capturing antibody, the antigen and the detection antibody. In this case, free 
antigen is in competition with captured antigen for detection antibody binding. 
  high levels of syphilis antibodies in HIV patients or high levels of cryptococcal antigen leadin g 
to false negative tests in undiluted samples. 
 This phenomenon is also seen in serological tests for Brucellosis.

 when the serum is diluted, the blocking antibody is as well and its concentration decrease s 
enough for the proper precipitation reaction to occur. 
Hereditary spherocytosis 
 
  most common hereditary haemolytic anaemia in people of northern European d escent 
Aetiology 
 autosomal dominant  defect of red blood cell cytoskeleton 
 the most frequent cause is a mutation in the spectrin gene;

 spectrin is a component of the red cell membrane.  
 The most common mutation in a Northern European population is a combined spectrin 
and ankyrin mutation , which is found in 40 –65% of patients. 
 the normal biconcave disc shape is replaced by a sphere-shaped red blood cell 
 red blood cell survival reduced as destroyed by the spleen 1153

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   27 
 Genetic mutation ĺ Defects in RBC membrane proteins (especially spectrin and/or ankyrin) 
responsible for tying the inner membrane skeleton with the outer lipid bilayer ĺ Continuou s loss 
of lipid bilayer components ĺ Decreased surface area of RBCs in relation to volume ĺ Sphere -

shaped RBCs with decreased membrane stability ĺ Inability to change form while going t hrough 
narrowed vessels: 
ĺ Entrapment within splenic vasculature ĺ Splenomegaly  
ĺ Destruction via splenic macrophages ĺ Extravascular hemolysis  
Features 
Patient with hereditary spherocytosis + acute abdomen  think of: Biliary colic or rupture 
spleen. 
 
normocytic anaemia, gallstones and family history  hereditary spherocytosis 
 
 failure to thrive

 failure to thrive 
 Congenital skeletal abnormalities (eg, tower-shaped skull, polydactylism) occasionally occu r.  
 Anemia and pallor 
 jaundice  (Ĺunconjugated bilirubin)  
 gallstones (pigment stones)  
 common and  may be the presenting symptom  
 (made of calcium bilirubinate) 
 may lead to cholecystitis 
 Splenomegaly with left upper quadrant pain 
 aplastic crisis precipitated by parvovirus infection 
 Aplastic crisis

 Aplastic crisis  
 can be triggered by parvovirus B19 infection. 
 
 Normocytic anemia (normal MCV)  
 increase in both RDW and MCHC  
 Findings of hemolytic anemia 
 Ĺ Unconjugated bilirubin 
 Ĺ LDH  
 Ļ Haptoglobin  
 Reticulocytosis   
 Direct antiglobulin (direct Coombs) test 
 to exclude autoimmune hemolytic anemia (positive Coombs test), since spherocytosis is 
seen in both clinical presentations

seen in both clinical presentations 
 Direct Coombs' test is negative in Hereditary spherocytosis , as it is not an immune 
haemolysis 
 Eosin-5- maleimide binding test ( EMA ): test of choice , as results are readily available (within two 
hours) 
 Osmotic fragility test (Rupture of Spherocytes in mildly hypotonic solution),  
 unreliable and is no longer recommended in routine clinical practice.  
 this has now been replaced by the eosin-5-maleimide binding to red cells  and then

being detected by  flow cytometry.  
 Osmotic gradient ektacytometry 
 used to differentiate hereditary spherocytosis from hereditary stomatocytosis, but is only  
available in specialised laboratories.  
 If the diagnosis is equivocal, the cryohaemolysis test and EMA binding can be used.  
 In atypical cases, gel electrophoresis analysis of erythrocyte membranes is the test of choice. 
 Blood smear 
 Characteristic spherocytes (absent central pallor)  
 Potentially anisocytosis

 Potentially anisocytosis 
 Ultrasound:  
 to evaluate gallbladder complications 
 
 1154

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   28 
 Diagnosis 
1. The first step in analysis of a spherocytic hemolytic anaemia is  direct antiglobulin test 
(to determine whether the process is hemolytic or not).  
2. If negative  confirm HS with other tests. 
3. The osmotic fragility test is unreliable and is no longer recommended in routine clinical 
practice.

practice.  
4. Osmotic gradient ektacytometry is used to differentiate hereditary spherocytosis from 
hereditary stomatocytosis 
 
 supportive for most patients: folate replacement 
 splenectomy  
 best avoided until at least 6 years of age to reduce the risk of post-splenectomy sepsis.  
 It is important to rule out stomatocytosis where splenectomy is contraindicated because of 
the thrombotic risk. 

Glucose-6-phosphate dehydrogenase (G6PD) deficiency 
Basics 
 (G6PD) plays a vital role in the hexose monophosphate pathway 
 It is involved in the oxidation of glucose 6-phosphate to 6-phosphoglycerate.This oxidation 
reaction is needed in RBCs as it provides the only source of  NADPH  
 NADPH   maintains the level of glutathione  protect the RBCs against oxidative damage from 
compounds like hydrogen peroxide  

 G6PD deficiency is the commonest red blood cell enzyme defect.  
 It is more common in people from the Mediterranean,  Africa  and Chinese  
Aetiology  
 inherited in a X-linked recessive fashion.  
 Homozygotes and heterozygotes can be symptomatic, although the disease typically is mo re 
severe in persons who are homozygous for the deficiency.  
Factors which Precipitates crisis: 
 drugs  
 infections ( the most common cause)

 drugs  
 infections ( the most common cause) 
 broad (fava) beans  
 Favism is most common in persons with G6PD class II variants, but rarely it can occur 
in patients with the G6PD A –variant (Class III  African descent). 
 henna  
 Ļ G6PD ĺ Ļ glutathione ĺ increased red cell susceptibility to oxidative stress  
 The haemolytic anaemia is non-immune (direct antiglobulin test [DAT] negative). 
Features 
 usually asymptomatic  
 neonatal jaundice is often seen

 neonatal jaundice is often seen 
 intravascular haemolysis  
 Decreased haptoglobin levels , hematuria, and presence of urinary hemosiderin  
indicate severe intravascular hemolysis. 
 acute hemolysis can cause back or abdominal pain and jaundice secondary to a rise in 
unconjugated bilirubin 
 Jaundice, in the setting of normal liver function, typically does not occur until > 50% of the 
erythrocytes have been hemolyzed. 
 gallstones are common 
 splenomegaly may be present

 splenomegaly may be present 
 Heinz bodies  (denatured hemoglobin) on blood films 
 made by using a G6PD enzyme assay  
 usually done by fluorescent spot test  detecting the generation of NADPH from NADP .  
 The test is positive if the blood spot fails to fluoresce under ultraviolet light. 
 In patients with acute hemolysis, testing for G6PD deficiency may be falsely negative beca use

older erythrocytes with a higher enzyme deficiency have been hemolyzed. Young erythrocyte s 
and reticulocytes have normal or near-normal enzyme activity.  1155

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   29 
  Female heterozygotes may be hard to diagnose because of X-chromosome mosaicism le ading 
to a partial deficiency that will not be detected reliably with screening tests. 
 Acute haemolytic reaction  
 Blood count is normal between attacks of haemolysis 
 During an attack the blood film may show:

 During an attack the blood film may show: 
 irregularly contracted cells 
 bite cells 
 blister cells 
 Heinz bodies 
 Reticulocytosis  
 Peripheral blood smear  Heinz bodies  (rarely seen in clinical practice) 
 Reticulocyte count: Increases four to seven days after hemolysis 
 Haptoglobin  Decreased 
Treatment 
 avoidance exposure to an oxidative stressor in the form of an infection, oxidative drug, or fava 
beans

beans 
 Acute hemolysis is self-limited, but in rare instances it can be severe enough to warrant a b lood 
  Hemolysis typically occurs 24 to 72 hours after ingestion, with resolution within 4 to 7 
days. 
Some drugs causing haemolysis 
 anti-malarials: primaquine 
 Quinine/quinidine. 
 Ciprofloxacin 
 Nitrofurantoin 
 chloramphenicol 
 sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas 
 vitamin K, probenecid  
 aspirin  and (NSAIDs)

 aspirin  and (NSAIDs) 
Some drugs thought to be safe 
 penicillins 
 cephalosporins 
 macrolides 
 tetracyclines 
 trimethoprim 
 In “Co-trimoxazole ”: the sulfamethoxazole causes haemolysis in G6PD, not the 
trimethoprim. 
 
Comparing G6PD deficiency to hereditary spherocytosis:  
G6PD deficiency Hereditary spherocytosis 
Gender  Male (X-linked recessive) Male + female (autosomal dominant) 
Ethnicity  African + Mediterranean descent Northern European descent

Typical history  • Neonatal jaundice  
• Infection/drugs precipitate haemolysis  
• Gallstones  • Neonatal jaundice 
• Chronic symptoms although haemolytic 
crises may be precipitated by infection 
• Gallstones  
• Splenomegaly is common  
Blood film  Heinz bodies Spherocytes (round, lack of central pallor) 
Diagnostic test  Measure enzyme activity of G6PD Osmotic fragility test 
 
 G6PD deficiency confers partial protection against malaria

 Hemolysis begins 24 to 72 hours after exposure to oxidant stress.  
 Hemolysis due to oxidant stresses are usually self-limiting within 8 to 14 days due to the 
compensatory production of young red blood cells with high levels of G6PD. 1156

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   30 
  Young RBCs are not vulnerable to oxidative damage and hence limit the duration of  hemolysis.  
 G6PD deficiency is an X-linked inherited disease that primarily affects men.  
 Women may be affected if: 
  they are homozygous , which occurs in populations in which the frequency of G6PD 
deficiency is quite high.

deficiency is quite high. 
 Heterozygous women (carriers) can experience clinical disease as a result of: 
1. X chromosome inactivation,  
2. gene mosaicism, or  
3. hemizygosity 
 Severe hemolysis due to G6PD deficiency may manifest as methemoglobinemia  
 Methaemoglobinaemia in G6PD-deficient patients is best treated with exchange 
transfusion. 
Paroxysmal nocturnal haemoglobinuria  (PNH)

Paroxysmal nocturnal haemoglobinuria  (PNH)  
The triad of hemolytic anemia, pancytopenia, and thrombosis  PNH  
 (PNH) is an acquired disorder leading to haemolysis (mainly intravascular) of haematological 
cells.  
 Caused by increased sensitivity of cell membranes to complement  due to a lack of 
glycoprotein glycosyl-phosphatidyl-inositol  (GPI).  
 Patients are more prone to venous thrombosis 
  50% of PNH affected individuals are died due to thrombotic complications

 GPI can be thought of as an anchor which attaches surface proteins to the cell  membrane 
 complement-regulating surface proteins, e.g. decay-accelerating factor CD 55 (DAF)  and 
Membrane Inhibitor of Reactive Lysis CD 59 (MIRL)., are not properly bound to the cell 
membrane due a lack of GPI 
 Hemolysis occurs when patients develop a mild acidosis at night, due to a relative 
hypoventilation, resulting in the passage of dark urine in the early morning.

 thrombosis is thought to be caused by a lack of CD59 on platelet membranes  predisposing 
to platelet aggregation 
 Intrinsic hemolytic anemia with intravascular hemolysis 
Features 
 symptoms of anemia (Pallor, fatigue, weakness) 
 Intermittent jaundice  
 haemoglobinuria 
 classically dark-coloured urine in the morning (although has been shown to occur 
throughout the day) 
 Abdominal pain  
 may be due to small mesenteric vein thrombi. 

 thrombosis e.g. Budd-Chiari syndrome 
 Vasoconstriction: headache, pulmonary hypertension 
 aplastic anaemia may develop in some patients 
 Ĺ Risk of acute leukemias  
 CBC 
 red blood cells, white blood cells, platelets or stem cells may be affected therefore 
pancytopaenia may be present 
 dipstick analysis of the urine: 
  will be positive for 'blood', but the microscopy will show no red blood cells.

 This because there is intravascular haemolysis, with intravascular release of 
haemoglobin. This then passes through the renal tubules, ending up in the uri ne, 
and turning the dipstick analysis positive. However, because there are no actual 
red blood cells in the urine, the microscopy will be negative. 
 flow cytometry ( immunophenotyping ) of blood  
 absence of CD55  and CD59  on the surface of RBCs  
 now replaced Ham's test as the gold standard investigation in PNH

 Ham's test: acid-induced haemolysis (normal red cells would not) 
 Coombs test: negative  
 1157

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   31 
  
 blood product replacement 
 anticoagulation 
 eculizumab , a monoclonal antibody directed against terminal protein C5 , is reducing 
intravascular haemolysis 
 stem cell transplantation 
 The gold standard curative treatment 
Splenectomy

 Following a splenectomy patients are particularly at risk of infections from: 
 pneumococcus,  
 Haemophilus,  
 meningococcus and  
 Capnocytophaga canimorsus*(*usually from dog bites)  
 Vaccination 
 if elective, should be done 2 weeks prior to operation 
 Hib, meningitis A & C 
 annual influenza vaccination 
 pneumococcal vaccine every 5 years 
 Antibiotic prophylaxis 
 penicillin V: unfortunately clear guidelines do not exist of how long antibiotic prophylax is

should be continued. It is generally accepted though that penicillin should be co ntinued for 
at least 2 years and at least until the patient is 16 years of age, although the majority o f 
patients are usually put on antibiotic prophylaxis for li fe 
 
Blood products 
Whole blood fractions  
Fraction Key points 
Packed red cells  Used for transfusion in chronic anaemia and cases where infusion of large 
volumes of fluid may result in cardiovascular compromise.

 Product obtained by centrifugation of whole blood. 
 In a stable patient, red cell packs may be transfused over 90-120 minutes  
 Rapid infusion of red cells or fresh frozen plasma may be required in an 
acutely bleeding patient but not in patient who is stable. 
Platelet rich 
plasma  Usually administered to patients who are thrombocytopaenic and are bleeding or 
require surgery.  
 It is obtained by low speed  centrifugation. 
Platelet

Platelet 
concentrate  Prepared by high speed  centrifugation  
 administered to patients with thrombocytopaenia. 
 the life span of transfused platelets is only 3-7 days. 
 platelet transfusion should not take more than 20-30 minutes.  
 Patients who are refractory to platelet transfusions:  
 should be first investigated to check for adequate platelet rises. This is 
best done on a one or two-hour post platelet transfusion sample.

 Further test would include checking for HLA antibodies 
Fresh frozen 
plasma  Prepared from single units of blood. 
 Contains clotting factors, albumin and immunoglobulin. 
 Unit is usually 200 to 250ml. 
 Usually used in correcting clotting deficiencies in patients with hepatic synthetic 
failure who are due to undergo surgery. 
 Usual dose is 12-15ml/Kg-1. 
 It should not be used as first line therapy for hypovolaemia. 
Cryoprecipitate  Formed from supernatant of FFP. 1158

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   32 
 Fraction Key points 
 Rich source of Factor VIII and fibrinogen. 
 Allows large concentration of factor VIII to be administered in small volume. 
SAG-Mannitol 
Blood Removal of all plasma from a blood unit and substitution with: 
 
 Sodium chloride 
 Adenine 
 Anhydrous glucose 
 Mannitol

 Adenine 
 Mannitol 
Up to 4 units of SAG M Blood may be administered. Thereafter whole blood is preferred. 
After 8 units, clotting factors and platelets should be considered. 
  
Plasma derivatives  
 plasma derivatives (such as factor VIII) are prepared from several thousand plasma donatio ns, 
typically 20,000, or 5,000 kg of plasma at a time. 
 Pooled plasma  has been sourced from outside the UK since 1999 to avoid vCJD risks.

 The process involves several chemical steps including: 
 ethanol extraction,  
 chromatography, and  
 viral inactivation steps which results in a freeze-dried product.  
 These products have a long shelf life of several months to years. 
 
Cell saver devices  
These collect patients own blood lost during surgery and then re-infuse it. There are two main types: 
 
 Those which wash the blood cells prior to re-infusion. These are more expensive to pu rchase

and more complicated to operate. However, they reduce the risk of re-infusing contaminat ed 
blood back into the patient. 
 Those which do not wash the blood prior to re-infusion. 
Their main advantage is that they avoid the use of infusion of blood fro m donors into patients and this 
may reduce risk of blood borne infection. It may be acceptable to Jehovah's witnesses. It  is 
contraindicated in malignant disease for risk of facilitating disease dissemination.

Blood products used in warfarin reversal  
Immediate or urgent surgery in patients taking warfarin: 
1. Stop warfarin 
2. Vitamin K (reversal within 4-24 hours) 
 IV takes 4-6h to work (at least 5mg) 
 Oral can take 24 hours to be clinically effective 
3. Fresh frozen plasma  
 Used less commonly now as 1st line warfarin reversal  
 30ml/kg-1 
 Need to give at least 1L fluid in 70kg person (therefore not appropriate in fluid overloa d) 
 Need blood group

 Need blood group 
 Only use if human prothrombin complex is not available 
4. Human Prothrombin Complex (reversal within 1 hour) 
 Bereplex 50 u/kg 
 Rapid action but factor 6 short half life, therefore give with vitamin K   
 
Neonatal exchange transfusion 
 An exchange transfusion requires blood which is plasma reduced whole blood  in CPD 
(citrate phosphate dextrose/anticoagulant), irradiated and less than five days old.

 The Rh group should either be Rh negative or identical to the neonate, to avoid haemolytic  
transfusion reaction in the neonate. 1159

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   33 
Blood product transfusion complications 
 haemolytic: immediate or delayed 
 febrile reactions 
 transmission of viruses, bacteria, parasites,  vCJD  
 iron overload 
 ARDS 
 clotting abnormalities

 ARDS 
 clotting abnormalities 
Immediate haemolytic reaction 
  occur during the transfusion. 
 e.g. ABO mismatch 
 massive intravascular haemolysis 
Delayed haemolytic transfusion reaction  
 occurs 24 hours after the transfusion. 
 This happens in a patient who has been previously immunised by transfusions or pregnancy. The 
antibodies are not detectable initially but become obvious as a secondary immune respo nse to 
the antigen exposure during the transfusion occurs.

Febrile reactions 
 due to white blood cell HLA antibodies 
 often the result of sensitization by previous pregnancies or transfusions 
 Febrile non-haemolytic reactions are very common, and are due to the presence of pyrogenic 
cytokines released from leucocytes during storage  of the blood units.  
 apart from a mild fever, the patient is very well.  
 rapid rise in temperature may be  due to ABO incompatibility, but With ABO 
incompatibility patients become shocked very quickly.

Causes a degree of immunosuppression 
 e.g. patients with colorectal cancer who have blood transfusions have a worse outcome tha n 
those who do not 
The risk of viral transmission  
 A broad knowledge of the risks may be required while consenting a patient for blood transfusion .  
 in the United Kingdom, the risks; 
 For hepatitis B are 1 per 1.3 million donations 
 For HIV are 1 in 6.5 million and 
 For hepatitis C 1 in 28 million donations. 
Transmission of vCJD

Transmission of vCJD  
 although the absolute risk is very small, vCJD may be transmitted via blood transfusion  
 a number of steps have been taken to minimise this risk, including: 
 ĺ from late 1999 onward, all donations have undergone removal of white cells (le ucodepletion) 
in order to reduce any vCJD infectivity present 
 ĺfrom 1999, plasma derivatives have been fractionated from imported p lasma rather than being

sourced from UK donors. Fresh Frozen Plasma (FFP) used for children and certain groups of 
adults needing frequent transfusions is also imported 
 ĺ from 2004 onward, recipients of blood components have been excluded from dona ting bloo d 
iron overload 
 secondary to chronic blood transfusion (eg : in myelodysplastic syndrome)  
 early signs: 
 grey skin  
 early hear failure  
 diabetes  
 treatment: 
 iron chelation with desferrioxamine subcutaneously  
 bind iron

 bind iron  
 needs to be given for 8 – 12 hours a day for 5 – 7 days per week  
 common side effects of desferrioxamine:  
 high frequency deafness 
 retinopathy  
 Yersinia infection 
 
irradiated blood products  
  the advantage of irradiated red cells 1160

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   34 
  Inactivates donor lymphocytes 
 Indications for irradiated blood products 
 Those at risk of transfusion associated with graft versus host disease such as neonates 
 Those receiving purine analogues based chemotherapy  
 Hodgkin's lymphoma  
 Immunodeficiency states 
 Post bone marrow transplants

 Post bone marrow transplants  
 
  Pre-operative request for the blood bank for elective surgeries 
 Group and save only  
 A 'group and save' is adequate for elective surgeries and is standard practice in most 
modern blood banks. This will involve blood grouping and its confirmation as well as an 
antibody screen. 
 Other options include cross match and a direct Coombs' test are not routinely done for 
elective surgery  
Transfusion errors

Transfusion errors 
 Mislabelling of samples, requests, or wrongly identifying recipients are the commonest 
transfusion errors. 
 
January 2016 exam:  What is the risk of variant Creutzfeldt-Jakob Disease (vCJD) transmission 
via blood transfusion?  
 Measures are taken to reduce the risk of vCJD transmission but there remains a very 
small risk of transmission 
 
Transfusion Related Acute Lung Injury (TRALI)

Transfusion Related Acute Lung Injury (TRALI) 
 (TRALI) is a rare but serious syndrome characterized by sudden acute respiratory distress within 
six hours after blood product administration 
 Caused by anti-HLA, Human Neutrophil Antigens (HNA) or anti-granulocytes antibody in donor 
blood. 
 Donor ’s blood sensitization occurs in: 
 Multiparous ♀ develop these antibodies through exposure to fetal blood 
 Previous transfusion 
 Transplantation patient

 Transplantation patient 
 When blood is obtained from above mentioned donors, it carries higher risk for recipien t to 
develop TRALI; those who have lung pathology are more susceptible. TRALI symptom s 
resemble ARDS. 
 transfused human leukocyte or neutrophil antigen (HLA or HNA) antibodies  activation of 
donor neutrophils  Neutrophils adhere to pulmonary endothelium to increase permeability 
and cause pulmonary edema.

and cause pulmonary edema. 
 Patients with certain clinical conditions (eg, infection, inflammation, surgery) have primed 
neutrophils that are susceptible to activation by transfused bioactive substances. 
 
 TRALI has two proposed pathophysiologic mechanisms:  
1. the antibody hypothesis . (antigen-antibody interactions)  
 The human leukocyte antigen (HLA class I, HLA class II) or human neutrophil antigen 
(HNA) antibody in the transfused component reacts with neutrophil antigens in the

recipient The recipient's neutrophils lodge in the pulmonary capillaries and release 
mediators that cause pulmonary capillary leakage.  
 As a consequence, many patients with TRALI will develop transient leukopenia.  
 However, transfusions of blood components containing neutrophil antibodies may cause  
leukopenia, that do not meet the definition of TRALI.  
2. The neutrophil priming hypothesis: 
 does not require antigen-antibody interactions  1161

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   35 
  occurs in patients with clinical conditions that predispose to neutrophil priming and 
endothelial activation such as infection, surgery, or inflammation.  
 Bioactive substances in the transfused component activate the primed, sequestere d 
neutrophils, and pulmonary endothelial damage occurs.

 Both mechanisms lead to pulmonary edema in the absence of circulatory ove rload. 
Feature 
 Occurring within 1 to 6 hours of transfusion of plasma-containing blood components.  
 Patients present with the rapid onset of dyspnea and tachypnea.  
 There may be associated fever, cyanosis, and hypotension.  
 Clinical examination reveals hypoxic respiratory distress, and pulmonary crackles may be 
present without signs of congestive heart failure or volume overload.

 Chest x-ray (CXR) shows evidence of bilateral pulmonary edema unassociated with heart failu re 
(non-cardiogenic pulmonary edema), with bilateral patchy infiltrates, which may rapidly progress 
to complete "white out" indistinguishable from acute respiratory distress syndrome (ARDS).  
 Physiologic findings include acute hypoxemia with PaO2/FiO2 less than 300 mmHg and normal 
cardiac function on echocardiogram.  
Diagnosis:

Diagnosis:  
 confirmed by finding of anti-HLA or anti-Neutrophil antibody in donors ’ or recipient blood. 
Treatment 
 Early and intensive pulmonary support reduces the risk of a fatal outcome. 
 Since the pulmonary edema in TRALI is not related to fluid overload or cardiac dy sfunction, but 
to altered vascular permeability in the lungs with exudation of fluid and protein into th e alveoli, it 
is logical that:

is logical that:  
  maintenance of adequate circulating volume is the most beneficial and  appropriate 
therapy. 
  Corticosteroids,  
 epinephrine  
 and also ventilatory support are treatment options.  
 
How to distinguish TRALI and ARDS from Pulmonary oedema? 
 In the exam take into account the clinical findings and scenario to distinguish. 
 The hallmark of ARDS is refractory hypoxia with non-cardiogenic pulmonary edem a

 Normal pulmonary capillary wedge pressure  is between 5 - 15 mmHg. A PCWP exceeding 15 
mmHg suggests mitral stenosis, mitral insufficiency, severe aortic stenosis, aortic regurgitation, 
ventricular failure, or other cardiac defects or pathologies.  
 When the PCWP exceeds 20 mmHg, the transmission of this pressure back into  the pulmonary 
vasculature increases pulmonary capillary hydrostatic pressure which can lead to pulmo nary 
oedema.

oedema. 
Graft versus host disease (GVHD)  See transplant topic in renal system  
Plasma exchange  
Indications for plasma exchange (also known as plasmapheresis) 
 ANCA positive vasculitis e.g. Wegener's, Churg-Strauss  TTP/HUS 
 hyperviscosity syndrome e.g. 
secondary to myeloma

secondary to myeloma 
Deep vein thrombosis (DVT) 
 
DVT Risk Factors:  
1162

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   36 
  Hematological  
 Thrombophilia: e.g. Activated protein C resistance, protein C and S deficiency 
 Polycythemia 
 Paroxysmal nocturnal hemoglobinuria 
 Hyperviscosity syndrome 
 
 Autoimmune  
 Antiphospholipid syndrome 
 Behcet's 
 Drugs

 Behcet's 
 Drugs  
 Combined oral contraceptive pill: 3rd generation more than 2nd generation 
 Antipsychotics (especially olanzapine) have recently been shown to be a risk factor 
 
 Other conditions  
 Homocystinuria 
Diagnosis  
If a patient is suspected of having a DVT a two-level DVT Wells score should be perform ed: 
Two-level DVT Wells score  
Active cancer (treatment ongoing, within 6 months, or palliative) 1

Paralysis, paresis or recent plaster immobilisation of the lower extremities 1 
Recently bedridden for 3 days or more or major surgery within 12 weeks 
requiring general or regional anaesthesia 1 
Localised tenderness along the distribution of the deep venous system 1 
Entire leg swollen 1 
Calf swelling at least 3 cm larger than asymptomatic side 1 
Pitting oedema confined to the symptomatic leg 1 
Collateral superficial veins (non-varicose) 1 
Previously documented DVT 1

Previously documented DVT 1 
An alternative diagnosis is at least as likely as DVT -2 
Clinical probability simplified score 
 DVT likely: 2 points or more 
 DVT unlikely: 1 point or less 
If a DVT is 'likely' (2 points or more) 
 a proximal leg vein ultrasound scan should be carried out within 4 hours and, if the result is 
negative, a D-dimer test 
 if a proximal leg vein ultrasound scan cannot be carried out within 4 hours a D-dimer test s hould

be performed and low-molecular weight heparin administered whilst waiting for the prox imal leg 
vein ultrasound scan (which should be performed within 24 hours) 
If a DVT is 'unlikely' (1 point or less) 
 perform a D-dimer test and if it is positive arrange: 
 a proximal leg vein ultrasound scan within 4 hours 
 if a proximal leg vein ultrasound scan cannot be carried out within 4 hours low-molecular weigh t

heparin should be administered whilst waiting for the proximal leg vein ultrasound scan (which 
should be performed within 24 hours) 
Low molecular weight heparin (LMWH) or fondaparinux should be given initially afte r a DVT is 
diagnosed. 
 a vitamin K antagonist (i.e. warfarin) should be given within 24 hours of the diagno sis 
 the LMWH or fondaparinux should be continued for at least 5 days or until the internatio nal

normalised ratio (INR) is 2.0 or above for at least 24 hours, whichever is longer, i.e. LMWH or 
fondaparinux is given at the same time as warfarin until the INR is in the therapeutic range 1163

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   37 
  warfarin should be continued for at least 3 months. At 3 months, NICE advise that clinici ans 
should 'assess the risks and benefits of extending treatment' 
 NICE add 'consider extending warfarin beyond 3 months for patients wi thunprovoked  proximal

DVT if their risk of VTE recurrence is high and there is no additional risk of major bleeding'. This 
essentially means that if there was no obvious cause or provoking factor (surgery, trauma, 
significant immobility) it may imply the patient has a tendency to thrombosis and should be  given 
treatment longer than the norm of 3 months. In practice most clinicians give 6 months of  warfarin 
for patients with an unprovoked DVT/PE

for patients with an unprovoked DVT/PE 
 for patients with active cancer NICE recommend using LMWH for 6 months 
 for patients with active ulcerative colitis who developed DVT  : 
 may require Emergency colectomy, as such warfarinisation would be inappropriate.  
 should be heparinised  as this would be easily reversible if it needs to be discontinued 
prior to surgery or if severe worsening of bleeding occurs. 
 
Time of starting prophylaxis in elective knee replacement surgery:

 LMWH or fondaparinux (s/c factor X inhibitor)  should be started 6 – 12 hours after surgery 
 Dabigatran (oral factor X inhibitor)  1 – 4 hours after surgery  
 
Unprovoked VTE  
 (Malignancy investigations and thrombophilia screening)  
 As both malignancy and thrombophilia are obvious risk factors for deep vein thrombosis NI CE 
make recommendations on how to investigate patients with unprovoked clots . 
Malignancy investigations

Malignancy investigations 
 Offer all patients diagnosed with unprovoked DVT or PE who are not already known to h ave 
cancer the following investigations for cancer: 
 a physical examination (guided by the patient's full history) and 
 a chest X-ray  and 
 blood tests (full blood count, serum calcium and liver function tests) and urinalysis . 
 Consider further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram

for women) in all patients aged over 40 years with a first unprovoked DVT or PE 
Thrombophilia screening  
 not offered if patients will be on lifelong warfarin (i.e. won't alter manageme nt) 
 consider testing for antiphospholipid antibodies if unprovoked DVT or PE 
 consider testing for hereditary thrombophilia in patients who have had unprovoked DVT  or PE 
and who have a first-degree relative who has had DVT or PE 
The next most important investigation:

The next most important investigation: 
 Unprovoked VTE   chest X-ray , blood tests and urinalysis 
 Unprovoked VTE + family history of VTE  Thrombophilia screening 
 
Pregnancy: DVT/PE 
Coagulation elements in pregnancy: 
 Increased  factors VII, VIII, IX, X, and XII ,fibrinogen, plasminogen, and D-dimer.  
 Decreased  factor XI and protein S.  
 Not changed   Factor II, protein C, and anti-thrombin III. 
Overview

Overview 
 pregnancy is a hypercoagulable state 
 majority occur in last trimester 
 increase in factors VII, VIII, X and fibrinogen 
 decrease in protein S 
 uterus presses on IVC causing venous stasis in legs 
 warfarin contraindicated 
 S/C low-molecular weight heparin preferred to IV heparin (less bleeding and thrombo cytopenia) 
Post-thrombotic syndrome

Post-thrombotic syndrome 
 It is increasingly recognised that patients may develop complications following a DVT.  
 Venous outflow obstruction and venous insufficiency result in chronic venous hypertension.  1164

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   38 
  The resulting clinical syndrome is known as post thrombotic syndrome.  
Features  
 painful, heavy calves 
 pruritus 
 swelling 
 varicose veins 
 venous ulceration 
 Compression stockings  should be offered to all patients with deep vein thrombosis to help

reduce the risk of post-thrombotic syndrome. 
 NICE state the following: 
 Offer below-knee graduated compression stockings with an ankle pressure greater than 
23 mmHg to patients with proximal DVT a week after diagnosis or when swelling is 
reduced sufficiently and if there are no contraindications, and:  
 advise patients to continue wearing the stockings for at least 2 years 
 ensure that the stockings are replaced two or three times per year or according to

the manufacturer's instructions 
 advise patients that the stockings need to be worn only on the affected leg or legs. 
Venous thromboembolism: prophylaxis in patients admitted to hospital 
Venous thromboembolism (VTE) still accounts for a significant proportion of avoidable hospital d eaths. 
In an effort to tackle this problem NICE produced guidelines in 2010. 
Before admission

Before admission  
 advise women to consider stopping oestrogen-containing oral contraception or HRT 4 weeks 
before surgery. 
 assess the risks and benefits of stopping antiplatelet therapy 1 week before surgery. 
The following patients are deemed at risk of VTE  
Medical patients 
 if mobility significantly reduced for >= 3 days or 
 if expected to have ongoing reduced mobility relative to normal state plus any VTE  risk factor 
(see below) 
Surgical patients and patients with trauma

Surgical patients and patients with trauma 
 if total anaesthetic + surgical time > 90 minutes or 
 if surgery involves pelvis or lower limb and total anaesthetic + surgical time > 60 minutes or 
 if acute surgical admission with inflammatory or intra-abdominal condition or 
 if expected to have significant reduction in mobility or 
 if any VTE risk factor present (see below) 
VTE risk factors 
 active cancer or cancer treatment 
 age > 60 years 
 critical care admission 

 known thrombophilias 
 obesity (BMI > 30 kg/m2) 
 one or more significant medical comorbidities (for example: heart disease; metabolic, end ocrine 
or respiratory pathologies; acute infectious diseases; inflammatory conditions) 
 personal history or first-degree relative with a history of VTE 
 use of HRT 
 use of oestrogen-containing contraceptive ther apy 
 varicose veins with phlebitis 
In-patient VTE prophylaxis

In-patient VTE prophylaxis  
As a general rule pharmacological VTE prophylaxis is used for medical patients unless there is a 
For surgical patients mechanical VTE prophylaxis is offered for patients at risk. Pharmacological VTE 
prophylaxis is also given for if the risk of major bleeding is low. 
Pharmacological VTE prophylaxis options: 
 fondaparinux sodium 
 low molecular weight heparin (LMWH) 
 unfractionated heparin (UFH) (for patients with renal failure)

Mechanical VTE prophylaxis options: 
 anti-embolism stockings (thigh or knee length) 1165

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   39 
  foot impulse devices 
 intermittent pneumatic compression devices (thigh or knee length) 
Post-procedure VTE prophylaxis  
For certain procedures pharmacological VTE prophylaxis is recommended for all patients, using one of 
 dabigatran, started 14 hours after surgery

 dabigatran, started 14 hours after surgery 
 fondaparinux, started 6 hours after surgery 
 LMWH, started 6-12 hours after surgery 
 rivaroxaban, started 6-10 hours after surgery. 
 Apixaban 
 
Procedure Length of prophylaxis 
Elective hip 28-35 days 
Elective knee 10-14 days 
Hip fracture 28-35 days 
Superficial thrombophlebitis 
 Superficial thrombophlebitis, as the name suggests describes the inflammation a ssociated with

thrombosis of one of the superficial veins, usually the long saphenous vein of the leg .  
 This process is usually non-infective in nature but secondary bacterial infection may  rarely occur 
resulting in septic thrombophlebitis.  
 Around 20% with superficial thrombophlebitis will have an underlying deep vein throm bosis 
(DVT) at presentation and 3-4% of patients will progress to a DVT if untreated.

 The risk of DVT is partly linked to the length of vein affected - an inflammed vein > 5  cm is more 
likely to have an associated DVT. 
 Traditionally NSAIDs have been used, with topical NSAIDs for limited and mild disease and oral 
NSAIDs for more severe disease. 
 Topical heparinoids have also be used in the management of superficial thro mbophlebitis. 
 A Cochrane review however found topical NSAIDs and heparinoids have no significant be nefit in

terms of reducing extension or progression to DVT.  
 Oral NSAIDs were however shown to reduce the risk of extension by 67%. 
 Compression stockings are also used.  
 Remember that the ankle-brachial pressure index (ABPI) should be measured before prescribing 
compression stockings, particularly if using class 2 or above stockings.  
 One of the major changes to the management of superficial thrombop hlebitis is the increased

use of low-molecular weight heparin. This has been shown to reduce extension and 
transformation to DVT.  
 SIGN produced guidelines in 2010:  
 Patients with clinical sig ns of superficial thrombophlebitis affecting the proximal 
long saphenous vein should have an ultrasound scan to exclude concurrent DVT.  
 Patients with superficial thrombophlebitis should have anti -embolism stockings and 
can be considered for treatment with prophylactic doses of LMWH for up to 30

days or fondaparinux for 45 days. 
 If LMWH is contraindicated, 8-12 days of oral NSAIDS should be offered. 
 Patients with superficial thrombophlebitis at, or extending towards, the sapheno -
femoral junction can be considered for therapeutic anticoagulation for 6-12 weeks.  
 This may be a significant departure from our current practice - the majority of patients with 
superficial thrombophlebitis (i.e. those affecting the long saphenous vein) should be  referred for 
an ultrasound scan.

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   40 
Thrombophilia: causes 
inherited thrombophilias:  
 the most common  Factor V Leiden  
 the higher risk of VTE   Anti-thrombin III deficiency  
 
Inherited thrombophilias  
 Gain of function polymorphisms

 Gain of function polymorphisms 
 factor V Leiden  (activated protein C resistance ): most common cause of thrombophilia 
 prothrombin gene mutation: second most common cause 
 Deficiencies of naturally occurring anticoagulants 
 antithrombin III deficiency 
 protein C deficiency  Reduced degradation of factors Va and Villa  
 protein S deficiency 
The table below shows the prevalence and relative risk of venous thromboembolism (VTE ) of the 
different inherited thrombophilias:

different inherited thrombophilias: 
Condition Prevalence Relative risk of VTE 
Factor V Leiden (heterozygous) 5% 4 
Prothrombin gene mutation (heterozygous) 1.5% 3 
Protein C deficiency 0.3% 10 
Protein S deficiency 0.1% 5-10 
Antithrombin III deficiency 0.02 10-20 
 
Acquired thrombophilias : 
 Antiphospholipid syndrome 
 Drugs 
NICE recommend testing for thrombophilia in case of unprovoked venous 
thromboembolism and family history.

thromboembolism and family history. 
Factor V Leiden 
 
 Factor V Leiden (activated protein C resistance) is the most common inherited thrombophilia,  
being present in around 5% of the UK population. 
 present in 5-9% of the European population but is rare in people of Asian and Af rican descent.  
Aetiology  
  It is due to a mutation in the Factor V Leiden mutation.

 mostly inherited in an autosomal dominant fashion  
 caused by an amino acid substitution  results in replacement of arginine with glutamine in the 
amino acid chain,  that impairs the ability of activated protein C and S to inactivate  factor Va.  
 Normally, activated protein C inactivates factor V in the clotting cascade ĺ decreases the 
activation of thrombin. 
1167

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   41 
  However, in patients with these defects, fact or V remains active ĺ activates prothrombin ĺ 
increases thrombotic events. 
Features 
 results in a 30% lifetime risk of VTE for homozygotes and 5-10% for heterozygotes. 
  Heterozygotes have a 4-5 fold risk of venous thrombosis. 
Diagnosis

Diagnosis 
 The gold standard for the diagnosis of factor V Leiden is genetic testing  for the mutation. 
 prophylaxis against thromboembolism. 
 Contraceptive medications and devices that contain the hormone estrogen should n ot be used 
 Non-hormonal and progesterone-only methods are safe for use in these patients 
 patients with no history of VTE are not indicated for prolonged anticoagulation prophy laxis. 

Protein C deficiency 
 Protein C deficiency is an autosomal codominant  condition which causes an increased risk of 
thrombosis 
 Protein C is synthesized in the liver. 
 Function of protein C 
  inactivation of factors Va and VIIIa. 
Features  
 venous thromboembolism 
 skin necrosis following the commencement of warfarin:  
 when warfarin is first started biosynthesis of protein C is reduced. This results in a

temporary procoagulant state after initially starting warfarin, normally avoided by 
concurrent heparin administration. Thrombosis may occur in venules leading to skin 
necrosis 
 The best initial step for the management of warfarin-induced skin necrosis is stoppin g 
warfarin. 
Diagnosis 
 Copperhead snake venom assay 
  the best test to detect protein-C deficiency  
 Patients with a history of a thrombotic event should receive prophylactic anticoagu lation for life.

Antithrombin III deficiency 
 Antithrombin III deficiency is an inherited cause of thrombophilia occurring in app roximately 
1:3,000 of the population.  
 Inheritance is autosomal dominant 
Function of Antithrombin III  
 Antithrombin III inhibits several clotting factors, primarily thrombin,  factors  II, IX, and  X.  
 the affinity of Antithrombin III for Factor II and X is much greater , and it thus has a much

stronger inactivation effect on these factors. 
 It mediates the effects of heparin 
Features  
 recurrent venous thromboses 
 arterial thromboses do occur but are uncommon 
Diagnosis 
 The best initial test for diagnosing antithrombin III deficiency is thrombin-heparin cofactor 
level.  
 
 thromboembolic events are treated with lifelong warfarinisation 
 heparinisation during pregnancy*

 heparinisation during pregnancy* 
 *as patients with antithrombin III deficiency have a  degree of resistance to heparin, 
anti-Xa levels should be monitored  carefully to ensure adequate anticoagulation 
 antithrombin III concentrates (often using during surgery or childbirth) 
 
 1168

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   42 
Antiphospholipid syndrome 
 Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to bo th 
venous and arterial thromboses, recurrent fetal loss and thrombocytopenia.

 It may occur as a primary disorder or secondary to other conditions, most commonly systemic 
lupus erythematosus (SLE) 
 A key point for the exam is to appreciate that antiphospholipid syndrome causes a  paradoxical 
rise in the APTT. This is due to an ex-vivo reaction of the lupus anticoagulant auto antibodies with 
phospholipids involved in the coagulation cascade 
Features 
 venous/arterial thrombosis 
 recurrent fetal loss 
 prolonged APTT

 prolonged APTT 
 (raised aPTT which fails to correct after the addition of normal human plasma). 
 other features: pre-eclampsia, pulmonary hypertension 
Associations other than SLE 
 other autoimmune disorders 
 phenothiazines (rare) 
Risk factor for thrombosis 
 Lupus anticoagulant is the greatest predictor of future thrombosis in patients with anti-
phospholipid syndrome  
Diagnosis

Diagnosis   
antiphospholipid antibody syndrome (APAS) can be diagnosed if: 
 the patient has anticardiolipin antibodies, or lupus anticoagulant on two occasions, over a peri od 
of 12 weeks, 
and either: 
 has had a thrombus, or 
 a history of recurrent < 10 week pregnancy loss, or one pregnancy loss > 10 weeks in gestation  
when other causes of pregnancy loss have been excluded. 
Antibodies

the most clinically important autoantibodies directed against phospholipid binding plasma  proteins 
are: 
1. The lupus anticoagulant 
2. Anti-beta-2 glycoproetin I antibodies, and 
3. The anticardiolipin antibodies. 
 
Management - based on BCSH guidelines 
 initial venous thromboembolic events: evidence currently supports use of warfarin with a target 
INR of 2-3 for 6 months 
 Other opinion : The occurrence of even a single thrombotic event in a patient with

antiphospholipid syndrome warrants lifelong anticoagulation , as the risk of 
recurrence is 20-70%.  
 recurrent venous thromboembolic events: lifelong warfarin; if occurred whilst taking  warfarin then 
increase target INR to 3-4 
 arterial thrombosis should be treated with lifelong warfarin with target INR 2-3 
 
Antiphospholipid syndrome: pregnancy 
 
Antiphospholipid syndrome: arterial/venous thrombosis, miscarriage, livedo reticularis 
 
1169

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   43 
  Antiphospholipid syndrome is an acquired disorder characterised by a predisposition to bo th 
venous and arterial thromboses, recurrent fetal loss and thrombocytopenia.  
lupus erythematosus (SLE)

In pregnancy the following complications may occur:  
 recurrent miscarriage 
 IUGR 
 placental abruption 
 pre-term delivery 
 low-dose aspirin should be commenced once the pregnancy is confirmed on urin e testing 
 low molecular weight heparin once a fetal heart is seen on ultrasound. This is usually 
discontinued at 34 weeks gestation 
 these interventions increase the live birth rate seven-fold

Hereditary haemorrhagic telangiectasia (HHT) 
 
 Also known as Osler-Weber-Rendu syndrome 
  autosomal dominant  
  characterised by (as the name suggests) multiple telangiectasia over the skin and mucous 
membranes. 
 occurs in approximately 1 in 5000 of the population. 
 20 % of cases occur spontaneously without prior family history. 
 commonly presents in teenagers. 62% are diagnosed by age 16. 
Genetic

Genetic 
 Two genes:  ENG  (endoglin) and ALK-1  (activin receptor like kinase-1) encode proteins 
expressed on vascular endothelial cells. Mutations in these genes cause an imbalance in 
angiogenesis.  
Features and complications  
 over 90% present with nosebleeds  (the most common initial mode of presentation) 
 GI telangiectasias and arteriovenous malformations (AVMS) may cause chronic slow bleeding 
leading to iron deficiency anemia

leading to iron deficiency anemia  
 AVMS in the respiratory system may cause dyspnoea and cyanosis and paradoxical cerebral 
emboli. 
 GI telangiectasias and arteriovenous malformations may cause acute haemorrhage  
 In the brain AVMS, angiomas and aneurysms may lead to  stroke  
Diagnosis 
 There are 4 main  diagnostic criteria  (Curacao criteria) .  
1. epistaxis : spontaneous, recurrent nosebleeds 
2. telangiectases: multiple at characteristic sites (lips, oral cavity, fingers, nose)

3. visceral lesions: for example gastrointestinal telangiectasia (with or without bleeding), 
pulmonary arteriovenous malformations (AVM), hepatic AVM, cerebral AVM, spinal AVM 
4. family history: a first-degree relative with HHT 
 The diagnosis is definite if 3 criteria are present, suspected  with 2 criteria and unlikely  if fewer 
than 2 criteria are present. 
1170

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   44 
 
The chest x-ray shows multiple pulmonary nodules  
representing arteriovenous malformations, the largest in 
the right mid-zone.  
 
The CT scan shows multiple hepatic 
arteriovenous malformations  
 
Mucocutaneous telangiectasias involve the lips  (HHT)  

Idiopathic thrombocytopenic purpura (ITP) 
 
  ITP is an immune mediated reduction in the platelet count.  
 Antibodies are directed against the glycoprotein IIb/IIIa or Ib-V-IX complex. 
 Most often the stimulus is unknown, but it can be secondary to other autoimmune disord ers (e.g. 
SLE), viral infections (e.g. CMV, VZV, hepatitis C, HIV), Helicobacter pylori , medication and 
lymphoproliferative disorders.

lymphoproliferative disorders.  
 It results in isolated thrombocytopenia , with the most common presenting sign being a purpuric 
rash. 
 ITP can be divided into acute and chronic forms: 
Acute ITP  
 more commonly seen in children 
 equal sex incidence 
 may follow an infection or vaccination 
 usually runs a self-limiting course over 1-2 weeks 
1171

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   45 
 Chronic ITP 
 more common in young/middle-aged women 
 tends to run a relapsing-remitting course 
Evan's syndrome 
 ITP in association with autoimmune haemolytic anaemia (AIHA) 
 antiplatelet autoantibodies (usually IgG)

 antiplatelet autoantibodies (usually IgG) 
 bone marrow aspiration shows megakaryocytes in the marrow. This should be carried o ut prior to 
the commencement of steroids in order to rule out leukaemia 
 No treatment is an option if asymptomatic. 
 oral prednisolone (80% of patients respond) 
 splenectomy if platelets < 30 after 3 months of steroid therapy 
 IV immunoglobulins 
 immunosuppressive drugs e.g. cyclophosphamide 
Prognosis

Prognosis 
 The principal cause of death in patients with ITP is intracranial haemorrhage  
 
Langerhans cell histiocytosis  
 Langerhans cell histiocytosis is a rare condition associated with the abnormal proliferation of 
histiocytes.  
 Also called (Eosinophilic granuloma, Histiocytosis X)   
 It typically presents in childhood with bony lesions. 
 
Features  
 bone pain, typically in the skull or proximal femur 
 cutaneous nodules 
 recurrent otitis media/mastoiditis

 recurrent otitis media/mastoiditis 
 
Young girl with multiple well defined 'punched out' osteolytic lesions with scalloped edge s (geographic 
skull) are seen in the bilateral parietal regions. The lesions have a characteristic bevelled  edge. 
 
 X-ray: osteolytic lesions 
 Biopsy (confirmatory test):  
 on electromicroscopy  tennis racket-shaped Birbeck granules   
 proliferation of Langerhans cells; polygonal cells with coffee-bean shaped nu clei,

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   46 
 
Overview 
 a myeloproliferative disorder 
 thought to be caused by hyperplasia of abnormal megakaryocytes 
 the resultant release of platelet derived growth factor is thought to stimulate f ibroblasts

 haematopoiesis develops in the liver and spleen 
 commonly associated with the JAK2 kinase mutation.  
Features 
 e.g. elderly person with symptoms of anaemia e.g. fatigue  (the most common presenting 
symptom)  
 massive splenomegaly 
  (due to extramedullary hematopoiesis) 
 hypermetabolic symptoms: weight loss, night sweats etc 
 Myelofibrosis can change to acute myeloid leukaemia. 
 
Laboratory findings 
 anaemia 
 high WBC and platelet count early in the disease

 'tear-drop' poikilocytes on blood film 
 unobtainable bone marrow biopsy - 'dry tap' therefore trephine biopsy neede d 
  bone marrow biopsy is characterized by excessive proliferation of megakaryocyte s. 
 high urate and LDH (reflect increased cell turnover) 
 
Blood film showing the typical 'tear-drop ' poikilocytes of myelofibrosis 
Treatment 
 Bone marrow transplant is the only curative treatment 
 
Myelodysplastic syndrome (MDS) 
 premalignant condition. 
 primarily affects elderly people (> 60 ). 
 more common in males than in females 
 clonal mutation predominates in the bone marrow, suppressing healthy stem cells. 
 the main cause of cytopenias  
 In the early stages of MDS   increased apoptosis (programmed cell death).  
 As the disease progresses and converts into leukemia,  proliferation of leukemic cells 
overwhelms the healthy marrow. 
Causes

Causes 
 primary or idiopathic MDS (80%) 
 genetic predisposition  
 hematopoietic stem cell injury caused by exposure to any of the following: 
 Cytotoxic chemotherapy 
 Radiation 
 Viral infection 
1173

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   47 
  Genotoxic chemicals (eg, benzene) 
 
Features 
macrocytic anaemia, thrombocytopenia and neutropenia with a small number of circulating 
blasts  suggests a diagnosis of myelodysplastic syndrome  
 80% of patients present because of symptoms of anaemia (fatigue and malaise )

 Petechiae, ecchymoses, and nose and gum bleeding are common manifestation s of a low 
platelet count.  
 neutropenia may leads to fever and infections 
  blood film: 
 dimorphic picture (some red cells are hypochromic and microcytic, while others appear 
macrocytic) 
 neutrophils are hypogranular and hyposegmented (Pelger-Huet cells). 
 The peripheral blood count may show; 
 single cytopenia (anemia, thrombocytopenia, or neutropenia) in the early phase or

 bicytopenia (2 deficient cell lines) or  
 pancytopenia (3 deficient cell lines) in later stages. 
 unexplained macrocytic anemia with no evidence of megaloblastic anemia  
 Bone marrow aspirate  stained with Perls' stain  showed ring sideroblasts  
 Ring sideroblasts contain an abnormally high concentration of iron, usually stored in 
perinuclear mitochondria. 
 Perls' stain (which stains for iron) shows this iron deposition as a dark ring around the 
margin of the nucleus.

margin of the nucleus. 
 Cytogenetic studies of the bone marrow cells: 
 Chromosomal abnormalities are clonal and include 5q-, monosomy 7 (-7) or 7q- , 
trisomy 8 (+8),  
 Multiple combinations indicates a very poor prognosis.  
 A single abnormality, except those involving chromosome 7, indicates good 
 The (French-American-British (FAB) system classifies MDS into the following five subgrou ps : 
 Refractory anemia (RA) 
 RA with ringed sideroblasts (RARS)

 RA with ringed sideroblasts (RARS) 
 RA and RARS are characterized by ≤ 5% myeloblasts in bone marrow.  
 RARS is defined morphologically as having 15% erythroid cells with abnormal 
ringed sideroblasts ,  
 Both RA and RARS have a prolonged clinical course and a low prevalence of 
progression to acute leukemia.  
 progression to acute leukemia occurred in 5% of RARS cases, compared 
with 25% of RAEB cases 
 RA with excess blasts (RAEB; 6-20% myeloblasts)

 RAEB in transition to AML (RAEB-T; 21-30% myeloblasts) 
  acute myeloid leukemia (AML; >30%). 
 Chronic myelomonocytic leukemia (CMML) 
 manifests as  
 monocytosis of ≥1000/μL,  
 total white blood cell (WBC) count of < 13,000/μL, and  
  trilineage dysplasia.  
 CMML must be differentiated from classic chronic myelocytic leukemia, which is 
characterized by a negative Ph chromosome. 
 WHO classification 2008:

 WHO classification 2008: 
 Refractory anaemia  with unilineage dysplasia- ie  anaemia, neutropaenia  or 
thrombocytopaenia (<5% blasts) 
 Refractory anaemia with ring sideroblasts (<5% blasts; >15% sideroblasts) 
 Refractory anaemia  with  multilineage dysplasia (  based on bone marrow  dysplasia in 2 
or more myeloid lineages) 
 Refractory anaemia with excess blasts-1(5-9% blasts)  and refractory anaemia  with 
excess blasts -2 (10-19%)

excess blasts -2 (10-19%) 
 Blasts > 20% is now classified as acute myeloid leukaemia. 
 Myelodysplasia unclassified 
 Myelodysplasia with isolated 5qdel( cytogenetic abnormality with prognostic significance) 1174

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   48 
  
Prognosis 
 Median survival is two years.  
 Patients are more likely to have serious infections or life-threatening bleeds than blastic 
transformation. 
 MDS who progress to acute leukemia have a poor prognosis than that of de novo acu te myeloid 
leukemia (response to chemotherapy is worse)

leukemia (response to chemotherapy is worse)  
 International Prognostic Scoring System (IPPS) 
 The revised I (IPSS-R)  score is calculated on the basis of five variables: 
1. Hemoglobin level 
2. Absolute neutrophil count 
3. Platelet count 
4. Percentage of bone marrow blasts 
5. Cytogenetic category 
 Supportive therapy,  
 including transfusions of the cells that are deficient (ie, red blood cells [RBCs], platelets),

and treatment of infections are the main components of care. 
 As the vast majority are elderly patients with other medical conditions, excessive 
intervention is unwarranted (لا مبرر له .) 
 Granulocyte-colony stimulating factor (G-CSF) and recombinant erythropoietin (r-Epo) can 
improve blood counts.  
 National Comprehensive Cancer Network (NCCN) guidelines recommend the use 
of  erythropoiesis-stimulating agents (ESAs)  for treatment of symptomatic anemia

in patients in the R-IPSS very low risk, low risk, or intermediate risk category whose 
tumor lacks the 5q31 deletion and whose level of endogenous EPO is ≤500 
mU/mL.  
 In cases of the presence of ringed sideroblasts or an absence of response , the 
addition of granulocyte colony-stimulating factor (G-CSF; filgrastim),  1–2 μg/kg 
1–3 times per week should be considered. 
 hypomethylating agent azacytidine, which has been shown to improve survival compared  with

either supportive or aggressive therapy and is approved for use in MDS by (FDA). 
 Aggressive cytotoxic chemotherapy is generally reserved for treatment of transformation to  acute 
myelogenous leukaemia (AML) in younger patients. 
Leuco-erythroblastic anaemia 
 leuco-erythroblastic anaemia (left-shifted granulocytic series and nucleated red blood 
cells) 
 This can be seen with:

cells) 
 This can be seen with: 
 high bone marrow turnover, e.g. in severe haemolytic anaemia  
 (the reticulocyte count will be high),  
 myelofibrosis and chronic myeloid leukaemia  
 (where there will be splenomegaly and the white cell and platelet count will usually  
be raised)  
 bone marrow invasion.  
 Often in bone marrow invasion the invading malignancy will already have 
been diagnosed previously.  
 The diagnosis requires a bone marrow trephine, which will usually show

replacement of haematopoietic tissue with malignant cells. 
Polycythaemia 
Polycythaemia may be relative, primary (polycythaemia rubra vera) or secondary 
Relative causes  
 stress: Gaisbock syndrome 
Primary 
Secondary causes 
 COPD 
 altitude 
 obstructive sleep apnoea 1175

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   49 
  excessive erythropoietin: cerebellar haemangioma, hypernephroma, hepatoma , uterine fibroids* 
 *uterine fibroids may cause menorrhagia which in turn leads to blood loss - polycythaemia i s rarely 
a clinical problem 
To differentiate between true (primary or secondary) polycythaemia and relative polycythaemia :

 red cell mass  studies are sometimes used. In true polycythaemia the total red cell mass in 
males > 35 ml/kg and in women > 32 ml/kg 
 The discovery of the JAK2 mutation has made red cell mass a second-line investigation  for 
patients with suspected JAK2-negative PRV.  
 JAK2 is a crucial tyrosine kinase which transmits the EPO signal to increase red cells production. 
 
Polycythaemia rubra vera (PRV)

Polycythaemia rubra vera (PRV) 
 
 Polycythaemia rubra vera (PRV) is a myeloproliferative disorder caused by clonal proliferation of 
a marrow stem cell leading to an increase in red cell volume, often accompanied by 
overproduction of neutrophils and platelets.  
 a mutation in JAK2 is present in approximately 95% of patients with PRV and this has resulted  in 
significant changes to the diagnostic criteria.  
 peak incidence in the sixth decade 
Features  
 hyperviscosity

Features  
 hyperviscosity 
 pruritus, typically after a hot bath 
 splenomegaly 
 haemorrhage (secondary to abnormal platelet function  NOT NUMBER) 
 plethoric appearance 
 hypertension in a third of patients 
 low ESR 
 Low EPO levels 
 the strongest pointer towards primary polycythaemia 
 myeloproliferative   increased red blood cell production by the marrow  turns off 
endogenous EPO production low EPO level. 
 raised leukocyte alkaline phosphatase (ALP)

 raised leukocyte alkaline phosphatase (ALP)  
 Mild prolonged PT & PTT : this is related to the ratio of plasma and citrate. In the blue tubes that 
are used for coagulation tests the ratio is normally 1 citrate to 9 of whole blood. If there is l ess 
plasma due to the polycythaemia there will be excess citrate and this will prolong coagulation 
tests such as the APTT and prothrombin time. 
 Others: hyperuricaemia, peptic ulceratio n. 
 
Following history and examination, the British Committee for Standards in Haematology (BCSH) 
recommend the following tests are performed 
 full blood count/film (raised haematocrit; neutrophils, basophils, platelets raised in ha lf of 
patients) 
 JAK2 mutation 
 serum ferritin 
 renal and liver function tests 
If the JAK2 mutation is negative and there is no obvious secondary causes the BCSH sugg est the 
following tests: 
 red cell mass 
 arterial oxygen saturation

 arterial oxygen saturation 
 abdominal ultrasound 
 serum erythropoietin level 
1176

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   50 
  bone marrow aspirate and trephine 
 cytogenetic analysis 
 erythroid burst-forming unit (BFU-E) culture 
 
JAK2-positive PRV  - diagnosis requires both criteria to be present 
Criteria Notes 
A1 High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell 
mass (>25% above predicted)

mass (>25% above predicted) 
A2 Mutation in JAK2 
 
JAK2-negative PRV  - diagnosis requires A1 + A2 + A3 + either another A or two B criteria 
 
A1 Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in 
men, >0.56 in women 
A2 Absence of mutation in JAK2 
A3 No cause of secondary erythrocytosis 
A4 Palpable splenomegaly 
A5 Presence of an acquired genetic abnormality (excluding BCR-ABL) in 
the haematopoietic cells 
B1 Thrombocytosis (platelet count >450 * 109/l)

B1 Thrombocytosis (platelet count >450 * 109/l) 
B2 Neutrophil leucocytosis (neutrophil count > 10 * 109/l in non-smokers; > 
12.5*109/l in smokers) 
B3 Radiological evidence of splenomegaly 
B4 Endogenous erythroid colonies or low serum erythropoietin 
 aspirin 
 venesection - first line treatment 
 hydroxyurea -slight increased risk of secondary leukaemia 
 phosphorus-32 therapy 
Prognosis 
 thrombotic events are a significant cause of morbidity and mortality

 5-15% of patients progress to myelofibrosis 
 Pastest note  Transition from primary polycythaemia to myelofibrosis occurs in 
about 30%of patients, therefore,  the probability of developing myelofibrosis is 
higher and thus more likely than acute leukaemia  
 5-15% of patients progress to acute leukaemia (risk increased with chemotherapy treatment) 
particularly if patients have been exposed to radioactive phosphorous treatment or busul fan 
therapy.

therapy. 
Myelofibrosis  
 Primary myelofibrosis is a disorder in which normal bone marrow tissue is gradually replaced 
with a fibrous scar-like material.  
 Over time this leads to progressive bone marrow failure.  
 Most commonly seen in older adults (5th/6th decade)  
 It is almost always accompanied by significant splenomegaly and is JAK2 mutation-positiv e in 
about 50% of cases.

about 50% of cases.  
 fatigue, splenomegaly and teardrop cells 1177

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   51 
 Complications 
 Portal hypertension 
 occurs in 7% of patients with primary myelofibrosis  
 may be related to increased portal flow resulting from marked splenomegaly and to 
intrahepatic obstruction resulting from thrombotic obliteration of small portal veins.  
 This may result in variceal bleeding or ascites.

 Hepatic or portal vein thrombosis may occur.  
 Symptomatic portal hypertension is managed by splenectomy, with or without the creation  
of a portosystemic shunt. 
 Peripheral blood smear 
 tear-drop  RBC  
 membrane is disrupted when RBC passed through fibrosis to leave bone marrow 
 nucleated RBCs 
 band granulocytes 
Treatment 
 It is generally incurable,  
 although bone marrow transplantation and JAK2 inhibitors have a role in younge r patients.

 Disseminated intravascular coagulation (DIC)  
 (DIC) is characterized by:  
 systemic activation of blood coagulation   deposition of fibrin microvascular thrombi in 
various organs and contributing to multiple organ dysfunction syndrome (MODS).   
 Consumption of coagulation proteins and platelets (from ongoing activation of coagulatio n) 
may induce severe bleeding  
 present in 1% of hospitalized patients.  
Common Causes

Common Causes 
 Sepsis and severe infection ( most commonly) 
 Trauma (neurotrauma) 
 Organ destruction (eg, pancreatitis) 
 Malignancy (solid and lymphoproliferative/myeloproliferative malignancies) 
 Severe transfusion reactions 
 Obstetric complications – Amniotic fluid embolism; abruptio placentae; hemolysis, elevated liver 
enzymes, low platelets (HELLP) syndrome; eclampsia 
Diagnosis 
 
 The platelet count and the fibrinogen level are almost always decreased in the presence of

DIC.Although these tests are not specific for DIC, normal levels exclude the possibility of DIC . 
 The presence of schistocytes, or red cell fragments, is a frequent but non-specific finding in DIC. 
 Increased levels of  fibrin degradation products (FDP)  occur in a variety of conditions in which 
clot formation and lysis occur. D-dimers  are produced by the action of plasmin on cross-linked 
fibrin.These tests reflect the microangiopathy of DIC and have been found to be  sensitive,

specific, and efficient in the diagnosis of DIC. 
 the combination of the D-dimer and the FDP assay provides the most rapid and specific 
diagnosis of DIC. 
Treatment 
 When bleeding is the major problem, the aim is to maintain the prothrombin and activa ted 
thromboplastin time at a ratio of 1.5 times of the control and the fibrinogen level abov e 1 g/L.  
 fibrinogen replacement infusion (cryoprecipitate) is the appropriate first choice

 Platelet transfusion is recommended if the count is less than 50 ×109/L. 
 
 1178

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   52 
Thrombocytopenia 
 
Causes of thrombocytopenia: 
 ↓production (bone marrow infiltration, suppression, or fibrosis),  
 ↑ destruction (DIC, ITP, and TTP/HUS),  
 dilution 
 sequestration due to splenomegaly. 
 
Causes of severe thrombocytopenia 
 ITP 
 DIC

 ITP 
 DIC 
 TTP 
 haematological malignancy 
Causes of moderate thrombocytopenia 
 heparin induced thrombocytopenia (HIT) 
 drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides) 
 alcohol 
 hypersplenism 
 viral infection (EBV, HIV, hepatitis) 
 SLE/antiphospholipid syndrome 
Gestational thrombocytopaenia  
 very common.

 very common.  
 Most importantly, the patient should be closely monitored from the present time until she d elivers  
 The platelet count is very mildly reduced 
 no specific intervention 
 Steroids may only need to be considered if the platelet count is persistently less than 30  within 
the last 2 weeks of pregnancy.  
 Steroids may be considered in the last couple of weeks of pregnancy to raise the plate let count

temporarily so that a caesarean section or epidural anaesthesia may be undertaken safely. This 
may well be combined with intravenous immunoglobulin 
 
immune thrombocytopenia 
 the patient is well.  
 There is post viral illness with quite marked thrombocytopenia but other full blood count (FBC) 
parameters are normal. 
 The diagnosis is one of exclusion,  
 The most important investigation is a blood film.  Although not diagnostic, this will confirm

the FBC findings and also exclude more sinister pathology such as leukaemia . 
  in the absence of major bleeding, management would be observation, as it can resolv e 
spontaneously. 
Thrombocytosis 
 Thrombocytosis is an abnormally high platelet count, usually > 400 * 109/l. 
 Thrombopoietin is the key hormone in the regulation of megakaryocyte differentiation.  
 
Causes

Causes   
 reactive: platelets are an acute phase reactant - platelet count can increase in respo nse to stress 
such as a severe infection or surgery 
 The most common cause of thrombocytosis is a reactive thrombocytosis. 
 May occur as a response to exercise 
 Secondary thrombocytosis does not place the patient at risk for haemostatic or 
cardiovascular events. 
 essential thrombocytosis (see below), or as part of another myeloproliferative disorder such as

chronic myeloid leukaemia or polycythaemia rubra vera 
 hyposplenism 1179

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   53 
Essential thrombocytosis (ET):  
 Essential thrombocytosis is one of the myeloproliferative disorders which overlaps with chronic 
myeloid leukaemia, polycythaemia rubra vera and myelofibrosis.

 Megakaryocyte proliferation results in an overproduction of platelets, in the absence o f any 
identifiable cause. 
  usually affects older people between the ages of 50 and 70 years 
 occurs equally in both males and females. 
Features  
 asymptomatic ( 25-33% ) 
 tingling or burning in the hands and feet, headache, visual problems, weakness and diz ziness.  
 burning sensation in the hands is a characteristic symptom 
 Erythromelalgia

 Erythromelalgia 
 burning pain, warmth, and redness of the extremities  
 The pain increases with exposure to heat and improves with cold  
 These symptoms result from excessive numbers of platelets causing blockages in small or 
large blood vessels in different parts of the body. 
 Other symptoms include sweating, low-grade fever, and pruritus.  
 Splenomegaly  (40-50%) 
  Hepatomegaly ( 20% ) 
 both thrombosis and haemorrhage can be seen 

 Complete blood cell count (CBC)  
 platelet count > 600 * 109/l 
 Around 30% will also have a mildly raised RBC and / or WBC. 
 A red blood cell (RBC) mass study helps to exclude polycythemia vera. The RBC 
mass is elevated in polycythemia vera, but is normal in essential thrombocytosis. 
 Genetic studies 
 The majority of patients have mutations in one of three genes: 
1. Janus kinase 2 ( JAK2 ), 
50-60% of patients. 
2. calreticulin ( CALR ), 
 found in 25%

 found in 25%  
3. myeloproliferative leukemia virus oncogene ( MPL).  
 about 3-5% of cases.  
 MPL codes for the thrombopoietin receptor protein, which promotes the 
growth and proliferation of megakaryocytes.  
 The mutations result in constitutive activation of the thrombopoietin receptor 
protein. 
 Rare cases involve mutations in the thrombopoietin gene ( THPO ), 
 associated with autosomal dominant hereditary thrombocytosis 
 Bone marrow examination

 Bone marrow examination 
 Ĺ bone marrow cellularity (found in 90% ) 
 Megakaryocytic hyperplasia is common 
 Bone marrow reticulin is usually increased, but collagen fibrosis is uncommon 
 Elevation of C-reactive protein (CRP), fibrinogen, and interleukin 6 levels suggests secondary 
thrombocytosis, because those are acute-phase reactants 
 Vitamin B- 12 levels are increased in 25% of patients 
 Uric acid levels are elevated in 25% of patients  
Diagnosis

Diagnosis 
 British guidelines propose the following five criteria for diagnosis of essential thrombocy tosis : 
1. Sustained platelet count ≥450 × 109/L 
2. Presence of an acquired pathogenetic mutation (eg, in the JAK2, CALR  or MPL genes) 
3. No other myeloid malignancy, especially polycythemia vera, primary myelofibrosis, chronic 
myeloid leukemia, or myelodysplastic syndrome 
4. No reactive cause for thrombocytosis and normal iron stores

5. Bone marrow aspirate and trephine biopsy showing increased megakaryocyte numbers 
displaying a spectrum of morphology with predominant large megakaryocytes with 
hyperlobated nuclei and abundant cytoplasm; reticulin is generally not increased (grades 
0–2/4 or grade 0/3) 
 Diagnosis requires the presence of criteria 1 –3 or criterion 1 plus criteria 3 –5.  1180

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   54 
  
adverse prognostic markers for essential thrombocythaemia (ET): 
 Age above 60 
 Symptomatology - particularly thrombosis and 
 Platelet count above 1500. 
 Previous thrombosis 
 Obesity 
 Cardiovascular risk factors such as smoking, hypertension, and hypercholesterolemia

 Markers of hypercoagulability such as factor V Leiden and antiphospholipid antibodies [4] 
Manageme nt 
 low risk  observation only  
 high-risk of thrombosis (eg, age  >60, history of thrombosis, or platelet counts >1500 ). 
 hydroxyurea (hydroxycarbamide) is widely used to reduce the platelet count 
 first-line treatment 
 interferon- α is also used in younger patients  
 Interferon alfa is a biologic response modifier.  
 used as second line in older patient

 used as second line in older patient  
 Interferon alfa is not known to be teratogenic and does not cross the place nta, 
perhaps making it safe for use during pregnancy. 
  Italian guidelines recommend interferon alfa as a first-line platelet-lowe ring therapy 
for patients younger than 40 years 
 low-dose aspirin may be used to reduce the thrombotic risk 
 low-dose aspirin may be useful in treating patients with symptoms of microvascular 
occlusion (eg, erythromelalgia ).

occlusion (eg, erythromelalgia ). 
 Patients with the JAK2 mutation or cardiovascular risk factors can be treated with 
daily low-dose aspirin 
 Extreme thrombocytosis may promote the abnormal adsorption of large von 
Willebrand factor (VWF) multimers.  
 These patients should be screened for the presence of acquired von 
Willebrand disease (VWD).  
 if ristocetin cofactor level  (Functional von Willebrand Factor)   is at 
least 30% in absence of other high risk factors; Low-

dose aspirin therapy (eg, ≤100 mg/day)  is acceptable  
 if it is less than 30%, all aspirin should be avoided.  
 Plateletpheresis  
 If platelet is very high with symptoms of clotting or bleeding 
Prognosis  
 extremely good in ET with survival of over two decades expected. 
  The risk of transforming to acute myeloid leukaemia is relatively low (<1% ). 
Thrombotic thrombocytopenic purpura (TTP)

Thrombotic thrombocytopenic purpura (TTP) 
 
(TTP) is classically characterised as a pentad of : thrombocytopenia, microvascular haemolysis, 
fluctuating neurological signs, renal impairment and fever.  
 
Pathogenesis of thrombotic thrombocytopenic purpura (TTP) 
 abnormally large and sticky multimers of von Willebrand's factor cause platelets to clump with in 
vessels 
 in TTP there is a deficiency of ADAMTS13 (a metalloprotease enzyme) which breakdowns la rge

multimers of von Willebrand's factor 
 The primary event that occurs appears to be endothelial damage, which then leads to  
thrombus formation,  end organ  damage (eg brain and kidneys) and platelet consumption  
 overlaps with haemolytic uraemic syndrome (HUS) 
1181

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   55 
 Causes 
 post-infection e.g. urinary, gastrointestinal (Escherichia coli 0157 subtype)  
 drugs:  
 ciclosporin,  
 oral contraceptive pill,  
 penicillin, metronidazole 
 antiplatelets : clopidogrel  or ticlodipine ( < 1%),  
 acyclovir,   
 FK506,  
 Penicillamine   
 sulphonamides 
 tumours

 tumours 
 SLE 
 HIV 
 
Features 
 rare, typically adult females 
 fever 
 fluctuating neuro signs (microemboli) 
 Which investigation will be most useful to establish the diagnosis? 
 Peripheral blood film 
  The peripheral blood film reveals fragmented RBCs (schistocytes, eg, spherocytes, 
segmented RBCs, burr cells, or helmet cells). 
 
 no antibiotics - may worsen outcome 
 plasma exchange is the treatment of choice 
 TTP has an untreated mortality of up to 90% and therefore rapid plasma exchange 
(PEX) may be a life saving intervention.  
 steroids, immunosuppressants 
 Intravenous methylprednisolone is indicated after treatment with PEX has been 
completed.  
 Vincristine 
 Platelet transfusion in TTP is only indicated if there is an on-going life-threatening bleed.

 There is no current role for intravenous immunoglobulin in the routine managem ent of TTP, 
however there have been reports of its successful use in PEX- and steroid-refractory cases.  
Prognosis 
 In adults, the mortality rate 20- 50% 
January 2013 exam: H/O ĐoŶfusioŶ + feǀer + ↓Platelets ϲϱ , ↑Urea Ϯϯ, ↑CreatiŶiŶe ϯϲϲ.What is the ŵost 
likely diagnosis? Thrombotic thrombocytopenic purpura  
Von Willebrand's disease

Von Willebrand's disease 
The combination of a petechial skin rash combined with a slightly elevated APTT and 
reduced factor VIII activity make Von Willebrand's disease the most likely diagnosis 
 
Overview 
 Von Willebrand's disease is the most common inherited bleeding disorder. 
 The majority of cases are inherited in an autosomal dominant  fashion*  
  characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are com mon

whilst haemoarthroses and muscle haematomas are rare 
 Symptoms are exacerbated by medications that inhibit platelet function, such as asp irin and 
other NSAIDs .  
1182

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   56 
 Role of von Willebrand factor  
 large glycoprotein which forms massive multimers  
 Von Willebrand factor is a coagulation protein that binds to collagen and to the GpIb platelet 
receptor during platelet adhesion.  
 promotes platelet adhesion to damaged endothelium 
 carrier molecule for factor VIII

 carrier molecule for factor VIII 
 Factor VIII circulates bound to von Willebrand factor (vWF), which protects factor VIII from 
degradation.  
 Decreased vWF (in part) prolongs the PTT by leading to decreased factor VIII. 
 In people with hemophilia, strategies to increase circulating levels of factor VIII include 
maximizing vWF levels.  
 increases vWF secretion (leading to increased functional levels of factor VIII).

 Even in hemophilia A, there is still a small amount of normal factor VIII (<5%). 
 The intrinsic  coagulation pathway is defective in von Willebrand disease. 
Types 
 type 1 : partial reduction in vWF (80% of patients) 
 the most common form  
 patients have up to a 50% reduction in von Willebrand factor (vWF). 
 Autosomal dominant with variable penetrance  
 Many are asymptomatic and are only diagnosed following an episode of bleeding

associated with a dental extraction or minor surgery. 
 type 2:  abnormal form of vWF 
 type 3 : total lack of vWF (autosomal recessive)  (most severe form) 
 prolonged bleeding time  (due to impaired platelet adhesion and aggregation) 
 The bleeding time would be a good screening test but it will not give a quantit ative 
measurement of bleeding tendency in type I vWBD   
 neither sensitive nor specific

 neither sensitive nor specific 
 platelet function analyser (PFA100), have better testing characteristics than the 
bleeding time 
 APTT may be prolonged (due to reduced circulating factor VIII). 
 factor VIII levels may be moderately reduced 
  the most useful test to assess bleeding tendency in Von Willebrand's disease ?  
Plasma factor VIII activity   
 vWB antigen and activity (Ristocetin cofactor assay )  (RICOF)

 The most useful test in practice is to do the vWB antigen and activity (RICOF),  but 
you would also do FVIIIc as this is also low in vWD. 
 In type I vWD the prothrombin time (PT) and Platelet count will be normal . 
 defective platelet aggregation with ristocetin 
 tranexamic acid for mild bleeding 
 desmopressin (DDAVP):  
 raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial 
cells

cells 
 DDAVP is the initial treatment of choice for patients with VWD type 1.  
 Other therapies such as factor VIII concentrates containing VWF are not 
usually required. 
 factor VIII concentrate 
 In minor trauma ,  
 desmopressin (DDAVP) can be used to increase the concentration of VWF. 
  The choice of treatment for a mild vWB facing a more invasive procedure would be  
DDAVP, providing there is no contraindication.

DDAVP, providing there is no contraindication.  
 vWB factor concentrate would be reserved as second line treatment to DDAVP. 
 for major surgery ,  
 factor VIII concentrate is used to increase the concentration of vWF.  
 The most commonly used is Humate- P. 
 Purified or recombinant preparations are avoided since they contain only small 
concentrations of vWF. 
 for Women with   menorrhagia: 
 Oral contraceptives (the Pill) raise the level of von Willebrand factor in the blood for

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   57 
Haemophilia 
Definitions 
 Haemophilia A is due to a deficiency of factor VIII whilst in haemophilia B (Christma s disease) 
there is a lack of factor IX 
 Hemophilia A (factor VIII): ∼ 80% of cases 
 Hemophilia B (factor IX): ∼ 20% of cases 
Etiology

Etiology 
 X-linked recessive disorder  
 Occurs almost exclusively in males due to an X-linked pattern of inheritance.  
 typically skips generations 
 A carrier mother has a 50% chance of passing down the disease to her sons and a 5 0% 
chance of passing down the carrier gene to her daughters.  
 Up to 30% of patients have no family history of the condition.  
 The pathological problem in both haemophilia A and haemophilia B is the inabil ity to form a

functional tenase complex to activate factor X to factor Xa  
 The intrinsic coagulation pathway is defective in hemophilia. 
Features  
 typically present initially with easy bruising secondary to minimal trauma,  
 haemoarthroses, haematomas 
 Musculoskeletal bleeding is the most common type of haemorrhage. 
 prolonged bleeding after surgery or trauma, 
 
Severity Clinical signs Factor VIII or IX activity 
Physiologic condition None ≥ 50%

Physiologic condition None ≥ 50%  
Mild hemophilia Hematomas following severe trauma > 5% to < 50% 
Moderate hemophilia Hematomas following mild trauma ≥ 1%  to 5% 
Severe hemophilia Spontaneous hematomas < 1% 
 
Petechial bleeding is a common sign of platelet disorders, NOT coagulation disorders such as 
hemophilia 
 
Blood tests 
 mixing study  
 requested if the aPTT is prolonged. 
 The patient's plasma is mixed with normal plasma and the aPTT repeated.

 Correction of aPTT with mixing study suggests coagulation factor deficiency. 
 plasma factor VIII and IX assay 
 bleeding time, thrombin time, prothrombin time normal 
 
Although female carriers of the haemophilia gene do not normally suffer from increased 
bleeding risk, APTT may be prolonged. 
Treatment  
 factor VIII or IX replacement. 
 Side effects: 
 Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII treatment 
 
 1184

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   58 
Methemoglobinemia  
 
Methemoglobin  
 hemoglobin is oxidized to the ferric (Fe3+) 
 Ļ affinity for O 2 
 Ĺ affinity for cyanide (CN-) 
 CN- poisoning treated with methemoglobin

CN- poisoning treated with methemoglobin 
  
 Methemoglobin (met-Hb) results from the presence of iron in the ferric form   (Fe3+)  instead of the 
usual ferrous form  (Fe2+).  
 met-Hb cannot carry oxygen  
 met-Hb  is a naturally occurring oxidized metabolite of hemoglobin, and physiologic leve ls (< 1%) 
are normal.  
 Methemoglobinemia (congenital or acquired) occurs when (RBCs) contain methemoglobin at 
levels higher than 1%.

levels higher than 1%.  
 Acquired methemoglobinemia is considerably more common than congenital forms.  
 The low level of methemoglobin is maintained through 2 important mechanisms.  
1. the hexose-monophosphate shunt pathway within the erythrocyte. Through th is pathway, 
oxidizing agents are reduced by glutathione. 
2. The second and more important mechanism involves two enzyme systems: 
 diaphorase I:  requires nicotinamide adenine dinucleotide (NADH)

 the major enzymatic system (This enzyme system is responsible for the 
removal of 95-99% of the methemoglobin that is produced under normal 
circumstances.) 
 Cytochrome b5 reductase plays a major role in this process by transferring 
electrons from NADH to methemoglobin, an action that results in the 
reduction of methemoglobin to hemoglobin. 
 diaphorase II: requires nicotinamide adenine dinucleotide phosphate (NADPH).  
 plays only a minor role in the removal of methemoglobin.

 This enzyme system utilizes glutathione production and glucose-6-
phosphate dehydrogenase (G6PD) to reduce methemoglobin to 
hemoglobin. 
 Play a more important role in methemoglobin regulation in patients with 
cytochrome b5 reductase deficiencies. 
 can be accelerated by exogenous cofactors such as methylene blue 
Effect of Methemoglobin: 
 does not bind oxygen, thus leading to a functional anemia .

 causes a left shift of the oxygen-hemoglobin dissociation curve , resulting in decreased 
release of oxygen to the tissues.  
 Normal people generate met-Hb but in very low levels in the range of 0.5% to 3%. 
 should be suspected when the oxygen saturation as measured by pulse oximetry is 
significantly different (lower) from the oxygen saturation calculated from arterial blood g as 
analysis (saturation gap). (low SpO 2 with normal PaO 2 and SaO 2(on ABG)

 presence of anemia and cyanosis  despite oxygen treatment results from both of these effects. 
 
Causes  
 congenital   (secondary to a deficiency in methemoglobinemia reductase) 
 acquired  
 Dapsone  
 local anesthetics (topical and injectable) 
 nitrates  
 amyl nitrite  
 aniline dyes  
 The presence of methemoglobin may also be a marker and predictor of sepsis, resulting 
from release of excessive amounts of nitrous oxide (NO)

 patients with low catalase activity (inherited or acquired) treated with rasburicase for tumor 
lysis syndrome  formation of hydrogen peroxide  methemoglobinemia 
 Some authors have suggested that catalase activity be measured before 
rasburicase therapy is initiated in this setting. 1185

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   59 
  Drugs that cause  methaemoglobinaemia  include: 
 Phenacetin 
 Sulphonamides 
 Dapsone 
 Primaquine 
 Lidocaine  
 Procaine  
 Benzo caine . 
 
Congenital (hereditary) Methemoglobinemia 
 two forms of congenital cytochrome b5 reductase (b5R) deficiency  exist:

type Ib5R deficiency type IIb5R 
more common  
cytochrome b5 reductase is absent only in RBCs 
Homozygotes appear cyanotic but usually are 
otherwise asymptomatic. 
Heterozygotes may develop acute, symptomatic 
methemoglobinemia after exposure to certain 
drugs or toxins. 
Methemoglobin levels typically range from 10% to 
35%. 
 Life expectancy is not influenced less common 
cytochrome b5 reductase is deficient in all cells, 
not just RBCs. 
associated with several other medical problems,

associated with several other medical problems, 
including mental retardation, microcephaly, and 
other neurologic complications.  
Life expectancy is severely compromised, and 
patients usually die at a very young age. 
 
presence of abnormal hemoglobins (hemoglobin M [Hb M]) 
  autosomal dominant 
 in most of these hemoglobins, tyrosine replaces the histidine residue, which binds heme to 
globin.

globin.  
 This replacement displaces the heme moiety and permits oxidation of the iron to th e ferric state.  
 Hb M is more resistant to reduction by the methemoglobin reduction enzymes 
 Patients with Hb M appear cyanotic but are otherwise generally asymptomatic. 
 
Feature  (are proportional to the methemoglobin level) : 
Classical presentation includes cyanosis with chocolate-colored blood

 3-15% - Slight discoloration (eg, pale, gray, blue) of the skin  and blood color changes (brown or 
chocolate color). 
 Discoloration of the skin and blood is the most striking physical finding. 
 Fatigue, flu-like symptoms, and headaches may be the only manifestations in th e initial 
phase. 
 15-20% - Cyanosis, though patients may be relatively asymptomatic 
 cyanosis is usually the first presenting symptom.

 25-50% - Headache, dyspnea, lightheadedness (even syncope), weakness, confusion, 
palpitations, chest pain 
 50-70% - Abnormal cardiac rhythms; altered mental status, delirium, seizures, coma; profou nd 
acidosis  
 >70% - Usually, death 
 
 Methylene blue :  
  the first line treatment 
 contraindicated in G6PD deficiency and ineffective with hemoglobin M. 
 reduction of met-Hb by methylene blue is dependent upon NADPH generated by 
G6PD.

G6PD. 
 methylene blue has an oxidant potential  hemolysis in G6PD deficient. 
 Second line treatment: when methylene blue therapy is ineffective or contraindicated 
 Exchange transfusion : for patients who do not respond to methylene blue or G6PD-
deficient individuals who are severely symptomatic 
 Hyperbaric oxygen treatment: another option 
 IV hydration and bicarbonate (for metabolic acidosis) 
 1186

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   60 
  
Anticoagulants  
Heparin  
 can be given as either: 
  unfractionated, intravenous heparin, or  
 low molecular weight heparin (LMWH), given subcutaneously.

 Heparins generally act by activating antithrombin III .  
 Unfractionated heparin  forms a complex which inhibits thrombin, factors Xa, IXa, XIa and XIIa.   
 LMWH hoǁeǀer oŶly ↑ the aĐtioŶ of aŶtithroŵďiŶ III on factor Xa  
 
The table below shows the differences between standard heparin and LMWH:  
 Standard Heparin  (LMWH)  
administration Intravenous Subcutaneous 
Action duration short long 
Mechanism of action  Activates antithrombin III. 
Forms a complex that inhibits

 thrombin, factors Xa, 
IXa, XIa and XIIa Activates antithrombin III. 
Forms  a complex that inhibits 
factor Xa 
 
 Bleeding 
HIT 
Osteoporosis  Bleeding 
Lower risk of HIT and 
osteoporosis  
Monitoring  Activated partial 
thromboplastin time (APTT) Anti-Factor Xa (although  
routine monitoring is not 
required) 
Notes  Useful in situations where 
there is  a↑ risk of ďleediŶg as 
anticoagulation can be 
terminated rapidly Now standard in the

terminated rapidly Now standard in the 
management of venous 
thromboembolism treatment
 and prophylaxis and 
acute coronary syndromes 
 
Heparin-induced thrombocytopaenia (HIT) 
 Types  
1. Type 1 HIT  
 non-immune mediated reaction  
 occur  soon after the initial administration of heparin (within two days)  
 due to a direct effect of the drug on platelets.  
 self-limiting condition and the platelet count will normalise with continued 
heparin administration.  
2. Type 2 HIT

2. Type 2 HIT   
 immune mediated condition  
 mechanism:  
 IgG antibodies against heparin bound to platelet facto r 4 (PF4). 
 Antibody-heparin-PF4 complex will be eliminated by the immune 
system (ĺ thrombocytopenia), and  activates platelets ĺ thrombosis  
 It is a prothrombotic condition despite being associated with low platelets.  
 typically arises 4 to 10 days after st arting heparin therapy.

 Patients may develop both venous and arterial thromboses,  
 low platelet counts and mild abnormalities of coagulation.  
 The D-dimer level is raised due to widespread thrombus formation.  
 Features  include a greater than 50% reduction in platelets, thrombosis and skin allergy 1187

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   61 
  Patients with (HIT), particularly those with associated thrombosis, often have evidence of 
increased thrombin generation that can lead to consumption of protein C . 
 If these patients are given warfarin without a concomitant parenteral anticoagulant

to inhibit thrombin or thrombin generation, the further decrease in protein C levels 
induced by the vitamin K antagonist can trigger skin necrosis.  
 To avoid this problem, patients with HIT should be treated with a direct thrombin 
inhibitor, or fondaparinux, until the platelet count returns to normal levels.  
 
 Diagnosis : HIT is confirmed by the presence of the HIT antibody and confirmed by the serotonin-
release assay (SRA). 
 Treatment

 Treatment   
 options include alternative anticoagulants such as lepirudin and danaparoid  
 Argatroban is not cleared via the kidneys; therefore, this drug is safer than 
lepirudin/fondaparinux for HIT patients with renal insufficiency.  
 Lepirudin is a direct thrombin inhibitor, which is cleared by kidneys exclusively, and 
is contraindicated in renal insufficiency.  
 Fondaparinux can be used in HIT as it does not bind to platelets, but it is

contraindicated in renal insufficiency. 
 
Heparin-induced hyperkalaemia   
 Both unfractionated and low-molecular weight heparin can cause hyperkalaemia. This is 
thought to be caused by inhibition of aldosterone secretion. 
Heparin overdose   
 Heparin overdose may be reversed by protamine sulphate, although this only partially reverses 
the effect of LMWH. 
 The dose of protamine sulphate given is dependent upon the dose of LMWH 
administered and the time of administration.

administered and the time of administration. 
 If protamine is given within eight hours  of the LMWH then a maximum 
neutralising dose is 1 mg protamine/100 units (or 1 mg) of LMWH given in the last 
dose.  
 If more than eight hours  have passed since the dose of LMWH was given, 
administer 0.5 mg  protamine per 100 units (or 1 mg) of LMWH given. 
 Protamine is administered by slow IV infusion (over 10 minutes) to avoid a hypotensive 
reaction .

reaction .  
 Protamine requires a high level of caution when being prescribed and administered. 
 
Heparin resistance  
 Heparin resistance is seen in up to 22% of patients undergoing cardiopulmonary bypass 
surgery. 
 Several mechanisms resulting in heparin resistance have been identified, including: 
 antithrombin deficiency,  
 increased heparin clearance, 
  elevated heparin-binding proteins, 
  and elevated factor VIII and fibrinogen levels.

 For cardiopulmonary bypass in particular, rapid neutralisation of thromb in is required. In 
order for heparin to be successful in this, it requires antithrombin III which is an alpha2-
globulin. It is therefore thought that antitthrombin III deficiency  is the underlying 
problem which is seen in patients resistant to heparin during cardiopulmonary bypass. 
 1188

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   62 
  Heparin and thyroid function test  
 Heparin is having an "in vitro" effect on thyroxine (T4) levels. 
 IV heparin interferes with the thyroid function tests assay on occasions displacing 
bound thyroid hormone. 
 Normal TSH + high T3 and T4 
 
Heparin and delivery

Heparin and delivery  
 Women who are anticoagulated with heparin until the onset of lab or generally experience  vaginal 
delivery with no greater blood loss than non-anticoagulated  gravidas.  
 However, Cesarean delivery in heparinized patients is accompanied by a significantly greater blood loss  
than would otherwise be anticipated. 
 If preterm labor develops in a patient receiving heparin, only the  mother is anticoagulated, and

protamine sulfate can be used  to reverse maternal heparinization. 
 
Novel oral anticoagulants (NOACs) 
The table below summaries the three NOACs: dabigatran, rivaroxaban and apixaba n. 
Dabigatran Rivaro xaban Apixaban 
UK brand 
name  Pradaxa Xarelto Eliquis 
Mechanism 
of action  Direct thrombin 
inhibitor  Direct factor Xa 
inhibitor  Direct factor Xa inhibitor 
Route  Oral Oral Oral

Route  Oral Oral Oral 
Excretion  Majority renal Majority liver Majority faecal 
NICE 
indications  Prevention of VTE 
following hip/knee 
surgery 
 
Treatment of DVT 
and PE 
 
Prevention of stroke 
in non-valvular AF* Prevention of VTE 
surgery  
 
and PE 
 
in non-valvular AF* Prevention of VTE following hip/knee 
surgery 
 
Treatment of DVT and PE 
 
Prevention of stroke in non-valvular AF*

Prevention of stroke in non-valvular AF* 
 
*NICE stipulate that certain other risk factors should be present. These are complicated and di ffer 
between the NOACs but generally require one of the following to be present: 
 prior stroke or transient ischaemic attack 
 age 75 years or older 
Dabigatran  
1189

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   63 
 Stop dabigatran two days before polypectomy 
 Mode of action:  Dabigatran is a direct thrombin inhibitor  with a rapid onset of action.  
 It is administered as a prodrug  
 The prodrug dabigatran etexilate is rapidly converted by tissue esterases to 
dabigatran.

dabigatran.  
 it is predominately (80%) excreted by the kidneys.  
 The anticoagulant effect starts within minutes of oral ingestion and peaks after 2-3 hours.  
 Advantage of dabigatran:  
 due to its short half-life, a patient's coagulation status will normalize more rapidly 
than that of a patient treated with warfarin in almost all cases.  
 No need for routine monitoring  
 Disadvantage of dabigatran

 Disadvantage of dabigatran  
 Dabigatran is not recommended in patients with prosthetic heart valves  because 
their safety and efficacy have not established.  
 The rates of thromboembolism are higher for valves in the mitral compared 
with those in the aortic position.  
 caged-ball valves are the most thrombogenic  followed by tilting-disk and bi-
leaflet valves.  
 more thromboembolic events (e.g., valve thrombosis, stroke, TIA, and myocardial

infarction) were observed with dabigatran than with warfarin;  
 excessive major bleeding (predominantly postoperative pericardial effusions 
requiring intervention for hemodynamic compromise) was observed with 
dabigatran, compared with warfarin.  
 Monitoring of the anticoagulant effects of dabigatran  
 In general, ͞routine ͟ monitoring  is not required in most cases.  
 However, in some clinical situations a clinician may wish to determine the degree to

which dabigatran is reducing the coagulant potential of the blood; e.g., if a patient 
taking dabigatran requires emergency surgery, has an intracranial or major systemic 
bleed, or is being considered for thrombolysis due to an ischemic stroke.  
 The thrombin time  (TT) and ecarin clotting time are considered the most accurate 
measures of dabigatran's anticoagulant effect.  
 The aPTT and, if available, the thrombin time (TT) should be used to measure

the anticoagulant effect of dabigatran,  
 INR and PT tests are unreliable  
  Effect of dabigatran on procedural bleeding risk  
  Dabigatran should be discontinued 1 to 2 days (creatinine ĐlearaŶĐe ≥ ϱ0 ŵL/ŵiŶ)  
or 3 to 5 days (creatinine clearance <50 mL/min) before invasive or surgical 
procedures.  
 Clinicians may want to consider ͞longer ͟ periods of discontinuation for patients 
undergoing major surgery in which bleeding could have serious consequences (e.g.,

cardiac, neurosurgery, major abdominal or pelvic, spinal puncture, or placement of 
a spinal or epidural catheter or port).  
 If surgery is urgent and cannot be delayed, there is an increased risk of bleeding; 
patients with a normal aPTT appear to have a low risk of serious bleeding.  
  conversion from warfarin to dabigatran  (eg :  patient had difficulty attending for 
regular INR)  
 if a patient is taking warfarin with a therapeutic INR, it is recommended to :

Stop warfarin, perform daily INR, start dabigatran when INR falls below 2.0 1190

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   64 
  The anticoagulant effect of dabigatran starts minutes after its oral administration 
and peaks after 2-3 hours.  
 Contraindications  
 Dabigatran is contraindicated if eGFR <30ml/min.  
 Rivaroxaban, a direct inhibitor of activated factor X, is contraindicated if

eGFR <15 and needs  dose adjustment if eGFR 15 –29 mL/minute . 
 
Ecarin clotting time is prolonged by direct thrombin inhibitors such as dabigatran.  
Treatment with aspirin, warfarin or heparins does not affect Ecarin  clotting time. 
 
Idarucizumab reverses dabigatran  
 
Ref  www.medical-masterclass.com   2017 -part 2 
 
_____________________________________________________________________ _ 
Warfarin   
Warfarin - clotting factors affected mnemonic - 1972 (10, 9, 7, 2)

P450 inhibitors ↑ INR INR also ↑ by ABX that kill intestinal flora by ↓ Vit K absorption  
 
Warfarin action   inhibition of vitamin K epoxide reductase  
 Warfarin is an oral anticoagulant which inhibits the reduction of vitamin K to its active 
hydroquinone form, which in turn acts as a cofactor in the carboxylation of clotting factor II, 
VII, IX and X (mnemonic = 1972) and protein C . ( warfarin reduces protein C levels in 
the blood)

the blood) 
 Warfarin inhibits epoxide reductase (specifically the VKORC1 subunit), thereby diminishing 
available vitamin K and vitamin K hydroquinone in the tissues which inhibits the carboxylation 
activity of the glutamyl carboxylase. 
 The half-life of warfarin is approximately 44 h 
 
 venous thromboembolism: target INR = 2.5, if recurrent 3.5 
 atrial fibrillation, target INR = 2.5

 atrial fibrillation, target INR = 2.5 
 mechanical heart valves, target INR depends on the valve type and location. Mitral valves 
generally require a higher INR than aortic valves. 
 
 haemorrhage 
 teratogenic, although can be used in breast-feeding mothers 
 the most common teratogenic effect is Nasal hypoplasia  
 skin necrosis: when warfarin is first started biosynthesis of protein C is reduced. This results

in a temporary procoagulant state after initially starting warfarin, normally avoided by 
concurrent heparin administration. Thrombosis may occur in venules leading to skin necrosis 
 purple toes 
 Warfarin is generally avoided in pregnancy.   
1191

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   65 
  In the first trimester  it is associated with an increased risk of miscarriage, and 
teratogenic side effects which include chondrodysplasia patellae, asplenia and 
diaphragmatic herniae.  
 In the second and third trimester  it is associated with retroplacental and

intracerebral foetal haemorrhage, as well as foetal microcephaly, optic atrophy and 
developmental delay.  
 Patients on warfarin are monitored using the INR (international normalised ration), the ratio of 
the prothrombin time for the patient over the normal prothrombin time.  
 Warfarin has a long half-life and achieving a stable INR may take several days.  
Factors that may potentiate warfarin  
 liver disease

 P450 enzyme inhibitors, e.g.: amiodarone, Clarithromycin, ciprofloxacin 
 Clarithromycin increase INR  more than ciprofloxacin   
 Clarithromycin is metabolised by CYP3A4 and is an inhibitor, meaning that it 
does affect INR to a limited extent, leading to an increase. 
 Ciprofloxacin is a moderate inhibitor of CYP1A2; some effect is expected on 
INR, but not as great as that for clarithromycin.  
 cranberry juice

 cranberry juice 
 drugs which displace warfarin from plasma albumin, e.g. NSAIDs 
 inhibit platelet function: NSAIDs 
Interaction  
 Lipid-lowering agents 
 Simvastatin, rosuvastatin and fibrate  potentiate the anticoagulant effects of warfarin 
 Atorvastatin and pravastatinare least likely to interfere with warfarin 
 Cholestyramine  (a cholesterol-binding resin) is known to reduce the anticoagulant 
action of warfarin

action of warfarin  
 Cholestyramine reduces absorption of a number of drugs including warfarin.  
 cranberry juice  (ĹĹwarfarin effect  ĹĹ INR). The cause is thought to be bioflavonoids 
contained in the cranberry juice, which block cytochrome-P450-related warfarin metabolism 
(CYP2C9) 
 Paracetamol  given in repeated doses  may lead to an enhanced response to warfarin 
and therefore an increased INR  
 Commonly used drugs that may lead to an increased INR include cephalosporins,

azathioprine, cimetidine, metronidazole and testosterone derivatives 
 Diazepam  is a p450 enzyme inducer  and is therefore likely to reduce INR 
 the concurrent use of clopidogrel with warfarin increases the bleeding risk. 
 Co-enzyme Q10 is similar to vitamin K and reduces warfarin's anticoagulant effect  
(warfarin exerts its anticoagulant effect though inhibition of the synthesis of vitamin K 
dependent clotting factors).  
Warfarin: management of high INR

Warfarin: management of high INR 
A 2005 update of the BCSH guidelines emphasised the preference of prothrombin complex concentrate over FFP 
in major bleeding. 
Situation Management 
Major bleeding  Stop warfarin 
Give intravenous vitamin K 5mg 
Prothrombin complex concentrate - if not available then FFP* 
INR > 8.0 
Minor bleeding  Stop warfarin 
Give intravenous vitamin K 1-3mg 
Repeat dose of vitamin K if INR still too high after 24 hours 
Restart warfarin when INR < 5.0 
INR > 8.0

INR > 8.0 
No bleeding  Stop warfarin 
Give vitamin K 1-5mg by mouth, using the intravenous preparation orally 
Restart when INR < 5.0 
INR 5.0-8.0 Stop warfarin 1192

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   66 
 Situation Management 
Minor bleeding  Give intravenous vitamin K 1-3mg 
INR 5.0-8.0 
No bleeding  Withhold 1 or 2 doses of warfarin 
Reduce subsequent maintenance dose 
*as FFP can take time to defrost prothrombin complex concentrate should be considered in cases of i ntracranial 
haemorrhage

haemorrhage 
 
Prothrombin concentrates are products of choice for warfarin reversal in the setting of active 
bleeding and a markedly raised INR.  
 
management of mother and neonate if preterm labor develops in a patient on warfarin  
(medical-masterclass.com 2017 part 2) 
 The management is difficult if preterm labor develops in a patient on warfarin, because both 
the mother and the fetus are anticoagulated.  
 the best management to prevent fetal/neonatal hemorrhage  Give fresh frozen

plasma to the neonate immediately after delivery 
 Vitamin K administration does not achieve immediate reversal  of maternal 
anticoagulation (which may persist for 24 hours); more rapid reversal requires the transfusion 
of fresh frozen plasma. 
 Fetal levels of coagulation factors do not correlate with maternal levels, and infusion of fresh 
frozen plasma into the mother does not reliably reverse fetal anticoagulation.

 A cesarean delivery may prevent hemorrhagic fetal death, and fresh frozen plasma should be 
administered to the neonate. 
 
 1193

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   67 
  
Oncology 
Hodgkin's lymphoma (HL) :  
 
Overview 
 Hodgkin's lymphoma is a malignant proliferation of lymphocytes characterised by the presence o f 
the Reed-Sternberg cell. 
 haematological malignancy arising from mature B cells.

 Lymphadenopathy, typically painless and most commonly involving the cervical and/or 
supraclavicular nodal chain, is the most common presenting symptom of HL. 
 It has a bimodal age distributions being most common in the third and seven th decades 
 
 history of EBV infection 
 family history of Hodgkin's lymphoma 
 young adults from higher socio-economic class 
 Immunodeficiency: e.g., organ or cell transplantation, immunosuppressants, HIV infe ction ,

chemotherapy 
 Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis) 
Features 
 Painless lymphadenopathy 
 Most common is cervical lymph nodes (in ∼ 60–70% of patients)  
 Mediastinal mass ĺ chest pain, dry cough, and shortness of breath  
 Splenomegaly or hepatomegaly may occur if the spleen or liver are involved. 
 B symptoms 
 Night sweats,  
 weight loss > 10% in the past 6 months, 
 fever > 38°C (100.4°F)

 fever > 38°C (100.4°F) 
 Can occur in a variety of diseases, such as non-Hodgkin lymphoma, other malignancies, 
tuberculosis, and various inflammatory diseases 
 Pel-Ebstein fever  
 Intermittent fever with periods of high temperature for 1 –2 weeks, followed by afebrile 
periods for 1 –2 weeks. Relatively rare but very specific for HL. 
 Alcohol-induced pain  
 Pruritus (focal or generalized) 
 
1194

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   68 
  
Histological classification  
Type Frequency Prognosis Notes 
Nodular 
sclerosing  Most common  
(around 70%) Good 
prognosis More common in women.  
Associated with lacunar cells  
Mixed cellularity Around 20% Good 
prognosis Associated with a large number of Reed-Sternberg 
cells 
Lymphocyte

cells 
Lymphocyte 
predominant  Around 5% Best 
prognosis   
depleted  Rare Worst 
prognosis   
Poor prognosis  
 weight loss > 10% in last 6 months 
 night sweats 
 Other factors associated with a poor prognosis  identified in a 1998 NEJM paper included: 
 age > 45 years 
 stage IV disease 
 haemoglobin < 10.5 g/dl 
 lymphocyte count < 600/l or < 8% 
 male 
 albumin < 40 g/l 
 white blood count > 15,000/l 
 A mass of >10 cm in size

 A mass of >10 cm in size  
 
Fatigue, pruritus, EBV infection although they are common, BUT they have no progn ostic 
significance. 
 
staging 
Ann-Arbor staging of Hodgkin's lymphoma   
 I: single lymph node 
 II: 2 or more lymph nodes/regions on same side of diaphragm 
 III: nodes on both sides of diaphragm 
 Spleen is regarded as a Lymph Node region,  So lymphoma with splenomegaly  Stage 
III 
 IV: spread beyond lymph nodes 
Each stage may be subdivided into A or B

Each stage may be subdivided into A or B 
 A = no systemic symptoms other than pruritus 
 B = weight loss > 10% in last 6 months, fever > 38c, night sweats ( poor prognosis)  
 
Diagnosis 
 Lymph node biopsy  would be more likely to be positive , RSC is evident on microscopy. 
 Bone marrow  
 Hodgkin results in patchy bone marrow infiltration, an isolated bone marrow biopsy may 
yield n on-specific results. 
 Bone marrow biopsy is more useful for staging of advanced disease 
Management :

Management : 
 Early stage (IA or IIA): Radiotherapy and chemotherapy. 
 Later stage (III, IVA or IVB): Chemotherapy alone.  
 Large mass in chest regardless of stage: Radiotherapy and chemotherapy.  
 Chemotherapy includes ABVD : Adriamycin  (also known as Doxorubicin) , Bleomycin, Vincristine, 
Doxorubicin, cyclophosphamide, prednisolone, Rituximab & others 
 Relapsed Hodgkin lymphoma  salvage chemotherapy followed by BEAM conditioned

autologous stem cell transplantation as the established gold standard. 
. 1195

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   69 
  Prognosis  is good overall, but it depends on classification and staging. 
Hodgkin's lymphoma (HL) Non-Hodgkin's lymphoma (NHL) 
Younger age  Older age 
more often restricted to lymph nodes in the neck. Peripheral  lymphadenopathy is common 
Reed-Sternberg cells are  present. Reed-Sternberg cells are  NOT present.

Extra-nodal involvement un common  Extra-nodal involvement is common 
 
Non-Hodgkin's lymphoma (NHL)  (NICE guideline 2016)  
 include any kind of lymphoma except Hodgkin ’s lymphomas. 
 Most of NHL are of B cell phenotype, although T cell tumours are increasingly being recogn ized. 
 subtypes of non-Hodgkin's lymphoma (NHL): 
 diffuse large B-cell lymphoma 
 Burkitt lymphoma. 
 Diagnosis 
 Type of biopsy:

Diagnosis 
 Type of biopsy: 
 first line  excision biopsy 
 if not  surgically feasible  needle core biopsy procedure 
 in patient with histologically high-grade B-cell lymphoma: 
 use FISH  (fluorescence in situ hybridisation) to identify a MYC  rearrangement  
 If a MYC  rearrangement is found,  use FISH  to identify the immunoglobulin partner and 
the presence of BCL2  and BCL6  rearrangements. 
 Indications of using FDG- PET-CT imaging (fluorodeoxyglucose-positron emission

tomography-CT) 
 Staging  
 to assess response  at completion of planned treatment for: 
 diffuse large B ‑cell lymphoma 
 Burkitt lymphoma. 
 to assess response to treatment before autologous stem cell transplantation for 
high-grade (NHL). 
 follicular lymphoma 
 stage IIA  local radiotherapy as first-line 
 stage IIA + asymptomatic + single radiotherapy volume is not suitable 'watch and wait' 
(observation without therapy)

(observation without therapy)  
 stage IIA + symptomatic + single radiotherapy volume is not suitable  treat 
as  advanced-stage (stages III and IV) symptomatic  
 advanced-stage (stages III and IV) asymptomatic  rituximab 
 advanced-stage (stages III and IV) symptomatic  rituximab + combination with: 
 cyclophosphamide, vincristine and prednisolone (CVP) 
 cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) 
 mitoxantrone, chlorambucil and prednisolone (MCP)

 cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon ‑α (CHVPi) 
or 
 chlorambucil 
 Relapsed or refractory  advanced-stage (stages III and IV) : 
 induction of remission  Rituximab + combination with chemotherapy 
 maintenance therapy  Rituximab monotherapy 
 in second or subsequent remission   stem cell transplantation 
 MALT lymphoma 
 H. pylori -positive gastric MALT lymphoma  Helicobacter pylori  eradication therapy

  H. pylori -negative gastric MALT lymphoma  Helicobacter pylori  eradication therapy 
  gastric MALT lymphoma that responds clinically and endoscopically 
to H. pylori  eradication therapy but who have residual disease shown by surveillance 
biopsies of the stomach, + no high-risk features.  'watch and wait' (observation without 
therapy)  1196

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   70 
  residual MALT lymphoma after H. pylori eradication therapy + high risk of progression [H. 
pylori ‑negative at initial presentation or t(11:18) translocation],  
 chemotherapy (for example, chlorambucil or CVP) + rituximab OR 
 gastric radiotherapy. 
 Non-gastric MALT lymphoma

 Non-gastric MALT lymphoma  
 localised disease sites  radiotherapy  
 if radiotherapy is not suitable or disseminated disease  chemotherapy (for 
example, chlorambucil or CVP) + rituximab 
 localised + asymptomatic + radiotherapy is not suitable   'watch and wait' 
 mantle cell lymphoma 
  advanced-stage , symptomatic   chemotherapy + rituximab  
  localised stage I or II  radiotherapy

  localised stage I or II  radiotherapy 
 non-progressive + asymptomatic + radiotherapy is not suitable   'watch and wait' 
 chemosensitive mantle cell lymphoma  autologous stem cell transplantation 
 previously untreated + stem cell transplantation is unsuitable  Bortezomib 
 
Haematological malignancies: genetics

Haematological malignancies: genetics 
Below is a brief summary of the common translocations associated with haematological maligna ncies 
 
t(9;22) - Philadelphia chromosome  
 present in > 95% of patients with CML 
 this results in part of the Abelson proto-oncogene being moved to the BCR gene on c hromosome 
22 
 the resulting BCR-ABL gene codes for a fusion protein which has tyrosine kinase activity in 
excess of normal 
 poor prognostic indicator in ALL 
t(15;17)

t(15;17) 
 seen in acute promyelocytic leukaemia (M3) 
 fusion of PML and RAR-alpha genes 
t(1:14) 
 This translocation is associated with MALT (mucosa-associated lymphoid tissue) lymphoma and 
deregulates BCL10 
t(8;14) 
 seen in Burkitt's  lymphoma 
 MYC oncogene is translocated to an immunoglobulin gene 
t(11;14)  
 Mantle cell lymphoma 
 deregulation of the cyclin D1 (BCL-1) gene 
t(11; 18) 
1197

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   71 
  This translocation is associated with MALT (mucosa-associated lymphoid tissue) lymphoma and 
deregulates MALT1 
t(14;18) 
 This translocation is associated with follicular lymphoma 
 results in a chimeric heavy-chain Ig (chromosome 14) and BCL2 (chromosome 18) gene.

 This disease presents with painless “waxing and waning ” lymphadenopathy in additional to 
constitutional symptoms. 
Haematological malignancies: infections  
Viruses 
 EBV: Hodgkin's and Burkitt's lymphoma, nasopharyngeal carcinoma 
 HTLV-1: Adult T-cell leukaemia/lymphoma 
 HIV-1: High-grade B-cell lymphoma 
Bacteria 
 Helicobacter pylori : gastric lymphoma (MALT) 
Protozoa 
 malaria: Burkitt's lymphoma

Protozoa 
 malaria: Burkitt's lymphoma 
Burkitt's lymphoma 
 
 Burkitt's lymphoma is a monoclonal proliferation of B lymphocytes, which results (in 
approximately 90% of the cases) from chromosome translocations  that involve the Myc gene. 
 chromosome translocation means that a chromosome is broken, which allows it to 
associate with parts of other chromosomes. 
 It is a high-grade B-cell neoplasm.  
 There are two major forms:

 There are two major forms: 
 
1. endemic  (African) form: typically involves maxilla or mandible 
2. sporadic form:  
 abdominal (e.g. ileo-caecal) tumours are the most common form.  
 More common in patients with HIV 
 Burkitt's lymphoma is associated with the c-myc gene  translocation, usually t(8:14).   
 The classic chromosome translocation in Burkitt's lymphoma involves chromosome 8, the 
site of the MYC gene.

site of the MYC gene. 
 The Epstein-Barr virus (EBV) is strongly implicated in the development of the African form of 
Burkitt's lymphoma and to a lesser extent the sporadic form. 
 
Microscopy findings  
 'starry sky' appearance: lymphocyte sheets interspersed with macrophages containing dead  
apoptotic tumour cells 
 Management is with chemotherapy.  
 This tends to produce a rapid response which may cause 'tumour lysis syndrome' .

 Rasburicase (a recombinant version of urate oxidase, an enzyme which catalyses 
the conversion of uric acid to allantoin*) is often given before the chemotherapy  to 
reduce the risk of this occurring.  
 *allantoin is 5-10 times more soluble than uric acid, so renal excretion is 
more effective 
 Complications  of tumour lysis syndrome include: 
 Hyperkalaemia 
 Hyperphosphataemia 
 Hypocalcaemia 
 Hyperuricaemia 
 acute renal failure 
1198

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   72 
 Prognosis 
 Localised Burkitt's is associated with around a 90% survival rate,  
 although the prognosis is less good in adults. 
Cancer in the UK 
The most common causes of cancer in the UK  are as follows* 
 
 1. Breast 
 2. Lung 
 3. Colorectal

 1. Breast 
 2. Lung 
 3. Colorectal 
 4. Prostate 
 5. Bladder 
  6. Non-Hodgkin's lymphoma 
 7. Melanoma 
 8. Stomach 
 9. Oesophagus 
 10. Pancreas 
 
The most common causes of death from cancer in the UK  are as follows: 
 1. Lung 
 2. Colorectal 
 3. Breast 
 5. Pancreas  6. Oesophagus 
 7. Stomach 
 8. Bladder 
 9. Non-Hodgkin's lymphoma 
 10. Ovarian 
 Cancer is the cause of 26% of deaths in the UK, and is a more common cause of death th an

cardiovascular disease.  
 Lung cancer is the biggest cancer killer in the UK (in both male and female) , although breast 
cancer has the highest incidence 
*excludes non-melanoma skin cancer 
Acute lymphoblastic leukaemia (ALL):  
 (ALL) is a disease of children.   
 Children with certain genetic and immunodeficiency syndromes are at increased risk.  These 
include:  
  Down syndrome ,  
 Neurofibromatosis type 1 ,

 Neurofibromatosis type 1 ,  
 Bloom syndrome, and 
  ataxia telangiectasia . 
 The most common presenting symptoms of ALL are nonspecific: fever, infectio n, bleeding, bone 
pain, or lymphadenopathy. 
Prognostic features 
Good prognostic factors Poor prognostic factors 
 French-American-British (FAB) L1 type 
 common ALL 
 pre-B phenotype 
 low initial WBC 
 del(9p) 
 t(12;21) 
  FAB L3 type 
 T or B cell surface markers 
 Philadelphia translocation, t(9;22)

 Philadelphia translocation, t(9;22) 
 t(8:14) the worst prognosis  
 age < 2 years or > 10 years 
 male sex 
 CNS involvement 
 high initial WBC (e.g. > 100 * 109/l) 
 non-Caucasian  
 The 8:14 chromosomal translocation  is associated with a particularly poor prognosis,  and is 
found in approximately 1% of adults with ALL. The incidence of CNS involvement is v ery high at 
the point of diagnosis, and median event free survival after chemotherapy is on ly two months.  
Treatment

Treatment 
 Before ALL treatment with chemotherapy, if blast cells count is very high ;˃ ϭϬϬ * ϭϬ9/lͿ 
 the patient needs Leukapheresis  to prevent sludge in of capillary beds, this can be life-
saving. 
 Central nervous system (CNS) therapy (intrathecal) is indicated in all patients with ALL 
 Lumber puncture (LP) should be delayed until chemotherapy has begun 1199

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   73 
  
Chronic lymphocytic leukaemia (CLL) 
 
  (CLL) is caused by a monoclonal proliferation of well-differentiated lymphocytes which are 
almost always B-cells (99%)  
 
 CLL is the most common form of leukemia found in adults  in Western countries .

 generally affects older populations (The median age at diagnosis is 72 years) 
Features  
 often none 
 constitutional: anorexia, weight loss 
 bleeding, infections 
 lymphadenopathy more marked than CML 
 hypogammaglobulinaemia leading to recurrent infections 
 Infections are the most frequent complication causing death in patients with CLL. 
 Although intravenous immunoglobulin prevents recurrent infections it does not p rolong 
survival.

survival. 
 warm autoimmune haemolytic anaemia  in 10-15% of patients 
 transformation to high-grade lymphoma (Richter's transformation) 
 blood film:  
 smudge cells (also known as smear cells) 
 smudge cells are the artifacts produced by the lymphocytes damaged during the  
slide preparation. 
 ≥ 5000 monoclonal B lymphocytes/µl. The clonality of the circulating B lymphocytes need s 
to be confirmed by flow cytometry.

to be confirmed by flow cytometry. 
 Immuno-phenotyping   will demonstrate the cells to be B-cells ( CD19  positive). CD5 and 
CD23 are also characteristically positive in CLL.  
 Peripheral blood flow cytometry is the most valuable test to confirm a diagnosis of 
CLL. 
 Although a bone marrow biopsy  is not required for diagnosis, it is recommended for the 
diagnostic evaluation of unclear cytopaenias, or FISH or molecular genetics if peripheral bloo d

cell lymphocytosis does not allow adequate immunophenotyping 
 An extended FISH analysis is recommended before the start of therapy because the detection  of 
additional cytogenetic abnormalities [del(11q) or trisomy 12] may have therapeutic conseq uences 
 
Peripheral blood film showing smudge B cells 
 
1200

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   74 
  
 observation policy is usual during the early stages of the disease. 
 Indications for treatment 
 progressive marrow failure: the development or worsening of anaemia and/or 
thrombocytopenia 
 massive (>10 cm) or progressive lymphadenopathy 
 massive (>6 cm) or progressive splenomegaly

 massive (>6 cm) or progressive splenomegaly 
 progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 
6 months 
 systemic symptoms:  
 weight loss > 10% in previous 6 months,  
 fever >38  C for > 2 weeks,  
 extreme fatigue,  
 night sweats 
 autoimmune cytopaenias e.g. ITP 
 Drugs 
 fludarabine, cyclophosphamide and rituximab (FCR) has now emerged as the initial 
treatment  of choice  for the majority of patients

 monitoring by regular blood counts  
 What antimicrobial prophylaxis should he receive before starting chemotherapy 
with fludarabine? 
 Co-trimoxazole  
 Fludarabine is a purine analogue that is phosphorylated intracellularly. 
 All of the purine analogues cause myelosuppression, but there is a significantly 
higher risk of patients developing Pneumocystis jirovecii pneumonia  while on 
 Use of prophylactic co-trimoxazole (Septrin) has dramatically reduced the

frequency of this severe opportunistic infection in these patients. 
 Co-trimoxazole should be continued after chemotherapy until the CD4 counts 
exceeds 200  cells/mm3 (0.2 ×109/L). 
 Regular infusions of immunoglobulin  to prevent infections  
 Recurrent infections are recognised in CLL due to hypogammaglobulinaemia and immune 
paresis; but are not an indication for disease control. 
 
CLL prognostic factors 
Poor prognostic factors  (median survival 3-5 years) 
 male sex

 male sex 
 lymphocyte count > 50 
 prolymphocytes comprising more than 10% of blood lymphocytes 
 lymphocyte doubling time < 12 months 
 raised LDH 
 CD38 expression positive 
 deletions of part of the short arm of chromosome 17 (del 17p) 
 
Chromosomal changes 
 deletion of the long arm of chromosome 13  (del 13q) is the most common  abnormality, being 
seen in around 50%  of patients. It is associated with a good prognosis

 deletions of part of the short arm of chromosome 17  (del 17p) are seen in around 5-10% of 
patients and are associated with a poor prognosis  
 
 mantle cell lymphoma  (MCL) 
 These tumour cells express B-cell surface antigens and also expresses CD5, but usually 
not CD23.  
 For cases that express CD23, staining for cyclin D1 or SOX11 and fluorescence in 
situ hybridisation (FISH) for detecting a translocation (11;14)  are useful for establishing

the diagnosis of MCL. 
 small lymphocytic lymphoma (SLL)  
 In the World Health Organization classification, small lymphocytic lymphoma (SLL) and 
CLL are considered to be a single entity.  1201

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   75 
  The diagnosis of SLL requires the presence of lymphadenopathy and/or splenomeg aly 
with a number of B lymphocytes in the peripheral blood not exceeding 5 × 109/l.  
 SLL cells show the same immunophenotype as CLL.  
 The diagnosis of SLL should be confirmed by histopathological evaluation of a ly mph node

biopsy, whenever possible. 
 monoclonal B-lymphocytosis ’ (MBL)  
 In absence of lymphadenopathy, organomegaly, cytopaenia and clinical symptom s, the 
presence of fewer than 5000 monoclonal B lymphocytes/µl defines ‘monoclonal B-
lymphocytosis ’ (MBL) 
 can be detected in 5% of subjects with normal blood count.  
 Progression to CLL occurs in 1% –2% of MBL cases per year. 
Acute myeloid leukaemia (AML )

Acute myeloid leukaemia (AML ) 
 
 AML is the most common form of acute leukaemia in adults .  
 It may occur as a primary disease or following a secondary transformation of a myeloproliferative 
disorder. 
 Acute leukemia is defined as an accumulation of more than 20 percent of immature blasts 
at the bone marrow.  
 Chronic myeloid leukaemia often ends in acute blastic transformation after a mean 
duration of approximately four years. 
 classically associated with Down syndrome .

 classically associated with Down syndrome . 
 Alkylating agents  is a chemotherapy drug class that increases the risk of developing AML. 
 characterized by cells with positive cytoplasmic staining for myeloperoxidase . 
 The median age of onset of AML is 65 years. 
 
 Vague and non-specific (flu-like symptoms)   
 Due to pancytopenia (Infection, anaemia , bleeding)  
 Splenomegaly may occur but typically mild and asymptomatic. 
 LN swelling is rare.

 LN swelling is rare.  
 High total leucocyte count (TLC) leads to leucostasis and hyperviscosity  drowsiness and 
retinal vein dilatation.  
 Blood film reveals white cells predominantly myeloblasts and promyelocytes. 
 
Poor prognostic features 
AML  Cytogenetics Karyotype is of most prognostic value . 
 
 > 60 years 
 > 20% blasts after first course of chemo 
 cytogenetics: deletions of chromosome 5 or 7

 cytogenetics: deletions of chromosome 5 or 7 
 bone marrow cytogenetics are the most important  aspect in determining prognosis in 
AML 
Good prognostic features 
 Karyotype of bone marrow 
 patients with t(8:21) or chromosomes 16 inversion have a low risk of relapse 
 
Classification - French-American-British (FAB) 
 MO - undifferentiated 
 M1 - without maturation 
 M2 - with granulocytic maturation 
 the most common  (25% of adult AML)  
 associated with a t(8;21) translocation.

 associated with a t(8;21) translocation. 
 M3 - acute promyelocytic (APL) 
1202

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   76 
  has the best prognosis  of all the subtypes of AML. 
 Unlike the other AML subtypes, APL is treated with all-trans retinoic acid (ATRA). 
 t(15;17) 
 M4 - granulocytic and monocytic maturation 
 associated with a t(16;16) translocation 
 M5 - monocytic 
 M6 - erythroleukaemia 
 M7 – megakaryoblastic

 M7 – megakaryoblastic 
 
AML (monocytic) M5: high count of circulating blasts  may lead to symptoms of cellular 
hyperviscosity (headache, confusion, fits, coma) and tissue deposits of leukaemia cells (gu ms 
hypertrophy) with cells stain positive with Sudan Black and myeloperoxidase plus NES. 
 
ALL cells characteristically stain positive for PAS (Periodic acid-Schiff) and NSE (Non-specific 
Esterase).

Esterase).  
AML  cells characteristically stain positive for Sudan Black  and myeloperoxidase , but M4 and M5 
cells stain positive for NSE, while M6 cells stain positive for PAS. 
 
 Combination chemotherapy including arabinosylcystosine after apheresis . 
 Cytarabine and Anthracycline is considered the initial treatment of choice for patients with AML. 
Bone marrow transplantation 
 The aim would be to choose a fully matched sibling who was also CMV-negative.

 In general, fully HLA matched, CMV matched, male donors are preferred over fully HLA 
matched, CMV matched female donors.  This is because of the increased  risk of graft versus 
host disease in stem cell donations from female donors to male recipients . 
Acute promyelocytic leukaemia (APML) 
 
 APML, the M3 subtype of AML.  
 The importance of identifying APML lies in both the presentation (classically disseminated

intravascular coagulation) and management 
 APML is associated with the t(15;17) translocation  
 causes fusion of the PML and RAR-alpha genes. 
 In 95% of cases, retinoic acid receptor-alpha (RARA) gene on chromosome 17 is involved 
in a reciprocal translocation with the promyelocytic leukaemia gene (PML) on 
chromosome 15. 
 The mechanism underlying leukaemogenesis is aberrant fusion of 2 genes PML and 
RARA.  
Features

RARA.  
Features  
 presents younger than other types of AML (average = 25 years old) 
 DIC or thrombocytopenia often at presentation 
 Auer rods  (seen with myeloperoxidase stain) 
 Auer rods are eosinophilic needle-like cytoplasmic inclusions found in blast cells 
1203

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   77 
  good prognosis   
 treatment of APML differs from that of all other AML forms 
 the most appropriate initial treatment regimen:  All trans retinoic acid (ATRA)  a derivative 
of vitamin A., plus Anthracycline based chemotherapy

The distinct elongated cytoplasmic structures are Auer rods  which are pathognomonic for AML. 
 
Retinoic acid syndrome  (or differentiation syndrome) 
 thought to be the result of the release of cytokines and subsequent lung infiltration  by the 
neutrophils created by the maturation of myelocytes in APML.  
 The presence of CD13 expression on leukemic cells can be a predictor of the future d evelopment 
of this syndrome.  
Causes

Causes 
 after treatment of APML with all-trans retinoic acid (ATRA) (present within a week of treatment) 
 after treatment of APML with arsenic trioxide.  
 usually occurs during induction therapy 
Incidence 
 14-16% of patients.  
Features 
 dyspnea, pulmonary edema and effusions, A chest X-ray shows interstitial infiltrates. 
 fevers,  
 hypotension,  
 Other complications include pericardial effusion, renal insufficiency, and hypertension.  
treatment

treatment 
 the drug is temporarily stopped, then started again at 50-75% of the earlier dose.  Alternatively, 
arsenic therapy can be tried. 
prognosis 
 Without prompt treatment with glucocorticoids, patients with this disorder have a mortality rate as 
high as 30% due to brain edema or hypoxemic respiratory failure.  
 Fortunately, most patients improve markedly within 12 hours and their symptoms resolved 
completely within 24 hours.

completely within 24 hours. 
Chronic myeloid leukaemia (CML) 
 
1204

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   78 
  
 The Philadelphia chromosome is present in more than 95% of patients with (CML). 
  It is due to a translocation between the long arm of chromosome 9 and 22 - t(9 :22)(q34; q11). 
This results in part of the ABL proto-oncogene from chromosome 9 being fused w ith the BCR

gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion p rotein which has 
tyrosine kinase activity in excess of normal 
 
Presentation  
 middle-age (40-50 years) 
 anaemia,  
 splenomegaly may be marked  abdominal discomfort 
 spectrum of myeloid cells seen in peripheral blood 
 The blood film shows both mature (neutrophils) and immature forms in variou s stages of 
differentiation (myelocytes and metamyelocytes)

differentiation (myelocytes and metamyelocytes)  
 In acute myelogenous leukemia (AML) one would expect only immature blasts. 
 decreased leukocyte alkaline phosphatase 
 may undergo blast transformation (AML in 80%, ALL in 20%) 
 
 Unlike (CLL), CML will progress to frank leukaemia quite rapidly, so treatment is needed.   
 imatinib  is now considered first-line treatment 
 inhibitor of the tyrosine kinase associated with the BCR-ABL defect

 very high response rate in chronic phase CML 
 If remission is not achieved with imatinib , then: 
 in a patient under 60-65 years, an allogeneic transplant would be considered if the re was 
a matched sibling donor; 
  in a 50-year-old patient or younger a matched unrelated donor transplant wo uld be 
considered too.  
 If the patient had been in blast crisis phase , then AML-type chemotherapy as well as Glivec 
(imatinib ) would be the choice.  
 hydroxyurea 
 interferon-alpha

 interferon-alpha 
 allogenic bone marrow transplant 
Allogenic bone marrow transplant 
Cytomegalovirus pneumonia  
 The microscopy shows owl ’s eye inclusion bodies, characteristic of CMV, but diagnosis is usually 
made by PCR of blood/lavage fluid.  
 It is the commonest life-threatening complication following allogenic bone marrow transplan t,

  usually occurring within the first 4 months following surgery.  
 the treatment of choice   Ganciclovir  
 Onset is rapid and mortality in the context of BMT is around 80%, even with antiviral th erapy 
(ganciclovir).  
 
Ref  medical-masterclass.com 2017 part 2 
Hairy cell leukaemia 
 Hairy cell leukaemia is malignant proliferation disorder of B cells .  
 Rare, about 2% of leukemias. 
 more common in males  (4:1)

 more common in males  (4:1) 
 frequently occurs in men in their fifth decade . 
Features  
 pancytopenia 
1205

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   79 
  splenomegaly 
 skin vasculitis in 1/3 patients 
 'dry tap' despite bone marrow hypercellularity 
 tartrate resistant acid phosphotase (TRAP) stain positive 
 characteristic hairy leukocyte on blood smear with a “fried egg ” appearance

 medium-sized lymphocytes with numerous spiky, peripheral, cytoplasmic projections. 
 chemotherapy is first-line : cladribine  ( adenosine deaminase inhibitor), pentostatin 
 Cladribine 
 Cladribine is a purine analog  inhibit DNA polymerase and cause DNA strand 
breaks.  
 SE  myelosuppression, nephrotoxicity, and neurotoxicity. 
 immunotherapy is second-line: rituximab, interferon-alpha 
Paraproteinaemia

Paraproteinaemia 
Causes of paraproteinaemia 
 myeloma 
 monoclonal gammopathy of uncertain significance (MGUS) 
 benign monoclonal gammopathy 
 Waldenstrom's macroglobulinaemia 
 CLL, lymphoma 
 heavy chain disease 
 POEMS 
Benign monoclonal gammopathy 
 non-lymphoid malignancy (e.g. colon, breast) 
 infections (CMV, hepatitis) 
 autoimmune disorders (RA, SLE) 
Multiple myeloma

Multiple myeloma  
classic symptoms of multiple myeloma: bone pain, pathological fracture, anaemia and 
hypercalcaemia (leading to thirst). 
 
Multiple myeloma causes a low anion gap . 
 Multiple myeloma is a neoplasm of the bone marrow plasma cells .  
 The peak incidence is patients aged 60-70 years. 
 Multiple myeloma is the most common primary tumor of the bone in patients older th an 50 years. 
 equal sex ratio

 equal sex ratio 
 more common in Afro-Caribbean ethnic groups than in Caucasians 
Monoclonal products produced 
 IgG (50-60%) 
 IgA (20-30%) 
 light chain disease (20%) 
 Type 2/Proximal renal tubular acidosis  is a type of renal tubular acidosis associated 
with multiple myeloma.  
 Neoplastic proliferation of plasma cells 
 Bone marrow infiltration ĺ suppression of hematopoiesis ĺ leukopenia, 
thrombocytopenia, anemia

thrombocytopenia, anemia 
 Cell proliferation ĺ osteolysis ĺ hypercalcemia  
 Overproduction of monoclonal immunoglobulin and/or light chains 
 Non-functioning antibodies ĺ functional antibody deficiency  
 Ĺ Serum viscosity ĺ hyperviscosity syndrome  
 
 bone disease:  
 due to neoplastic plasma cells activating RANKL receptors on osteoclasts. 1206

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   80 
  bone pain, (Bones commonly affected are the flat bones of the spine, and  as such lower 
back pain is one of the most common presenting features) 
 osteoporosis + pathological fractures (typically vertebral),  osteolytic lesions 
 weakness and paresthesias in the lower extremities due to vertebral compression

fractures 
 anaemia 
 fatigue and malaise 
 The most common presenting manifestations of multiple myeloma are those related 
to anemia. 
 infection 
 hypercalcaemia  nausea, fatigue, confusion, polyuria, constipation  
 hyperphosphataemia  
 due to reduced renal excretion  which may be directly due to renal impairment  or 
interference with excessive protein load. 
 Foamy urine,  
 caused by Bence Jones proteinuria 

 renal failure  
 the most common cause is from light chain deposition . 
 Usually , the renal damage in MM is tubular . Occasionally there may be glomerular 
damage with consequent albumin loss. 
 amyloidosis e.g. Macroglossia, carpal tunnel syndrome; neuropathy; hyperviscosity 
 carpal tunnel syndrome - the most common peripheral neuropathy associated with 
multiple myeloma 
 
 Multiple myeloma may present with roleaux formation on blood film and raised total

protein (globulin component). 
 The globulin level is markedly raised (albumin + globulin = total protein), suggesting the 
presence of a paraprotein. 
 (globulin level = total protein ). A normal level should be below 36 g/L. 
 Hypercalcaemia in myeloma 
 primary factor: due primarily to increased osteoclastic bone resorption caused by local  
cytokines (e.g. IL-1, tumour necrosis factor) released by the myeloma cells

 much less common contributing factors: impaired renal function, increased renal tubular 
calcium reabsorption and elevated PTH-rP levels   
 
Which acid-base disorders may be found in an IgG multiple myeloma? 
 Low anion-gap metabolic acidosis  
 IgG tends to be cationic, whereas IgA tends to be anionic. As a consequence, patie nts 
with IgG myeloma will tend to have a lower than normal serum anion gap.

Diagnostic criteria  for multiple myeloma requires one major and one minor criteria or three minor 
criteria in an individual who has signs or symptoms of multiple myeloma.  
 Plasmacytoma (as demonstrated on evaluation of biopsy specimen) 
 30% plasma cells in a bone marrow sample 
 Elevated levels of M protein in the blood or urine 
 monoclonal proteins: 
 in the serum  (usually IgG or IgA)  
 in the urine (Bence Jones proteins)

 in the urine (Bence Jones proteins) 
 there is Negative dipstick for protein and positive in 
biochemistry , because Bence jones proteins are not detected by 
dipstick   
 Minor criteria  
 10% to 30% plasma cells in a bone marrow sample. 
 Minor elevations in the level of M protein in the blood or urine. 
 Osteolytic lesions (as demonstrated on imaging studies). 
 Low levels of antibodies (not produced by the cancer cells) in the blood. 
 
 Investigations: (NICE 2016)

Investigations: (NICE 2016)  
1.  to confirm the presence of a paraprotein  indicating possible myeloma or (MGUS): 1207

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   81 
  serum protein electrophoresis  and serum-free light-chain assay 
 (best initial test)  serum protein electrophoresis 
 If serum protein electrophoresis is abnormal  use serum immunofixation 
 Do not use serum protein electrophoresis, serum immunofixation, serum-free light-chain

assay or urine electrophoresis (urine Bence –Jones protein assessment)  alone  to exclude 
a diagnosis of myeloma. 
2.  to confirm a diagnosis of myeloma : 
 bone marrow aspirate  and trephine biopsy 
 the bone marrow aspirate would confirm the diagnosis irrefutably.  
 morphology to determine plasma cell percentage 
 Bone marrow examination would reveal increased plasma cells (greater than 
4% and usually greater than 30%). 
 flow cytometry to determine plasma cell phenotype

 bone marrow aspirate  dark red jelly-like material in the syringe (Plasma 
cells ) 
 
3. in a patient presenting with spinal cord compression: 
   the most appropriate initial investigation is  Urgent MRI of her spine  
 This should be done before investigation that used to confirm myeloma. 
 skeletal survey  bone lesions 
 
Treatment : general view  
 The best initial treatment of multiple myeloma is chemotherapy 
induction.

induction. 
 autologous bone marrow transplant in addition to chemotherapy 
has better results than chemotherapy alone. 
 
 Asymptomatic patients:  watch and wait, unless patients have: 
  ≥ 60%  clonal cells,  
 excessive free light chains or 
  ≥ 1 bone lesion 
 Symptomatic patients 
 HCT eligible : induction therapy followed by autologous HCT 
 HCT ineligible: chemotherapy alone (e.g., dexamethasone and lenalidomi de) 
 Supportive therapy 
 Osteolysis a nd bone pain

 Osteolysis a nd bone pain 
 Bisphosphonates 
 Radiation therapy of osteolytic regions 
 Pancytopenia with anemia and increased risk of infection 
 Blood transfusions 
 Granulocyte-colony stimulating factor (G-CSF) and erythropoietin (EPO) 
 
Treatment (NICE 2016)  
 previously untreated multiple myeloma ( newly diagnosed) 
 Patients who are eligible for high-dose chemotherapy with stem cell 
transplantation 
 bortezomib + dexamethasone,

 bortezomib + dexamethasone,  
 or bortezomib + dexamethasone + thalidomide 
 if high-dose chemotherapy with stem cell transplantation is considered 
 thalidomide + alkylating agent + corticosteroid 
 People who are at first relapse having received one prior therapy and who have 
undergone, or are unsuitable for, bone marrow transplantation: 
 bortezomib (a proteasome inhibitor) monotherapy 
 People who have received two or more prior therapies :

 lenalidomide + dexamethasone 
 lenalidomide  immunomodulatory derivatives (structural derivatives of 
thalidomide) 
 People with untreated, newly diagnosed, myeloma-induced acute renal disease : 
 bortezomib + dexamethasone 1208

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   82 
  If a bortezomib is unsuitable  thalidomide + dexamethasone  
 Do not perform plasma exchange for myeloma-induced acute renal disease. 
 Preventing bone disease, managing non ‑spinal and spinal bone disease 
 bisphosphonates should be given routinely, even in the absence of hypercalcaem ia.

 Bisphosphonates reduce bony disease in myeloma, lowering the frequency of patho logical 
fractures, modulate the disease and have some antitumour activity.  
 zoledronic acid or 
 disodium pamidronate, if zoledronic acid is contraindicated or not tolerated or 
 sodium clodronate, if zoledronic acid and disodium pamidronate are 
contraindicated, not tolerated or not suitable 
 surgical stabilisation followed by radiotherapy for non-spinal bones that have fractured o r

are at high risk of fractures. 
 Consider radiotherapy for people who need additional pain relief  
 Managing peripheral neuropathy 
 If patient on bortezomib 
 switch to subcutaneous injections and/or 
 reduce to weekly doses and/or 
 reduce the dose. 
 if patient on other than bortezomib  
 Temporarily stop neuropathy-inducing myeloma treatments if people develop eith er 
of the following: 
 grade 2 neuropathy with pain 
 grade 3 or 4 neuropathy 
 Managing fatigue

 Managing fatigue 
 Erythropoietin analogues (adjusted to maintain a steady state of haemoglobin at 110 –120 
g/litre) to improve fatigue in people with myeloma who have symptomatic anaemia. 
 Cord compression  secondary to bony involvement of multiple myeloma:  
 I.V Steroids should be commenced  immediately   
 However, the treatment of choice is local radiotherapy.  NICE suggest localised 
radiotherapy should be the first point of call for urgent treatment.

 Vertebroplasty  is typically considered in patients of whom have evidence of metastatic 
changes in the spine, but show no signs of spinal cord compression.  
 Surgical decompression:  is also considered if imaging suggests any form of spinal 
instability or structural defects, but often after steroids and radiotherapy has been 
administered.  
 Other treatment options include analgesia, with non-steroidal anti-inflammatory drugs of 
particular use.  
Myeloma: prognosis

Myeloma: prognosis 
 B2-microglobulin is a useful marker of prognosis  - raised levels imply poor prognosis.  
 Beta-2-microglobulin has been shown to be predictive of risk of progression of disease in  
myeloma, myelodysplastic syndrome, and chronic myeloid leukaemia. 
 In myeloma it is an accurate estimate of total disease load, with guidelines suggesting tha t 
a beta-2-microglobulin level of >3.5 mg/L is strongly associated with increased mortality 
and morbidity.

and morbidity. 
 Low levels of albumin are also associated with a poor prognosis 
 Increased lactate dehydrogenase  levels more than  double  the normal is considered a bad 
prognostic sign in multiple myeloma. 
 
International prognostic index  
Stage Criteria Median survival (months) 
I B2 microglobulin < 3.5 mg/l  
Albumin > 35 g/l 62 
II Not I or III 45 
III B2 microglobulin > 5.5 mg/l 29 
 1209

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   83 
  
Abnormal serum protein electrophoresis pattern in a patient with multiple myeloma. Note the 
large spike in the gamma region. 
 In the interpretation of serum protein electrophoresis, most attention focuses on the gamm a 
region(gamma-globulin zone), which is composed predominantly of antibodies of the IgG type.

Monoclonal gammopathy of undetermined significance (MGUS ) 
  MGUS also known as benign paraproteinaemia and monoclonal gammopathy) is a com mon 
condition that causes a paraproteinaemia and is often mistaken for myeloma. Diffe rentiating 
features are listed below. 
 can be seen in >5% of people over 70 years of age. 
Risk of transmission to malignancy:

Risk of transmission to malignancy: 
 Around 10% of patients eventually develop myeloma at 5 years, with 50% at 15 yea rs 
 1 percent per year develop multiple myeloma. 
Features  
 no bone pain or increased risk of infections 
 around 10-30% of patients have a demyelinating neuropathy  
Differentiating features from myeloma 
 normal immune function 
 normal beta-2 microglobulin levels

 normal beta-2 microglobulin levels 
 lower level of paraproteinaemia than myeloma (e.g. < 30g/l IgG, or < 20g/l IgA) 
 stable level of paraproteinaemia 
 no clinical features of myeloma (e.g. lytic lesions on x-rays or renal disease) 
 
feature  MGUS  myeloma  
M protein concentration in serum <30 g/l >30 g/l  
bone marrow plasma cells  <10 %  >10 %  
 organ and tissue impairment no end organ damage including 
bone lesions  organ or tissue impairment 
(including bone lesions)

(including bone lesions)  
 
Treatment 
 Observation  
 if there is neuropathy  
 MGUS patients are associated with osteoporosis and osteopenia. They may benefit from 
treatment with  bisphosphonates  
 pyrophosphate analogue  
 act by binding to hydroxyapatite in bone which leads to low osteoclastic 
activity. 
1210

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   84 
 March 2017 part 2 : A 72-year-old man C/O  persistent tiredness over the past 3 months. No 
other abnormality. Investigations reveals  Albumin: 38 g/l, IgG paraprotein band: 14 g/l, Bone 
marrow: 7% plasma cells. Which of the following is the most appropriate intervention? 
 Observation

 Observation  
 MGUS is defined by paraprotein (<30 g/l), bone marrow plasma cells <10% and 
the absence of myeloma-related organ or tissue damage (predominantly renal, 
skeletal or bone marrow impairment).  
 Annual overall progression to myeloma is 1%  and, as such, no intervention is 
required. 
 
Smoldering myeloma   
 Smoldering multiple myeloma   multiple myeloma (M-protein >3g/dL or >10% plasma cells in 
bone marrow)  + no end organ damage.

bone marrow)  + no end organ damage.   
 criteria for end-organ damage , which are: 
 Serum calcium >11.5 mg/dL 
 Serum creatinine >2 mg/dL or estimated creatinine clearance <40 ml/min 
 Anemia with hemoglobin <10 g/dL 
 Bone lesions: osteolytic, pathological fracture; osteopenia 
 Treatment  Observe and monitor  
 
Non-secretory myeloma 
 Bone marrow clonal plasma cells =10%, Myeloma-related end-organ damage,  No M pro tein in 
blood or urine

blood or urine 
Thymoma  are the most common tumour of the anterior mediastinum and is usually dete cted 
between the sixth and seventh decades of life. 
 
 myasthenia gravis (30-40% of patients with thymoma) 
 red cell aplasia 
 dermatomyositis 
 also : SLE, SIADH 
Causes of death 
 compression of airway 
 cardiac tamponade 
Tumour lysis syndrome (TLS)

Tumour lysis syndrome (TLS) 
 
 Tumour lysis syndrome (TLS) is a potentially deadly condition  
causes:   
 treatment of high grade lymphomas and leukaemias.  
 It can occur in the absence of chemotherapy but is usually triggered by the intro duction of 
combination chemotherapy.  
 breakdown of the tumour cells and the subsequent release of chemicals from the cell.  
Features:   
 high  potassium  
 high  phosphate  
 low calcium .

 low calcium .  
 It should be suspected in any patient presenting with an acute kidney injury  in the presence of 
a high phosphate and high uric acid level.  
 From 2004 TLS has been graded using the Cairo-Bishop scoring system -  
Laboratory tumor lysis syndrome: abnormality in two or more of the following, occurring 
within three days before or seven days after chemotherapy.  
 uric acid > 475umol/l or 25% increase 
1211

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   85 
  potassium > 6 mmol/l or 25% increase 
 phosphate > 1.125mmol/l or 25% increase 
 calcium < 1.75mmol/l or 25% decrease 
 Clinical tumor lysis syndrome: laboratory tumor lysis syndrome plus one or more of the following: 
 increased serum creatinine (1.5 times upper limit of normal)

 cardiac arrhythmia or sudden death 
 seizure 
Prevention:   
 Patients at high risk of TLS should be given IV allopurinol or IV rasburicase immediately p rior to 
and during the first days of chemotherapy. 
 Rasburicase is a recombinant version of urate oxidase, an enzyme that metaboli zes uric 
acid to allantoin.  Allantoin is much more water soluble than uric acid and is therefore 
more easily excreted by the kidneys.  
 The commonest reported side effect of rasburicase is fever.

 rasburicase overdose may lead to accumulation of hydrogen peroxide. 
 patients at low risk  oral allopurinol during chemotherapy 
 Other options for the management of tumour lysis syndrome include 
 Acetazolamide to drive urine alkalinisation. 
Waldenstrom's macroglobulinaemia 
 
Overview 
 It is a lymphoplasmacytoid malignancy seen in older men , characterised by the secretion of a

monoclonal IgM paraprotein ,  
 indolent B-cell lymphoma  
 Also known as Lymphoplasmacytoid lymphoma  
 most common in older white men 
  
 monoclonal IgM production by a malignant lymphoplasmacytic clone that can cause dam age to 
multiple organs. 
 The tumor cells in Waldenstrom macroglobulinemia are positive to CD20 markers.  
Features 
 monoclonal IgM paraproteinaemia 
 systemic upset: weight loss, lethargy 
 hyperviscosity syndrome e.g.: 
 visual disturbance ,

 visual disturbance ,  
 neurological symptoms such as headache, dizziness, and vertigo   
 raynaud phenomenon 
 Bleeding is a possible complication  as viscous serum causes defective platelet aggregation.  
 hepatosplenomegaly 
 cryoglobulinaemia e.g. Raynaud's 
 protein electrophoresis  elevated IgM 
 Bone marrow biopsy  (the gold standard for the diagnosis) 
 Shows  abnormal plasma cells with Dutcher bodies (intranuclear inclusions of IgM

deposits) 
  usually presents with IgG or IgA secretion and lytic bone lesions.  
Treatment 
 Treatment only indicated in symptomatic patients 
 asymptomatic  Follow- up  
 Causative: CD20 antibodies (e.g., rituximab) 
 Hyperviscosity syndrome: plasmapheresis 
 
1212

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   86 
ECOG score 
 The ECOG score ( Eastern Cooperative Oncology Group (ECOG) score) is a 'performance 
status' scale, or a score that measures the functional status of a patient.  
 It is used to decide if a patient is a good or poor candidate for future oncological

therapies.  
 Those with a poor functional status is a poor candidate for further chemotherapy.   
0 Fully active, able to carry on all pre-disease performance without restrict ion 
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 
e.g., light house work, office work 
2 Ambulatory and capable of all selfcare but unable to carry out any work acti vities; up and about more than 50% of 
waking hours

waking hours 
3 Capable of only limited selfcare; confined to bed or chair more than 5 0% of waking hours 
4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 Dead 
 
Testicular seminoma 
 The triad of a testicular lump, a mass on chest X-ray and a raised (3-HCG (human 
chorionic gonadotrophin) are suggestive of testicular seminoma 
 A raised (3-HCG is found in around 15% of seminomas

 Orchidectomy with chemotherapy is curative in 90% of cases 
 (3-HCG) levels may be a useful correlate with response to treatment  
 
Tumour markers 
Tumour markers may be divided into: 
 monoclonal antibodies against carbohydrate or glycoprotein tumour antigens 
 tumour antigens 
 enzymes (alkaline phosphatase, neurone specific enolase) 
 hormones (e.g. calcitonin, ADH)

 hormones (e.g. calcitonin, ADH) 
 
It should be noted that tumour markers usually have a low specificity 
 
Monoclonal antibodies  
 
Tumour marker Association 
CA 125  Ovarian cancer 
 primary peritoneal cancer  
CA 19-9 Pancreatic cancer 
CA 15-3 Breast cancer 
 
Tumour antigens  
 
Prostate specific antigen (PSA) Prostatic carcinoma 
Alpha-feto protein (AFP) Hepatocellular carcinoma,  
teratoma ,  1213

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   87 
 Tumour marker Association 
non-seminomatous germ-cell tumours  
Carcinoembryonic antigen 
(CEA) Colorectal cancer 
S-100 Melanoma, schwannomas 
Bombesin Small cell lung carcinoma, gastric cancer, neuroblastoma 
β-human chorionic 
gonadotrophin  choriocarcinomas, germ-cell tumours and lung cancers

  Bence Jones protein  specific for myeloma. false positives are rare, and therefore it is  more 
specific than the other markers . The most specific tumour marker  
  Alpha-fetoprotein  (AFP), beta-hCG  and PLAP  (placental like isoenzyme of alkaline 
phosphatase) are the major tumour markers in use for the monitoring of testicular teratoma . 
Neutropenic sepsis (Febrile neutropenia)

Neutropenic sepsis (Febrile neutropenia)  
 Neutropenic sepsis is a relatively common complication of cancer therapy (chemotherapy).  
 It may be defined as a neutrophil count of < 0.5 * 109 in a patient who is having anticancer 
treatment and has one of the following: 
 a temperature higher than 38  C or 
 other signs or symptoms consistent with clinically significant sepsis 
 the most common pathogens are now gram-positive organisms. such as Staphylococcus

epidermidis  or Streptococcus viridans (around 60% of cases)  
 Source of infection 
- Indwelling lines  Staph.epidermidis infection  
- mucositis or previous quinolone treatment  viridans streptococci  
 if it is anticipated that patients are likely to have a neutrophil count of < 0.5 * 109 as a 
consequence of their treatment they should be offered a fluoroquinolone 

 antibiotics must be started immediately, do not wait for the WBC ,(N.B. after taking cultures).  
 NICE recommend starting empirical antibiotic therapy with piperacillin with tazobactam  
(Tazocin) immediately 
 
 many units add vancomycin if the patient has central venous access but NICE do not support this 
approach 
 following this initial treatment patients are usually assessed by a specialist and risk-stratified to 
see if they may be able to have outpatient treatment

 if patients are still febrile and unwell after 48 hours an alternative antibiotic such as m eropenem 
is often prescribed +/- vancomycin 
 if patients are not responding after 4-6 days the Christie guidelines suggest ordering 
investigations for fungal infections (e.g. HRCT), rather than just starting antifungal therap y blindly 
 there may be a role for G-CSF in selected patients 
 
1214

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   88 
  
May 2016 exam: When is the risk of febrile neutropenia thought to be highest following 
chemotherapy?  10 days in to treatment  
 
Systemic mastocytosis 
Systemic mastocytosis results from a neoplastic proliferation of mast cells 
 
Features

Features  
 urticaria pigmentosa - produces a wheal on rubbing (Darier's sign) 
 flushing 
 monocytosis on the blood film 
Diagnosis   
 raised serum tryptase levels 
 urinary histamine   
Cervical cancer 
 Cervical cancer is the most common cancer worldwide 
 The incidence of cervical cancer peaks around the 6th decade.  
 It may be divided into 
 squamous cell cancer (80%) 
 adenocarcinoma (20%) 
Features

Features 
 may be detected during routine cervical cancer screening 
 abnormal vaginal bleeding: postcoital, intermenstrual or postmenopausal bleeding 
 vaginal discharge 
 human papilloma virus (HPV) 16,18 & 33  the most common  
 associated with HPV 16 and 18  in approximately 70% of cases. 
 New vaccines are currently available in the United Kingdom to help immunise against this 
virus and hopefully prevent future cases of cervical cancer.

 smoking 
 human immunodeficiency virus 
 early first intercourse, many sexual partners 
 high parity 
 lower socioeconomic status 
 combined oral contraceptive pill* 
 *the strength of this association is sometimes debated but a large study published in the Lancet 
(2007 Nov confirmed the link 
Mechanism of HPV causing cervical cancer 
 HPV 16 & 18 produces the oncogenes E6 and E7 genes respectively 
 E6 inhibits the p53 tumour suppressor gene 
 E7 inhibits RB suppressor gene

 E7 inhibits RB suppressor gene 
Ovarian tumours  
 germ cell tumours  
 Patients are usually young .  
 most commonly seen in adolescents due to embryologic remnants 
 early pulmonary metastases 
 The fact that this lady is young, and has early pulmonary metastases, make a 
germ cell tumour much more likely 
 The diagnosis is usually made on biopsy in the case of ovarian tumours.

 treatment usually consists of surgery followed by chemotherapy (BEP).  
 Epithelial cell tumours  1215

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   89 
  usually disseminate through the abdomen and peritoneum prior to metastasisin g to the 
lungs. 
 Markers such as AFP, ȕ -human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH) 
may be raised 
 the most sensitive marker used for monitoring treatment efficacy and risk of 
relapse is AFP.

relapse is AFP. 
 
 A young man with a germ cell tumour (raised ȕ -HCG) can expect a greater than 95% cure 
rate, especially with seminomas. 
 ȕ-HCG  is the best tumour marker confers the best prognosis 
Breast cancer  
The triple assessment of a breast lump is essential to diagnose a breast lump accurately. It 
involves physical examination, mammography and then ultrasound guided fine needle 
aspiration (FNA). 
 
 inherited BRCA-1 mutation (or BRCA-2)  
  the greatest risk   
 family history of breast cancer at a young age makes this more likely. 
 What is the DNA repair mechanism by which the BRCA1 and BRCA2 proteins act? 
 Double strand DNA break repair  
 BRCA  involved in repair of double strand DNA breaks by homologous 
recombination. 
 Early menarche 
 late menopause 
 due to increased hormone exposure throughout life.  
 Nulliparity

 Nulliparity  
 Oral contraceptive use is also associated with a slight increase in risk of developing breast and 
also endometrial cancer.  
 
Screening  
 Mammograms screening  
 sensitive in older (because of less dense breast tissue)  
 not sensitive in younger (because of denser breast tissue)  MRI and ultrasound are 
better in them.  
 In young patients with a BRCA mutation, mammographic screening has a low 
sensitivity for detecting tumours

sensitivity for detecting tumours  
 Mammographic screening of all women between the ages of 50 and 70 ye ars can reduce 
mortality from breast cancer by 25%. There is no evidence for routine screening below this ag e. 
 mutation of BRCA1 or BRCA2 gene increases the risk of breast cancer   should be 
screened at younger than 50 years.  
 
Breast MRI is used for patients with invasive breast cancer in the following circumstances:

 if there is a discrepancy regarding the extent of disease from clinical examination, mammo graphy 
and ultrasound assessment for planning treatment 
 if breast density precludes accurate mammographic assessment 
 to assess tumour size if breast conserving surgery is being considered for invasive lobular 
cancer 
 Staging CT is not used routinely in primary breast cancer, only if there is suspicion of metastatic 
sprea d. 
Tumour marker

sprea d. 
Tumour marker   
 CA15- 3 tumour marker are used to assess disease activity in metastatic breast cancer  1216

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   90 
 Adjuvant radiotherapy  is recommended by (NICE) given after wide local excision of a breast 
tumour to reduce the risk of local recurrence.  
  There is growing evidence that adjuvant radiotherapy also increases survival for those 
patients at high risk of relapse.

patients at high risk of relapse.  
 There is however a risk of increased cardiovascular mortality after 15-20 years, which may 
be reduced with the use of modern techniques such as conformal radiotherapy a nd 
intensity-modulated radiotherapy. 
 Wound healing can be reduced after radiotherapy, and a period of at least a few weeks is 
usually given between surgery and initiation of radiotherapy. 
Drug therapy

Drug therapy 
 Hormonal treatment is used to remove the proliferative stimulus of oestrogen from tumou r cells. 
 Tamoxifen  is used for adjuvant hormone treatment in pre-menopausal  women first line .  
 Tamoxifen acts by blocking the binding of oestrogen to its receptor within the nucleus. 
 long-term use is associated with: 
 vaginal bleeding,  
 endometrial thickening and increased risk of endometrial cancer  
 thromboembolism.

 thromboembolism. 
 The lack of oestrogen receptor staining suggests a poor response to hormonal th erapy 
with tamoxifen. 
 Anastrozole  is used for adjuvant hormone treatment in post-menopausal  women first line . 
 aromatase inhibitor 
 Three aromatase inhibitors are licensed for treatment of early oestrogen-receptor-po sitive 
breast cancer: 
1. anastrozole,  
2. exemestane, 
3. letrozole.  
 Aromatase inhibitors work by preventing peripheral conversion of oestrogen  and

therefore cause profound oestrogen deprivation in a post-menopausal woman . 
 This increases the risk of osteoporosis and fragility fractures. 
 A DEXA scan must be done at the start of treatment  to identify those patients in whom 
a bisphosphonate must be considered for bone protection. 
 Aromatase inhibitors can be continued  in a patient who has suffered no fragility 
fractures  providing adequate measures are taken for bone protection, for example, 
prescribing a bisphosphonate .

prescribing a bisphosphonate . 
 In patients who suffer a fragility fracture tamoxifen must be considered  as this 
does have a partial oestrogen agonist action on bone, reducing the risk of 
osteoporosis. 
 A common side-effect is reduced bone mineral density , and bone densitometry is 
therefore often carried out prior to and during treatment. 
 Anastrozole is currently indicated for early oestrogen-receptor-positive breast carcinoma 
at a dose of 1 mg daily for 5 years.

at a dose of 1 mg daily for 5 years.  
 Fulvestrant is a new pure anti-oestrogen agent which appears to be as effective as anas trozole. 
It is given by sub-cutaneous injection once every three weeks. 
 Fulvestrant is not currently given first line in post-menopausal women but this ma y change 
in the near future. 
 The positive C-erb B2 ( HER2 /neu) staining suggests that trast uzumab (Herceptin) may be 
effective. 1217

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   91 
  the best test for monitoring the patient while she is receiving Herceptin 
(trastuzumab)? 
 Three monthly echocardiogram  
 Herceptin appears to be directly toxic to the cardiac muscle itself with 
relative sparing of the electrical conductivity of the heart.

 As such regular echocardiograms are the best test to assess treatment 
safety, a reduction of greater than 10% in ejection fraction indicating 
the need to stop treatmen t. 
What is the best predictive factor for local recurrence of breast cancer after  surgery, 
chemotherapy and radiotherapy? 
 Age  
 Patients below the age of 40 are significantly more likely to develop local 
recurrence of a breast cancer than those aged 41+. 
Prognosis 
 Poor prognostic factors  include:

Prognosis 
 Poor prognostic factors  include:  
 high-grade tumour,  
 positive lymph node status,  
 oestrogen-receptor-negative tumour,  
 progesterone-receptor-negative tumour,  
 young age (< 40 years),  
 premenopausal at diagnosis  
 increased tumour size.  
 Paget's disease of the breast 
 Overview 
 Paget's disease of the breast is a rare (1-4% of breast cancers) form of breast can cer that

affects the nipple and areola.  
 underlying invasive breast cancer, or ductal carcinoma in situ (DCIS)  almost always 
present  
 unlike Paget's disease of the vulva 
 Malignant cells infiltrate into the epidermis via the mammary duct epithelium, leading to  
thickening of the affected skin. 
 Features 
 Presents with dermatitis or macular rash over nipple or areola 
 It presents insidiously and is similar in appearance to eczema ; as such it often goes 
undiagnosed for several months.

undiagnosed for several months. 
 Skin biopsy with immunohistochemistry is the first line investigation.  
 Investigations should also be done for underlying malignancy: 
 biopsy if a lump is palpable,  
 imaging if no lump is palpable. 
 usually surgical with post-operative radiotherapy  
 high chance of recurrence. 
 1218

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   92 
  
Paget's disease of the breast 
Radiotherapy 
 External beam radiotherapy or use of targeted intraoperative radiotherapy does not render th e 
patient radioactive.  No radiation precautions need to be taken

 Use of brachytherapy methods can involve insertion of radioactive seeds or beads which ma y 
require some radiation protection precautions depending on the site. 
 Use of an unsealed source, for example radio-iodine treatment of thyroid cancer, ha s substantial 
need for precautions and patients need to be isolated in a lead-lined side room, often for 
several days.  
Chemotherapy

Chemotherapy 
 Adjuvant chemotherapy is commonly given in many cancers to reduce  the risk of local or distant 
recurrence or metastasis . 
 multi-drug chemotherapy resistance 
 Upregulation of which protein is associated with multi-drug chemotherapy 
resistance?  P-glycoprotein  
 P-glycoprotein, which is also known as multidrug resistance protein 1, is a member 
of the adenosine triphosphate (ATP)-binding cassette transporters which actively

remove harmful substances from the cytoplasm. 
 If upregulated these proteins can pump chemotherapeutic agents out of tumou r 
cells leading to drug resistance. 
 
Chemotherapy complications 
 Oral mucositis 
 Severe mucositis  is common with head and neck cancer treatment due to the 
combination of chemotherapy and external beam radiotherapy.  
 Admit the patient for IV fluids and nutritional support   
 Often patients require a PEG or RIG to provide adequate nutritional support

during their potentially curative treatment. 
 Oral hygiene is the mainstay of treatment in prevention of mucositis however it will n ot 
treat an existing mucositis.  
 Chlorhexidine mouthwash can improve a grade 1-2 mucositis. 
 
1219

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   93 
 _______________________________________________________  
Salivary Gland Tumors 
 Most commonly occur in the parotid gland  
 generally benign  
 if the tumor involves a non-parotid gland it is more likely to be malignant 
 Types 
 pleomorphic adenoma 
 the most common benign salivary gland neoplasm.

 70% to 80% of all benign salivary gland tumours. 
 more common in females  (middle-aged women > 40 ) 
 It is found mostly in the parotid gland (84%) .  
 90% of parotid gland pleomorphic adenomas arise lateral to the facial nerve. 
 benign with high rate of recurrence but may become malignant 
 Usually they do not enhance  following intravenous contrast injection in CT.  
 The optimal treatment is superficial or total parotidectomy with facial nerve 
preservation 
 Warthin's tumor

 Warthin's tumor 
 benign 
 more common in  males  
 heterotopic salivary gland tissue located in a lymph node 
 surrounded by lymphatic tissue 
 mucoepidermoid carcinoma 
 most common malignant  tumor 
 note: muco = malignant 
 generally involves parotid gland 
 combination of neoplastic mucus and squamous  cells 
 Physical exam  
 painless, moveable mass found at the angle of the jaw 
 pleomorphic adenoma 
 disturbance in CN VII function

 disturbance in CN VII function 
 more likely to be malignant pleomorphic adenoma 
 
Palliative care prescribing: pain 
 
The breakthrough dose of short acting morphine should be 1/6th of the total 24-hour dose. 
 
1220

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   94 
  
NICE guidelines ( 2012 ) and SIGN guidelines  (2008) 
 metastatic bone pain may respond to NSAIDs, bisphosphonates or radiotherapy 
 
Starting morphine  
 Morphine is the opioid of choice for treating moderate to severe cancer pain.  
 Choices between morphine preparations

 Choices between morphine preparations 
 when starting treatment, offer patients with advanced and progressive disease regular oral 
modified-release (MR)  or oral immediate-release morphine (IR)  (depending on patient 
preference), with oral immediate-release morphine for breakthrough pain 
 oral modified-release morphine should be used in preference to transdermal patche s 
 Immediate release preparations  are used for titration  as they offer greatest flexibility.

Most patients should be started on 5-10mg orally every 4-hours, with the same d ose 
prescribed as a breakthrough (or ‘rescue ’) dose wherever needed. Once drug 
requirements are constant, the patient can be converted to modified-release 
morphine.  
 Once a patient has been titrated on immediate release opioids these can be co nverted to 
the equivalent dose of a modified release preparation.  
 If a patient has good pain control on one drug, the modified release version of this drug

should be used.  
 Morphine doses  
 if no comorbidities use 20-30mg of MR a day with 5mg morphine for breakthrough pa in. 
For example, 15mg modified-release morphine tablets twice a day with 5mg of oral 
morphine solution as required 
 When increasing the dose of opioids the next dose should be increased by 30-50 %. 
 An appropriate starting dose of morphine sulphate immediate release (IR) should 
not be more than 10mg every 4 hours.  Alternatively, morphine sulphate modified

release (MR) 30mg 12 hourly could be used.  
 Opioids Side effects:  
 Constipation: laxatives should be prescribed for all patients initiating strong opioids 
 Morphine causes constipation by enhancing intestinal ring contractions . This 
results in hypersegmentation which in turn impairs peristalsis. 
 90% of patients taking morphine require a laxative and a stimulant is the best 
choice (such as senna).  Senna is the most commonly used laxative for this 
indication

indication  
 Nausea: patients should be advised that nausea is often transient. If it persists then an 
antiemetic should be offered 
 drowsiness is usually transient - if it does not settle then adjustment of the dose should b e 
considered 
Preferred opioids for patients with chronic kidney disease 
 
 Opioids should be used with caution in patients with chronic kidney disease. Alfentanil, 
buprenorphine  and fentanyl  are preferred

buprenorphine  and fentanyl  are preferred 
 Fentanyl patches are difficult to titrate because they are used for 72 hours. therefore only 
used once a patient has a stable opiate usage. 
 Fentanyl is a selective µ receptor agonist.  
 It has extensive first-pass metabolism so is not especially effective orally.  
 However, buccal absorption is good so lozenges are an effective mode of administration

and have a rapid onset of action (five minutes).  This is therefore very useful for patients 
with "breakthrough pain". 
  It is very useful in renal failure as it is metabolised mainly in the liver and it has inactive 
metabolites. 
What is the most appropriate opioid to prescribe for a syringe driver in renal failure? 
 Alfentanil   
 
Combination therapies antagonism 
 Partial opioid agonists (for example, buprenorphine),  when used in association with morphine ,

may produce a reduction in the analgesic effect  due to partial  antagonism . 
1221

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   95 
  This is an aspect of pain management that needs to be considered when using com bination 
 
Oxycodone  
 Oxycodone is often used as a second line opioid for patients who experience eith er inadequate 
analgesia or excessive side effects with morphine.

 It has similar analgesic properties to morphine but is twice as potent.  
 It is available in immediate-release and modified- release oral preparations and can a lso be used 
parentally.  
 Parental oxycodone is twice as potent as oral oxycodone .  
 The total daily dose of immediate and modified release oral oxycodone is the same. 
 Oxycodone generally causes less sedation, vomiting and pruritis than morphine but more 
constipation.  
 
Opioid side-effects

Opioid side-effects  
Usually transient Usually persistent 
Nausea 
Drowsiness Constipation 
 
Conversion between opioids  
 
From To Conversion factor 
Oral codeine Oral morphine Divide by 10 
Oral tramadol Oral morphine Divide by 10 
 
Oral morphine Oral oxycodone Divide by 1.5-2** 
**historically a conversion factor of 2 has been used (i.e. oral oxycodone is twice as strong as o ral morphine).

The current BNF however uses a conversion rate of 1.5  
 
Transdermal perparations:  
The current BNF gives the following conversion factors for transdermal perparations 
 a transdermal fentanyl 12 microgram patch equates to approximately 30 mg oral morphine  
daily  
 a transdermal buprenorphine 10 microgram patch equates to approximately 24 m g oral morphine 
daily. 
Oral morphine Subcutaneous morphine Divide by 2

Oral morphine Subcutaneous morphine Divide by 2 
Oral morphine Subcutaneous diamorphine Divide by 3 
Oral oxycodone Subcutaneous diamorphine Divide by 1.5 
 
Diamorphine  
Concerning diamorphine elixir for the relief of pain in terminal patients: 
 Diamorphine has a rapid onset so could be used for breakthrough pain if the renal function i s 
normal.  
 Constipation is a characteristic sequel to treatment  
 Hallucinations also tend to occur.

 Hallucinations also tend to occur. 
 An aperient (laxative) should always be added to the treatment regime . 1222

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   96 
  Addiction is not a problem. 
 An intramuscular injection is three times more effective than the same oral dose. 
 the best option for controlling pain associated with vomiting in palliative care  
Subcutaneous diamorphine by continuous infusion  (able to effectively titrate the dose to

achieve adequate analgesia) 
 
Other notes: 
 Nifedipine  
 Nifedipine helps relieve painful oesophageal spasm  and tenesmus associated with 
gastrointestinal tumours and could be used to relieve odynophagia. 
 Bisphosphonates are useful adjuncts for bone pain, especially in breast cancer and 
myeloma. 
 Clodronate inhibits osteoclastic bone resorption and is used to treat malignant bone p ain 
and the associated hypercalcaemia.

and the associated hypercalcaemia. 
 The risk of osteonecrosis of the jaw is much greater for patients receiving 
intravenous bisphosphonates in the treatment of cancer.   
 All patients receiving bisphosphonates for cancer should have a dental check-up 
before bisphosphonate treatment.   
 other patients who are prescribed bisphosphonates should have a dental 
examination only if they have poor dental health.

 The beneficial effect of bisphosphonates can be delayed for up to two weeks a nd can last 
for one month, and treatments are therefore usually given monthly (typically for 6 months).  
 increase analgesia while waiting for the bisphosphonates to work and review over the next 
few days to see whether you could reduce them again.  
 Corticosteroids  
 Corticosteroids are used to treat pain from central nervous system tumours  
 Oxybutynin

 Oxybutynin  
 painful bladder spasm may be relieved by oxybutynin. 
 hyoscine  
 to reduce air way secretions in palliative care  Both hyoscine  and atropine when 
given subcutaneously are thought to be equally appropriate for drying up 
secretions.   
 hyoscine s/c can be given up to three times per day in boluses of 10-20 mg. 
 Haloperidol  
 Haloperidol is a first line antiemetic for opioid-induced nausea in the palliative care 
setting .

setting .  
 Its action is predominantly via D2-receptor antagonism in the chemoreceptor trigger zone 
(CTZ) in the brain stem. 
 90% of patients taking morphine require antiemetics (morphine stimulates D2 receptors i n 
the CTZ).  Cyclizine, although commonly used, is less effective. 
 haloperidol  dopamine receptor antagonist (D2) activity  drug-induced 
parkinsonism (DIP).  
 Cyclizine  
 Cyclizine is a commonly used antihistamine antiemetic and its primary site of action is the

vomiting centre (which is rich in histamine and muscarinic cholinergic receptors). 
 Cyclizine has a strong affinity for muscarinic receptors and therefore 
anticholinergic side effects (dry mouth, drowsiness, blurred vision, constipation, 
etc) are common,  especially in the first few days. 
 Ondansetron  
 Ondansetron is a 5HT 3 antagonist and is mainly used in post-chemotherapy or 
radiotherapy induced nausea.

radiotherapy induced nausea.   
 In the United Kingdom 5HT 3 antagonists are licensed only for post-chemotherapy and 
post-operative nausea. 
 Which antiemetics is most useful following treatment with a platinum based 
chemotherapy?   Ondansetron  
 Examples of platinum based chemotherapies are cisplatin, carboplatin and 
oxaliplatin  
 Opioid toxicity  
 Reduced conscious level, hallucinations, vomiting, myoclonic jerks and pinpoint 
pupils are features of opioid toxicity. 1223

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   97 
  Pain management 
 The pain may be due to metastatic deposits within the ribs, but may also have an elem ent 
of neuropathic pain. Nerve pain often also has a nociceptive opioid responsive element 
and hence opioids (with a combination of nonsteroidal anti-inflammatory drugs

[NSAIDs]) should be tried first (eg: ibuprofen and tramadol) and used as part of the 
WHO analgesic ladder. Morphine would be tried next, followed by the other age nts. 
 Gabapentin   
 Gabapentin  is a commonly used adjunctive agent for neuropathic pain.  
 mechanism of action : (Activation of GABA inhibitory system).   
 Four to six weeks of treatment are often needed before the patient experien ces benefit. 
 Hypercalcaemia is a common problem in palliative care.

 prostate cancer with bone metastasis is a frequent cause.  
 Hypercalcaemia can cause constipation (a constipation in cancer  do blood tests, 
including bone profile )  
 Codeine  
 The analgesic effect of codeine depends on its conversion to morphine by the 
CYP2D6 hepatic enzyme. Up to 10% of Caucasians are CYP2D6 poor metabolisers 
and are unlikely to derive any analgesia from it.   
 If hepatic metabolise is impaired for any other reason (drugs or hepatic impairment)

patients are also unlikely to benefit from codeine. 
 
Acupuncture is playing an increasing role in pain management.  Which structures are involved in 
mediating the effects of acupuncture?   Cerebral cortex and A beta nerve fibres.  
 The A beta nerve fibres are the path for fast transmission of sensation. 
 Acupuncture also has a central effect. 
Palliative care prescribing: agitation and confusion

 Underlying causes of confusion need to be looked for and treated as appropriate,  for example 
hypercalcaemia, infection, urinary retention and medication.  
 If specific treatments fail then the following may be tried: 
 first choice: haloperidol 
 other options: chlorpromazine, levomepromazine 
 In the terminal phase of the illness then agitation or restlessness is best treated with 
midazolam 

Palliative care prescribing: hiccups 
 
Management of hiccups 
 chlorpromazine is licensed for the treatment of intractable hiccups 
 haloperidol, gabapentin are also used 
 dexamethasone is also used, particularly if there are hepatic lesions 
Palliative care : end of life care 
 
1224

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   98 
Epstein-Barr virus: associated conditions 
 
 Epstein-Barr virus  infects B lymphocytes and squamous epithelial cells of the oropharynx. The 
virus can transform B cells and epithelial cells to produce tumors  
 Malignancies associated with EBV infection

 Malignancies associated with EBV infection 
 Burkitt's lymphoma (both African and sporadic Burkitt's)  
 Hodgkin's lymphoma 
 nasopharyngeal carcinoma 
 Epstein-Barr virus is detectable in over 90% of nasopharyngeal cancers  
 the most common type is the undifferentiated form. 
 HIV-associated central nervous system lymphomas 
 The non-malignant condition hairy leukoplakia is also associated with EBV infection.

September 2009 exam:  What type of virus family is associated with nasopharyngeal 
carcinoma? Herpesvirus (Epstein-Barr virus is one of the herpes viruses)  
T cell lymphoma ( Adult T-cell lymphoma (ATLL) 
 makes up about 10- 20% of non-Hodgkin's lymphomas  
 has a worse prognosis than B cell lymphoma.  
 Adult T-cell leukaemia/lymphoma (ATLL) is a potentially aggressive type of mature T-cell non-
Hodgkin lymphoma.

Hodgkin lymphoma.  
 It is linked to the viral infection, HTLV-1 (human T-cell lymphotropic virus 1). 
  It is more prevalent in countries where infection with HTLV-1 is common, such as Japan, China, 
the Caribbean, South and Central America and West Africa. 
 ATLL occurs in 2%-5% of people who are infected with the HTLV-1 virus. 
 The HTLV-1 virus is a retrovirus, and is in the same class of virus as the HIV/AIDS virus. It is

believed that the HTLV-1 virus is a key factor in the development of this rare lymph oma which is 
transmitted through sexual contact, exposure to contaminated blood or breastfeeding.   
 slightly more common in men than in women, 
 In acute ATLL , symptoms develop rapidly and include: 
  fatigue,  
 skin rash  
 enlarged lymph nodes 
 hypercalcaemia may also be present which can cause confusion, bone pain and seve re 
 lymphomatous form of ATLL  presents with:

 lymphomatous form of ATLL  presents with: 
 enlarged lymph nodes.  
 Chronic ATLL  is slow growing and frequently characterised by: 
  enlarged lymph nodes  
 Skin rash and  
 fatigue .  
 Smouldering ATLL develops slowly and presents with very mild symptoms such as a few le sions 
on the skin.  
 Patients with the chronic or smouldering types of ATLL can progress to the acute form in  about 
25% of cases.

25% of cases. 
 for the acute and lymphomatous types: Therapies include antiviral drugs, such as acyclovir and  
interferon, together with chemotherapy regimens 
 
1225

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   99 
Testicular cancer 
Features  
 fatigue, weight loss, and a testicular mass  
 Rarely gynaecomastia can be the trigger by which a young man will seek medical 
attention; testicular examination should therefore be done in every case.

 What is the mechanism by which patients with testicular cancer develop 
gynaecomastia? 
  Raised oestrogen levels  
 testicular cancers  ↑ȕ-HCG  ↑oestrogen  stimulates hypertrophy of 
breast tissue. 
 Raised oestrogen levels   
Treatment 
 In testicular cancer  the BEP combination is used: Bleomycin, Etoposide and Cisplatin 
(Platinum). 
 Etoposide  
 works by inhibiting topoisomerase II and causing DNA degradation.

 Etoposide is also used in the treatment of small cell lung cancer, leukemias, and 
lymphomas.  
 adverse effects: myelosuppression and alopecia.  
Tumor markers  
 
Common tumor markers 
Tumor marker Associated conditions 
Alpha fetoprotein (AFP)   Hepatocellular carcinoma (HCC) 
 Hepatoblastoma 
 Yolk sac tumor of the ovary (endodermal sinus tumor) 
 Mixed germ cell tumor 
 Transient elevation during pregnancy

 Transient elevation during pregnancy 
 Ĺ AFP: abdominal wall defects, neural tube defects 
 Ļ AFP: associated with trisomy 21, 18, and 13 (See prenatal 
diagnostics for details) 
ȕ-HCG   Testicular germ cell tumors (choriocarcinoma, embryonal cell 
carcinoma, mixed germ cell tumor, seminoma) 
 Ovarian cancer: choriocarcinoma (gestational trophoblastic 
disease) 
 If detectable in urine 
 Pregnancy marker  
 Molar pregnancy (hydatidiform mole) 
Carcinoembryonic

Carcinoembryonic 
antigen (CEA)   Colorectal cancer  
 Pancreatic cancer  
 Breast cancer 
 Lung cancer (especially in non-small cell cancers) 
 Gastric cancer 
 Endometrial cancer 
 Medullary thyroid cancer 
 Smokers 
Prostate-specific 
antigen (PSA)  Prostate cancer 
 Benign prostatic hyperplasia 
 Prostatitis 
Calcitonin  Medullary thyroid cancer 1226

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   100 
 Common tumor markers 
Alkaline phosphatase  Metastases to bone or liver 
 Paget disease of the bone 
Lactate dehydrogenase   Ovarian cancer (dysgerminoma) 
 Testicular germ cell 
tumors (both seminoma and nonseminoma) 
 Lymphomas 
 Ewing's sarcoma 
 Hepatitis 
 Hemolysis

 Hemolysis 
 Myocardial infarction 
Neuron specific enolase (NSE)  Small cell lung cancer 
 Neuroendocrine tumors 
 Neuroblastoma 
 NSE is released secondary to brain injury (e.g., stroke)  
CA 19 –9  Pancreatic adenocarcinoma 
CA 15 –3/CA 27 –29  Breast cancer 
CA 125  Ovarian carcinoma (80–100%) 
Chromogranin A  Neuroendocrine tumors 
S-100 protein (S100A) and 
(S100B)  Malignant melanoma

(S100B)  Malignant melanoma 
ȕ2 microglobulin  (ȕ2M)   Multiple myeloma 
 Chronic lymphocytic leukemia 
 Renal disease 
Thyroglobulin  Papillary thyroid carcinoma 
 Follicular thyroid carcinoma 
Monoclonal immunoglobulins  Multiple myeloma 
 Waldenstroms macroglobulinemia 
 Monoclonal gammopathy 
 Infections 
 Certain autoimmune conditions (e.g., rheumatoid arthritis) 
Von Hippel-Lindau syndrome 

 Von Hippel-Lindau (VHL) syndrome is an autosomal dominant  condition predisposing to 
neoplasia. 
Aetiology 
 due to an abnormality in the VHL gene located on short arm of chromosome 3  
 von-Hippel- Lindau= 3 words for chromosome 3. 
 VHL gene normally act as a tumor suppressor gene 
 VHL gene normally is responsible for regulating the hypoxia-inducible factor (HIF),  
a transcription factor.

a transcription factor.  
 In patients with VHL, there is constitutive expression of HIF resulting in angiogenesis and 
cancer development.  
 it has over 90% penetrance by the age of 65.  
 prevalence is 1 in 39,000. 
 Mean age at presentation of 27 years. 
Types 1227

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   101 
  Type 1 VHL is associated with tumours in eye, brain, spinal cord, kidney and pancreas.  
 Type 2 is associated with phaeochromocytoma: 
 
Features  
 haemangioblastomas of the CNS (The most common presentation) 
 retinal haemangiomas: vitreous haemorrhage

 retinal haemangiomas: vitreous haemorrhage 
 Retinal haemangioblastomas  is the initial presentation in 40% of patients. 
 Annual ophthalmological exam for haemangioblastoma is the most 
appropriate screening investigation 
 cerebellar haemangiomas  is another common initial presentation.  
 CNS  haemangioblastomas tend to be infratentorial. 
 cerebellar haemangiomas secretes erythropoietin-like substance, leading to a 
secondary polycythaemia.

secondary polycythaemia.  
 haemangioblastomas are typically not cancerous, but they can compress the 
brain and spinal cord resulting in headaches, vomiting, paralysis, and ataxia. 
 cysts in various organs (e.g., kidney, pancreas, liver)  
 renal cysts (premalignant)  
 ↑ risk of developing clear cell renal cell carcinoma.  
 Renal cell carcinoma (Clear cell  ) is the commonest cause of death  (70% 
of patients having renal cysts and carcinomas by age of 60 years).

 extra-renal cysts: epididymal, pancreatic, hepatic 
 phaeochromocytoma   
 occurs in 20% of patients,  although the incidence is much higher in those with von 
Hippel Lindau type 2 
 endolymphatic sac tumours 
Diagnosis 
 genetic testing  mutations in the VHL gene. 
 Ideally, genetic testing in affected families should take place around the age o f 5 years. 
Treatment 
 Asymptomatic small haemangioblastomas  observation. 
 Renal cell carcinoma  surgery. 
Monitoring

 Affected individuals require: 
 yearly urinalysis, catecholamine screening, fluorescein angiography  
 3-yearly brain magnetic resonance imaging. 
 
CT scan showing a cerebellar haemangioma in a 
patient with Von Hippel-Lindau syndrome. MRI showing renal cysts in patient with known Von Hippel-Lindau 
syndrome. 
1228

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   102 
  
Haemangiomas  
 Hemangiomas   are benign vascular tumors that lead to a messy clump of dilated blood 
vessels.   
 Hepatic hemangioma  
 a benign liver tumor composed of masses of blood vessels

 the most common benign tumor affecting the liver.  
 The most common site of hemangiomas in internal organs is the liver. 
 mesenchymal in origin and usually, are solitary  
 oral contraceptives and steroi ds may accelerate the growth of a hemangioma.  
 Investigations 
 biopsies are contraindicated because of the risk of bleeding.  
 A good way to determine if a structure is hypervascular is to look for IV contrast 
enhancement.   
 Capillary hemangioma   
 cherry hemangioma:

 cherry hemangioma:  
 also known as  (Campbell de Morgan spots)  
 benign capillary hemangioma of the elderly that does not regress 
 benign skin lesions which contain an abnormal proliferation of capillaries. 
 frequency increases with age.  
 The most common benign capillary skin tumor found in elderly  
 affect men and women equally. 
 Features 
 erythematous, papular lesions 
 typically 1-3 mm in size 
 non-blanching

 non-blanching 
 not found on the mucous membranes 
 As they are benign no treatment is usually required. 
  
 Infants with large hemangiomas should have ultrasonography of the abdomen to rule out 
the presence of other hemangiomas in the viscera. 
 Propranolol is the first line of treatment  of hemangiomas causing disfigurement. 
 
1229

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   103 
  
Oncology drugs 
Cytotoxic agents 
The tables below summarises the mechanism of action and major adverse effects o f commonly used 
cytotoxic agents.  
 
Alkylating agents

Alkylating agents 
Cytotoxic Mechanism of action Adverse effects 
Cyclophosphamide Alkylating agent - 
causes cross-linking in 
DNA  Haemorrhagic cystitis, 
myelosuppression, transitional cell 
carcinoma 
 
Cytotoxic antibiotics  
 
Bleomycin  Degrades preformed DNA Lung fibrosis  
Doxorubicin Stabilizes DNA-topoisomerase II complex 
inhibits DNA & RNA synthesis Cardiomyopathy 
 
Antimetabolites

Antimetabolites  
 
Methotrexate Inhibits dihydrofolate reductase and 
thymidylate synthesis Myelosuppression, mucositis, liver 
fibrosis, lung fibrosis 
Fluorouracil (5-
FU) Pyrimidine analogue inducing cell cycle 
arrest and apoptosis by blocking thymidylate 
synthase (works during S phase) Myelosuppression, mucositis, 
dermatitis 
6-
mercaptopurine Purine analogue that is activated by 
HGPRTase, decreasing purine synthesis Myelosuppression

Cytarabine Pyrimidine antagonist. Interferes with DNA 
synthesis specifically at the S-phase of the 
cell cycle and inhibits DNA polymerase Myelosuppression, ataxia 
 
Acts on microtubules 
Vincristine, 
vinblastine Inhibits formation of microtubules Vincristine: Peripheral neuropathy  
(reversible) , paralytic ileus 
Vinblastine: myelosuppression 
Docetaxel Prevents microtubule depolymerisation & 
disassembly, decreasing free tubulin.  has a

disassembly, decreasing free tubulin.  has a 
further action in blocking bcl-2 Neutropaenia 
 
 1230

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   104 
  
Other cytotoxic drugs  
Cisplatin Causes cross-linking in DNA Ototoxicity, peripheral neuropathy, 
hypomagnesaemia 
Hydroxyurea 
(hydroxycarbam
ide) Inhibits ribonucleotide reductase, decreasing 
DNA synthesis Myelosuppression

DNA synthesis Myelosuppression 
 
Busulfan  
 alkylating antineoplastic agent,  
 Busulfan was the mainstay of the chemotherapeutic treatment of chronic myeloid leu kemia 
(CML) until it was displaced by the new gold standard, imatinib  
 Busulfan is used in pediatrics and adults in combination 
with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow

transplantation, especially in chronic myelogenous leukemia (CML) and 
other leukemias, lymphomas, and myeloproliferative disorders.   
 Busulfan lung  
 Busulfan lung is a form of drug-induced pulmonary toxicity with an idiopathic 
pulmonary fibrosis-like picture .  
 It is clinically symptomatic in 5% of patients.  
 There are no predictors of toxicity and pulmonary function testing is not a useful 
“screening ” test.  
 Withdrawal of busulfan is the key step in treatment.

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   105 
 Combinations of chemotherapeutic agents  
 what is the rationale behind using combinations of chemotherapeutic agents rather than 
single agents? 
 Combination therapy decreases the chances of drug resistance developing 
 There are two main reasons for using combinations of different chemotherapy 
agents:

agents: 
1. Different drugs will exert their effects through different mechanisms , 
so combining them will increase the number of tumour cells killed in each 
cycle.  
2. It also reduces the chances therefore of drug resistance developing. 
 
Vinblastine  
 Vinblastine is an M phase -specific chemotherapeutic agent that works by disrupting the 
assembly of microtubules  via binding tubulin .  
 Cell death results because anaphase cannot commence without the formation of the m itotic

spindle and kinetochore.  
 Which cellular event occurs in the same phase of the cell cycle at 
which vinblastine functions?   Breakdown of the nuclear membrane  
 Breakdown of the nuclear membrane  occurs during the prometaphase portion of mitosis. 
 
Cyclophosphamide 
 
 Cyclophosphamide is an alkylating agent  used in the management of cancer and autoimmune 
conditions.  
 It works by causing cross-linking of DNA

 It works by causing cross-linking of DNA   
 Cyclophosphamide is inactive unless metabolised by the liver to 4-hydroxyl 
cyclophosphamide , which decomposes into alkylating species as well as to chloroacetaldehyde 
and acrolein 
 
 haemorrhagic cystitis  (Acrolein  causes chemical cystitis ):  
 incidence reduced by the use of hydration and mesna 
 myelosuppression 
 transitional cell carcinoma 
 premature ovarian failure ,  
 infertility in both men and women.

 infertility in both men and women. 
 
Mesna 
 2-mercaptoethane sulfonate Na 
 a metabolite of cyclophosphamide called acrolein  is toxic to urothelium 
 mesna binds to and inactivates acrolein helping to prevent haemorrhagic cystitis 
Cisplatin  
 
 Platin um-based antineoplastic (end with: - platin ) 
Mechanism of action

 Causes crosslinking in DNA   makes it impossible for rapidly dividing cells to duplicate their 
1232

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   106 
 DNA for mitosis.  
 Marrow toxicity 
 Ototoxicity 
 Due to vestibulocochlear nerve damage (CNVIII) 
 Sodium Thiosulfate Prevents Cisplatin-Induced Hearing Loss in Children With Ca ncer 
 Peripheral neuropathy 
 Nephrotoxicity

 Nephrotoxicity 
 The nephrotoxicity of platinum-class drugs seems to be related to reactive oxygen 
species  
 Hypocalcaemia, hypomagnesaemia  and hypokalaemia may occur as a result of 
nephrotoxicity  
 Amifostine is an antidote for cisplatin treatment to counteract nephroto xicity. 
 Adequate hydration and diuresis is used to prevent renal damage. 
 Chloride diuresis is a renal procedure that can be performed to prevent the 
nephrotoxicity caused by cisplatin.

nephrotoxicity caused by cisplatin. 
 Alopecia,  
 Changes in taste. 
 Although optic neuritis is described it is not a typical side effect.   
Trastuzumab 
 
 A baseline echocardiogram to assess heart function is recommended prior to starting trast uzumab. 
 
 Trastuzumab (Herceptin) is a monoclonal antibody directed against the HER2/neu receptor.

 It is used mainly in metastatic breast cancer although some patients with early disease are now 
also given trastuzumab. 
 flu-like symptoms and diarrhoea are common 
 cardiotoxicity : associated with Dilated  cardiomyopathy  in 2% to 7% of users  
 more common when anthracyclines have also been used (eg : Doxorubicin) .  
 Toxic to cardiac muscle itself with relative sparing of the electrical conductivity of the heart

 Studies have shown that activation of Erb-b2 (also known as HER-2), the receptor 
blocked by trastuzumab (Herceptin), is important in preventing the development of 
 Mechanism 
 Anthracyclines  activate stress signal pathways within the heart  cardiac 
damage 
 HER2 activation is protective against the damage that this stress signaling induces 
 HER2 inhibition removes this layer of protection, leading to  dilated 
cardiomyopathy.

cardiomyopathy. 
 An echo is usually performed before starting treatment 
 Regular echocardiogram (three monthly) is the best test to assess treatment safety  
 Reduction of greater than 10% in ejection fraction indicating the need to stop treatment.  
 
In which chemotherapeutic agents is the  cumulative dose  limited due to  cardiotoxicity ? 
 anthracycline chemotherapeutic agents  (eg: Epirubicin  ) 
 Epirubicin and the other anthracycline chemotherapeutic agents are extremely

potent but are limited by dose constraints . 
 Cumulative doses of over 900 mg/m2 can lead to significant cardiac toxicity and 
heart failure. 
 Trastuzumab can cause direct myocardial damage and must be monitored with 
regular echocardiograms but it is not limited to a maximum lifetime dose. 
 
1233

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   107 
  
Erlotinib  
 Erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase (wh ich 
is required for the conformational change) and binds in a reversible fashion to the adeno sine 
triphosphate binding site.

triphosphate binding site. 
 For the signal to be transmitted, two members of the EGFR family need to come to gether to form 
a homodimer. These then use the molecule of adenosine triphosphate (ATP) to 
autophosphorylate each other, which causes a conformational change in their intrace llular 
structure, exposing a further binding site for binding proteins that cause a signal cascade to the 
nucleus. By inhibiting the ATP, autophosphorylation is not possible and the signal is stoppe d.

 A key issue with EGFR-directed treatments is that after a period of 8-12 months, the cancer 
cells become resistant to the treatment. This most commonly occurs due to a mutation in 
the ATP binding pocket of the EGFR kinase domain. This prevents the binding of erlotinib 
(Tarceva).   
Imatinib  
 Belong to the class of  Signal transduction inhibitor

 Imatinib is a tyrosine kinase inhibitor  which is fairly specific for the bcr/abl protein. It blocks the 
active site, which has a number of downstream effects.  
 The result is reduced cell proliferation, reduced cell motility, decreased adhesion and  
increased apoptosis. 
 NICE recommend that imatinib should be used to treat people in the accelerated or blast 
crisis phase of CML.  
 It is also indicated in the treatment of gastrointestinal stromal tumours.

Tamoxifen 
Tamoxifen is a selective estrogen receptor modulator (SERM) which acts as an oestrogen receptor 
antagonist and partial agonist. It is used in the management of oestrogen receptor positive  breast 
cancer 
 menstrual disturbance: vaginal bleeding, amenorrhoea 
 hot flushes 
Particularly during and immediately after major surgery or periods of immobility

 endometrial cancer 
Tamoxifen is typically used for 5 years following removal of the tumour. 
Raloxifene is a pure oestrogen receptor antagonist, and carries a lower risk of endometrial cancer 
 
 1234

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   108 
 __________________________________________________________________  
UK lic ensed monoclonal antibodies 
Name Type of antibody Target Licensed indication 
Infliximab Human –mouse 
chimaera IgG1 TNF- α Refractory Crohn's, Crohn's fistulas, 
refractory rheumatoid arthritis

refractory rheumatoid arthritis 
Palivizumab Humanised IgG1 F protein on RSV Prophylaxis, RSV in premature infants 
or brochopulmonary dysplasia 
Abciximab Human –mouse 
chimaera Platelet glycoprotein 
IIb/IIIa High risk coronary intervention 
Rituximab Human –mouse 
chimaera IgG1 CD20 Refractory low grade or follicular B 
cell lymphoma 
Basiliximab Human –mouse 
chimaera IgG1K IL-2 receptor α chain  Prophylaxis of acute rejection in 
allogeneic renal transplantation

allogeneic renal transplantation 
Daclizumab Humanised IgG1 IL-2 receptor α  As Basiliximab 
Trastuzumab  Humanised IgG1 HER 2 growth 
receptor Relapsed HER2 (high) breast 
IL-2, interleukin 2; TNF- α, tuŵour ŶeĐrosis faĐtor α; RSV, respiratory syŶĐitial virus.  
Rituximab 
 Rituximab binds to CD20,  an antigen located on pre-B and mature B-lymphocytes

 The receptor is thought to mediate B-cell lysis and apoptosis 
 After rituximab therapy, levels of B-lymphocytes appear suppressed for around 6 mo nths, with 
levels slowly increasing after this time 
 As well as for rheumatoid arthritis, rituximab is also used for the treatment of non-Hodgkin's 
lymphoma  
 Infusion reactions associated with cytokine release occur in up to 15% of patients receiving 
rituximab, and the medicine is administered in a specialist centre for this reason

Cetuximab  
 Action  epidermal growth factor receptor (EGFR) inhibitor 
 Cetuximab works by blocking the extracellular domain of EGFR preventing ligand binding 
and therefore preventing downstream signal transduction.  
 . Cetuximab is a monoclonal antibody given by intravenous infusion   
 The patient's tumour must express k-ras wi ld-type as k-ras mutated is constitutively active

regardless of whether a ligand is attached or not. 
 Which histopathological subtypes is essential for successful treatment with 
cetuximab?  
 K-ras wild-type 
 Cetuximab and other EGFR inhibitors only work on tumors in which K-ras is 
not mutated  
 it has no effect in colorectal tumors with a K-ras mutation (this also applied 
to the EGFR antibody panitumumab). 
 genetic testing to confirm the absence of K-ras mutations (and so the

presence of the K-ras wild-type gene), is now clinically routine before the 
start of treatment with EGFR inhibitors. 
 Cetuximab is licensed by NICE in metastatic colorectal cancer for k-ras wild-type proven patients  
who require downstaging prior to surgical resection of liver metastatic disease.  
 75% of patients with metastatic colorectal cancer have an EGFR-expressing tumor  and 
are therefore considered eligible for treatment with cetuximab or panitumumab  
 Side effect

 Side effect   
 acne type rash (the most important and serious SE).  
 
Alpha interferon  at 2 million U/m2 subcutaneously three times a week for 12-18 months can be 
used to  salvage relapsed or refractory hairy cell leukemia. 
 
 1235

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   109 
Capecitabine versus 5-fluorouracil (5-FU) 
 Advantages of capecitabine versus 5-fluorouracil (5-FU)  Can be orally administered  
 The major difference between capecitabine and 5-FU is that capecitabine is an oral pro drug of 5-

FU. The final step in metabolism to 5-FU is thymidine phosphorylase, higher activity of thym idine 
phosphorylase occurring in tumour tissues. 
 Evidence suggests that efficacy of capecitabine versus 5-FU is broadly similar, 
Chemotherapy side-effects: nausea and vomiting 
 Nausea and vomiting are common side-effects of chemotherapy.  
 Risk factors for the development of symptoms include: 
 anxiety

 anxiety 
 age less than 50 years old 
 concurrent use of opioids 
 the type of chemotherapy used 
 For patients at low-risk of symptoms then drugs such as metoclopramide may be used f irst-line.  
 For high-risk patients, then 5HT3 receptor antagonists such as ondansetron  are often 
effective, especially if combined with dexamethasone 
Adverse effects of other cancer treatment

Adverse effects of other cancer treatment  
Purine analogue (eg: fludarabine) for CLL  Pneumocyscis jirovecii infection  
 This cytotoxic agent affects T-cell function. Patients are therefore prone to opportunistic 
infections including pneumocystis infection.  
 Patients therefore receiving purine analogues should also receive co-trimoxazole to reduc e this 
risk. 
 All patients who receive purine analogues are at risk of transfusion-associated graft-versus-

host disease and therefore should receive irradiated blood products. The clinical features of 
transfusion associated graft-versus-host disease are: 
1.  pancytopaenia,  
2. liver dysfunction,  
3. diarrhoea and 
4.  rash 
Etoposide  secondary haematological malignancy 
 In patients who have received Etoposide, secondary haematological malignancy m ay develop in 
as little as 1-3 years.  
 It is currently indicated for the treatment of small cell lung cancer and non-seminomatous

testicular carcinoma. 
Filgra stim 
 Action 
 granulocyte colony-stimulating factor (G-CSF) 
 Filgrastim is similar to naturally occurring granulocyte colony-stimulating factor (G-CSF). 
 produced by recombinant DNA technology using genetic material of Escherichia coli . 
 stimulating the bone marrow to increase production of neutrophils. 
 used to treat  neutropenia caused by: 
 chemotherapy,

 chemotherapy,  
 radiation poisoning,  
 congenital neutropenia 
 aplastic anemia 
 also used to increase white blood cells for gathering during leukapheresis.  
 It is given either by injection into a vein or under the skin. 
 side effects  
 The most commonly observed adverse effect is mild bone pain after repeated 
administration and local skin reactions at the site of injection 
 Severe side effects include splenic rupture and allergic reactions.

Notes & Notes for MRCP                                                                                              By  Dr. Yousif  Abdallah Hamad   110 
  serious allergic reactions (including a rash over the whole body, shortness of 
breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and  
sweating), 
  alveolar hemorrhage, acute respiratory distress syndrome, and hemoptysis.

 Severe sickle cell crises, in patients with sickle cell disorders. 
 
Sargramo stim 
 Action 
 granulocyte macrophage colony-stimulating factor (GM-CSF) 
 It is produced in yeast 
 stimulate other myeloid and megakaryocyte  
 for myeloid reconstitution after bone marrow transplantation.  
 neutropenia induced by chemotherapy  
 side effects 
 GM-CSF can cause more severe effects, including fever, arthralgias, and capillary 
damage with edema. 
 edema 
 1237

Infectious diseases 
 
Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   1 
  
By
 
Infectious diseases
 
Updated 
 
2017
 
Contains: 
 
 1238

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   2 
  
Classification of bacteria 
cocci  
 Remember: 
 Gram positive cocci = staphylococci + streptococci (including enterococci ) 
 Gram negative cocci  = Neisseria  meningitidis  + Neisseria  gonorrhoeae , 
also Moraxella  
Rods (bacilli)  
 only a small list of Gram positive rods  (bacilli) need to be memorised to categorise all

bacteria - mnemonic = ABCD L  
 Actinomyces  
 Bacillus anthracis  (anthrax) 
 Clostridium  
 Diphtheria: Corynebacterium diphtheria  
 Listeria monocytogenes  
 Remaining organisms are Gram negative rods 
 
Bacterial shapes  
 
 Staphylococcus aureus  appears as large Gram-positive cocci in clusters .  
 
1239

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   3 
 _______________________________________________________ 
Identifying gram-positive bacteria 
Gram positive bacteria will turn purple/blue following the gram staining. Microscopy will then rev eal the 
shape, either cocci or rods. 
 
Rods (bacilli) 
 Actinomyces  
 Bacillus antracis  
 Clostridium

 Clostridium  
 Corynebacterium diphtheriae  
 Listeria monocytogenes  
Cocci 
 makes catalase: Staphylococci  
 does not make catalase: Streptococci  
Staphylococci 
 makes coagulase: S. aureus  
 does not make coagulase: S. epidermidis  (novobiocin sensitive), S. saprophyticus (novobiocin 
resistant) 
Streptococci 
 partial haemolysis (green colour on blood agar): α-haemolytic  
 optochin sensitive: S. pneumoniae  
1240

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   4 
  optochin resistant: Viridans streptococci 
 complete haemolysis (clear): ȕ-haemolytic  
 bacitracin sensitive: Group A: S. pyogenes  
 bacitracin resistant: Group B: S. agalactiae  
 no haemolysis: γ -haemolytic 
Staphylococci

 Staphylococci are a common type of bacteria which are often found normal comme nsal 
organisms but may also cause invasive disease. 
 Staphylococci  are skin organisms most commonly introduced during pacemaker insertion 
and such a discitis would present with back pain.   
Basic facts : 
 Gram-positive cocci 
 facultative anaerobes 
 produce catalase 
 
Types  
 The two main types of Staphylococci you need to know about are  Staphylococcus

aureus  and Staphylococcus epidermidis . 
Staphylococcus aureus  Staphylococcus epidermidis  
• Coagulase -positive 
• Causes skin infections (e.g. cellulitis),  
abscesses, osteomyelitis, toxic shock 
syndrome • Coagulase -negative 
• Cause of central line 
infections and infective 
endocarditis 
 
Effective antibiotics: 
 Staphylococcal and streptococcal organisms are effectively treated by semisynthetic

penicillins , including oxacillin, nafcillin, dicloxacillin, and cloxacillin . Also first- and second-
generation cephalosporin  
 Penicillin G, penicillin VK, ampicillin , and amoxicillin  : These agents are effective against 
streptococci, such as S. pyogenes, viridans group streptococci, and S. pneumonia,  but not 
against staphylococci  
 Ampicillin and amoxicillin are only effective against staph when ampicillin is comb ined with the

beta-lactamase inhibitor sulbactam  or when amoxicillin is combined with clavulanate . 
  The Gram stain shows Gram positive cocci 
growing in clusters, typical 
of Staphylococcus aureus . 
 This is the most likely organism to cause 
post-operative infection of prosthetic joints 
within the first one to four weeks following 
surgery. 
 
1241

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   5 
  
 Streptococci are gram-positive cocci.  
 divided into alpha and beta haemolytic types 
Alpha haemolytic streptococci  (partial haemolysis)  
 The most important alpha haemolytic Streptococcus  is Streptococcus 
pneumoniae  (pneumococcus).

pneumoniae  (pneumococcus).  
  carried asymptomatically in approximately 50% of people. 
  It can cause both non-invasive and invasive disease.  
 Non-invasive :   
 includes otitis media, sinusitis, pneumonia and bronchitis.  
 Invasive pneumococcal disease (IPD)   
 refers to disease in which the bacterium enters a sterile site such as blood, 
cerebrospinal fluid, pleural fluid or pericardial fluid. 
 If grow in blood cultures  IPD by definition.

 more common in HIV-infected patients (20-30 times) compared to non-HIV 
infected patients.  
 offer HIV testing to all patients with IPD presenting to hospital. 
 Other immunodeficiency syndromes are associated with an increased risk of 
IPD, include: 
 X-linked (Bruton's) agammaglobulinaemia,  
 common variable immunodeficiency,  
 asplenia (anatomical or functional) and sickle cell disease. 
 the mechanism of resistance for penicillin resistant Streptococcus pneumoniae  

Alteration of penicillin binding proteins (PBPs)  
 Penicillin is a bactericidal antibiotic which acts by inhibiting cell wall synthesis. 
 Mutations in PBPs (enzymes required for cell wall synthesis) result in penicillin 
 Another clinical example is Streptococcus viridans  
Beta haemolytic streptococci  (complete haemolysis)  
These can be subdivided into groups A-H. Only groups A, B & D are important in  humans. 
 Group A

 Group A  
 most important organism is Streptococcus pyogenes  
 responsible for erysipelas, impetigo, cellulitis, type 2 necrotizing fasciitis and 
pharyngitis/tonsillitis 
 immunological reactions can cause rheumatic fever or post-streptococcal glomerulonephritis 
 erythrogenic toxins cause scarlet fever 
 Penicillin is the antibiotic of choice for group A streptococcal infections. The BNF 
suggests stopping flucloxacillin if streptococcal infection is confirmed in patients with

cellulitis, due to the high sensitivity . 
 Group B  
 Streptococcus  (GBS) agalactiae   
 Maternal vaginal colonization with GBS, primarily Streptococcus agalactiae , is 
associated with serious and highly fatal neonatal infections, such as sepsis and 
meningitis. 
 Lipoteichoic acid is the primary virulence factor of this organism   
 A prerequisite to mucosal colonization or infection is bacterial adherence to the

epithelium. Lipoteichoic acid, a cell wall glycolipid polymer, mediates attachmen t of 
GBS to the vaginal epithelial cells. Lipoteichoic acid is also involved in host cell 
adherence of other Gram-positive bacteria as well. Without this adhesion, it would n ot 
be possible to have infection. 
 Group D 
 Enterococcus  
 
 1242

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   6 
Bacteria and growing media 
Bacteria  Type Growth media  
Staphylococci  Gram-positive cocci in 
clusters   LB broth agar 
  Streptococcal species (hemolytic 
Streptococcal species such 
as Streptococcus pyogenes ).  Gram-positive cocci in 
chains  Trypticase Soy Agar (TSA)

chains  Trypticase Soy Agar (TSA) 
supplemented with 5% Sheep 
Blood  
Streptococcus pneumoniae  Gram-positive bullet-
shaped diplococci   Todd Hewitt Broth 
 
E. coli, Klebsiella, or Enterobacter. 
 Gram-negative lactose 
fermenting bacilli  Super Optimal Broth (SOB) 
 
Neisseria meningitidis  gram-negative 
diplococcus chocolate agar 
 
quellung test 
 The quellung reaction is a test which uses antibodies to test for the presence of a

bacterial capsule. The bacterial capsule helps the organism prevent phagocytosis 
and is therefore necessary for infection.  
 S. pneumoniae displays a positive quellung reaction , owing to its capsule.  
 When incubated together with a specific anti-capsule antibody, the bacterial 
capsule (if present) swells and can be visualized under a microscope as a 
positive quellung reaction  
 the capsule is necessary for pathogenesis and an immune response to this

bacteria generally contains antibodies against this target.  
 direct quellung testing on sputum smears was a 95% sensitive test for predicting 
pneumococcal isolation by sputum culture.  
  quellung test produce a difference in pathogenesis. 
 Negative quellung test  NO capsule  bacteria is unable to cause disease 
 
Vancomycin-resistant enterococci

Vancomycin-resistant enterococci 
 When they cause clinical problems they are usually urinary tract infections (UTI), 
bacteraemia, wound infections, neonatal infections, endocarditis, etc. 
 May be found in healthy community volunteers not recently hospitalised   
 Community reservoir in meat, poultry and perhaps cheese.  
 Vancomycin-resistant enterococci alter peptidoglycan precursors used to build cell walls.

Vancomycin binds to D- ala-D-ala but the resistant enterococci have D- ala-D-lac or D- ala 
terminating precursors.  
 They acquire genes that produce enzymes to change the precursors. 
Anthrax 
 Anthrax is caused by Bacillus anthracis , a Gram positive rod . aerobic, non-motile 
 It is spread by infected carcasses  (جثث .)
 It produces serious disease in the herbivore (عشبيhost and carnivores (لحميacquire the

disease from either consuming the spores from the dead animal or by contact. 
 It is also known as Wool -sorters' disease (مرض فارزي الصوف .) 
 Cutaneous disease is the commonest form of the infection in humans and is usually due 
to contact with infected animals or animal products.  
  Bacillus anthracis produces a tripartite (composed of 3 parts) protein toxin 
1. protective antigen 
2. oedema factor: a bacterial adenylate cyclase which increases cAMP

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   7 
 Featur es 
 painless  non-tender  black eschar  (cutaneous  'malignant pustule', but no pus) 
 Following exposure, the skin lesion evolves over a period of ~2 weeks into a papule, 
pustule, vesicle and eventually forms an ulcer with a central black eschar.  
 The surrounding skin is usually boggy and oedematous.

 Lesions are usually painless with tender regional lymph nodes.   
 may cause marked oedema 
 anthrax can cause gastrointestinal bleeding 
 Inhalational anthrax is associated with a poor yield from sputum culture with the greatest 
yield from blood culture . 
 Lesions heal spontaneously in 80-90% of cases;  
 10-20% of patients progress and become bacteraemic - associated with a high mortality.  
 Penicillin is effective in treating the infection.

 the current Health Protection Agency advice for the initial management  of cutaneous 
anthrax  is ciprofloxacin  
 further treatment is based on microbiological investigations and expert advice  
Prognosis 
 Mortality from cutaneous disease is 20% if untreated whereas inhalational anthrax may 
have a mortality of 90% if untreated . 
 
Cutaneous anthrax  
Clostridium difficile

Clostridium difficile  
 
 Clostridium difficile  is a Gram positive anaerobic  rod often encountered in hospital 
practice.  
 It produces an exotoxin which causes intestinal damage leading to a syndrome called 
pseudomembranous colitis.  
 Clostridium difficile  develops when the normal gut flora are suppressed by broad-
spectrum antibiotics.  
  Symptoms are typically occur 5-10 days  after commencing antibiotic 
Causes

Causes  
 Clindamycin is historically associated with causing Clostridium difficile   
 penicillins and quinolones.  
Features  
 Diarrhea  
 The commonest symptoms are profuse watery diarrhoea (usually without blood or 
mucus) 
1244

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   8 
  Diarrhoea may not begin until several days after initial symptoms, especially in the 
elderly, in post-operative patients and in those who have received opiates for 
treatment of pain. 
 fever 
 raised white blood cell count  is characteristic 
 if severe, toxic megacolon  may develop

 if severe, toxic megacolon  may develop 
 
Features suggestive of severe Clostridium difficile   infection include  
 Temperature greater than 38.5°C 
  WCC >15  
 Severe abdominal pain  
 Hypovolaemia (low BP) 
 Lactic acidosis.  
 Diagnosis  is made by detecting Clostridium difficile  toxin (CDT) in the stool  
 abdominal X-ray   is useful for diagnosing toxic dilatation and would be the investigation

of choice in patient with abdominal distension. Toxic dilatation should be excluded 
prior to sigmoidoscopy. However it does not establish the diagnosis.  
 Sigmoidoscopy  is not used routinely, but can reveal distal ulceration and possible yellow 
slough or pseudo membrane in around half of patients (will shows multiple white plaques 
adhered to the gastrointestinal mucosa.).  
 first-line therapy is oral metronidazo le for 10-14 days

 if severe or not responding to metronidazole then oral vancomycin  may be used (it has 
no systemic absorption) 
 The major pharmacologic advantage of oral vancomycin over metronidazole is that 
oral vancomycin is not absorbed, so maximal concentrations of the drug can act 
intracolonically at the site of infection.  
 The instillation of intracolonic vancomycin  (as a retention enema) is sometimes 
used as an adjunct to the treatment of severe disease. 
 IV Vancomycin is not effective.

 IV Vancomycin is not effective. 
 for life -threatening infections a combination of oral vancomycin and intravenous 
metronidazole should be used 
Prognosis  
 Mortality is high in elderly patients it may be as high as 10% 
 
The main Clostridium  species  
 Clostridium botulinum : produce botulinum toxin in food or wounds and can 
cause botulism. This same toxin is known as Botox and is used in cosmetic surgery to

paralyze facial muscles to reduce the signs of aging; it also has numerous 
other  therapeutic uses. 
 Clostridium difficile  can flourish when other gut flora bacteria are killed 
during antibiotic therapy, leading to  pseudomembranous colitis  
 Clostridium perfringens  causes food poisoning to cellulitis, fasciitis, and gas 
gangrene.  
 Clostridium tetani  causes tetanus. 
 Clostridium sordellii  can cause a fatal infection in exceptionally rare cases after 
medical abortions

medical abortions 
 
Diphtheria 
 caused by Corynebacterium diphtheriae ,  
 Corynebacterium diphtheriae  is a Gram positive , non-spore-forming, pleomorphic 
bacteria that is also a facultative anaerobe. 
 There are three recognised strains of C.diphtheria : gravis, intermedius, and mitis.  1245

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   9 
  Intermedius is thought to be the one most associated with the exotoxin and is more 
virulent than the mitis strain. 
 Incubation period : 2 - 5 days,  
 patients may be infectious for 4 weeks.  
 Diphtheria is spread by droplets, through contact with soiled articles (fomites), and, in

areas of poor hygiene, from cutaneous spread. 
 The inflammatory exudate forms a greyish membrane on the tonsils and respiratory tract 
which may cause respiratory obstruction. 
 Diphtheria toxin inhibits elogation factor (EF-2)  
 Diphtheria toxin commonly causes a 'diphtheric membrane' on tonsils caused by necrotic 
mucosal cells. Attempts to remove the pseudomembrane result in bleeding. Systemic 
distribution may produce necrosis of myocardial, neural and renal tissue.

 Exotoxins produced by the organism may cause myocarditis or neurological defects. 
  secretion of an exotoxin that interferes with cellular protein synthesis, resulting in tissue 
necrosis. 
  The exotoxin is composed of two chains:  
1. chain B  is responsible for entry into host cells,  
2. chain A  inhibits protein synthesis and causes cell death 
Feature  
history of severe exudative pharyngitis in a person who has recently travelled to

eastern Europe is highly suggestive of diphtheria.  
 
 Typically, diphtheria attacks the respiratory system, but may also affect the skin , 
conjunctiva, and external genitalia. 
 Cutaneous diphtheria presents with non-healing ulcers covered with a grey 
membrane , which can develop bacterial co-infection.  
 If isolated, the disease is indolent, but the ulcers can act as a reservoir which 
can subsequently lead to pharyngeal infection. 
 Pharyngeal diphtheria  presents with: 
 fever

 fever 
 sore throat 
 cervical lymphadenopathy,  
 'bulls neck' which results from cervical lymphadenopathy and mucosal 
swelling. 
 adherent, grayish pharyngeal membrane. 
 Neurological: cranial neuropathies, predominantly motor peripheral neuropathy 
(occasionally sensory neuropathy). 
 Cardiac involvement is usually in the form of a cardiomyopathy and myositis, which is

evident from the 10-14th day and may lead to arrhythmias. This accounts for 50% of 
deaths  
Treatment 
  isolation, securing a definitive airway, cardiac monitoring,   
 antibiotic therapy and diphtheria antitoxin.  
 benzylpenicillin: children: 2.4 to 4.8 g/day intravenously/intramuscularly given in 
divided doses every 6 hours for 14 days 
 OR procaine benzylpenicillin 600,000 units intramuscularly once daily for 14 days

 OR Erythromycin 250-500 mg orally four times daily for 14 days 1246

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   10 
   Early administration of antitoxin is necessary to enable it to bind to and de-activate the 
free toxin in serum. Antitoxin cannot de-activate toxin once it has entered cells , 
which is signalled by the presence of mucocutaneous symptoms. 
 Patients with respi ratory diphtheria are placed in respiratory isolation (masks and

standard measures such as hand-washing), and those with cutaneous diphtheria are 
placed in contact isolation (gloves and gowns), until cultures taken after cessation of 
therapy are negative. 
 close contacts of respiratory and cutaneous cases:  
 cultures taken immediately  
  prophylactic antibiotic  (Erythromycin 250 mg orally four times daily for 7-10 days 
Or benzathine benzylpenicillin 1.2 million units intramuscularly as a single dose. 
 diphtheria toxoid immunisation

 diphtheria toxoid immunisation  
 The toxin affects the myocardium, nervous and adrenal tissues.  
Listeria 
Listeria  meningitis should always be considered in patients with meningitis associated 
with brain stem involvement, in  elderly and in  immunosuppressed patients. The 
treatment of choice is gentamicin and ampicillin. 
 Listeria monocytogenes  is a Gram positive bacillus

 has the unusual ability to multiply at low temperatures.  
 It is typically spread via contaminated food, typically unpasteurised dairy products.  
 infection is particularly dangerous to the unborn child where it can lead to miscarriage.  
 Listeriosis is associated with the consumption of soft cheese. 
 
Features  - can present in a variety of ways 
 diarrhoea,  
 flu-like illness  
 pneumonia ,  
 meningoencephalitis 
 ataxia and seizures 
 
 Suspected Listeria infection should be investigated by taking blood cultures .  
 CSF may reveal a pleocytosis, with 'tumbling motility' on wet mounts 
 
 Listeria is sensitive to amoxicillin/ampicillin  (cephalosporins usually inadequate) 
 Listeria meningitis should be treated with IV amoxicillin/ampicillin and gentamicin 
In pregnant women  
 pregnant women are almost 20 times more likely to develop listeriosis  compared

with the rest of the population due to changes in the immune system 
 fetal/neonatal infection can occur both transplacentally and vertically during child birth  
 complications include miscarriage, premature labour, stillbirth and chorioamnionitis 
 diagnosis can only be made from blood cultures 
 treatment is with amoxicillin  
Campylobacter 
 Campylobacter is the commonest bacterial cause of infectious intestinal disease in the

UK.  
 The majority of cases are caused by the Gram-negative bacillus Campylobacter jejuni . 
  It is spre ad by the faecal-oral route 1247

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   11 
  has an incubation period of 1 -6 days. 
 
Features 
 prodrome: headache malaise 
 diarrhoea: often bloody 
 the most appropriate therapy is IV fluids. appropriate fluid replacement and anti-
emetics are initially indicated - most units advocate no antibiotic treatment.

 the BNF advises treatment if severe  or the patient is immunocompromised . Clinical 
Knowledge summaries also recommend antibiotics if severe symptoms (high fever, 
bloody diarrhoea, or more than eight stools per day) or symptoms have last more than 
one week 
 the first -line antibiotic is clarithromycin  
 Guillain -Barre syndrome may follow Campylobacter jejuni  infections 
 septicaemia,  
 endocarditis,  
 arthritis

Escherichia coli  
 Escherichia coli  is a facultative anaerobic, lactose-fermenting, Gram negative rod  which 
is a normal gut commensal.   
 E. coli  infections lead to a variety of diseases in humans including: 
 diarrhoeal illnesses 
 UTIs 
 neonatal meningitis 
 
Serotypes  
E. coli  may be classified according to the antigens which may trigger an immune response:

Antigen Origin  Notes  
O Lipopolysaccharide 
layer   
K Capsule Neonatal meningitis secondary to E. coli  is usually caused 
by a serotype that contains the capsular antigen K-1 
H Flagellin   
 
E. coli  O157:H7   
 is a particular strain associated with severe, haemorrhagic, watery diarrhoea.  
  It has a high mortality rate and can be complicated by haemolytic uraemic syndrome.  
 It is often spread by contaminated ground beef. 
multiple drug resistant  Escherichia coli  :

multiple drug resistant  Escherichia coli  : 
 mechanism of resistance  Extended spectrum beta-lactamase (ESBL) production 
 Some  E. coli  isolates produce an Extended spectrum beta-lactamase (ESBL) that 
inactivates second and third generation cephalosporins. 
 The class of drugs that will most reliably treat these infections are the carbapenems. 
 Extended spectrum B-lactamase (ESBL) producing organisms are typically resistant to

penicillins and cephalosporins and as such the carbapenem class of antibiotics are 
typically first line  although nitrofurantoin or fosfomycin are also frequently effective.  
 ESBL producers are most commonly Escherichia coli  (E. coli) and Klebsiella  species. 1248

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   12 
Incubation periods 
Questions may either ask directly about incubation periods or they may be used to provide a 
clue in a differential diagnosis.  
Less than 1 week 1 - 2 weeks 2 - 3 weeks Longer than 3 weeks  
 meningococcus 
 influenza

 influenza  
 scarlet fever  malaria 
 dengue 
fever 
 typhoid  
 measles  mumps 
 rubella 
 chickenpox 
  infectious 
mononucleosis 
 cytomegalovirus 
 HIV 
 
Bacterial resistance  
Plasmids  
 
 plasmid  is a small DNA molecule within a cell , separated from a chromosomal DNA and 
can replicate independently.

can replicate independently.  
 plasmids carry genes that may benefit the survival of the organism, for example antibiotic 
resistance.   
 Bacteria develop resistance to antibiotics by gaining genes that encode for particular 
proteins that offer protection to the organism. 
 Sometimes this is by mutation and at other times the gene may be acquired from another 
bacterial species. 
 The genes are usually found in plasmids - circular segments of DNA separate from

the bacterial chromosome.  
 They usually are  
 small 
 consist of a few thousand base pairs 
 carry one or a few genes, and 
 have a single origin of replication. 
 Plasmids can be used to clone genes by splicing a particular gene into a plasmid and 
then allowing the bacteria to multiply - this is then called recombinant plasmid DNA. 
  Plasmids can easily spread from one bacteria to another - a sort of resistance package 
that bacteria can share.

that bacteria can share.  
 Which best explains the loss of antibiotic resistance in bacterial strain? 
  Loss of a plasmid containing the resistance gene 
 
1249

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   13 
Antibiotic resistance mechanism  
 
Antibiotic  Resistance mechanism  
fluoroquinolones  (eg: 
ciprofloxacin ) Change in the bacterial DNA gyrase  due to genetic 
mutation 
Macrolides  (eg: Erythromycin) Bacterial ribosomal methylation

Tetracycline  Bacterial efflux of antibiotic  
chloramphenicol  Antibiotic inactivation by acetyltransferase  
 
Penicillin Production of penicillinase  by the bacteria is the 
most common  mechanism of bacterial resistance 
to penicillin. 
However, penicillin resistance in streptococcus 
pneumonia  is due to alteration in the penicillin-
binding protein , not production of penicillinase. 
Vancomycin  D-ala-D-ala mutates to D-ala-D-lac 

Vaginal discharge 
Vaginal discharge is a common presenting symptom and is not always pathological 
Common causes  Less common causes 
 physiological 
 Candida  
 Trichomonas vaginalis  
 bacterial vaginosis 
  Gonorrhoea  
 Chlamydia  can cause a vaginal 
discharge although this is rarely the 
presenting symptoms 
 ectropion 
 foreign body  
 cervical cancer 
 Black women report higher incidence of candidiasis infections compared with white 
women.

women.  
 
Key features  of the common causes are listed below 
Condition  Key features 
Candida   'Cottage cheese'  discharge 
 Vulvitis 
 Itch 
Trichomonas 
vaginalis   Offensive, yellow/green , frothy discharge 
 Vulvovaginitis 
 Strawberry cervix 
Bacterial vaginosis  Offensive, thin, white /grey, 'fishy' discharge 
 
 1250

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   14 
Bacterial vaginosis ( BV) 
 
Bacterial vaginosis - overgrowth of predominately Gardnerella vaginalis  
 
 Bacterial vaginosis (BV) describes an overgrowth of predominately anaerobic organisms 
such as Gardnerella vaginalis .

such as Gardnerella vaginalis . 
 This leads to a consequent fall in lactic acid  producing aerobic lactobacilli  resulting in a 
raised vaginal pH . 
 BV is the commonest cause of abnormal vaginal discharge  in women of childbearing 
age. It is t wice as common as vaginal candidiasis. 
 Whilst BV is not a sexually transmitted infection it is seen almost exclusively in sexually 
active women. 
 
Features 
 vaginal discharge: 'fishy', offensive , Gray, thin, and homogeneous

 asymptomatic in 50% 
Diagnosis  
Epithelial cells with a stippled border  (Clue cells ) are the hallmark microscopic findings 
of bacterial vaginosis 
 
Amsel's criteria for diagnosis of BV  - 3 of the following 4 points should be present 
1. thin, white homogenous discharge 
2. clue cells  on microscopy: stippled vaginal epithelial cells 
3. vaginal pH > 4.5 
4. positive whiff test (addition of potassium hydroxide results in fishy odour) 
 
Bacterial vaginosis treatment  oral metronidazole 
 
 oral metronidazole for 5-7 days 
 initial cure rate  70-80% 
 relapse rate > 50% within 3 months 
 the BNF suggests topical metronidazole or topical clindamycin as alternatives  
Bacterial vaginosis in pregnancy 
 results in an increased risk of preterm labour, low birth weight and chorioamnionitis, late 
miscarriage 
 it was previously taught that oral metronidazole should be avoided in the first trimester

and topical clindamycin  used instead. Recent guidelines however recommend that 
oral metronidazole is used throughout pregnancy.  The BNF still advises against the 
use of high dose metronidazole regimes  1251

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   15 
  
Comparison of bacterial vaginosis and Trichomonas vaginalis  
January 2015 exam: H/O offensive vaginal discharge. Diagnosed as bacterial 
vaginosis. What is the most appropriate initial management? Oral metronidazole  
Trichomonas vaginalis

Trichomonas vaginalis  
 anaerobic flagellated protozoan, which thrive in more alkaline  conditions. 
 incubation period is 5 to 28 days.  
 transmitted directly, for example, through sexual transmission. 
Feature:  
  asymptomatic (in most men and 50% of women)  
 yellow-green, frothy vaginal discharge  
 vulvar pruritus  
 dysuria, dyspareunia, and lower abdominal pain.   
 Punctuate hemorrhages on the cervix, i.e. " strawberry cervix ", or along the vaginal wall

are less common signs, but are highly suggestive of infection with Trichomonas vaginalis .  
 The PH of the discharge is greater than 4 .5 
Diagnosis  
 The most rapid and practical method for detection is the use of a wet mount  in clinic, 
which demonstrates motile flagellated  protozoans .  
 
Differential diagnosis:  
 Whilst bacterial vaginosis is also associated with a discharge with a fishy odour, 
classically there is no soreness or irritation  associated with it. 

 A large dose of metronidazole  (2 g as a single course), or a seven day course at lower 
dose is the treatment of choice.  
 Single -dose therapy increases drug adherence.  
 If standard treatment with either single -dose or multidose therapy fails, a regimen 
of 2 g of oral metroni dazole or tinidazole for 5 days may be considered  
 Patients should not consume alcohol during the course of treatment or during the 
24 hours after the completion of the medication.

 Patients on tinidazole therapy should not consume alcohol during therapy or for 72 
hours after completion of the medication.  
1252

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   16 
  Drinking alcohol while taking tinidazole causes disulfiram-like 
reaction , which includes (nausea, vomiting, headache, ĹBP, flushing, 
and shortness of breath). 
 Tinidazole has a longer half-life (12-14 h) than metronidazole (6-7 h).  
 metronidazole and tinidazole are equally effective  
 Partner

 Partner   
 Partners  should be identified and also screened for infection as men rarely exhibit 
symptoms of a T. vaginalis  infection. 
 The epithelial damage caused by  T. vaginalis  increases susceptibility to HIV 
virus infection and transmission. 
 Both patient and partner should abstain from sex until pharmacological treatment 
has been completed and they have no symptoms.  
 HIV-positive women with Trichomoniasis.

 HIV-positive women with Trichomoniasis.  
 the CDC recommends considering the multidose treatment in HIV- positive 
women with Trichomoniasis.  
 (metronidazole 500 mg twice daily for 7 days) are more effective in treating T 
vaginalis  in HIV-positive women than a single-dose treatment (metronidazole 
2 g single dose).  
 In pregnant women  
 The CDC recommends that infected  symptomatic pregnant women be considered

for treatment, as metronidazole has not been definitively shown to be harmful 
during pregnancy and may prevent transmission to the newborn.  
 Infected asymptomatic  pregnant women may wish to defer treatment to after 37 
weeks ’ gestation.  
 Pregnant women should be treated with 2 g metronidazole in a single dose, 
according to the CDC.  
 The safety of tinidazole in pregnancy is not known.  
 Tinidazole is a pregnancy class C agent; animal studies have demonstrated

adverse effects on fetal development. Its use is not recommended in pregnant 
women.  
 In breastfeeding women  
 In breastfeeding women, the CDC recommends sto pping breastfeeding during the 
course of metronidazole treatment and for 12-24 hours after the last day. For 
treatment with tinidazole, the CDC recommends stopping breastfeeding for the 
course of treatment and for 3 days after the last dose.  
 Screening and Rescreening

 Screening and Rescreening   
 Patients should be screened for other sexually transmitted infections . 
 the CDC recommends rescreening at 3 months post therapy  for sexually active 
women, as they have a high rate of reinfection.  
Brucellosis 
 Brucellosis is a zoonosis more common in the Middle East and in farmers. 
 Gram negative bacilli

 Gram negative bacilli 
 It is considered a class B bioterrorist agent, is easily spread by aerosol, and is a significant 
hazard in microbiology laboratories.  
 Four major species cause infection in humans: B melitensis (sheep), B abortus (cattle), B canis 
and B suis (pigs).  
 incubation period 2 - 6 weeks 
 Most cases of brucellosis in Northern Europe and North America are acquired overseas and /or 
from consuming unpasteurised milk products, including cheese. 
 
Features

Features 
 non-specific:  
 fever, (prolonged fever of unknown origin) 
 malaise 1253

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   17 
  hepatosplenomegaly 
 sacroilitis: spinal tenderness may be seen.  Brucellosis is a recognised cause of spondylitis  
 associated rheumatic features in about 50% of cases.  
 complications: osteomyelitis, infective endocarditis, meningoencephalitis, orchitis 
 leukopenia is common 
Diagnosis

Diagnosis 
 the Rose Bengal plate test can be used for screening but other tests are required to con firm the 
diagnosis 
 Brucella serology is the best test for diagnosis 
 blood and bone marrow cultures may be suitable in certain patients, but these tests are often  
negative 
 75% have a positive blood culture (90% of bone marrow cultures will be positive). 
 doxycycline and streptomycin 

Cat scratch disease (CSD) 
 
Cat scratch disease is generally caused by the Gram negative rod Bartonella henselae  
 
Features  
 fever 
 history of a cat scratch 
 regional lymphadenopathy 
 headache, malaise 
 immunocompromised patient: 
 Self-limiting  only supportive therapy (paracetamol and NSAID)  
 Systemic features resolve over few days  
 Lymph nodes regress in size over 2 – 5 months  
 Immunocompromised or patient with sever systemic symptoms

 Severe disease was defined as persistent high fever (>39.5˚C) with severe systemic signs 
(eg, malaise, fatigue, blindness, headache) and lymphadenitis. 
 the following 4 antibiotics were the most effective for patients with severe CSD: 
 Rifampin - Efficacy of 87% 
 Ciprofloxacin - Efficacy of 84% 
 Gentamicin intramuscularly - Efficacy of 73% 
 Trimethoprim/sulfamethoxazole (TMP-SMZ) - Efficacy of 58%

 azithromycin administered for 5 days decreased lymph node size within the fir st month of 
treatment. No other differences in clinical outcome were noted. 
Cellulitis 
 Staphylococcus aureus  and Streptococci  are the commonest causative 
organisms. 
 Group B  Streptococcus  has a predilection for diabetic patients  
 
 inflammation of the skin and subcutaneous tissues,   
causes

causes  
 Staphylococcus aureus  and Streptococci  are the commonest causative organisms. 
 Group B  Streptococcus  has a predilection for diabetic patients and is the likeliest 
causative organism in diabetics 
Features  
 commonly occurs on the shins 
 erythema, pain, swelling 
 systemic upset such as fever 
 Cellulitis  does not  have sharp, well-defined borders, unlike an erysipelas infection.  
1254

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   18 
  
Eron classification  
NICE Clinical Knowledge Summaries recommend we use the Eron classification to guide how 
we manage patients with cellulitis: 
Class  Features 
I There are no signs of systemic toxicity and the person has no uncontrolled co-
morbidities

morbidities 
II The person is either systemically unwell or systemically well but with a co-morbidity 
(for example peripheral arterial disease, chronic venous insufficiency, or morbid 
obesity) which may complicate or delay resolution of infection 
III The person has significant systemic upset such as acute confusion, tachycardia, 
tachypnoea, hypotension, or unstable co-morbidities that may interfere with a response 
to treatment, or a limb -threatening infection due to vascular compromise

IV The person has sepsis syndrome or a severe life-threatening infection such as 
necrotizing fasciitis 
 
 Criteria for admission  for intravenous antibiotics  
 Eron Class III or Class IV cellulitis . 
 severe or rapidly deteriorating cellulitis (for example extensive areas of skin). 
 very young (under 1 year of age) or frail. 
 immunocompromised. 
 significant lymphoedema. 
 facial cellulitis (unless very mild) or periorbital cellulitis.

 Management  Eron Class II cellulitis : 
 Admission may not be necessary if the facilities and expertise are available in the 
community to give intravenous antibiotics and monitor the person.  
 Other patients can be treated with oral antibiotics.  
 Antibiotics  
 mild/moderate cellulitis  
 First line   flucloxacillin  (BNF recommendation)  
 first choice to treat sensitive staphylococcal infections  
 MRSA is resistant to flucloxacillin

 MRSA is resistant to flucloxacillin 
 in patients allergic to penicillin  Clarithromycin or clindamycin.  
 in patients who have failed to respond to flucloxacillin   oral 
clindamycin   
 The most appropriate treatment is clindamycin and flucloxacillin , 
which covers the majority of organisms responsible for cellulitis.  
 Flucloxacillin is bactericidal for both Staphylococcus and 
Streptococcus, whereas clindamycin has a n anti-toxin effect for

both these groups of organisms (in addition to Clostridium 
perfringen). Their effect is therefore synergistic, and they should 
be used together where rapid control is required (e.g. in finger 
cellulitis) or in severe cases 
 Although clindamycin  is a bacteriostatic antibiotic, it acts by 
switching off protein synthesis within bacteria; this in turn will 
lead to decreased exotoxin expression, thereby removing the 
mediators of toxic shock syndrome (TSS).

mediators of toxic shock syndrome (TSS). 
 If no significant improvement  within 48 hours , the patient should be 
readmitted for intravenous antibiotics . 
 Severe cellulitis  1255

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   19 
  should be treated with intravenous benzylpenicillin + flucloxacillin . 
 If there is any suspicion of tendon involvement (Intact joint movements make 
this less l ikely)  the plastics or orthopaedics team should be asked to 
review and intravenous antibiotics  initiated.

review and intravenous antibiotics  initiated.  
Methicillin-resistant Staphylococcus aureus  (MRSA)  
 
Mechanism of resistance  
 Penicillin binding proteins are the characteristic mutated proteins in methicillin-
resistant Staphylococcus aureus . 
Who should be screened for MRSA?  
 all patients awaiting elective admissions  
 exceptions include: 
 terminations of pregnancy  
 ophthalmic surgery

 ophthalmic surgery 
 Patients admitted to mental health trusts. 
 all emergency admissions. 
Where is the site of most concern for staff carriage of MRSA?  
 The nose  is the area of carriage for MRSA which gives most area for concern with 
respect to carriage by staff.  
How should a patient be screened for MRSA? 
 nasal swab and skin lesions or wounds 
 the swab should be wiped around the inside rim of a patient's nose for 5 seconds

 the microbiology form must be labelled 'MRSA screen'  
Suppression of MRSA from a carrier once identified 
 nose:  
 mupirocin 2% in white soft paraffin, TDS for 5 days 
 skin:  
 chlorhexidine gluconate, OD for 5 days.  
 Apply all over but particularly to the axilla, groin and perineum 
 
The following antibiotics are commonly used in the treatment of MRSA infections:  
 Vancomycin 
 the first line  
 teicoplanin 
 linezolid

 linezolid  
 Linezolid is the only oral medication available against MRSA.  
 Ceftaroline  
 fifth generation  cephalosporin   
 Ceftaroline  is the only cephalosporin to cover MRSA. 
 Some strains may be sensitive to the antibiotics listed below but they should not 
generally be used alone  because resistance may develop: 
 rifampicin 
 macrolides 
 tetracyclines 
 aminoglycosides 
 clindamycin

 clindamycin 
 Relatively new antibiotics such as linezolid , quinupristin /dalfopristin combinations  
and tigecycline have activity against MRSA but should be reserved for resistant cases 
 
January 2009 exam : What is the most effective single step to reduce the incidence of 
MRSA ?  Hand hygiene  
 
 1256

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   20 
  
What is the most appropriate antibiotic regimen for possible line sepsis from an 
indwelling permacath?   
 Vancomycin + Gentamicin 
 The antibiotic chosen should have both gram-positive and gram-negative 
cover, including MRSA.  
 vancomycin and doxycycline are able to treat MRSA, but doxycycline has

limited gram -negative cover, unlike gentamicin.  
Necrotising fasciitis 
Overview 
 Necrotising fasciitis is a medical emergency that is difficult to  recognise in the early 
stages. 
Classification  (according to the causative organism):  
 Type 1  is caused by mixed anaerobes and aerobes (often occurs post-surgery in 
diabetics)  
 Type 2  is caused by Streptococcus  pyogenes   
 commonly caused by group A Streptococ ci  
Features

Features 
 acute onset 
 painful, erythematous lesions  
 extremely tender over infected tissue 
 urgent surgical referral debridement  
 Clindamycin and Tazocin 
 Clindamycin 
 bacteriostatic  
 inhibits  formation of peptides bonds at 50S ribosomal subunit   
 It is also  a potent suppressor of bacterial toxin synthesis.  
 Group A  Streptocooci  are usually very sensitive to benzylpenicillin so this is

frequently added though this does not neutralises the toxin. 
Toxic shock syndrome (TSS) 
Causes  
 exotoxin-mediated illness caused by bacterial infection, most commonly group A 
streptococcus or  Staphylococcus aureus . 
Risk factors  include: 
 Recent menstruation 
 Although the earliest described cases involved mostly menstruating women using 
highly absorbent tampons, only 55% of current cases are associated with 
menstruation.

menstruation.  
 Recent use of barrier contraceptives such as diaphragms and vaginal sponges 
 Vaginal tampon use (especially prolonged) 
 Recent childbirth 
 Recent surgery, and 
 Current S. aureus infection.  
Features  
 can be non-specific 
 toxicity occurs early, resulting in serious life-threatening disease  
 multi-organ system failure. 
Types  
 Streptococcal toxic shock  syndrome (TSS)  can occur with infection at any site but is

more commonly associated with an infected cutaneous site . 
 Staphylococcal TSS  (menstrual or non-menstrual)  1257

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   21 
  severe systemic reaction to staphylococcal exotoxins.  
 associated with extended tampon use, postpartum infections, and other sites of 
infection with the organism.  
Centers for Disease Control and Prevention diagnostic criteria  
 fever: temperature > 38.9 C 
 hypotension: systolic blood pressure < 90 mmHg

 hypotension: systolic blood pressure < 90 mmHg 
 diffuse erythematous rash  
 desquamation of rash, especially of the palms and soles 
 involvement of three or more organ systems: e.g. gastrointestinal (diarrhoea and 
vomiting), mucous membrane erythema, renal failure, hepatitis, thrombocytopenia, CNS 
involvement (e.g. confusion) 
 
Trea tment   
 supportive care in an ICU,  
 early empirical antibiotic treatment, and further culture-sensitive antibiotic treatment.

 Although clindamycin is a bacteriostatic antibiotic, it acts by switching off protein 
synthesis within bacteria; this in turn will lead to decreased exotoxin expression, 
thereby removing the mediators of TSS. 
 Surgical debridement may be needed for deep -seated streptococcal infections. 
Ludwig ’s angina  
  
 Ludwig's angina is a form of severe diffuse  cellulitis  that presents an acute onset and

spreads rapidly, bilaterally affecting the submandibular, sublingual and submental spaces 
resulting in a state of emergency. 
Overview 
 The majority of cases of Ludwig's angina are odontogenic in etiology, primarily resulting 
from infections of the second and third molars teeth.  
 the submandibular space is the primary site of infection 
 the most life -threatening complication of Ludwig's angina is airway obstruction.  
Treatment

Treatment 
 IV ant ibiotic against streptococci and oral anaerobes and take care of airway (call 
anaesthesiologist). 
 Combinations of penicillin, clindamycin, and metronidazole are typically used. 
 Up to 65% require surgical drainage 
 Physical examination alone is insufficient in determining which patients require a 
surgical procedure. 
 As a result, a CT scan with intravenous contrast  is recommended to detect 
patients who have developed suppurative complications  
Prognosis

Prognosis  
 Without a treatment, it is frequently fatal from the risk of asphyxia with a mortality rate of 
50%.  
 The aggressive surgical intervention, the antibiotic introduction, and the improvement of 
dental care have determined a significant reduction of the mortality rate to less than 10%  
Chickenpox (Varicella-zoster virus)  
 Chickenpox is caused by primary infection with varicella zoster virus.

 Shingles is reactivation of dormant virus in dorsal root ganglion 
 Chickenpox is highly infectious (infection rate in household contacts of 90%).  
 spread via the respiratory route 
 can be caught from someone with shingles 
 infectivity = 4 days before rash, until 5 days after the rash first appeared* 
 incubation period = 10 -21 days 1258

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   22 
  It is commonest in sprin g time  
 Causes congenital limb deformity 
 HIV 
 HIV-positive patients are more prone to herpes zoster regardless of their CD4 
count. 
 In addition to the typical dermatomal distribution of the vesicular rash, HIV patients 
occasionally have vesicles scattered in adjacent dermatomes.

 In advanced HIV disease VZV can manifest as severe disseminated disease. 
 
Clinical features  (tend to be more severe in older children/adults) 
 fever initially 
 itchy, rash starting on head/trunk before spreading. Initially macular then papular then 
vesicular 
 systemic upset is usually mild 
Management is supportive  
 keep cool, trim nails 
 calamine lotion 
 school exclusion: current HPA advice is 5 days from start of skin eruption. They also state

'Traditionally children have been excluded until all lesions are crusted. However, 
transmission has never been reported beyond the fifth day of the rash.'  
 immunocompromised patients and newborns with peripartum exposure should receive 
varicella zoster immunoglobulin (VZIG). If chickenpox develops then IV aciclovir should 
 Aciclovir  (also famciclovir, and ganciclovir) acts through inhibition of viral (DNA)

polymerase  but it is a pro-drug  and first requires phosphorylation by thymidine 
kinase . 
  Resistance arises when the virus lacks thymidine kinase  
 For thymidine kinase-deficient varicella-zoster virus strain: 
 Cidofovir does not require activation by viral thymidine kinase; 
therefore, it would be best suited to treat the thymidine kinase-deficient 
varicella-zoster virus. 
 adults chicken pox should be treated with acyclovir within 24 hours of the appearance of

rash because it can lessen the occurrence of post herpetic neuralgia. 
 Common complication is secondary bacterial infection of the lesions. 
 Chicken pox in the first and second trimester can produce a syndrome of skin scarring, 
hypoplastic limbs, eye and central nervous system impairments. 
 Rare complications include 
 Pneumonia 
 Varicella pneumonia occurs in up to 20% of adults with chickenpox,  
 appearing three to five days into the course of the illness.

 Pneumonitis is uncommon in children 
 incidence 0.3% in immunocompetent adults.  
 The risk is higher in smokers and pregnancy. 
 Symptoms include tachypnoea, cough, dyspnoea, and fever. 
 Cyanosis, pleuritic chest pain and haemoptysis are common. 
 In adults with pneumonitis, treatment with aciclovir is warranted.  
 
 encephalitis (cerebellar involvement may be seen) 
 disseminated haemorrhagic chickenpox 
 arthritis, nephritis and pancreatitis may very rarely be seen

mechanism of acyclovir resistance   reduced production of viral thymidine kinase  
 
 1259

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   23 
  
Chest x-ray showing miliary opacities secondary to healed varicella pneumonia. Multiple tiny  calcific 
miliary opacities noted throughout both lungs. These are of uniform size and dense su ggesting 
calcification. There is no focal lung parenchymal mass or cavitating lesion seen.The appearan ces are

characteristic for healed varicella pneumonia. 
 
*it was traditionally taught that patients were infective until all lesions had scabbed over 
 
Chickenpox exposure in pregnancy 
Chickenpox exposure in pregnancy - first step is to check antibodies 
 In pregnancy there is a risk to both the mother and also the fetus, a syndrome now 
termed fetal varicella syndrome  
Risks to the fetus and neonate relate to the time of infection:  
 Less than 20 weeks pregnancy:

 Less than 20 weeks pregnancy:   
 congenital varicella (limb hypoplasia, microcephaly, cataracts, growth retardation, 
skin scarring). High mortality. 
 The incidence of congenital varicella syndrome is about 2% in mothers who 
develop primary chickenpox in the first half of the pregnancy. 
 Second to thir d trimester:   
 herpes zoster in an otherwise healthy infant. 
 Minus seven days to plus seven days after delivery:   
 severe and even fatal disease (30% mortality).

Risks to the mother  
 5 times greater risk of pneumonitis 
Fetal varicella syndrome (FVS) 
 risk of FVS following maternal varicella exposure is around 1% if occurs before 20 weeks 
gestation  
 studies have shown a very small number of cases occurring between 20-28 weeks 
gestation and none following 28 weeks  
 features of FVS include skin scarring, eye defect s (microphthalmia), limb hypoplasia, 
microcephaly and learning disabilities 
Other risks to the fetus

Other risks to the fetus  
 shingles in infancy: 1-2% risk if maternal exposure in the second or third trimester 
1260

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   24 
  severe neonatal varicella: if mother develops rash between 5 days before and 2 days 
after birth there is a risk of neonatal varicella, which may be fatal to the newborn child in 
around 20% of cases 
Management of chickenpox exposure 
 if there is any doubt about the mother previously having chickenpox maternal blood

should be urgently checked for varicella antibodies  
 if the pregnant women is not immune to varicella she should be given varicella zoster 
immunoglobulin (VZIG) as soon as possible. RCOG and Greenbook guidelines suggest 
VZIG is effective up to 10 days post exposure  
 consensus guidelines suggest oral aciclovir should be given if pregnant women with 
chickenpox present within 24 hours of onset of the rash 
Varicella zoster immunoglobulin  (VZIG)

Varicella zoster immunoglobulin  (VZIG)  
 prepared from pooled plasma of UK blood donors with a history of recent chickenpox or 
herpes zoster. 
 Donors are screened for HIV, hepatitis B and hepatitis C. 
 VZIG prophylaxis is recommended for patients who fulfil all the following criteria: 
1. A clinical condition that increases the risk of severe varicella, (for example, 
immun osuppression, neonates, pregnant women ) 
2. No antibodies to varicella zoster

2. No antibodies to varicella zoster 
3. Significant exposure to chickenpox or herpes.  
 VZIG prophylaxis is of no benefit if chickenpox has already developed. 
 Severe or fatal varicella can occur despite VZIG prophylaxis. Active immunisation should 
therefore be used for susceptible immunosuppressed patients at long term risk.  
Chlamydia  
Chlamydia  - treat with azithromycin or doxycycline

 Chlamydia  is the most prevalent sexually transmitted infection in the UK  
 Approximately 1 in 10 young women in the UK have Chlamydia . 
 Caused  by Chlamydia trachomatis , an obligate intracellular pathogen.  
 The incubation period is around 7-21 days, although it should be remembered a large 
percentage of cases are asymptomatic 
 persistent discharge in spite of adequately treated gonorrhoea   there is a co-
infection with Chlamydia . 
 
Features

Features 
 asymptomatic in around 70% of women and 50% of men 
 women: cervicitis (discharge, bleeding), dysuria 
 men: urethral discharge, dysuria 
Potential complications  
 epididymitis 
 pelvic inflammatory disease 
 endometritis 
 increased incidence of ectopic pregnancies 
 infertility  
 reactive arthritis 
 perihepatitis (Fitz-Hugh-Curtis syndrome) 
 traditional cell culture is no longer widely used

 nuclear acid amplification tests (NAATs) are now rapidly emerging as the investigation of 
choice 
 urine (first void urine sample), vulvovaginal swab or cervical swab may be tested using 
the NAA T technique 
Screening 
 in England the National Chlamydia  Screening Programme is open to all men and women 
aged 15-24 years 
 the 2009 SIGN guidelines support this approach, suggesting screening all sexually active 
patients aged 15 -24 years 1261

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   25 
  relies heavily on opportunistic testing 
 
Pap smear demonstrating infected endocervical cells. Red inclusion bodies are typical 
 
 doxycycline (7 day course) or azithromycin (single dose). The 2009 SIGN guidelines 
suggest azithromycin should be used first- line due to potentially poor compliance with

a 7 day course of doxycycline 
 if pregnant then erythromycin or amoxicillin may be used. The SIGN guidelines suggest 
considering azithromycin 'following discussion of the balance of benefits and risks with 
the patient'  
 patients diagnosed with  Chlamydia  should be offered a choice of provider for initial 
partner notification - either trained practice nurses with support from GUM, or referral to 
GUM

GUM 
 for men with symptomatic infection all partners from the four weeks prio r to the onset of 
symptoms should be contacted 
 for women and asymptomatic men all partners from the last six months or the most 
recent sexual partner should be contacted 
 contacts of confirmed Chlamydia  cases should be offered treatment prior to the 
results  of their investigations being known (treat then test) 
 September 2008 exam:  A swab taken in the clinic showed a Gram-negative

diplococcus and treatment with IM ceftriaxone was given. his symptoms have not 
resolved. What is the most likely explanation? Co-existent Chlamydia  infection  (Co-
existent infection with Chlamydia  is extremely common in patients with gonorrhoea).  
 
September 2012 exam: A 27-year-old pregnant woman is found to have Chlamydia . 
She has had a previous adverse reaction to azithromycin. What is the most 
appropriate treatment? Erythromycin  
 
1262

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   26 
  
Trachoma  
 caused by Chlamydia  trachomatis,  
 the leading infectious cause of blindness worldwide. 
 Transmission is commonly through five routes (five Fs): Flies; Fomites; Fingers; within 
the Family; or among close Friends.  
 Cases are rare in high-income countries, but the condition is endemic in many low- and

middle-income countries; risks are increased in rural areas without good water supplies 
and sanitation. 
 Features 
 May be asymptomatic,  
 inflammatory conjunctivitis  
 punctate keratitis. 
 Repeated infection  immune response  gradual scarring of the eyelid  
blindness. 
 single dose of azithromycin  
 WHO aims to eliminate trachoma by 2020, using the SAFE strategy (Surgery, Antibiotics, 
Facial cleanliness, and Environmental improvement).

Cholera 
 
electron microscope image of Vibrio cholerae bacteria  
 
Overview 
 caused by Vibro cholerae - Gram negative bacteria 
 Because the organism is not acid-resistant, it depends on its large inoculum size  
( infectious dose) to withstand gastric acidity.  
  If  ingested with water, a higher  infectious dose is needed. When ingested with 
food, fewer organisms are required to produce disease.

 Ļ gastric acidity (anti -acid drugs, gastrectomy)  Ĺrisk of cholera infection and 
severity  
Mechanism by which cholera leads to fluid loss: 
 Cholera toxin has two parts, A and B. 
 B subunits are responsible for binding to a ganglioside (monosialosyl ganglioside, 
GM1 receptor ) located on the surface of the cells that line the intestinal mucosa.  
 B binds while A activates G protein   activates adenylate cyclase   ↑(cAMP)  
 unrestricted chloride secretion from villous  crypts .

cholera toxin stimulates the generation of cyclic AMP as the second 
messenger 
 
Features 
 profuse 'rice water' diarrhoea 
1263

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   27 
  hypoglycaemia 
 After dehydration, hypoglycemia is the most common lethal complication of cholera 
in children.  
 oral rehydration therapy 
 antibiotics: doxycycline, ciprofloxacin  
Congenital infections

Congenital infections 
 
The major congenital infections encountered in examinations are rubella, toxoplasmosis and 
cytomegalovirus 
 
Cytomegalovirus is the most common congenital infection in the UK.  Maternal infection is 
usually asymptomatic 
 
 Rubella  Toxoplasmosis Cytomegalovirus 
Characteristic 
features  Sensorineural 
deafness 
Congenital cataracts 
Congenital heart 
disease (e.g. patent 
ductus arteriosus) 
Glaucoma Cerebral calcification  
Chorioretinitis

Chorioretinitis  
Hydrocephalus Growth retardation 
Purpuric skin lesions  
Other 
features  Growth retardation 
Purpuric skin lesions 
'Salt and pepper' 
chorioretinitis 
Microphthalmia 
Cerebral palsy  Anaemia 
Cerebral palsy  Sensorineural deafness 
Encephalitis/seizures 
Pneumonitis 
Anaemia 
Jaundice 
Cytomegalovirus

Cytomegalovirus 
 Cytomegalovirus ( CMV, HHV- 5), is one of the herpes viruses.  
 Herpes viridae   is the family of viruses to which cytomegalovirus belongs. 
 Double stranded DNA virus. 
 Mononuclear cells  are the class of leukocytes in which cytomegalovirus lies dormant.  
 It is thought that around 50% of people have been exposed to the CMV virus although it 
only usually causes disease in the immunocompromised, for example people with HIV or

those on immunosuppressants following organ transplantation. 
Diagnosis  
 infected cells have a 'Owl's eye' appearance due to intranuclear inclusion bodies  
Patterns of disease  
Congenital CMV infection 
 features include growth retardation, pinpoint petechial 'blueberry muffin' skin lesions, 
microcephaly, sensorineural deafness, encephalitis (seizures) and hepatosplenomegaly 
CMV mononucleosis 
 infectious mononucleosis-like illness 
 may develop in immunocompetent individuals 
1264

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   28 
 CMV retinitis 
 common in HIV patients with a low CD4 count (< 50) 
 presents with visual impairment e.g. 'blurred vision'. Fundoscopy shows retinal 
haemorrhages and necrosis, often called 'pizza' retina 
 IV ganciclovir is the treatment of choice

 IV ganciclovir is the treatment of choice 
 Valganciclovir is an oral pro-drug for ganciclovir, with similar bioavailability 
but without the need to deliver it IV, making it the preferred option here.  
 The efficacy of valganciclovir is similar to ganciclovir without the need for IV 
administration, and this drives ganciclovir as the option where oral therapy isn ’t 
tolerated.  
 The toxicity profile for valganciclovir is the same as that for ganciclovir, with bone

marrow suppression the main concern. 
 Foscarnet is the drug of choice for ganciclovir-resistant cytomegalovirus retinitis . 
 
CMV encephalopathy 
 seen in patients with HIV who have low CD4 counts 
CMV pneumonitis 
 
CMV colitis  
 HIV+ bloody diarrhea+ no abdominal pain +normal stool examination  Do Colonoscopy 
to diagnose CMV colitis 
 Patients with inflammatory bowel disease are at increased risk of CMV colitis particularly 
those on immunosuppression.

those on immunosuppression.  
 COLONOSCOPY finding  multiple ulcer and mucosal erosion 
 The most appropriate investigation is  Flexible sigmoidoscopy and  biopsy  
 in severe colitis endoscopy should be limited to flexible sigmoidoscopy only due to 
an increased risk of perforation.  
 Biopsy shows: cytomegalic cell+ intranuclear  inclusion body  
Dengue fever

Dengue fever 
Dengue fever is a viral infection which can progress to viral haemorrhagic fever (also yellow 
fever, Lassa fever, Ebola) 
 
Basics  
 caused by an arthropod-borne Flavivirus .  
 transmitted by the Aedes aegyti mosquito  
 incubation period 4-10 days. 
 a form of disseminated intravascular coagulation (DIC) known as dengue haemorrhagic 
fever (DHF) may develop. Around 20-30% of these patients go on to develop dengue 
shock syndrome (DSS) 
 
Features

Features 
 causes headache (often retro-orbital) 
 fever 
 myalgia (severe musculoskeletal pain is a prominent feature) 
 pleuritic pain 
 facial flushing (dengue)  
 maculopapular rash (confluent erythematous rash over the precordium) 
Treatment  is entirely symptomatic e.g. fluid resuscitation, blood transfusion etc 
 
 1265

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   29 
Epididymo-orchitis 
 Epididymo-orchitis describes an infection of the epididymis +/- testes resulting in pain and 
swelling. 
  It is most commonly caused by local spread of infections from the genital tract (such

as Chlamydia trachomatis  and Neisseria gonorrhoeae ) or the bladder. 
 The most important differential diagnosis is testicular torsion. This needs to be 
excluded urgently to prevent ischaemia of the testicle.  
 
Features 
 unilateral testicular pain and swelling  
 urethral discharge may be present, but urethritis is often asymptomatic 
 factors suggesting testicular torsion include patients < 20 years, severe pain and an acute 
onset  

onset  
 the British Association for Sexual Health and HIV (BASHH) produced guidelines in 2010  
 if the organism is unknown BASHH recommend: ceftriaxone 500mg intramuscularly 
single dose, plus doxycycline 100mg by mouth twice daily for 10 -14 days  
 further investigations following treatment are recommended to exclude any underlying 
structural abnormalities 
Genital warts

Genital warts 
 
 Genital warts (also known as condylomata accuminata) are a common cause of 
attendance at genitourinary clinics. 
  They are caused by the many varieties of the human papilloma virus HPV, especially 
types 6 & 11.  
  It is now well established that HPV (primarily types 16,18 & 33) predisposes to cervical 
cancer.  
 HPV 16 is an oncogenic virus  and causes squamous cell carcinomas in the oral cavity, 
cervix, anus and penis. 
 
Features

Features 
 small (2 - 5 mm) fleshy protuberances which are slightly pigmented 
 may bleed or itch 
 first- line  topical podophyllum or cryotherapy, depending on the location and type of 
lesion.  
 Multiple, non-keratinised warts  best treated with topical agents  
 solitary, keratinised warts  respond better to cryotherapy 
 second line   topical imiquimod

 second line   topical imiquimod   
 genital warts are often resistant to treatment and recurrence is common although the 
majority of anogenital infections with HPV clear without intervention within 1-2 years 
 
1266

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   30 
  
Gonorrhoea 
 
 Gonorrhoea is the second most common bacterial STI in the UK after chlamydia.  
 caused by the Gram negative diplococcus  Neisseria gonorrhoea.  
 Acute infection can occur on any mucous membrane surface, typically genitourinary but 
also rectum and pharynx.  
 The incubation p eriod of gonorrhoea is 2-5 days

 immunisation is not possible  
 reinfection is common due to antigen variation of type IV pili (proteins which adhere to 
surfaces) and Opa proteins (surface proteins which bind to receptors on immune cells) 
 There is an increased risk of acquiring HIV infection if patient is infected with gonococcus.  
Features 
More commonly patients present with co- infection with  Chlamydia trachomatis . 
 
 Primary infection is symptomatic in 90-95% of men, but only 50% of women.

 males: urethral discharge, dysuria 
 females: cervicitis e.g. leading to vaginal discharge  
 rectal and pharyngeal infection is usually asymptomatic 
 Spread can occur to involve the epididymis, prostate, endometrium and pelvic organs 
although this is rare (<10%). 
 haematological dissemination is less common, which results in skin lesions, 
arthralgia, arthritis and meningitis. 
 Neisseria gonorrhoeae  may cause either a purulent arthritis without skin

lesions  or a triad of polyarthritis (migratory), tenosynovitis, and dermatitis. 
Microbiology 
 Standard aerobic and anaerobic cultures often fail to grow the organism; selective media 
are often required and the organism grows best in an atmosphere containing 3-10% CO 2. 
 Culture is the traditional first line dia gnosis test, but rapid diagnosis can be 
undertaken using light microscopy of genital specimens to detect the bacteria.

 The negative culture of urethral discharge on Thayer-Martin medium , 
excluding gonococcal infection. 
 Increasingly, nucleic acid amplification tests are used but if positive it should be 
followed by culture to confirm diagnosis and check antibiotic sensitivities.  
Complications :  
Acute monoarthritis, a pustular rash and synovial fluid analysis suggestive of joint sepsis in a 
young woman make gonococcal arthritis the most likely diagnosis.

 local complications  may develop include  
 urethral strictures,  
 epididymitis  
 and salpingitis (hence may lead to infertility). 
 Disseminated gonococcal infection (DGI)  and gonococcal arthritis , 
 gonococcal infection being the most common cause of septic arthritis in young 
adults. 
 Fever, rashes, and migratory arthritis is the main presenting feature.  
 Diagnosis is made by culture  of synovial fluid, skin lesions, and specimen 
from urethral swab.

from urethral swab.  
 The pathophysiology of DGI thought to be due to haematogenous spread from 
mucosal infection (e.g. Asymptomatic genital infection).  
 Key features of disseminated gonococcal infection : 
1. tenosynovitis 
2. migratory polyarthritis 
1267

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   31 
 3. dermatitis (lesions can be maculopapular or vesicular) 
 Later complications  include septic arthritis, endocarditis and perihepatitis (Fitz-
Hugh -Curtis syndrome) 
 management of DGI is IV ceftriaxone 1 g od . This should continue for seven 
days . 

days . 
 the 2011 British Society for Sexual Health and HIV (BASHH) guidelines recommend 
ceftriaxone 500 mg intramuscularly as a single dose with azithromycin 1 g oral as a 
single dose . The azithromycin is thought to act synergistically with ceftriaxone and is 
also useful for eradicating any co-existent Chlamydia infections 
 if ceftriaxone is refused or contraindicated other options include cefixime  400mg PO 
(single dose)

(single dose) 
 A test of cure (with culture >72 hours or nucleic acid amplification  testing >2 weeks) is 
recommended in all cases, and treatment failure should be reported to Public Health 
England or your local Health Protection Agency. 
 
Non-gonococcal urethritis: 
 The smear of urethral discharge which shows neutrophils without visible organisms , 
is typical of nongonococcal urethritis. 
 Purulent nongonococcal urethritis can be caused by Chlamydia  and Trichomonas 
vaginalis .

vaginalis .  
 The treatment of choice for chlamydial urethritis is azithromycin (single-dose course) or 
doxycycline (seven-day course).  
 However if the infection is not resolved with doxycycline then it likely is not 
chlamydia and is most likely Trichomonas vaginalis  and metronidazole  should be 
prescribed. 
 
May 2014 exam : H/O a purulent urethral discharge. A sample of the discharge is 
shown to be a Gram negative diplococcus. What is the most appropriate

antimicrobial therapy?  Intramuscular ceftriaxone stat dose + oral azithromycin stat 
dose   
 
January 2016 exam : What is the most likely complication from repeated Neisseria 
gonorrhoea  infection? Infertility   
(Infertility secondary to pelvic inflammatory disease (PID) is the most common complication 
of gonorrhoea) 
Helminths 
Nematodes (roundworms)  
Worm  Notes  Treatment 
Strongyloides

Strongyloides 
stercoralis  Larvae are present in soil and gain access to the body by 
penetrating the skin 
 
Features include diarrhoea, abdominal pain, 
papulovesicular lesions where the skin has been 
penetrated by infective larvae e.g. soles of feet and 
buttocks, larva currens: pruritic, linear, urticarial rash, if 
the larvae migrate to the lungs a pneumonitis similar to 
Loeffler's syndrome may be triggered  Ivermectin and -
bendazoles are 
used  
Enterobius

used  
Enterobius 
vermicularis 
(pinworm) asymptomatic in 90% of cases, possible features include 
perianal itching, particularly at night; girls may have vulval 
symptoms -bendazoles  1268

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   32 
 Worm  Notes  Treatment 
 
Diagnosis may be made by the applying sticky plastic 
tape to the perianal area and sending it to the laboratory 
for microscopy to see the eggs  
duodenale , N
ecator 
americanus (h
ookworms) Larvae penetrate skin of feet; gastrointestinal infection ĺ 
anaemia 
Thin-shelled ova -bendazoles

anaemia 
Thin-shelled ova -bendazoles 
Loa loa  Transmission by deer fly and mango fly 
 
Causes red itchy swellings below the skin called 'Calabar 
swellings', may be observed when crossing conjunctivae Diethylcarbamazin
e 
Trichinella 
spiralis  Typically develops after eating raw  pork . 
Features include fever, periorbital oedema  and myositis 
(larvae encyst in muscle) -bendazoles 
Onchocerca 
volvulus  Causes 'river blindness'. Spread by female blackflies

Features include blindness, hyperpigmented skin and 
possible allergic reaction to microfilaria Ivermectin  
rIVER blindness 
= IVER mectin 
Wuchereria 
bancrofti  Transmission by female mosquito 
 
Causes blockage of lymphatics ĺ elephantiasis  Diethylcarbamazin
e 
Toxocara 
canis  (dog 
roundworm) Transmitted through ingestion of infective eggs. 
 
Features include visceral larva migrans and retinal 
granulomas  
VISCious dogs ĺ blindness  Diethylcarbamazin
e 
Ascaris 
lumbricoide
s(giant

e 
Ascaris 
s(giant 
roundworm)  the most common nematode parasite of humans.    
 Eggs are visible in faeces 
 large roundworm, growing up to 35 cm in length  
 result of pneumonitis caused by the worm's migration 
through the lungs  
 May cause intestinal obstruction and occasional 
migrate to lung (Loffler's syndrome) 
 biliary/pancreatic duct obstruction.  -benda zoles 
Piperazine  is the 
treatment of 
choice in 
patients 
presenting with 
bowel 
obstruction ;

patients 
bowel 
obstruction ; 
mebendazole  
may be used to 
treat other 
infections.  
 
 1269

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   33 
  
Cestodes (tapeworms)  
 
Echinococcus 
granulosus   Responsible for hydatid disease  
 Transmission through ingestion of eggs in dog 
faeces.  
 Definite host is dog, which ingests hydatid cysts from 
sheep, who act as an intermediate host.  
 Often seen in farmers .

 Often seen in farmers . 
 Features include liver cysts  and anaphylaxis if cyst 
ruptures  (e.g. during surgical removal) -bendazoles 
Taenia solium  Often transmitted after eating undercooked pork. 
Causes cysticercosis and neurocysticercosis, mass 
lesions in the brain 'swiss cheese appearance'  -bendazoles 
Fasciola 
hepatica  (the 
liver fluke)  May cause biliary obstruction Triclabendazole 
 
Trematodes (flukes)  
 
Schistosoma

Schistosoma 
haematobium  Hosted by snails, which release cercariae that penetrate 
skin. 
Causes 'swimmer's itch' - frequency, haematuria. Risk 
factor for squamous cell bladder cancer Praziquantel 
Paragonimus 
westermani  Caused by undercooked crabmeat, results in secondary 
bacterial infection of lungs Praziquantel 
Clonorchis 
sinensis  Caused by undercooked fish 
Features include biliary tract inflammation.

Features include biliary tract inflammation.  
Known risk factor for cholangiocarcinoma  Praziquantel 
 
Paragonimiasis or (lung fluke infection)  
 Paragonimiasis is a common tropical disease, which often presents in a similar fashion to 
tuberculosis.  
 Trematodes (flukes)  organism  Paragonimus westermani   
 Caused by undercooked crabmeat, results in secondary bacterial infection of lungs

 The patient will have a productive cough of classically brown or red sputum (which may 
be misinterpreted as haemoptysis).  
 also present with fever and night sweats as well as rashes or urticaria.  
 Constitutional symptoms will often not be as severe as in tuberculosis and the patient 
may also have an eosinophilia.  
 Treatment of paragonimiasis is with praziquantel 
Herpes simplex virus

Herpes simplex virus 
 There are two strains of the herpes simplex virus (HSV) in humans:  1270

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   34 
 1. HSV-1  
 most commonly cause  orofacial disease  
2. HSV-2.  
 most commonly cause  genital disease . 
 Whilst it was previously thought HSV-1 accounted for oral lesions (cold sores) and HSV- 2 
for genital herpes it is now known there is considerable overlap

  Worldwide seroprevalence is high, with antibodies detectable in over 90% of the 
 Of these cases, approx. 60% are caused by HSV-1. 
 Incubation period    2 days to 2 weeks. 
 Recurrent attacks tend to be shorter and less severe. 
 Viral shedding can occur in the absence of lesions.  
 Transmission  
 Only from direct contact  
 Because the virus dies quickly outside of the body, it's nearly impossible to get the

infection through contact with toilets, towels or other objects used by an infected 
person 
 Antiviral treatment reduces the severity of episodes but is not curative. 
 
Features 
 Up to 80% of herpes simplex infections are asymptomatic . 
 Gingivostomatitis 
 In orofacial HSV infections, the trigeminal ganglia  are most commonly involved 
 cold sores 
 painful genital ulceration  
 Blistering and ulceration of the external genitalia or perianal region (c ervix/rectum)

 Tender inguinal lymphadenitis, usually bilateral. 
 in genital HSV infection, the sacral nerve root ganglia (S2-S5)  are involved. 
 
 nucleic acid amplification test (NAAT)  are recommended as the preferred diagnostic 
method for genital herpes. now regarded as the test of choice . 
 PCR (a type of NAAT) : detects HSV RNA; identification of virus genotype  
 Western blot   
 the gold standard for the detection of antibodies to HSV, but it is not commercially

available.  
 expensive, time consuming and requires skilled interpretation.  
 high sensitivity   
 have ability to discriminate between HSV-1 and HSV-2 antibodies.  
 Viral culture :  
 gold standard for definitive diagnosis;  
 100% specificity for HSV-1 or HSV-2 
 Sensitivity 
 depends on the stage of the lesion at the time of specimen collection. 
 varies from 75% for first episodes to 50% for recurrences 
 results available in 48 hours 
 Tzanck smear

 Tzanck smear 
 rarely used now for diagnosis.  
 can be performed when an urgent result is needed and no alternative test is 
immediately available  
 Microscopic examination of scrapings from the base of a lesion to look for Tzanck 
cells  
 Positive if multinucleated giant cells  are present  
 Tzanck cells (multinucleated giant cells) are present in: 
 Herpes simplex type 1 (HSV-1) infection

 Herpes simplex type 1 (HSV-1) infection 
 Varicella zoster virus infection (chickenpox or shingles)  1271

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   35 
  Cytomegalovirus 
 Pemphigus vulgaris 
 No detection of Tzanck cells in: 
 Bullous pemphigoid  
 Dermatitis herpetiformis  
 Results available within 1 hour  
 Unable to differentiate between HSV-1 and HSV-2 
 
 gingivostomatitis:  
 oral aciclovir,  
 chlorhexidine mouthwash 
 cold sores:

 cold sores:  
 topical aciclovir although the evidence base for this is modest  
 genital herpes: oral aciclovir .  
 Topical anaesthetic agents, e.g. 5% lidocaine (lignocaine) ointment  
 Recommended regimens (all for 5 days): 
 Preferred regimens:  
 Aciclovir 400 mg three times daily 
 Valaciclovir 500 mg twice daily  
 Alternative regimens:  
 Aciclovir 200 mg five times daily 
 Famciclovir 250 mg three times daily

 Famciclovir 250 mg three times daily  
 Some patients with frequent exacerbations may benefit from longer term aciclovir 
 more than six herpes episodes over the past 12 months  trial of 
suppressive therapy ( aciclovir 400 mg BD for 12 months ).  
 Following cessation of suppressive therapy, reactivation may occur and 
patients therefore are counselled that up to two episodes of reactivation can 
present before the impact on the long-term pattern of recurrence can be 
evaluated.

 genital herpes  in pregnant lady: 
 Aciclovir is not licensed for use in pregnancy but is considered safe and well 
 Recommend caesarean to all women presenting with primary episode genital 
herpes lesions at the time of delivery, or within 6 weeks expected delivery 
date.  
 if genital herpes is not recurrent and healed after a course of aciclovir:  
 there is no need to continue suppressive therapy throughout the 

  She should take acyclovir 400 mg TDS from week 36 
 Restarting a suppressive dose from week 36 is, however, 
appropriate to prevent active lesions being present at the time of 
delivery, where caesarean would definitely be needed. 
 If there is a history of recurrent genital herpes  
 She should continue taking acyclovir 400 mg TDS until the end of the 
pregnancy 
 If there are active lesions or prodromal symptoms at the time of delivery.

 A caesarean section should be considered  
 
Early treatment of herpes infections is essential to prevent complications 
because antiviral drugs only inhibit the virus during its replication phase  
 
 Ref:  ((BASH guidelines (British Association for Sexual Health and HIV – ano-genital herpes 2014))  
 
 1272

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   36 
Herpetic whitlow  
 Pathogen :  
 HSV-1 in 60% of cases; HSV-2 in 40% of cases (in the adult population) 
 Etiology 
 Direct contact with infected secretions 
 Main groups: 
 Children  (via sucking of thumb/fingers (may have a history of labial herpes)

 Health care workers  exposed to oral secretions (e.g., dentists ) 
 Incubation period : 2–20 days 
 Clinical features  
 Possibly history of fever and malaise 
 Infection of the dermal and subcutaneous tissue 
 One or more fingers involved ( especially the thumb and index fingers ); 
mostly found on terminal phalanx 
 Feeling of pain, tingling, and burning in infected finger; edema 
 Grouped, non-purulent vesicles on an erythematous base  
 Vesicles may rupture or ulcerate

 Vesicles may rupture or ulcerate 
 Axillary and epitrochlear lymphadenopathy  
 oral acyclovir  
 
HIV and pregnancy 
Efavirenz is the only antiretroviral medication that is contraindicated in pregnancy 
(teratogen ic) 
 In London the incidence may be as high as 0.4% of pregnant women.  
 The aim of treating HIV positive women during pregnancy is to minimise harm to both the

mother and fetus, and to reduce the chance of vertical transmission.  
Factors which reduce vertical t ransmission  (from 25-30% to 2%) 
 maternal antiretroviral therapy 
 mode of delivery (caesarean section) 
 neonatal antiretroviral therapy 
 infant feeding (bottle feeding)  
Screening 
 NICE guidelines recommend offering HIV screening to all pregnant women 
Antiretroviral therapy 
 all pregnant women should be offered antiretroviral therapy regardless of whether they

were taking it previously 
 if women are not currently taking antiretroviral therapy the RCOG recommend that it is 
commenced between 28 and 32 weeks of gestation and should be continued intrapartum. 
1273

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   37 
 BHIVA recommend that antiretroviral therapy may be started at an earlier gestation 
depending upon the individual situation 
Mode of delivery  
 vaginal delivery is recommended if viral load is less than 50 copies/ml at 36 weeks, 
otherwise caesarian section is recommended

otherwise caesarian section is recommended 
 a zidovudine infusion should be started four hours before beginning the caesarean 
section 
Neonatal antiretroviral therapy 
 zidovudine is usually administered orally to the neonate if maternal viral load is <50 
copies/ml. Otherwise triple ART should be used. Therapy should be continued for 4- 6 
weeks. 
Infant feeding  
 in the UK all women should be advised not to breast feed 

HIV: anti-retrovirals 
 
 Highly active anti-retroviral therapy (HAART) involves a combination of at least three 
drugs, typically two nucleoside reverse transcriptase inhibitors (NRTI) and either a 
protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). This 
combination both decreases viral replication but also reduces the risk of viral resistance 
emerging 
 Following the 2015 BHIVA guidelines it is now recommended that patients start HAART

as soon as they have been diagnosed with HIV , rather than waiting until a particular 
CD4 count, as was previously advocated.  
 ART should be made up of two nucleoside reverse transcriptase inhibitors (NRTIs) and 
one other agent;  
 Atripla® (efavirenz, tenofovir, emtricitabi ne) is an acceptable choice. 
 
Nucleoside analogue reverse transcriptase inhibitors (NRTI)  (ine at the end) 
Emtricitabine causes hyperpigmentation  of skin including palmar creases in 8% of 
black patients.

black patients.  
 
 examples: zido vudine  (AZT), lami vudine , stavudine , didanos ine,  zalcitab ine 
 general NRTI side-effects: peripheral neuropathy 
 zidovudine : anaemia, myopathy, black nails 
 most frequently causes anaemia, usually by bone marrow suppression and 
patients can become transfusion -dependent in severe cases. 
 Macrocytosis is a typical finding in patients on zidovudine and can be 
used as a parameter to monitor adherence to therapy.

 Other side -effects of zidovudine include: 
 Myalgia, Myopathy, Myositis 
1274

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   38 
  Pancytopenia, 
 Lactic acidosis.  
 Blue or black discolouration of the nails is a rare side-effect. May be 
misdiagnosed as cyanosis and melanoma. 
 
 didanosine: pancreatitis (Didanosine and stavudine cause mitochondrial toxicity, hence 
peripheral neuropathy, pancreatitis and hyperlactataemia.)

 NRTIs - in particular stavudine, didanosine and zidovudine - classically cause 
mitochondrial toxicity  as an unwanted side effect. This can result in nausea, 
pancreatitis , lactic acidosis and lipoatrophy  
 Truvada   combination of two (Nucleoside analog reverse-transcriptase inhibitors 
(NRTIs) : tenofovir disoproxil and emtricitabine   
 tenofovir may cause: 
1. life-threatening liver damage  
2. lactic acidosis

2. lactic acidosis  
3. sudden worsen of hepatitis B after stopping tenofovir   lab tests regularly 
for several months after stop. 
Non-nucleoside reverse transcriptase inhibitors (NNRTI) (vir in the middle)  
 Currently four drugs of NNRTIs have been approved. These are the first generation 
NNRTIs ne virapine, dela virdine and efa virenz and the next generation NNRTI etravirine. 
examples: nevirapine, efavirenz 
 side-effects: P450 enzyme interaction (nevirapine induces ), rashes

 Nevirapine  can cause acute hepatitis  and skin rash  as a part of hypersensitive 
reaction  .this  is the rationale for starting low-dose therapy with nevirapine in the first 2 
weeks 
 Rashes are common on starting treatment with nevirapine, occurring in ~15% 
of patients.   
 Acute hepatitis is also common  and fatal reactions have occurred with this drug.  
 Serious side effects are more common in patients with relatively well preserved 
immune function.

immune function. 
Protease inhibitors (PI) (vir at the end)  
 examples: indi navir , nelfi navir , ritonavir , saqui navir  
 side-effects:  
 diabetes,  
 hyperlipidaemia , Hypertriglyceridaemia  
 buffalo hump, central obesity,  
 P450 enzyme inhibition 
 lipodystrophy 
 indinavir: renal stones , asymptomatic hyperbilirubinaemia 
 ritonavir: a potent inhibitor of the P450 system (3A4 inhibitor) 
  produces very significant elevations in plasma fluticasone  (even an inhaled

preparation).  
 These levels are sufficient to suppress endogenous cortisol levels and 
produce Cushing's syndrome.   
 
co-trimoxazole prophylaxis for Pneumocystis (PCP) is not necessary unless the CD4 
count is below 200 
 
Patient who have high viral load despite treatment: 
 Causes  of treatment failure: 
 poor adherence 
 drug interactions or absorption issues 
 primary resistance or superinfection with a new resistant strain.

 All patients should have had a resistance test at baseline 
 The most appropriate course of action is to arrange an urgent resistance test  
and manage the antiretrovirals accordingly with this result. 
 1275

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   39 
 Preventing Opportunistic Infections in Patients With HIV  
 Initiation of Prophylaxis and Treatment  
 Patients not taking ART who present with disseminated  Mycobacterium 
avium  complex (MAC) infection should be treated for the infection without ART for

2 weeks, and then started as soon as possible on ART while monitored closely for 
symptoms of the immune reconstitution inflammatory syndrome (IRIS).  
 Severe IRIS has also been reported after early ART in the management of 
cryptococcal and tuberculous meningitis , and it has been suggested that such 
patients delay ART until 4-6 weeks after control of the opportunistic infection.   
 Patients with CD4 counts of less than 50 cells/μL at p resentation should be

considered for cryptococcal antigen testing, 
 among those diagnosed with cryptococcal meningitis, initial ART should be 
delayed at least 2 weeks into cryptococcal therapy and as long as 10 weeks. 
 which must be treated initially with amphotericin and flucytosine. 
 CD4 counts are useful landmarks for initiation of antimicrobial prophylaxis: 
 Less than 250 cells/μL - Coccidioidomycosis prophylaxis if seropositive in high-risk 
area

area 
 Patients with a new positive immunoglobulin M (IgM) or IgG serologic test 
result who live in endemic areas and have a CD4 count of less than 250 
cells/μL should receive fluconazole 400 mg PO daily  
 Less than 200 cells/μL - PCP prophylaxis 
 The preferred regimen is trimethoprim-sulfamethoxazole 1 double-strength 
tablet orally daily or 1 double-strength tablet orally 3 times weekly. 
 Less than 150 cells/μL - Histoplasmosis prophylaxis if high-risk exposure

 Patients with a CD4 count of less than 150 cells/μL at high risk for exposure 
or who live in a hyperendemic area should receive itraconazole 200 mg PO 
daily 
 Less than 100 cells/μL - Toxoplasmosis prophylaxis (if seropositive) 
 Trimethoprim-sulfamethoxazole, one double-strength tablet orally once daily 
is preferred  
 Less than 100 cells/μL - Penicilliosis prophylaxis if living in high-risk area 
 
 Less than 50 cells/μL - MAC infection prophylaxis

 Patients with CD4 count of fewer than 50 cells/μL should be 
given  azithromycin  1200 mg orally  weekly  after ruling out disseminated 
MAC infection on clinical assessment  
 Alternatives include clarithromycin 500 mg orally twice daily or rifabutin 300 
mg orally daily  
 Clinical Landmarks for Terminating Primary Prophylaxis  
 Mycobacterium avium -intracellulare  (MAI) infection prophylaxis: 
 should be continued with antiretroviral therapy (ART) until the CD4 count

exceeds 100 cells/μL for 3 months . 
 P carinii  pneumonia ( PCP) and toxoplasmosis  prophylaxis: 
  should be continued until the CD4 count exceeds 200 cells/μL for 3 
months . 
 Histoplasmosis prophylaxis : 
  can be discontinued when the CD4 count has exceeded 150 cells/μL for 6 
months,  
 coccidioidomycosis prophylaxis: 
  can be discontinued when CD4 counts exceed 250 cells/μL for 6 months,  
 penicilliosis prophylaxis :

 penicilliosis prophylaxis : 
  can be discontinued when CD4 counts exceed 100 cells/μL for 6 months.  
 
 1276

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   40 
HIV lipodystrophy (Antiretroviral-related lipodystrophy)  
Lipodystrophy  
 Lipodystrophy, lipoatrophy and alterations in serum lipid values have been observed in 
patients with human immunodeficiency virus (HIV) disease taking highly active

antiretroviral therapy (HAART).  
 Consequences  
 Elevated serum lipid levels have been associated with premature coronary artery 
disease. 
 Hypertriglyceridaemia is also thought to contribute to central fat deposition and 
insulin resistance.  
 Causes  
 Abnormalities of serum lipid levels are likely to be multifactorial  in patients with 
HIV disease  but appear much commoner in patients taking protease inhibitors.

 Isolated hypertriglyceridaemia can occur in HIV disease in the absence of 
protease inhibitors  but extremely high serum triglycerides have been documented 
in some patients treated with these drugs. 
 In addition, patients with HIV disease may also have elevated serum lipid levels 
due to familial hyperlipidaemia.  
 If the elevation in lipid levels is modest, measures such as dietary modification and 
exercise may be tried first.

exercise may be tried first. 
  predomina nt hypercholesterolaemia  or with a mixed picture  statin 
 caution must be exercised since some protease inhibitors  interact with 
some statins due to metabolism by CYP3A4 pathway. 
 Simvastatin is contraindicated in patients on protease inhibitors and plasma 
levels of atorvastatin are also  greatly elevated in these patients.  
 For this reason, pravastatin is usually the drug of choice.

 Pravastatin is preferred because its metabolism is not as 
dependent on the CP450s  as other agents in this group. 
  hypertriglyceridaemia  fenofibrate  
 Omega -3 fatty acids may also be beneficial in reducing modestly-elevated serum 
triglycerides. 
 Switching therapy might be an option, to non-nucleoside reverse transcriptase 
inhibitors (NNRTIs)  
 
 Lipodystrophy refers to the loss of adipose tissue  
  
Antiretroviral insulin-resistance syndrome

Antiretroviral insulin-resistance syndrome  
 Long -term use of combination antiretroviral therapy including protease inhibitor regimens 
is associated with a re -distribution of body fat in some patients 
 HIV lipodystrophy follows an  insulin-resistance pattern, with: 
 loss of fat on the face,  
 increasing abdominal fat  
 increase in the size of the dorsocervical fat pad (buffalo hump).  
 deposition of subcutaneous fat on the back

 deposition of subcutaneous fat on the back  
 low high-density lipoprotein (HDL) cholesterol  
 high triglyceride levels,  
 impaired glucose tolerance or frank type -2 diabetes 1277

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   41 
  there is some evidence that the insulin sensitisers (glitazones) may be effective in some 
patients  
 
 Acquired partial lipodystrophy , also known as Barraquer-Simons syndrome  
 usually begins in childhood, at a median age of 7 years. The median age at 
presentation has been about 25 years.

presentation has been about 25 years.  
 It predominantly affects females  
 often f ollows an acute febrile illness, most commonly measles.   
 Most patients are asymptomatic until the development of advanced renal 
impairment or acute decompensation.  
 Fat loss is usually limited to the face, trunk, and upper extremities. Simultaneously, 
fat hypertrophy occurs in the lower extremities.  
 Characteristic fat distribution, as measured by skinfold thickness or images from

magnetic resonance imaging (MRI) studies  
 Hepatomegaly has been reported in over 60%  
 Membranoproliferative glomerulonephritis  in about 20%   
 Patien ts with membranoproliferative glomerulonephritis are more likely to 
have low C3  levels and the presence of C3 nephritic factor (C3NeF).  
 low C3  reported in about 70%  
 Presence of C3NeF in about 80%, a polyclonal (IgG), able to break down C3 
in normal human serum  
 Activation of alternate complement pathway

 Activation of alternate complement pathway  
  Associated with Autoimmune diseases (eg: SLE most commonly )  
 Propensity to bacterial infections  
 Increased circulating free fatty acids  
 Excessive accumulation of triglycerides in multiple sites, especially the liver and 
muscles  
 Diabetes  
 mechanisms that may explain insulin resistance  
 Inability to store triglycerides: Leads to abnormal deposition of 
triglycerides in other tissues (eg, liver, skeletal muscle, and pancreas

[lipotoxicity]), resulting in hypertriglyceridemia, insulin resistance, 
hepatic steatosis (fatty liver), impaired insulin secretion, and, 
eventually, type 2 diabetes  
 Absent or immature adipocytes: Inability to synthesize and release 
adipocytokines (eg, leptin, adiponectin) that may be important to 
maintain normal metabolism  
  Pathophysiology  
 Activation of an alternate complement pathway, C3 hypocomplementemia 
with lysis of adipocytes induced by C3NeF, has been implicated.

 Other causes of acquired lipodystrophy: Aggressive treatment of patients infected 
with HIV, particularly with protease inhibitors  
 In women with lipoatrophy syndromes, oral estrogens should be avoided as they can 
exacerbate the hypertriglyceridemia and result in acute pancreatitis.  
 1278

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   42 
  
Immune reconstitution syndrome 
 due to activation of the immune system following HIV therapy against persisting antigen   
 typically occurs a few weeks after commencing anti-retroviral therapy in a patient 
with underlying tuberculosis

with underlying tuberculosis 
HIV: biliary and pancreatic disease 
 The most common cause of biliary disease in patients with HIV is sclerosing cholangitis 
due to infections such as CMV, Cry ptosporidium and Microsporidia 
 Pancreatitis in the context of HIV infection may be secondary to anti-retroviral 
treatment (especially didanosine)  or by opportunistic infections e.g. CMV 

HIV: diarrhoea 
Supportive therapy is the mainstay of treatment in Cryptosporidium diarrhoea  
 
 Diarrhoea is common in patients with HIV. This may be due to the effects of the virus 
itself (HIV enteritis) or opportunistic infections 
 Possible causes 
 Cryptosporidium + other protozoa (most common) 
 Cytomegalovirus 
1279

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   43 
  Mycobacterium avium intracellulare  
 Giardia  
 Both Cryptosporidium  and Cytomegalovirus  are found in patients with CD4 count less 
than 300 cells/µL. It causes chronic diarrhoea (more than four week's duration).  
 Cryptosporidium  is the most common infective cause of diarrhoea in HIV patients.

 It is an intracellular protozoa and has an incubation period of 7 days.  
 Presentation is very variable, ranging from mild to severe diarrhoea.  
 A modified Ziehl -Neelsen stain (acid-fast stain) of the stool may reveal the 
characteristic red cysts of Cryptosporidium.  
 Treatment is difficult, with the mainstay of management being supportive therapy * 
 *nitazoxanide is licensed in the US for immunocompetent patients 
 Mycobacterium avium intracellulare

 Mycobacterium avium intracellulare   
 is an atypical mycobacteria seen with the CD4 count is below 50.  
 Typical features include fever, sweats, abdominal pain and diarrhoea. 
 There may be hepatomegaly and deranged LFTs. 
 Diagnosis is made by blood cultures and bone marrow examination. 
 Management is with rifabutin, ethambutol and clarithromycin 
HIV nephropathy 
 HIV nephropathy is characterised by: 
 raised creatinine

 raised creatinine 
 nephrotic range proteinuria 
 normal sized kidneys on ultrasound scan, and 
 focal segmental glomerulosclerosis on renal biopsy. 
 Somewhat surprisingly the blood pressure of patients with HIV nephropathy is 
usually normal. 
 raised immunoglobulins and raised cholesterol. 
Cryptococcal disease in AIDS (Cryptococcosis) 
 the most common fungal infection of the CNS  
 the most common fungal disease in  HIV

 the most common fungal disease in  HIV  
 may present as: 
  a space-occupying lesion,  
 meningitis, or  
 meningoencephalitis.  
 Risk factor:  
 usually develops only when CD4+ lymphocyte counts fall below 100 cells/mL.  
 MRI, with and without contrast, is the preferred diagnostic imaging modality.  
 Treatment is with amphotericin B and flucytosine (5FC);  
 patients then require lifetime suppression  with fluconazole . 
 
1280

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   44 
HIV: immunisation 
The Department of Health 'Greenbook' on immunisation defers to the British HIV Association for 
guidelines relating to immunisation of HIV -infected adults 
 
Vaccines that can be used in all 
HIV-infected adults Vaccines that can be

HIV-infected adults Vaccines that can be 
used if CD4 > 200  Contraindicat ed in HIV-
infected adults  
 Hepatitis A   
 Hepatitis B  
 Haemophilus influenzae  B (Hib)  
 Influenza -parenteral 
 Japanese encephalitis 
 Meningococcus-MenC  
 Meningococcus-ACWY I 
 Pneumococcus-PPV23  
 Poliomyelitis-parenteral (IPV)  
 Rabies   
 Tetanus-Diphtheria (Td)  Measles, Mumps, 
Rubella ( MMR ) 
 Varicella  
 Yellow Fever  Cholera CVD103- HgR 
 Influenza -intranasal

 Influenza -intranasal 
 Poliomyelitis- oral 
(OPV)  
 Tuberculosis (BCG) 
 
HIV: Kaposi's sarcoma 
 
 Kaposi sarcoma is a neoplasm of endothelial cells  (vascular tumor ) that is caused 
by human herpes virus 8 (HHV-8) 
 most commonly seen in patients with HIV  and transplant patients.  
 can be seen in HIV patients with a CD4+ cell count of less than 500/mm3.

 Human herpes virus 8, which causes Kaposi sarcoma in HIV patients, is transmitted 
by sexual contact.  
 Aside from affecting the skin,  Kaposi sarcoma can also affect the gastrointestinal 
tract and lungs. 
Feature  
 presents as purple papules or plaques on the skin or mucosa  (e.g. gastrointestinal and 
respiratory tract)  
 lesions occur most commonly on the face  
 skin lesions may later ulcerate 
 respiratory involvement may cause massive haemoptysis and pleural effusion, Chest x

ray may show pulmonary nodules. 
 Histopathology classically show  
 lymphocytic inflammation . 
 proliferation of endothelial cells ( spindle cells ) 
Treatment  
 radiotherapy + resection 
 Radiotherapy may be used to treat painful or highly visible lesions. 
 AIDS -related Kaposi's sarcoma becomes smaller as immune function improves such as 
with treatment with highly active antiretroviral therapy (HAART). 
 In some circumstances chemotherapy may be added to HAART.

 Human herpes virus 8  is also associated with: 
 primary effusion lymphoma (a rare lymphoma of serous cavities)  
 Castleman's disease. 
1281

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   45 
  
Kaposi's sarcoma in a patient with HIV  
 
Human immunodeficiency virus (HIV) 
Etiology 
 Consists of the two species  :  
 HIV-1: most common species worldwide  
 HIV-2: restricted almost completely to West Africa 
Mechanisms

Mechanisms 
 The gp41  protein mediates fusion and entry of HIV into host cells, and is the structural 
component that first physically invades the host cell wall.  
 The gp120  protein of HIV allows its attachment to h ost CD4+ T cells.  
 gp120  is the HIV glycoprotein that can cross the placenta and infect the fetus. 
 Site of replication  
 The lymph nodes are the organs in which HIV replicates during the latent phase.  

 Epstein -Barr virus reactivation, leading to B-cell lymphoma, typically occurs 
in AIDS  patients with a CD4+ cell count less than 100/mm3. 
Acute HIV disease (seroconversion illness) 
 
 HIV seroconversion is symptomatic in 60 -80% of patients  
 typically presents as a glandular fever type illness.  
 The presentation may mimic glandular fever, though the pharyngitis associated

with acute HIV is usually more severe and a rash only occurs in glandular fever 
when ampicillin has been given.  
 Increased symptomatic severity is associated with poorer long term prognosis.  
 It typically occurs 2-12 weeks after infection 
 The time from exposure to onset of symptoms is usually 2-4 weeks, but the 
incubation may be as long as 10 months in rare cases.  
 
Features 
 Fever 
 sore throat 
 maculopapular rash 
 malaise, myalgia, arthralgia

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   46 
  mouth ulcers 
 rarely meningoencephalitis 
Diagnosis  
 HIV PCR and p24 antigen tests can confirm diagnosis 
 P24 antigen testing may detect HIV infection one to three weeks after the 
event and is the most appropriate option when earlier result is needed 
 p24 is the  capsid  protein of HIV, coded for by the gag gene.

 The alternative is HIV RNA testing to estimate viral load. 
 the diagnosis is made by (PCR) of peripheral blood for HIV (RNA);  
 in acute HIV the viral load is very high.  
 
 Flow cytometry is the lab technique used to measure CD4 cell count in HIV patients.  
 The CD4 (T-helper cell) count is a reliable indicator of HIV-related immune 
 The most useful investigation in estimating his risk of developing an 
opportunistic infection  (OI)

opportunistic infection  (OI) 
 CD4 of < 350 cells/µl is associated with an increase in the risk of some 
opportunistic infections 
 CD4 < 200 cells/µl indicates an 80% risk of developing an ( OI) over the next 
3 years. 
 oesophageal candidiasis and Pneumocystis pneumonia are common at CD4 
100–200 cells/µl;  
 disseminated Mycobacterium avium complex infection and cytomegalovirus 
retinitis are rarely seen until CD4 < 50 cells/µl.

 Blood cultures   the best investigation to confirm the diagnosis 
 Since late 2015, the World Health Organization (WHO) has recommended starting 
ART in every HIV-positive individual, regardless of CD4 count . 
 
 antibodies to HIV may not be present 
 During seroconversion it is likely that the HIV antibody test will be negative 
 HIV antibody testing by western blot has a lower false positive rate than HIV

antibody by ELISA and may be an option when a false positive result is suspected. 
 
CMV retinitis in a patient with HIV 
 AIDS  retinitis is typically caused by cytomegalovirus. 
 
The slide shows the typical 'cottage cheese 
and tomato ketchup' or 'pizza' appearance of 
CMV retinitis in a patient with HIV disease. 1283

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   47 
Toxoplasmosis 
 
 Toxoplasma gondii is an obligate intracellular protozoa which infects the body via the GI 
tract, lung or broken skin.  
 It's oocysts release trophozoites which migrate widely around the body including to the 
eye, brain and muscle.

eye, brain and muscle.  
Transmission (fecal-oral route)  
 Toxoplasmosis can be contracted through:  
1. cysts in meat, ( from undercooked meat ) 
 The usual animal reservoir is the cat, although other animals such as rats 
carry the disease. 
 Kittens are the primary host (mature cats are less likely to secrete 
toxoplasma) 
  sheep and cattle eat food contaminated with soil contaminated by kitten 
faeces; and humans ingest the organism s in poorly cooked meat.

 Oocysts excreted with cat faeces can remain in soil for months. 
2. oocysts in cat feces,  
 ingestion of fresh food contaminated by toxoplasma excreted in cats' faeces.  
3. transplacental   Congenital toxoplasmosis  .  
 30% risk of reactivation in immunocompromised (especially CD4+ count < 100 cells/μL)  
 in those not receiving prophylaxis or antiretroviral therapy  
 ~ 30% of the worldwide population is infected 

 HIV patients when the CD4+ count is less than 100cells/microL 
 Toxoplasmosis is the most common central nervous system protozoal infection that 
presents with brain abscesses in patients with HIV. 
 
 HIV is associated with  reactivation  of the disease.  
 
Feature  
 Most infections are asymptomatic.  
 often features resembling infectious mononucleosis (fever, malaise, 
lymphadenopathy).

lymphadenopathy).  
 Highly characteristic of toxoplasmosis is asymmetrical lymphadenopathy  limited 
to an isolated lymph node group.  
 Other less common manifestations include meningio -encephalitis and myocarditis.  
 Can present with fits in patients with AIDS 
 Most common infection of the central nervous system in patients with AIDS 
 ring-enhancing lesion on head imaging 
 MRI is more sensitive and preferred 
 CD4+ count < 100 cells/μL  
 Eye manifestations include:

 Eye manifestations include: 
 Focal choroido -retinitis 
 Granulomatous uveitis 
 Optic atrophy  
 Retinal detachment  
 Cataract  
 Posterior uveitis  
1284

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   48 
  Glaucoma. 
 Congenital toxoplasmosis   presents with a classic  triad  of: 
1. chorioretinitis ,  
2. hydrocephalus and  
3. intracranial calcifications . 
 antibody test: Serology testing  for anti-toxoplasma IgM and IgG antibodies via ELISA

 The serologic diagnosis of toxoplasmosis in immunocompromised patients is 
based on the presence of IgG antibodies. 
 Sabin -Feldman dye test 
 Congenital toxoplasmosis is associated with elevated platelet count. 
 HIV patients usually presents with multiple ring-enhancing lesions on brain MRI.  
Treatment   
 Symptomatic patients usually have a self- limiting infection,  
 Treatment usually reserved for those with severe infections or patients who are 
immunosuppressed

immunosuppressed 
 pyrimethamine plus sulphadiazine for at least 6 weeks 
 Folinic acid, (also known as leucovorin), should be added to prevent 
pyrimethamine- associated hematologic toxicity 
 Trimethoprim-sulfamethoxazole is the therapy of choice for prophylaxis against 
toxoplasmosis reactivation. 
 pregnant women  
 Since the  protozoal infection is commonly contracted through the handling of cat 
feces, pregnant women should be advised to avoid contact with cat litter  to

reduce their fetus's risk for congenital infection. 
 for infected pregnant to prevent maternal-fetal transmission   spiramycin ,  
 Risk of fetopathy is reduced by more than 50% if spiramycin, which can prevent 
maternal-fetal transmission, is given to mothers  
 
Pyrimethamine   
 MOA  Dihydrofolate Reductase (DHFR) Inhibitor  (competitive inhibitor) 
 DHFR is a key enzyme for production of tetrahydrofolate, a cofactor that is required 
for the synthesis of DNA and proteins.

for the synthesis of DNA and proteins.   
 Indications:  
  used as an antimalarial or  
 with a sulfonamide to treat toxoplasmosis.  
Sulfadiazine  
 bacteriostatic, inhibits bacterial folic acid synthesis by competing with para amino benzoic 
acid.  
spiramycin   
 Macrolide antibiotics inhibit bacterial growth by targeting the 50S ribosomal subunit  
 Resistance to spiramycin is commonly attributed to mutations in 50S rRNA

January 2008 exam : HIV positive man is admitted with right-sided hemiplegia. CT scan 
shows multiple ring enhancing lesions. A diagnosis of cerebral toxoplasmosis is suspected. 
What is the most suitable management?  Pyrimethamine and sulphadiazine  
 
At which CD4 count  should proph ylaxis against toxoplasmosis begin? 
 <100 cells/μL   (with trimethoprim-sulfamethoxazole). 
 although prophylaxis for toxoplasmosis is not required until the CD4 count is <100

cells/microL, the patient will be covered at a CD4 count <200 cells/microL when 
prophylaxis against P. jiroveci  is instituted.  1285

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   49 
  
What is risk of transmission of HIV to a health care worker after percutaneous exposure? 
 0.3% with  no prophylaxis .  
 the risk is reduced by ~80% when post exposure prophylaxis is 
 
HIV- white lesion in oral mucosa  
 Oral hairy leukoplakia  are white oral lesions caused by the Epstein -Barr virus .

Unlike  oral candidiasis (thrush), these lesions cannot be scraped off  the tongue 
and buccal mucosa. 
H1N1 influenza pandemic  
 
 The H1N1 virus is a subtype of the influenza A virus  
 the most common cause of flu in humans.   
 Only influenza type A viruses are known to have caused pandemics.  
 Influenza A and B viruses circulate and cause outbreaks and epidemics.

 The 2009 pandemic was caused by a new strain of the H1N1 virus.  
 incubation period is about 2 days.  
 In temperate climates, seasonal epidemics occur mainly during winter, while in tropical 
regions, influenza may occur throughout the year, causing outbreaks more irregularly. 
 
The following groups are particularly at risk:  
 patients with chronic illnesses and those on immunosuppressants  
 pregnant women 
 young children under 5 years old

 young children under 5 years old 
 
Features : The majority of symptoms are typical of those seen in a flu-like illness: 
 fever greater than 38ºC 
 myalgia 
 lethargy 
 headache  rhinitis 
 cough 
 diarrhoea and vomiting 
A minority of patients may go on to develop an acute respiratory distress syndrome which may 
require ventilatory support. 
 
Treatment  
There is evidence to support the use of oseltamivir as a prophylactic agent against 
influenza

influenza  
There are two main treatments currently available: 
Oseltamivir  (Tamiflu) 
 For critically ill patients with confirmed or suspected H1N1, oseltamivir 150 mg bd  
for ten days is the recommended treatment.  
 oral medication 
 a neuraminidase inhibitor  which prevents new viral particles from being released by 
infected cells . thus, slowing viral replication down rather than directly killing the virus 
particle.

particle. 
 This slowing down of replication is important in permitting time for the body's own immune 
system to deal with the virus. 
 It is of value in prophylaxis against influenza.  may be used in the prophylactic 
treatment of healthcare workers during flu epidemics.  
 However, viral replication is rapid and to be effective the drug must be given as early as 
possible after the development of symptoms of flu and preferably within 48 hours.

 common side-effects include nausea, vomiting, diarrhoea and headaches.  
Gastrointest inal symptoms are the most common side-effects of oseltamivir 
(Tamiflu).  1286

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   50 
  
Zanamivir (Relenza) 
 inhaled  medication* 
 *intravenous preparations are available for patients who are acutely unwell 
 The only parenteral alternative is zanamivir (300 mg IV for 10 days ).  
 can be safely given using peripheral venous access.

 For hospitalized influenza patients  with suspected or known gastric statis, 
gastric malabsorption , gastrointestinal bleeding, or for patients suspected 
or confirmed with oseltamivir-resistant influenza virus infection, intravenous 
zanamivir should be considered. 
 also a neuraminidase inhibitor  
 may induce bronchospasm in asthmatics 
 
Intensive Care Management of Pandemic (H1N1) Influenza 
 Ideally patients should be nursed in a negative pressure room.  
 NIV

 NIV  
 Whilst there is no evidence that NIV prevents invasive ventilation in H1N1 patients, 
it is commonly used as bridging therapy.  
 It is important to remember that these are open circuits and still require personal 
protection for staff.  
 NIV should be sta rted after the mask is secured to the face  
 Ensuring that a well-fitting mask is in place before airflow starts can reduce 
the amount of aerosol production.

the amount of aerosol production.  
 Experience with helmet devices is limited but increasing, and it has been 
successful in patients who are unable to tolerate the nasal or orofacial devices. The 
advantage is that it may provide a tighter seal than nasal or orofacial devices.  
 avoiding water humidification and use of a closed hood(غطاء الرأسis also advised. 
Infectious mononucleosis & (Epstein-Barr virus) 
 
Aetiology

Aetiology 
 Infectious mononucleosis (glandular fever) is caused by the Epstein-Barr virus  (also 
known as human herpesvirus 4, HHV-4).  
 The incubation period of EBV infectious mononucleosis is 1-2 months.  
 most common in adolescents and young adults. 
 
 The  CD8+  T-cell response  caused by infectious mononucleosis, leads to generalized 
lymphadenopathy, splenomegaly, and high WBC count with atypical lymphocytes. 
 
Features

Features 
EBV infectious mononucleosis   triad of fever, pharyngitis, and lymphadenopathy.  
 Bilateral posterior cervical adenopathy is most highly suggestive of EBV infectious 
mononucleosis. 
 pyrexia 
 malaise, anorexia, headache 
 palatal petechiae  
 Palatal petechiae of the posterior oropharynx distinguish infectious mononucleosis 
from other causes of  viral pharyngitis but do not distinguish it from group A

streptococcal pharyngitis, in which palatal petechiae may occur. 
1287

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   51 
  Uvular edema is an uncommon, but, if present, it is a helpful sign in distinguishing EBV 
infectious mononucleosis from other causes o f viral pharyngitis or from group A 
streptococcal pharyngitis.  
 splenomegaly - occurs in around 50% of patients and may rarely predispose to splenic 
rupture 
 hepatitis

rupture 
 hepatitis  
 haemolytic anaemia secondary to cold agglutins (IgM) 
 a maculopapular, pruritic rash develops in around 99% of patients who take 
ampicillin/amoxicillin  whilst they have infectious mononucleosis 
 Drug -induced rash is usually pruritic and is prolonged, in contrast to the viral rash 
of EBV infectious mononucleosis.  
 Early infectious mononucleosis may present with a maculopapular generalized 
rash.It is nonpruritic and rapidly disappears.

rash.It is nonpruritic and rapidly disappears.  
 Because leukocytosis  is the rule in infectious mononucleosis, the presence of a  normal 
or decreased WBC count should suggest an alternative diagnosis.  
 Lymphocytos is 
 Relative lymphocytosis (≥ 60%) plus atypical lymphocytosis (≥ 10%) are the 
characteristic findings of EBV infectious mononucleosis.  
 presence of 50% lymphocytes with at least 10% atypical lymphocytes  
 Atypical lymphocytes

 Atypical lymphocytes   
 most commonly  seen in patients who have infectious mononucleosis.  
 Other causes  
 drug reactions (phenytoin),  
 stress,  
 viral or bacterial infections ,  
 allergies, 
  autoimmune diseases, thyroid problems  
 malignancy.  
 ESR is most useful in differentiating group A streptococcal pharyngitis from EBV 
infectious mononucleosis.  
 (ESR elevated with EBV infectious mononucleosis, not elevated in group A 
streptococcal pharyngitis).

streptococcal pharyngitis).  
atypical lymphocytosis point towards a viral illness 
 
Diagnosis  
 heterophile  antibody test (Monospot test)  (immunoglobulin IgM to EBV) 
 the initial screening test  
 sensitivity 85% and specificity 100%. 
 Cytomegalovirus is a herpesvirus that causes  infectious mononucleosis with a 
negative monospot test . 
 EBV ser ological tests 
 Definitive diagnosis  
 should be obtained in patients with a mononucleosis-like illness and a negative

finding on the Monospot test.  
Management  is supportive and includes: 
 rest during the early stages, drink plenty of fluid, avoid alcohol 
 simple analgesia for any aches or pains 
 consensus guidance in the UK is to avoid playing contact sports for 8 weeks after 
having glandular fever to reduce the risk of splenic rupture  
 unfortunately on clinical appearances it is not possible to distinguish bacterial from viral or 
throat infections with any degree of reliability.

 If the child has EBV infection, then the administration of Amoxicillin will give an 
erythematous rash.  Non-vomiting patients can be treated with oral penicillin- v.' 
 Patients with EBV infectious mononucleosis who have positive throat cultures for group A 
streptococci should not be treated because this represents colonization rather than 
infection  
 complicated EBV infectious mononucleosis :  1288

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   52 
  Short courses of corticosteroids are i ndicated for EBV infectious mononucleosis 
with: 
 hemolytic anemia,  
 thrombocytopenia,  
 CNS involvement, or  
 extreme tonsillar enlargement (impending airway obstruction).  
 
In which structure is the immune response most likely localized?  Paracortex

 immune response to the virus takes place through T-cell mediated immune responses, 
which take place in the lymphocyte-rich areas of the lymph node , namely 
the paracortex.  
 A biopsy of the lymph node of this patient would show reactive hyperplasia due to 
increased activity of the paracortex. 
Influenza  
 Methods used in the laboratory diagnosis of respiratory viral infections :

 (ELISA):Enzyme-linked immunosorbent assay is used to look for antibodies in 
acute and convalescent sera.  
 Haemagglutination:  Influenza is a haemagglutinating virus as red cells stick to the 
infected cells after addition to the culture.  
 Immunofluorescence:  Rapid antigen detection kits utilising direct 
immunofluorescence are used to demonstrate the following in respiratory 
secretions: 
 Respiratory syncytial virus (RSV)  
 Influenza  
 Parainfluenza, and

 Parainfluenza, and  
Single radial haemolysis (SRH)   test is used to screen for rubella antibodies in pregnant 
women. NOT used in diagnosis of respiratory viral infections. 
Treatment  
 Adenovirus. Oseltamivir (tamiflu) is the first line treatment recommended for patients with 
suspected or confirmed Influenza A.  
 Ribavirin has not be shown to be efficacious in the management of influenza.

 Zanamivir is useful in patients with poor swallow or in those with suspected or confirmed 
exposure to oseltamivir-resistant influenza.  
 Salbutamol nebulisers can be useful in patients with wheeze, however appropriate 
isolation precautions should be secured prior to the administr ation of nebulisers in 
patients with Influenza infection.  
 
Parvovirus B19  
 Parvovirus B19 is a single-strand DNA virus.

 Parvovirus B19 is a single-strand DNA virus.  
 The most widely known clinical manifestation of parvovirus B19 is erythema infectiosum 
('slapped cheek syndrome'), a mild viral illness of childhood characterised by a classic 
exanthema in which both cheeks appear bright red as though they had been slapped. 
 Although usually a benign self-limiting viral illness, parvovirus B19 infection may have 
more serious sequelae.  
1289

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   53 
  The virus has a tropism for rapidly dividing erythrocyte precursors which they infect and 
destroy. Thus, no reticulocytes (immature erythrocytes) are available to replace aging or 
damaged erythrocytes as they are cleared by the reticuloendothelial system. This may

not have any significant impact on otherwise healthy individuals, but can trigger an 
aplastic crisis - particularly in patients with haemoglobinopathies. 
 Parvovirus B19 infection may also be associated with a symmetrical post-infectious 
arthritis, affecting the small joints of the hands and feet. The knees or elbows are rarely 
involved. 
 The arthritis is much more common in adults, particularly in women, and may persist for

weeks to months (even years in a small number of patients). The arthritis may mimic 
rheumatoid arthritis. Unlike rheumatoid arthritis, the post-infectious arthritis associated 
with parvovirus B19 does not cause permanent damage to bones or joints. 
Leishmaniasis 
 
 Leishmaniasis is caused by the intracellular protozoa Leishmania, (intra-macrophage 
protozoa) 
 transmitted to humans by phlebotomine sand flies.

 There are four main clinical syndromes: cutaneous, muco-cutaneous, visceral (also 
known as kala-azar) and post kala-azar dermal leishmaniasis. 
 
Cutaneous leishmaniasis 
 caused by Leishmania tropica  or Leishmania mexicana  
 crusted lesion at site of bite 
 present with ulcers or nodules.  
 usually heal spontaneously, but slowly, in immuncompetent individuals with resultant 
disfiguring scars.  
Mucocutaneous leishmaniasis 
 caused by Leishmania braziliensis

 caused by Leishmania braziliensis  
 skin lesions may spread to involve mucosae of nose, pharynx etc 
 characterised by progressively destructive ulcerations of the mucosa extending from the 
nose and mouth to the pharynx and larynx,  
 are not self-healing. 
Visceral leishmaniasis (kala-azar) 
 mostly caused by Leishmania donovani  
 caused by the Leishmania donovani complex  
 (L. donovani sensu stricto in East Africa and India,

  L. infantum in Europe, North Africa and Latin America).  
 incubation period of 2 -6 months  
 patients present with persistent systemic infection (fever, sweating, rigor, malaise, loss of 
appetite and weight loss) (*occasionally patients may report increased appetite with 
paradoxical weight loss) 
 parasitic infection of the blood and reticulo-endothelial system  lymphadenopathy, 
massive splenomegaly and hepatomegaly 
 grey skin - 'kala-azar' means black sickness 
 investigations

 investigations  
 panc ytopaenia secondary to hypersplenism 
 There is also often marked polyclonal hypergammaglobulinaemia. 
 Visualisation of the parasite (amastigote form) from lymph nodes, bone 
marrow or spleen is used as a confirmatory test. 
 PCR can be used to detect the parasite in the blood.  
 Anti-leishmanial antibodies can be detected, but they remain positive up to several 
years after cure and therefore cannot be used to detect relapse. 
1290

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   54 
  First line antimonials are sodium stibogluc onate and meglumine antimoniate. 
Adverse effects influde cardiac arrhythmias and acute pancreatitis.  
 Amphotericin B is increasingly being used.  
 
Post kala -azar dermal leishmaniasis  
 a complication of visceral leishmaniasis

 a complication of visceral leishmaniasis  
 characterised by a macular, maculo-papular or nodular rash    
 frequently observed after treatment.It can also occur in immunosuppressed individuals. 
 highly infectious. 
Leptospirosis (Also known as Weil's disease *) 
 
 *the term Weil's disease is sometimes reserved for the most severe form 
  If the infection causes jaundice, kidney failure and bleeding, it is then known as

Weil's disease.  
 If it affects the lung and causes pulmonary haemorrhage, then it is known as 
severe pulmonary haemorrhage syndrome.  
 leptospirosis is commonly seen in questions referring to sewage workers, farmers , vets 
or people who work in abattoir.  
 It is caused by the spirochaete Leptospira interrogans (serogroup L 
icterohaemorrhagiae),  
 classically being spread by contact with infected rat urine.

 Weil's disease should always be considered in high-risk patients with hepato- renal 
failure 
 
Features 
 fever 
 renal failure (seen in 50% of patients)  
 jaundice 
 headache, may herald the onset of meningitis 
 subconjunctival haemorrhage 
 Haemorrhagic tendencies with purpura or petechiae, and 
 Enlargement of liver and spleen. 
 Presentation with heart failure is uncommon but has been described in severe 
leptospirosis.  

 high-dose benzylpenicillin or doxycycline 
 other options:  cefotaxime or ceftriaxone. 
Leprosy 
Leprosy is a granulomatous disease primarily affecting the peripheral nerves and skin. It is 
caused by Mycobacterium leprae . 
 
Features  
 
 patches of hypopigmented skin typically affecting the buttocks, face, and extensor 
surfaces of limbs 
 sensory loss

 sensory loss 
The degree of cell mediated immunity determines the type of leprosy a patient will develop: 
 Low degree of cell mediated immunity ĺ lepromatous leprosy ('multibacillary')  
 extensive skin involvement 
1291

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   55 
  symmetrical nerve involvement 
 High degree of cell mediated immunity ĺ tuberculoid leprosy ('paucibacillary')  
 limited skin disease  
 asymmetric nerve involvement 
 
 WHO-recommended triple therapy: rifampicin, dapsone and clofazimine 
 BNF advice:

 BNF advice:  
 multibacillary leprosy (>6 lesions)  rifampicin, dapsone and clofazimine for 
12 months.  
 paucibacillary leprosy (5 or less lesions)  rifampicin and dapsone for 6 months. 
Filariasis  
 Manifestations of filariasis  
 Remember 3 L's:  
 Lymphatic filariasis (caused by Wuchereria bancrofti and Brugia malayi)  
 Loiasis (caused by Loa loa)   
 Light (light, sight, blindness - river blindness caused by Onchocerca

volvulus) 
 Tropical eosinophilia:  
 Tropical eosinophilia is an allergic reaction to microfilaria of Wuchereria 
bancrofti.  
 Characteristic features include:  
 myalgia; fatigue;  
 weight loss;  
 cough and dyspnoea with wheeze;  
 fever;  
 current or previous residence in an area endemic for filariasis 
(southern Asia, Africa, India, South America);  
 lymphadenopathy;  
 marked peripheral blood eosinophilia  
 high titres of anti -filarial antibodies.

 high titres of anti -filarial antibodies. 
 The chest x ray shows bilateral reticulonodular shadowing.  
 This condition is commonly accompanied by false positive serological tests 
for syphilis and high titres of cold agglutinins.  
 There is typically a rapid response to treatment with diethylcarbamazi ne. 
 finger prick test  
 identifying microfilariae on Giemsa stained, thin and thick blood film smears, 
 "Filariasis fills the blood at night."

 "Filariasis fills the blood at night."  
 To remember that Microfilaria can be demonstrated in peripheral smear only at 
night.  
 W. bancrofti , whose vector is a mosquito; night is the preferred time for blood 
collection. 
 Loa loa's  vector is the deer fly; daytime collection is preferred.  
 Which immune mechanisms does the body employ against the live filarial worms ?  
 Antibody-dependent cell-mediated cytotoxicity  

Loiasis  
 Loiasis is a filarial infection caused by Loa Loa.  
 It is transmitted by the Chrysops  deerfly and tends to occur in rainforest regions of 
Western and Central Africa.  
 It has less pathological features than other the microfilarial infections Onchocerciasis and 
Lymphatic Filariasis.  
 pruritus 1292

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   56 
  urticaria 
 Calabar  swellings: transient, non-erythematous, hot swelling of soft-tissue around joints 
 'eye worm' - the dramatic presentation of subconjuctival migration of the adult worm. 
 
Treatment 
 Ivermectin is currently the drug of choice for control of both Onchocerciasi s and 
Lymphatic Filariasis in Africa.

Lymphatic Filariasis in Africa. 
 high loa loa microfilaraemia is associated with encephalopathy following treatment 
with either Ivermectin  or DEC. This occurs due to the death of vast numbers of blood 
microfilaria. Both of these drugs are contraindicated if loa loa microfilaraemia exceeds 
2500 mf/ml.  
 
Adult Loa loa parasite. Loa loa is the filarial nematode (roundworm) species th at causes loa loa

filariasis. It is commonly known as the 'eye worm.' Its geographic distribution includes Afri ca and India. 
Credit: NIAID 
Lyme disease 
 Lyme disease is caused by the spirochaete Borrelia burgdorferi  and is spread by ticks  
of the  genus Ixodes  
 Ixodes ricinus  is predominantly responsible for its transmission in Europe. 
 Ixodes pacificus  and Ixodes scapularis  are the ticks responsible for transmission of 
in the USA.

in the USA.  
Features  
Early features  
 erythema chronicum migrans  (small papule often at site of the tick bite which develops 
into a larger annular lesion with central clearing, 'bulls -eye'. Occurs in 70% of patients) 
 Erythema migrans is often the presenting sign of Lyme disease 
 systemic symptoms: malaise, fever, arthralgia 
Later features  
 CVS: heart block, myocarditis 
 neurological: cranial nerve palsies, meningitis 
 polyarthritis 

 serology: antibodies to Borrelia burgdorferi  (ELISA test for antibodies to Borrelia 
burgdorferi ) 
 Serological tests are the most appropriate first line investigation for diagnosing 
Lyme disease.  
 ELISA tests are preferred to Western blots as they are more sensitive.  
1293

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   57 
  
 doxycycline if early disease. Amoxicillin is an alternative if doxycycline is contraindicated 
(e.g. pregnancy) 
 ceftriaxone if disseminated disease 
 Jarisch-Herxheimer reaction is sometimes seen after initiating therapy: fever, rash, 
tachycardia after first dose of antibiotic (more commonly seen in syphilis, another

spirochaetal disease) 
 
September 2013 exam : H/O returning from a camping holiday in the New Forest. C/O 
lethargy, arthralgia, rash consistent with erythema chronicum migrans. What is the 
most appropriate test to perform given the likely diagnosis? ELISA test for 
antibodies to Borrelia burgdorferi  
Lymphadenopathy 
There are many causes of generalised lymphadenopathy 
 
Infective  
 infectious mononucleosis

Infective  
 infectious mononucleosis  
 HIV, including seroconversion illness  
 eczema with secondary infection 
 rubella 
 toxoplasmosis 
 CMV  
 tuberculosis  
 roseola infantum 
Neoplastic 
 leukaemia 
 lymphoma 
 
Others  
 autoimmune conditions: SLE, rheumatoid arthritis 
 graft versus host disease 
 drugs: phenytoin and to a lesser extent allopurinol, isoniazid 
 
1294

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   58 
Malaria  
Malaria: Falciparum
 
 P. falciparum  typically presents within the first three months  of return from an endemic 
area. 
 
 In the slide shown, the blood film shows 
ring forms within erythrocytes; some 
erythrocytes contain two to

erythrocytes contain two to 
three  parasites per cell - typical of 
falciparum ; other forms of malaria 
seldom have more than one parasite per 
red cell. 
 
Feature of severe malaria  
 schizonts on a blood film 
 parasitaemia > 2% 
 acidosis  
 temperature > 39 C 
 severe anaemia 
 complications as below 
 cerebral malaria: seizures, coma 
 acute renal failure: blackwater fever, secondary to intravascular haemolysis, 
mechanism unknown

mechanism unknown 
 acute respiratory distress syndrome (ARDS)  (Respiratory rate 30 per minute ) 
 disseminated intravascular coagulation (DIC) 
Uncomplicated falciparum malaria 
 strains resistant to chloroquine are prevalent in certain areas of Asia and Africa 
 the 2010 WHO guidelines recommend artemisinin-based combination therapies (ACTs) 
as first-line therapy 
 examples include artemether plus lumefantrine, artesunate plus amodiaquine, artesunate

plus mefloquine, artesunate plus sulfadoxine-pyrimethamine, dihydroartemisinin plus 
piperaquine 
Severe falciparum malaria 
 a parasite counts of more than 2% will usually need parenteral treatment irrespective of 
clinical state 
 Hyperparasitemia , where more than 5% of the red blood cells are infected by malaria 
parasites 
 In 2010, WHO defined hyperparasitemia as >2%/100 000/µL in low intensity 
transmission areas or >5% or 250  000/µL in areas of high stable malaria

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   59 
  intravenous artesunate is now recommended by WHO in preference to intravenous 
quinine  
 I.V quinine is reserved for severe or cerebral malaria (most deaths from  M. 
falciparum  occur in first 96 hours of starting treatment). 
 The initial dose should NOT be reduced in those severely ill with renal/hepatic 
impairment.

impairment.  
 High doses of quinine in pregnancy are teratogenic in the first trimester. However 
in malaria, the benefit of treatment outweighs the risk.   
 WHO Guidelines (2006)  recommend artemisinins are first line in the second and 
third trimester. In the first trimester, both artesunate and quinine are considered 
treatment options.  
 Hypoglycaemia is an important side effect of quinine 
 Quinine  Ĺ insulin secretion and the sensitivity of cells to insulin  
hypoglycaemia

 Malaria itself can cause hypoglycaemia too, so blood glucose should be 
monitored every 2 h. 
 if parasite count > 10% then exchange transfusion should be considered  
 shock may indicate coexistent bacterial septicaemia - malaria rarely causes 
haemodynamic collapse 
Malaria: n on-falciparum 
 
 The most common cause of non-falciparum malaria is Plasmodium vivax , with 
Plasmodium ovale  and Plasmodium malariae  accounting for the other cases.

 Plasmodium vivax  is often found in Central America and the Indian Subcontinent 
whilst Plasmodium ovale  typically comes from Africa 
 The Duffy antigen on RBCs  acts as a receptor for P. vivax .  facilitate the entry of 
P. vivax in to RBCs. 
 Duffy negative individuals are therefore resistant to this strain 
 West Africans lack the Duffy blood group and therefore P. ovale  replaces P. 
vivax  in this region.

vivax  in this region. 
 Both P. vivax  and P. ovale  have a liver hypnozoite stage which can cause repeated 
relapses. 
 May present six months  after return from an endemic area  
Features 
 fever,  
 Plasmodium vivax/ovale : cyclical fever every 48 hours.  
 Plasmodium malariae : cyclical fever every 72 hours 
 headache,  
 Plasmodium malariae : is associated with nephrotic syndrome  
 Plasmodium ovale ,

 Plasmodium ovale , 
 all stages of the parasite and not just trophozoites and gametocytes are 
visible in the peripheral blood. 
 In P. falciparum malaria, only trophozoite-ring forms and gametocytes are usually seen. 
 
Treatment 
 non-falciparum malarias are almost always chloroquine sensitive 
 patients with ovale or vivax malaria should be given primaquine following acute treatment 
with chloroquine to destroy liver hypnozoites and prevent relapse.

 all individuals should be screened for glucose -6-phosphate dehydrogenase (G6PD) 
deficiency, as primaquine may cause haemolysis in those without  the enzyme. 
 
1296

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   60 
  
fast-acting intermediate-acting  slow -acting 
high-efficacy blood 
schizonticides that may be 
effective as monotherapy  low-efficacy schizonticides 
that normally need to be 
administered in combination.  
Artemesinin  
Mepacrine Quinine  
Mefloquine Pyrimethamine 
Doxycycline is also a very 
slow-acting antimalarial.

slow-acting antimalarial. 
Pyrimethamine 
 used in the treatment of uncomplicated malaria, particularly for chloroquine -resistant P. 
falciparum .  
 It acts on both the erythrocytic and hepatic phases of infec tion. 
 It inhibits dihydrofolate reductase in the parasite thus preventing the biosynthesis of 
purines and pyrimidines, and thereby halting the processes of DNA replication, cell 
division and reproduction.  
 It is normally used alongside a sulfonamide.  
 
Malaria: prophylaxis

Malaria: prophylaxis 
 There are around 1,500-2,000 cases each year of malaria in patients returning from 
endemic countries.  
 The majority of these cases (around 75%) are caused by the potentially 
fatal  Plasmodium falciparum  protozoa.   
 The majority of patients who develop malaria did not take prophylaxis. 
  It should also be remembered that UK citizens who originate from malaria endemic areas 
quickly lose their innate immunity. 
 
Drug  Side -effects + notes Time to

Drug  Side -effects + notes Time to 
begin before 
travel Time to end after 
travel 
Atovaquone + 
proguanil 
(Malarone) GI upset  1 - 2 days 7 days 
Chloroquine Headache 
 
Contraindicated in epilepsy 
Taken weekly 1 week 4 weeks 
Doxycycline Photosensitivity 
Oesophagitis 1 - 2 days 4 weeks 
Mefloquine 
(Lariam) Dizziness  
disturbance 
 
Taken weekly 2 - 3 weeks 4 weeks 
Proguanil 
(Paludrine)  1 week 4 weeks 
Proguanil +

Proguanil + 
chloroquine See above 1 week 4 weeks 1297

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   61 
  In certain parts of South -East Asia there is widespread chloroquine resistance. 
Chemoprophylaxis using atovaquone + proguanil (Malarone), mefloquine (Lariam) 
or doxycycline is therefore recommended. 
 Pregnant women should be advised to avoid travelling to regions where malaria is

endemic. Diagnosis can also be difficult as parasites may not be detectable in the blood 
film due to placental sequestration. Howeve r, if travel cannot be avoided:  
 chloroquine can be taken 
 proguanil: folate supplementation (5mg od) should be given 
 Malarone (atovaquone + proguanil): the BNF advises to avoid these drugs unless 
essential. If taken then folate supplementation should be given 
 mefloquine: caution advised 
 doxycycline is contraindicated

 doxycycline is contraindicated 
 It is again advisable to avoid travel  to malaria endemic regions with children if avoidable. 
However, if travel is essential then children should take malarial prophylaxis as they are 
more at risk of serious complications. 
 diethyltoluamide (DEET) 20-50% can be used in children over 2 months of age 
 doxycycline is only licensed in the UK for children over the age of 12 years

May 2013 exam: H/O vivax malaria treated initially with chloroquine then later given 
primaquine. What is the benefit of the primaquine? Destroy liver hypnozoites and 
prevent relapse  
 
May 2014 exam: A 25-year-old man with a history of epilepsy presents for advice 
regarding malarial prophylaxis. Next month he plans to travel to Vietnam. What is the 
most appropriate medication to prevent him developing malaria? Atovaquone + 
proguanil

proguanil  
Measles 
Overview 
 RNA paramyxovirus 
 spread by droplets 
 infective from prodrome until 4 days after rash starts 
 incubation period = 10 -14 days 
Features 
 prodrome: irritable, conjunctivitis, fever 
 Patients present with the three C's: cough, coryza, and conjunctivitis.  
  Rash usually develops on the head and torso, typically sparing the wrists and 
hands.

hands.   
 Koplik spots (before rash): white spots ('grain of salt') on buccal mucosa  
 Koplik's spots are small, irregular, bright red spots with blue-white centres, 
occurring on the inside of the cheek next to the premolars.Seen only in measles, 
they are diagnostic. 
 The spots usually occur briefly after the fever begins and a couple of days before 
the generalised rash appears.  
 Not infrequently, the spots disappear as the eruption develops.

 rash: starts behind ears then to whole body, discrete maculopapular rash becoming 
blotchy & confluent 
 1298

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   62 
  
Koplik spots  
 
 encephalitis: typically occurs 1-2 weeks following the onset of the illness) 
 subacute sclerosing panencephalitis: very rare, may present 5-10 years following the 
illness  
 febrile convulsions  
 giant cell pneumonia  
 keratoconjunctivitis, corneal ulceration 
 diarrhoea

 increased incidence of appendicitis 
 
The rash typically starts behind the ears and then spreads to the whole body 
 
Management of contacts 
 if a child not immunized against measles comes into contact with measles then MMR 
should be offered (vaccine-induced measles antibody develops more rapidly than that 
following natural infection) 
 this should be given within 72 hours  
Rubella

Rubella  
 also known as german measles. 
 RNA  virus , part of the togavirus family 
 rubella  has positive single -stranded RNA . 
 rubeola  virus (measles)  contains negative  single-stranded RNA    
 affects  unimmunized children and presents with a rash that begins at the head and 
moves down with postauricular lymphadenopathy. 
1299

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   63 
  A positive rubella haemagglutination inhibition (HAI) combined with a negative 
rubella IgM  is consistent with:  
1. Early acute infection with rubella 
 The IgM may take several days to rise and the test should be repeated 
one to two weeks later.  
2. Previous vaccination, or 
3. Previous rubella infection.

3. Previous rubella infection. 
Meningitis 
Causes  
The most common cause of bacterial meningitis is Streptococcus pneumoniae (Gram 
positive diplococci), accounting for >50% cases. 
 Listeria is a less common Gram positive cause of meningitis.   
 
0 - 3 months 
 3 months - 6 
years 
 6 years - 60 
years 
 > 60 years 
 Immunosuppressed 
 
Group 
B Streptococcus  (most 
common cause in 
neonates) 
 Neisseria 
meningitides

neonates) 
 Neisseria 
meningitides  
 
 Neisseria 
 
 Streptococcus 
pneumoniae  
 
 Listeria 
monocytogenes  
 
E. coli  
 
pneumoniae  Streptococcus 
 Neisseria 
meningitides   
Listeria 
monocytogenes  Haemophilus 
influenzae   Listeria 
 
Coxsackie  virus is the most common viral cause of meningitis.  
 
Pneumococcal meningitis 
 caused by the Gram positive coccus Strep. pneumoniae .

 the second commonest cause of bacterial meningitis (commonest in the elderly)  
 associated with the highest mortality (20%) and highest morbidity, such as deafness 
which may occur in 50% (Nerve deafness is a common complication)  
 Chronic  adhesive arachnoiditis is a complication of pneumococcal meningitis 
characterized by fibrosis of the arachnoid granulations. 
 Contacts do not require treatment 
 there is no rash associated with pneumococcal meningitis.

In the context of  septic menin gitis, the petechial rash is diagnostic for infection 
with Neisseria meningitidis  
 
Listeria meningitis  
 Risk factors for listeria meningitis include 
  neonates   
 Older age  
 immunosuppression. 
 It is typically associated with brain stem signs. 
 Beta -hemolysis  is the type of hemolysis exhibited by  Listeria monocytogenes , 
an organism showing tumbling motility that causes meningitis in newborns.  1300

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   64 
  Cerebrospinal fluid shows: 
 Neutrophilic pleocytosis 
 Low glucose, and 
 High protein. 
Fungal meningitis 
 Patients at risk for fungal  meningitis  include: 
 those who are significantly immunocompromised,  
 those who have received intrathecal injections in the past.  
 Cerebrospinal fluid analysis

 Cerebrospinal fluid analysis 
 elevated opening pressure 
  detectable b-D-glucan  
 Testing for  b-D-glucan  has been an approved blood test to detect systemic fungal 
 
Partially treated bacterial meningitis 
Partial treatment of bacterial meningitis can result in false negative CSF culture  and Gram 
stain , but the CSF white cell count should be unaffected.  
 
 The assessment of children with suspected bacterial meningitis who have already

received antibiotic therapy from their GP is a common diagnostic problem. 
 Partial treatment may reduce the incidence of positive CSF Gram stains to less than 
60%, and it also reduces the ability to grow the bacteria, particularly meningococcus. 
 Partial treatment may induce:  
 negative CSF culture  
 negative Gram stain 
 CSF glucose, protein, neutrophils and bacterial antigen testing or polymerase chain 
reaction (PCR) should be completely unaffected.

reaction (PCR) should be completely unaffected.  
 A normal white cell count would make the diagnosis very unlikely. 
 In normal CSF the glucose is usually > 65% of blood glucose.  
 
Meningitis: Investigations 
 Investigations suggested by NICE 
 full blood count  
 CRP  
 coagulation screen 
 blood culture 
 whole-blood PCR 
 blood glucose 
 blood gas 
 Lumbar puncture if no signs of raised intracranial pressure 
 
Meningitis: CSF analysis  
 
1301

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   65 
  
The table below summarises the characteristic cerebrospinal fluid (CSF) findings in meningitis: 
 Bacterial Viral  Tuberculous  
Appearance  Cloudy Clear/cloudy  Slight cloudy, fibrin web  
Glucose  Low (< 1/2 plasma) 60-80% of plasma glucose* Low (< 1/2 plasma) 
Protein  High (> 1 g/l) Normal/raised  High (> 1 g/l)

White cells  10 - 5,000 
polymorphs/mm³ 15 - 1,000 lymphocytes/mm³ 10 - 1,000 
lymphocytes/mm³ 
*mumps is unusual in being associated with a low glucose level in a proportion of cases. A low glucose 
may also be seen in herpes encephalitis 
 
 The Ziehl-Neelsen stain is only 20% sensitive in the detection of tuberculous meningitis 
and therefore PCR is sometimes used (sensitivity = 75%) 
 Bacterial culture of cerebrospinal fluid  is the gold-standard  test for determining if a

case of meningitis  is bacterial in etiology.  
 
The CSF lymphocytosis combined with a glucose greater than half the serum level points 
towards a viral meningitis.  
 
In patients presenting with  symptoms and signs of meningitis, treat empirically for 
bacterial meningitis while awaiting test results from the lumbar puncture. 
 All patients should be transferred to hospital urgently.  
 If patients are in a pre -hospital setting (for example a GP surgery) and meningococcal

disease is suspected then intramuscular benzylpenicillin may be given, as long as th is 
doesn't delay transit to hospital. 
 In bacterial meningitis, dexamethasone should also be given with the first dose of 
antibiotics .  
BNF recommendations on antibiotics  
Scenario BNF recommendation 
Initial empirical therapy aged < 3 months  Intravenous cefotaxime + amoxicillin 
Initial empirical therapy aged 3 months - 50 
years Intravenous cefotaxime

years Intravenous cefotaxime 
Initial empirical therapy aged > 50 years  Intravenous cefotaxime + amoxicillin 
Meningococcal meningitis Intravenous benzylpenicillin or cefotaxime 
Pneuomococcal meningitis Intravenous cefotaxime 
Meningitis caused by Haemophilus 
influenzae  Intravenous cefotaxime 
Meningitis caused by Listeria Intravenous amoxicillin + gentamicin 
 
 If the patient has a history of immediate hypersensitivity reaction to  penicillin or to

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   66 
  Ceftriaxone does not cover  Listeria well, and in the over 60s or 
immunosuppressed, amoxicillin should be added in to empirical meningitis 
management to cover this. 
 
Management of contacts  
 prophylaxis needs to be offered to household and close contacts of patients affected with 
meningococcal meningitis

meningococcal meningitis 
 oral ciprofloxacin or rifampicin may be used.  
 The BNF recommends a twice a day dose of rifampicin for two days, based on the 
patien ts weight. 
 The Health Protection Agency (HPA) guidelines now state that whilst either may be 
used  ciprofloxacin is the drug of choice as it is widely available and only 
requires one dose  
 Rifampicin may reduce the efficacy of the oral contraceptive through liver

enzyme induction. So not preferred in sexually active. Therefore 
ciprofloxacin would be the most appropriate agent as it does not induce 
cytochrome p450. 
 the risk is highest in the first 7 days but persists for at least 4 weeks 
 meningococcal vaccination should be offered to close contacts when serotype results are 
available, including booster doses to those who had the vaccine in infancy  
 for pneumococcal meningitis  no prophylaxis is generally needed.  There are

however exceptions to this. If a cluster of cases of pneumococcal meninigitis occur the 
HPA have a protocol for offering close contacts antibiotic prophylaxis.  
September 2010 exam.  A 57-year-old female presents with headache, fever, neck 
stiffness with a positive Kernig's sign. CSF culture: Gram positive bacilli . What is the 
most likely causative organism? Listeria monocytogenes  
 
January 2013 exam : A 47-year-old lady with Feature of fever, headache and nuchal

rigidity. Lumbar puncture reveals:  Appearance: Cloudy. Glucose:1.7 mmol/l. 
Protein:1.9 g/l. White cells: 900 / mm³ (90% polymorphs). What is the most likely 
infective agent? Streptococcus pneumoniae (CSF results  bacterial meningitis (low 
glucose, high protein, high polymorphs). In this age group Streptococcus pneumoniae and 
Neisseria meningitidis  are the most common causes of bacterial meningitis)  
 
May 2014 exam: A diagnosis of pneumococcal meningitis is made. There are no

other reports of meningitis in the local ar ea over the past 4 weeks. How should the 
close contacts of this boy be managed? No action is needed  (unless cluster of cases 
develop) 
 
May 2009 exam: A 23-year-old man is admitted with purpuric rash, pyrexia and 
confusion. His GP had given him intramuscular benzylpenicillin. Which one of the 
following investigations is most likely to reveal the diagnosis?  Blood PCR for 
meningococcus

meningococcus   
(The blood cultures are likely to be negative as antibiotics have already been given. 
PCR has a sensitivity of over 90%)  
 
 1303

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   67 
 
Encephalitis usually presents with altered mental status, erratic behavior, etc (brain 
parenchyma involved). 
Etiology.  
 The most common cause is herpes simplex, usually type I (HSV-1). 
Clinical Presentation.

Clinical Presentation.  
 Altered mental status with fever and headache is the  primary clue to the diagnosis.  
 Neck stiffness similar to that found in meningitis can occur, making it difficult to 
distinguish encephalitis from meningitis.  
 Seizures may also occur. 
Diagnosis.  
 Although CT or MRI scan of the head should be performed, it cannot give a specific 
diagnosis. HSV has a predilection for involvement of the temporal lobes, which can 
sometimes be seen on CT.

sometimes be seen on CT.  
 A lumbar puncture is the key to the diagnosis.  
 PCR (polymerase chain reaction) for HSV has a 98% sensitivity and >95% specificity, 
making it at least equal to the biopsy. 
Treatment.  
 HSV encephalitis is best treated with IV acyclovir.  
 Acyclovir-resistant herpes is treated with foscarnet 
Meningococcal septicaemia 
 It is associated with a high morbidity and mortality unless treated early

 meningococcal disease is the leading infectious cause of death in early childhood.  
 A high index of  suspicion is therefore needed. 
 
Presentation of meningococcal disease: 
 15% - meningitis 
 25% - septicaemia 
 60% - a combination of meningitis and septicaemia 
 blood cultures 
 blood PCR 
 lumbar puncture is usually contraindicated 
 full blood count and clotting to assess for disseminated intravascular coagulation  
management

 the most important initial step  administration of intravenous antibiotics 
(cefotaxime) is the greatest priority, regardless of whether cultures have been sent. 
 
1304

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   68 
Sepsis  (Nice guidelines 2016) 
 Sepsis is a life -threatening organ dysfunction due to a dysregulated host response to 
 Sepsis with shock is a life-threatening condition that is characterised by low blood

pressure despite adequate fluid replacement, and organ dysfunction or failure.  
 The new definition attempts to draw upon up- to-date pathobiology and distinguish 
between sepsis and uncomplicated infection. A new tool has been developed for this 
purpose - the SOFA or qSOFA. 
 The qSOFA (Quick SOFA) criteria are: 
 Respiratory rate > or equal to 22/min  
 Altered GCS  
 Systolic blood pressure < or equal to 100mmHg

 Systolic blood pressure < or equal to 100mmHg  
 Septic shock is defined as "a subset of sepsis in which underlying circulatory and cellular 
metabolism abnormalities are profound enough to substantially increase mortality. This 
changes from the previous definition to recognise the importance of cellular 
 Septic shock is defined by persisting hypotension requiring vasopressors to maintain a

mean arterial pressure of 65 mm Hg or higher and a serum lactate level greater than 2 
mmol/L (18 mg/dL) despite adequate volume resuscitation. 
 
Risk factors for sepsis 
 Age (< 1 year and > 75 years) 
 very frail people  
 Immunocompromised  
 impaired immune function (eg, DM, splenectomy, sickle cell disease)  
 drugs( long-term steroids, chemotherapy, immunosuppressant) 
 surgery, or other invasive procedures, in the past 6 weeks

 any breach of skin integrity (eg, cuts, burns, blisters or skin infections)  
 misuse drugs intravenously 
 indwelling lines or catheters 
 
 1305

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   69 
  
Risk stratification tool for adults, children and young people aged 12  years and over with 
suspected sepsis 
High risk criteria  Moderate to high risk criteria 
Objective evidence of new altered mental 
state  History from patient or relative of new 
onset of altered behaviour or mental 
state

state 
 History of acute deterioration of 
functional ability  
 Impaired immune system (illness or 
drugs including oral steroids) 
 Trauma, surgery or invasive 
procedures in the last 6 weeks 
 respiratory rate: ≥ 25 breaths per 
minute  
 New need for oxygen (more than 40% 
FiO 2) to maintain saturation more than 
92% (or more than 88% in known 
chronic obstructive pulmonary disease) Raised respiratory rate: 21 –24 breaths per 
minute

minute 
Systolic blood pressure ≤ 90 mmHg 
or more than 40 mmHg below normal Systolic blood pressure 91 –100 mmHg 
heart rate: > 130 beats per minute heart rate: 91 –130 beats per minute (for 
pregnant women 100 –130 beats per minute) 
or new onset arrhythmia 
Not passed urine in previous 18 hours. 
For catheterised patients, passed less than 
0.5 ml/kg of urine per hour Not passed urine in the past 12 –18 hours 
For catheterised patients, passed 0.5 –1 ml/kg 
of urine per hour

of urine per hour 
- Tympanic temperature less than 36°C 
 Mottled or ashen appearance 
 Cyanosis of skin, lips or tongue 
 Non-blanching rash of skin Signs of potential infection, including redness, 
swelling or discharge at surgical site or 
breakdown of wound. 
Low risk criteria : 
 Normal behavior 
 No high risk or moderate to high risk criteria met 
Temperature in suspected sepsis 
 Do not rely on fever or hypothermia to rule sepsis either in or out.

  Some people with sepsis may not develop a raised temperature: 
 older or very frail 
  severely ill  
 people having treatment for cancer 
 young infants or children. 
 a rise in temperature can be a physiological response (eg: after surgery or trauma). 
 
Heart rate in suspected sepsis 
 baseline heart rate may be lower in young people and adults who are fit 
 baseline heart rate in pregnancy is 10 –15 beats per minute more than normal

 older people with an infection may not develop an increased heart rate 
 older people may develop a new arrhythmia in response to infection rather than an 
increased heart rate 
 may be affected by medicines such as beta-blockers. 
 
1 or more high risk criteria: 
 blood test  for blood gas including glucose and lactate measurement, blood culture, full 
blood count, C-reactive protein, urea and electrolytes, creatinine, clotting screen.

 Sepsis may be complicated by disseminated intravascular coagulation 1306

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   70 
  give a broad -spectrum antimicrobial at the maximum recommended dose without delay 
(within 1 hour) 
any high risk criteria and lactate > 4 mmol/litre, or systolic BP < 90 mmHg: 
 I.V fluid bolus without delay (within 1  hour) 
 refer to critical care for review of management including need for central venous access ,

inotropes or vasopressors.   
any high risk criteria and lactate between 2 and 4 mmol/litre: 
any high risk criteria and lactate < 2 mmol/litre: 
 consider I.V fluid bolus 
failure  to respond within 1 hour of initial antibiotic and/or intravenous fluid resuscitation  
 Failure to respond is indicated by any of:  
 systolic blood pressure persistently below 90 mmHg 
 reduced level of consciousness despite resuscitation

 respiratory rate over 25 breaths per minute or a new need for mechanical 
 lactate not reduced by more than 20% of initial value within 1 hour.  
2 or more moderate to high risk criteria  
 blood test for blood gas including glucose and lactate measurement, blood culture, full 
blood count, C-reactive protein, urea and electrolytes, creatinine 
 review the person's condition and venous lactate results within 1 hour

2 or more moderate to high risk criteria and lactate > 2  mmol/litre or evidence of acute 
kidney injury 
 treat as high risk  
2 or more moderate to high risk criteria, have lactate < 2  mmol/litre, no evidence of acute 
kidney injury and in whom a definitive condition cannot be identified: 
 repeat structured assessment at least hourly 
 review by a senior within 3 hours for consideration of antibiotics.

2 or more moderate to high risk criteria, have lactate < 2 mmol/litre, no evidence of acute 
kidney injury and in whom a definitive condition or infection can be identified and 
treated: 
 manage the definitive condition 
 if appropriate, discharge  
Intravenous fluids in people with suspected sepsis 
 If patients over 16  years need intravenous fluid resuscitation, use crystalloids that contain 
sodium in the range 130 –154 mmol/litre with a bolus of 500 ml over less than 
15 minutes.

15 minutes.   
 
management  
 The Surviving Sepsis Campaign (a partnership of the Society of Critical Care Medicine, the 
European Society of Intensive Care Medicine, and the International Sepsis Forum) has 
teamed up with the Institute for Healthcare Improvement to develop severe sepsis bundles. 
A 'bundle' is a group of interventions related to a disease process that, when executed 
together, result in better outcomes than when implemented individually. 
Sepsis Resuscitation Bundle:

Sepsis Resuscitation Bundle:  
 Should begin immediately, but must be accomplished within the first six hours of 
1. Serum lactate measured. 
2. Blood cultures obtained prior to antibiotic administration.  
3. From the time of presentation, broad -spectrum antibiotics administered within three 
hours for ED admissions and one hour for non-ED ICU admissions. 
4. In the event of hypotension and/or lactate > 4 mmol/l (36 mg/dl):

 Deliver an initial minimum of 30 ml/kg of crystalloid (or colloid equivalent). 1307

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   71 
  Apply vasopressors for hypotension not responding to initial fluid resuscitation 
to maintain mean arterial pressure (MAP) > 65 mm Hg.  
5. In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or 
lactate > 4 mmol/l (36 mg/dl):  
 Achieve central venous pressure (CVP) of > 8 mm H g.

 Achieve central venous oxygen saturation (ScvO2) of > 70%. 
Sepsis Management Bundle:  
To be accomplished as soon as possible may be completed within twenty-four hours of 
1. Steroids administered for septic shock  in accordance with a standardis ed ICU policy. 
ACTH stimulation test not required prior to this. 
2. Glucose control maintained > lower limit of normal, but < 150 mg/dl (8.3 mmol/l).

3. Inspiratory plateau pressures maintained < 30 cm H2O for mechanically ventilated 
patients.  
 
H/O sepsis secondary to pneumonia. treated with 4.5 L sodium chloride 0.9%. blood pressure 
was 82/40 mmHg.  In attempting to restore the blood pressure, what is the most appropriate 
intravenous therapy? 
 noradrenaline (norepinephrine)  
Ref: www.mrcpuk.org/ Acute Medicine Specialty Certificate Examination/ sample questions 
Nematodes

Nematodes 
 most common cause of cutaneous larva migrans  Ancylostoma braziliense 
 commonest cause of visceral larva migrans  Toxocara canis  
Ancylostoma braziliense 
 most common cause of cutaneous  larva migrans 
 common in Central and Southern America 
 The infection is acquired by direct contact with dog or cat faeces - often acquired when 
sunbathing on contaminated sand, etc. The larvae burrow in the dermo-epidermal 
junction.

junction.  
 Symptoms  include pruritus and a raised, serpiginous erythematous rash that migrates at 
a rate of up to 1 cm/day. 
 Treatment  i 
 The disease is self-limiting but the duration of disease varies considerably 
  Oral ivermectin  in a single dose of 200 µg/kg body weight is the main treatment.  
 Other treatment options include oral albendazole or topical thiabendazole. 
Strongyloides stercoralis 
 acquired percutaneously (e.g. walking barefoot)

 causes pruritus and larva currens - this has a similar appearance to cutaneous larva 
migrans but moves through the skin at a far greater rate 
 abdo  pain, diarrhoea, pneumonitis 
 may cause Gram negative septicaemia due carrying of bacteria into bloodstream 
 eosinophilia sometimes seen 
 management: thiabendazole, albendazole. Ivermectin also used, particularly in chronic 
Toxocara canis 
 commonly acquired by ingesting eggs from soil contaminated by dog faeces

 commonest cause of  visceral larva migrans 
 other features: eye granulomas, liver/lung involvement 1308

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   72 
  
cutaneous  larva migrans   
cutaneous larva migrans  
 
Orf 
Orf is generally a condition found in sheep and goats although it can be transmitted to humans. 
It is caused by the parapox virus.  
 
In animals  
 'scabby' lesions around the mouth and nose 
In humans

In humans 
 generally affects the hands and arms 
 initially small, raised, red -blue papules 
 later may increase in size to 2 -3 cm and become flat-topped and haemorrhagic 
 
Pelvic inflammatory disease 
Pelvic inflammatory disease (PID) is a term used to describe infection and inflammation of the 
female pelvic organs including the uterus, fallopian tubes, ovaries and the surrounding

peritoneum. It is usually the result of ascending infection from the endocervix 
 
Causative organisms  
 
 Chlamydia trachomatis  - the most common cause 
 Neisseria gonorrhoeae  
 Mycoplasma genitalium  
 Mycoplasma hominis  
 
Features 
 
 lower abdominal pain 
 fever 
 deep dyspareunia 
 dysuria and menstrual irregularities may occur 
 vaginal or cervical discharge 
 cervical excitation 
 
 screen for Chlamydia and Gonorrhoea 
 
 due to the difficulty in making an accurate diagnosis, and the potential complications of 
untreated PID, consensus guidelines recommend having a low threshold for treatment 
1309

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   73 
  Consensus guidelines recommend treatment once a diagnosis of pelvic inflammatory 
disease is suspected, rather than waiting for the results of swabs 
 oral ofloxacin + oral metronidazole  or intramuscular ceftriaxone + oral doxycycline + 
oral metronidazole

oral metronidazole 
 RCOG guidelines suggest that in mild cases of PID intrauterine contraceptive devices 
may be left in. The more recent BASHH guidelines suggest that the evidence is limited 
but that  ' Removal of the IUD should be considered and may be associated with better 
short term clinical outcomes'  
 
 infertility - the risk may be as high as 10-20% after a single episode 
 chronic pelvic pain 
 ectopic pregnancy  
 Fitz-Hugh -Curtis syndrome

 Fitz-Hugh -Curtis syndrome   
 is a rare complication of pelvic inflammatory disease, resulting in liver capsule 
 It is most often caused by untreated sexually transmitted infections 
including  Chlamydia trachomatis  and Neisseria gonorrhoeae .  
 a patient may present with septic shock secondary to the untreated liver capsule 
Psittacosis (ornithosis)

Psittacosis (ornithosis) 
 Chlamydia psittaci is endemic in birds including psittacine birds, canaries, finches, 
pigeons and poultry. 
 Person to person transmission occurs  especially in a hospital environment. 
 Sputum Gram stain reveals a few leucocytes and no predominant bacteria.  
 There are few signs and few laboratory/x ray findings. 
 Positive serology is with complement-fixing antibodies.

 It is treated with tetracycline.  
 The most common organisms found in pyogenic liver abscesses are Staphylococcus 
aureus  in children and Escherichia coli  in adults.   
 
 amoxicillin + ciprofloxacin + metronidazole 
 if penicillin allergic: ciprofloxacin + clindamycin  
January 2008 exam : What is the most appropriate antibiotic therapy to accompany

drainage of liver abscess? Amoxicillin + ciprofloxacin + metronidazole  
Pyrexia of unknown origin 
Defined as a prolonged fever of > 3 weeks which resists diagnosis after a week in hospital 
 
Neoplasia  
 lymphoma 
 hypernephroma 
 preleukaemia 
 atrial myxoma 
Infections  
 abscess  
 TB 
Connective tissue disorders  1310

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   74 
Q fever 
Q fever - Coxiella burnetti  
 
 Q fever is a zoonotic disease caused by Coxiella burnetii  an obligate gram-negative 
intracellular bacterium.   
 The organism is very resistant to drying.  
 does not grow on standard culture media. 
 
Transmission  
 The organism is usually inhaled from infected dust  (animal products) 
 acquired through contact with animals. 
 Cattle, sheep and goats are the primary reservoirs of  C. burnetii . 
 drinking unpasteurised milk from infected cows. 
 It is not notifiable, but can occur in outbreaks in farming communities  and in abattoirs. 
and therefore an occupational history  is very important. 
 
Features :  
 high fevers, chills, sweats

Features :  
 high fevers, chills, sweats  
 severe headache, (typically retrobulbar) 
 general malaise, myalgia,  
 confusion,  
 sore throat, ,  
 non-productive cough,  
 nausea, vomiting, diarrhoea, abdominal pain 
 chest pain. 
 Between 30% and 50% of patients with a symptomatic infection will develop pneumonia. 
 may be complicated by immune complex-mediated glomerulonephritis   
 Chronic infection can manifest as hepatitis, osteomyelitis or endocarditis.

 In Q fever endocarditis : 
 the aortic valve is involved in over 80% of cases.  
 A murmur is not always present, but augmentation of an existing murmur may 
occur.  
 Low-grade fever (or no fever ),  
 signs of heart failure,  
 hepatosplenomegaly,  
 clubbing,  
 arterial emboli,  
 leukocytoclastic vasculitic rash . 
 Confirming a diagnosis of Q fever requires serological testing  to detect the presence of 
C. burnetii.

C. burnetii.  
 phase I antibody titre to  Coxiella burnetti  (IgG and/or IgA) greater than 1:200 is 
virtually diagnostic of Q fever. 
 chest X-ray might show multilobar consolidation.  
 Anaemia  
 Thrombocytopenia   
 Elevated erythrocyte sedimentation rate  
 Hypergammaglobulinaemia  
 liver function tests  
 the majority of patients have abnormal results on and some will develop hepatitis. 
 Microscopic haematuria may be present. 
 
 Most patients will recover within a few months with no treatment. 1311

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   75 
  Doxycycline  is the treatment of choice for acute Q fever. OR prolonged courses of 
tetracyclines . 
Prognosis  
 Only 1 –2% of people with acute Q fever die of the disease.  
 Chronic Q fever  
 Endocarditis with negative culture  findings and seropositivity  is the main clinical 
presentation of chronic Q fever ,

presentation of chronic Q fever ,  
 usually occurring in patients with preexisting cardiac disease including valve 
defects, rheumatic heart disease, and prosthetic valves.  
Rabies 
 
Rabies is a viral disease that causes an acute encephalitis. The rabies virus is classed as a 
RNA rhabdovirus and has a bullet shaped capsid. It is commonly transmitted by bat, raccoon

and skunk bites. Following a bite the virus travels up the nerve axons towards the central 
nervous system in a retrograde fashion. 
 
Features  
 prodrome: headache, fever, agitation 
 hydrophobia: water-provoking muscle spasms 
 hypersalivation 
 Negri bodies: cytoplasmic inclusion bodies found in infected neurons 
 
There is now considered to be 'no risk' of developing rabies following an animal bite in the UK 
and the majority of developed countries.

and the majority of developed countries.  
 
Following an animal bite in at risk countries:  
 
 if an individual is already immunised then 2 further doses of vaccine should be given  
 if not previously immunised then human rabies immunoglobulin (HRIG) should be given 
along with a full course of vaccination 
 Lyssaviruses such as rabies cannot cross intact skin  and humans are regarded as an 
end-host (outside of transplantation-associated transmission). Therefore , only standard

infection -prevention precautions such as gloves and gowns are required.  
Salmonella   &(Typhoid fever ) 
 
Humans are the main reservoir 
for Salmonella typhi  
 
Bacteriology  
 Gram negative rods   
 grow under both an aerobic  and anaerobic conditions.  
 not normally present as commensals in the gut.  
 5–30 days (most commonly 7 –14 days) 
 Transmission :  
 fecal -oral 
Types

Types 
 Salmonella typhi  causes Typhoid  
 Salmonella paratyphi  (types A, B & C) causes paratyphoid  
 They are often termed enteric fevers. 
1312

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   76 
  Blood and bone infections caused by non-typhi salmonella (NTS) are typically 
associated with malaria and homozygous sickle cell disease , especially in 
children. The reason for this perceived susceptibility is not fully understood - but it 
may be in part due to the haemolysis and subsequent iron availability to the

bacteria, which is 'siderophilic' in nature.  
 Lifecycle 
1. Oral uptake of pathogen   
2. Distal ileum: migration into the P eyer patches  
3. Infection of macrophages and reticuloendothelial system  ĺ nonspecific symptoms  
4. Spread from macrophages to the bloodstream: septicemia ĺ systemic disease   
5. Migrates back to intestine ĺ excretion in feces  
  
Typhoid vaccines  
 typhoid vaccines ar e currently available

 typhoid vaccines ar e currently available  
 (Typhoid vaccine does not protect from paratyphoid infection) 
 There are 3 types of typhoid vaccine:  
1. parenteral (Typh- I),  inactivated vaccine (i.e. killed) 
2. parenteral combined with hepatitis A (HA-Typh-I), and  
3. oral (Typh- O)  Live-attenuated vaccine  
 These vaccines provide approximately 50% protection  against clinical disease. 
 No vaccine is available against paratyphoid fever.

 Vaccinated individuals who develop the disease will have a higher threshold  but the 
same disease.  
Features  
 initially systemic upset (headache, fever, arthralgia) 
 abdominal pain, distension 
 diarrhoeal disease 
 Yellow-green diarrhea, comparable to pea soup (caused by purulent, 
bloody necrosis of the Peyer patches) 
 constipation:  
 although Salmonella  is a recognised cause of diarrhoea, constipation is more 
common in typhoid

common in typhoid  
 obstipation  and ileus (as a result of swollen Peyer patches in the ileum) 
 Rose spots : 
 present on the trunk in 40% of patients,  
 (most commonly around the navel) حول السرة  
 more common in paratyphoid 
 Neurological symptoms (delirium, coma) 
 Rarely causes sepsis, meningitis, myocarditis, and renal failure 
 Chronic Salmonella carrier  
 Definition:  
 positive stool cultures 12 months after overcoming the disease 
 Incidence:

 Incidence:  
 up to 6% of the patients become chronic carriers 
 Presentation:  
 typically asymptomatic  
 Treatment:  
 fluoroquinolones (e.g., ciprofloxacin) administered for at least 1 month 
 Chronic carriers are not allowed to work in the food industry.  
 Increased risk for cholangiocarcinoma (bile duct cancer) 
 normal or low leukocyte count with eosinopenia  
 Blood culture,  
 the most effective investigation for diagnosis  1313

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   77 
   (should be done prior to starting antibiotic) 
 Bone marrow culture 
  highly sensitive diagnostic test even in later stages of infection after antibiotic 
therapy has begun.  
 indicated for all patients with prolonged pyrexia if routine investigations have not 
provided a diagnosis. 
 in chronic carriers

 in chronic carriers  
 Blood cultures  will be negative in chronic carriers because the organism resides 
mainly in the gallbladder.  
 Salmonella typhi can be cultured from intestinal secretions , faeces or urine  
 Widal's test 
 Serological test  
 poor sensitivity  
 negative in early infection. 
 indicated only after 5 to 7 days of fever. 
 not useful for detecting chronic carriage.  
 Faecal culture

 Faecal culture  
 positive in only 50% of cases during the first week of illness. 
 
 osteomyelitis  
 (especially in sickle cell disease where Salmonella  is one of the most common 
pathogens) 
 GI bleed/perforation 
 meningitis 
 cholecystitis 
 chronic carriage (1%) 
 more likely if adult females ) 
Treatment 
 best treated with quinolones, chloramphenicol or cotrimoxazole. 
 However, with breast feeding chloramphenicol is relatively contraindicated as are

quinolones due to potential risk even if small. 
 Also cotrimoxazole  is safe in breast feeding except with infants less than 2 months due to 
possible risk of increased bilirubin. 
 In pregnancy or children the drug of choice is parenteral ceftriaxone. 
 The gallbladder may act as a reservoir of infection and cause relapse in individuals 
treated with antibiotics. Cholecystectomy may be indicated.  
 According to the NICE guidelines, anyone above the age of 50, immunocompromised or

has cardiac valve disease/endovascular abnormalities should be treating empirically with 
ciprofloxacin 500mg BD when they have been diagnosed with non-
typhoidal Salmonella  gastroenteritis.  
Scabies 
 
Scabies  should be suspected in any sexually active young person who presents with 
generalised pruritus  without any specific signs.  
 
Overview 
 Scabies is caused by  the mite Sarcoptes scabiei and is spread by  prolonged skin

contact.  
 It typically affects children and young adults.  
 The scabies mite burrows into the skin, laying its eggs in the stratum corneum.  1314

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   78 
  The intense pruritus associated with scabies is due to a delayed type IV hypersensitivity 
reaction to mites/eggs which occurs about 30 days after the initial infection. 
Features  
 widespread pruritus 
 linear burrows on the side of fingers, interdigital webs and flexor aspects of the wrist

 The tiny erythematous burrows in the web spaces of the fingers are almost 
 in infants the face and scalp may also be affected 
 secondary features are seen due to scratching: excoriation, infection 
 
 Skin  scrapings   demonstrate Sarcoptes scabiei   
 
 first-line is  permethrin 5%  
 second- line is  malathion 0.5%  
 Application should be repeated seven days after initial treatment to kill any mites hatched 
from eggs in that time

from eggs in that time 
 give appropriate guidance on use (see below) 
 pruritus persists for up to 4-6 weeks post eradication 
 
Patient guidance on treatment  (from Clinical Knowledge Summaries) 
 avoid close physical contact with others until treatment is complete  
 all household and close physical contacts should be treated at the same time, even if 
asymptomatic 
 Re-infection most likely means  Other household members were not 
treated

treated  
 launder, iron or tumble dry clothing, bedding, towels, etc., on the first day of treatment to 
kill off mites. 
 
Patients should be given the following instructions:  
 The BNF advises to apply the insecticide to all areas, including the face and scalp, 
contrary to the manufacturer's recommendation.  
 apply the insecticide cream or liquid to cool, dry skin 
 pay close attention to areas between fingers and toes, under nails, armpit area, creases

of the skin such as at the wrist and elbow 
 allow to dry and leave on the skin for 8-12 hours for permethrin,  or for 24 hours for 
malathion , before washing off 
 reapply if insecticide is removed during the treatment period, e.g. If wash hands, change 
nappy, etc 
 repeat treatment 7 days later 
 
Crusted (Norwegian) scabies  
 Crusted scabies  is seen in patients with suppressed immunity, especially HIV .  
 The crusted skin will be teeming with hundreds of thousands of organisms.

 Ivermectin  is the treatment of choice and isolation is essential  
 
1315

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   79 
Schistosomiasis 
Schistosoma haematobium causes haematuria 
Schistosomiasis, or bilharzia, is a parasitic flatworm infection. The following types of 
schistosomiasis are recognised: 
 Schistosoma mansoni and Schistosoma intercalatum: intestinal schistosomiasis

 Schistosoma haematobium: urinary schistosomiasis  
 
Schistosoma haematobium  
This typically presents as a 'swimmer's itch' in patients who have recently returned from Africa. 
Schistosoma haemato bium is a risk factor for squamous cell bladder cancer 
Features  
 frequency 
 bladder calcification 
 single oral dose of praziquantel 
 
 S. mansoni  Eggs can migrate to liver through the portal venous system where they can

elicit a granulomatous fibrosing reaction  venous blockade  Portal venous 
hypertension  varicies and upper GIT bleeding.  
 S. haematobium  leads to granulomatous inflammation, ulceration of the vesicle and 
ureteral walls. Subsequent fibrosis can cause bladder neck obstruction, hydroureter and 
hydronephrosis. These changes can cause a chronic renal impairment and predispose to 
secondary bacterial infection as well as squamous cell carcinoma.

 all schistosome species  can result in immune complex deposition in the kidneys 
leading to a proteinuria and nephrotic syndrome.  
Shigella  
Overview 
 causes bloody diarrhoea, abdo pain 
 severity depends on type: S sonnei (e.g. from UK) may be mild, S flexneri or S 
dysenteriae from abroad may cause severe disease 
 treat with ciprofloxacin   

 Following a splenectomy patients are particularly at risk from pneumococcus, 
Haemophilus, meningococcus and Capnocytophaga canimorsus* infections 
 *usually from dog bites 
 
Vaccination  
 if elective, should be done 2 weeks prior to operation  
 Hib, meningitis A & C 
 pneumococcal vaccine every 5 years 
Antibiotic prophylaxis 
 penicillin V: unfortunately clear guidelines do not exist of how long antibiotic prophylaxis

should be continued. It is generally accepted though that penicillin should be continued 
for at least 2 years and at least until the patient is 16 years of age, although the majority 
of patients are usually put on antibiotic prophylaxis for life  
 
 1316

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   80 
  
January 2011 exam: H/O emergency splenectomy. Following this he takes pen icillin V 
on a daily basis. He is unsure of his vaccination history. Which organism is he 
particularly suscepitble to?  Haemophilus influenza  (Penicillin V would protect him

against  Streptococcus pneumoniae but notHaemophilus influenzae due to the production of 
beta-lactamases by the organism)  
 
September 2009 exam: A 12-year-old boy who had a splenectomy following RTA , he 
had his full immunisation course as a child and was given a repeat pneumococcal 
vaccination 5 days following surgery. What is the most appropriate ongoing 
management?  Booster dose of Hib and MenC vaccine + annual influenza vaccination 
+ lifelong penicillin V

+ lifelong penicillin V  
Strongyloides stercoralis  
Strongyloides  stercoralis  is a human parasitic nematode worm. The larvae are present in soil 
and gain access to the body by penetrating the skin. Infection with Strongyloides 
stercoralis  causes strongyloidiasis. 
 
Features  
 abdominal pain/bloating 
 papulovesicular lesions where the skin has been penetrated by infective larvae e.g. soles 
of feet and buttocks

of feet and buttocks  
 larva currens: pruritic, linear, urticarial rash 
 if the larvae migrate to the lungs a pneumonitis similar to Loeffler's syndrome may be 
triggered  
Treatment 
 ivermectin and albendazole are used 
STI: ulcers 
 
Genital herpes   
 most often caused by the herpes simplex virus (HSV) type 2 (cold sores are usually due 
to HSV type 1).  
 Multiple painful penile vesicles and ulcers are characteristic.

 Primary attacks are often severe and associated with fever whilst subsequent attacks are 
generally less severe and localised to one site. 
 The lesions generally heal within 2 weeks.  
 Recurrence of painful genital lesions is a characteristic.  
 Oral Acyclovir is the treatment of choice. 
Syphilis   
 is a sexually transmitted infection caused by the spirochaete Treponema pallidum .  
 Infection is characterised by primary, secondary and tertiary stages.

 A painless ulcer  (chancre) is seen in the primary stage.  
 The incubation period= 9-90 da ys 
 IM penicillin is the intervention of choice 
1317

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   81 
  In case of severe penicillin allergy, a single dose of (2 g) azithromycin is the 
preferred option because it is effective and doesn ’t raise compliance issues. 
 
primary chancre associated with syphilis 
Chancroid  
  is a tropical disease caused by Haemophilus ducreyi .

 It causes painful genital ulcers  associated with unilateral, painful inguinal lymph node 
enlargement.  
 (Remember the saying: “You do cry with ducreyi ”.) 
 The ulcers typically have a sharply defined, ragged, undermined border, which readily 
bleeds on contact.  
 Antibiotic treatment: single dose oral azithromycin or IM ceftriaxone  
 Examine and treat sexual partner(s). 
 
Lymphogranuloma venereum (LGV)   
 caused by Chlamydia trachomatis .

 caused by Chlamydia trachomatis .  
 caused by infection with the L1, L2 or L3 serovars of Chlamydia trachomatis .  
 It infects phagocytes rather than epithelium, which accounts for the rapid spread of 
infection to r egional lymph nodes.  
 The bacterium gains entry through breaches in the epithelial/mucous membranes, 
travelling through the lymphatics via macrophages to local nodes.  
 Typically, infection comprises of three stages

 Typically, infection comprises of three stages 
 stage 1: small painless pustule which later forms an ulcer. at the site of inoculation 
3-12 days later.  
 stage 2: painful inguinal lymphadenopathy (Presents 1-6 months later). 
 Enlarged lymph nodes are known as buboes, they are often painful and can 
lead to thinning of the overlying skin causin g abscesses.  
 Groove sign is separation inguinal nodes by the inguinal ligament and is 
characteristic of the disease.

characteristic of the disease. 
 stage 3: proctocolitis (if rectally, then tenesmus, proctocolitis, strictures and fistulas 
can ensue. Cervicitis and urethritis are also common features.) 
 LGV is treated using doxycycline.  
 Diagnosis is achieved by enzyme linked immunoassays or polymerase chain reaction of 
infected sample areas/pus. Acute and convalescent sera can be used, but requires two 
samples 2 weeks apart.  
 Treatment:

 Antibiotics either doxycycline or macrolides (azithromycin or erythromycin)  
  the most appropriate intervention  Doxycycline for 21 days  
1318

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   82 
  In patients where this is unsuitable, azithromycin is also thought to be 
effective.  
 surgical drainage/aspiration of the buboes or abscesses.  
 Complications include: genital elephantiasis, hepatitis, infertility, pelvic inflammatory 
disease, arthritis and fitz hugh curtis syndrome. 
 
Other causes of genital ulcers

Other causes of genital ulcers  
 Behcet's disease 
 carcinoma 
 granuloma inguinale: Klebsiella granulomatis  (previously called Calymmatobacterium 
granulomatis ) 
Syphilis 
 Definition:  Syphilis is a sexually transmitted infection caused by the spirochaete  
Treponema pallidum .  
 Approximately one-third of sexual contacts of infectious syphilis will develop the disease.  
 The incubation period  is between 9-90 days

 The incubation period  is between 9-90 days   
 Stages:  Infection is characterised by primary, secondary and tertiary stages.  
Primary features 
 chancre - painless ulcer at the site of sexual contact 
 local non -tender lymphadenopathy 
 often not seen in women (the lesion may be on the cervix) 
Secondary features  - occurs 6-10 weeks after primary infection 
 systemic symptoms: fevers, lymphadenopathy 
 rash on trunk, palms and soles 
 buccal 'sn ail track' ulcers (30%)

 buccal 'sn ail track' ulcers (30%) 
 condylomata lata 
 
Classical pal m lesions of secondary syphilis  
 
More generalised rash of secondary syphilis 
 
1319

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   83 
  
Tertiary features 
 occurs in one-third of untreated patients around 15 –30 years after initial infection. 
 gummas (granulomatous lesions of the skin and bones)  most common (15% of patients)  
 ascending aortic aneurysms 
 general paralysis of the insane 
 tabes dorsalis 
 Argyll-Robertson pupil

Features of congenital syphilis 
 blunted upper incisor teeth (Hutchinson's teeth), 'mulberry' molars 
 rhagades (linear scars at the angle of the mouth) 
 keratitis 
 saber shins 
 saddle nose 
 deafness 
The diagnosis usually based on clinical features, serology and microscopic examination of 
infected tissue  
 
Serolo gical tests  can be divided into 
 cardiolipin tests (not treponeme specific)

 cardiolipin tests (not treponeme specific) 
 treponemal specific antibody tests 
Cardiolipin tests  
 syphilis infection leads to the production of non-specific antibodies that react to cardiolipin 
 examples include VDRL (Venereal Disease Research Laboratory) & RPR (rapid plasma 
reagin) 
 insensitive in late syphilis  
 becomes negative after treatment 
 Causes of false positive cardiolipin tests  
 SLE, anti-phospholipid 
syndrome 
 TB  leprosy 
 malaria 
 HIV

syndrome 
 malaria 
 HIV 
Treponemal specific antibody tests  
 example: TPHA ( Treponema pallidum  Haem Agglutination test) 
 remains positive after treatment 
 benzylpenicillin 
 First line treatment  
 benzathine penicillin 2.4 million units given intramuscularly. This is administered 
either as a single dose or two doses given one week apart. 
 alternatives: doxycycline or erythromycin 
 may be given in patients with allergies to penicillins .

 the Jarisch-Herxheimer reaction  
 This is an acute febrile illness with headache, myalgia, chills and rigors 
starting within 12 hours of the first dose of treatment and resolving within 24 
hours  
 Fever, rash, tachycardia after first dose of antibiotic.  
 It is thought to be due to the release of endotoxi ns following bacterial death   
  It is usually not important in early syphilis unless there is neurological or

ophthalmic involvement or in pregnancy when it may cause fetal distress and 
premature labour. 
 It occurs in ~50% of patients with primary syphilis, 90% with secondary syphilis  
and 25 % with early latent syphilis. 
 also occurs in Lyme disease  and Q fever . 
 Patients should be counselled about the reaction prior to receiving therapy for 
syphilis. 1320

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   84 
  the appropriate management   reassurance  and paracetamol for symptom 
control  
UK national guidelines on the management of syphilis 2015 
 Infected patient  should be advised to abstain from sex until any lesions (if any) have 
resolved or until two weeks after treatment completion

  first-line: Procaine penicillin is now an alternative treatment where benzathine penicillin is 
suitable.  due to the pain and multiple injections associated  
 Benzathine dose: 2.4 Mega units IM weekly for up to 3 weeks 
 Procaine dose: 1.8 –2.4 mega units IM daily for 14 days. 
 second- line  oral azithromycin single dose. 
 Treatment during pregnancy :  
 first and second trimesters  give single dose benzathine penicillin;

 third trimester  two doses of benzathine penicillin one week apart.  
 Neurosyphilis:  procaine penicillin 1.8-2.4 units once daily (IM, for 14 days) with oral 
probenecid 500 mg four times a day. 
 Tests for monitoring the effect of treatment  RPR/VDRL test 
 Treponemal enzyme immunoassay (EIA)/chemiluminescent assay (CLIA), preferably 
detecti ng both IgM and IgG is the screening test of choice. 
 Treatment during pregnancy: depends upon which trimester the presentation is in:

 first and second trimesters - give single dose benzathine penicillin;  
 third trimester - two doses of benzathine penicillin one week apart. 
Tape worms 
Tape worms are made up of repeated segments called proglottids. These are often present in 
faeces and are useful diagnostically 
 
Cysticercosis  
 caused by Taenia solium (from pork) and Taenia saginata (from beef)

 These may affect any tissue in the body but are commonest in subcutaneous tissues and 
(CNS) patient with a palpable nodule who has an epileptic seizure 
 management: niclosamide   
Hydatid disease 
 caused by the dog tapeworm Echinococcus granulosus  
 life-cycle involves dogs ingesting hydatid cysts from sheep liver 
 often seen in farmers  
 may cause liver cysts 
 management: albendazole 
Tetanus

Tetanus 
 Tetanus is caused by the tetanospasmin exotoxin released from Clostridium tetani .  
 Tetanus spores are present in soil and may be introduced into the body from a wound, 
which is often unnoticed. Absence of a wound does not exclude tetanus. 
 Tetanospasmin prevents release of GABA 
 The absence of a wound does not exclude tetanus. 
 The toxin tetanospasmin does not cross the blood brain barrier, it diffuses through the

blood to bind to receptors containing gangliosides on the neuronal membranes of 
presynaptic nerve terminals in muscles. The toxin does reach the brain by axonal 
transport.  
 Tetanus toxin cleaves specific sites of synaptobrevin (VAMP)  
Features  
 prodrome fever, lethargy, headache 
 trismus (lockjaw)  
 risus sardonicus 
 opisthotonus  (arched back, hyperextended neck) 
 spasms (e.g. dysphagia ).  
 1321

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   85 
 supportive therapy including ventilatory support and muscle relaxants 
 intramuscular human tetanus immunoglobulin for high -risk wounds (e.g. compound 
fractures, delayed surgical interv ention, significant degree of devitalised tissue)

 While Clostridium -specific intravenous immunoglobulin is ineffective once the toxin 
is attached to nervous tissue it may prevent progression.  
 metronidazole is now preferred to benzylpenicillin as the antibiotic of choice 
 
Tetanus: vaccination  
 The tetanus vaccine is a cell-free purified toxin that is normally given as part of a 
combined vaccine. 
 Tetanus vaccine is currently given in the UK as part of the routine immunisation schedule 
at: 
 2 months 
 3 mont hs 
 4 months

at: 
 2 months 
 3 mont hs 
 4 months 
 3-5 years 
 13-18 years 
 This therefore provides 5 doses of tetanus-containing vaccine. 
  Five doses is now considered to provide adequate long- term protection against tetanus. 
 A tetanus booster is not recommended in the UK if the patient is already immunized. 
Tetanus antitoxin may be used in developing countries as it is cheaper but it has a higher 
rate of anaphylaxis and a shorter half life so is not recommended in the UK.

 Intramuscular  human tetanus immunoglobulin should be given to patients with high-
risk wounds (e.g. Compound fractures, delayed surgical intervention, significant degree of 
devitalised tissue) irrespective of whether 5 doses of tetanus vaccine have previously 
been given 
 High risk wounds  
 Wounds burns needing surgery delayed more than 6 hours 
 Wounds contaminated with soil 
 Compound fractures 
 Wounds containing foreign bodies 
 Wounds/burns in people with systemic sepsis

 Wounds/burns in people with systemic sepsis 
 If vaccination history is incomplete or unknown  then a dose of tetanus vaccine 
should be given combined with intramuscular human tetanus immunoglobulin for high-
risk wounds  
 
January 2015 exam: H/O 4 cm laceration to the dorsum of left hand after cutting 
using a Stanley knife. no sign of a foreign body. He has 'no idea' about his tetanus 
vaccination. What is the most appropriate action with respect to tetanus? Requires

tetanus vaccine + complete vaccine course at a later date  
(This wound is not high risk for tetanus) 
Trypanosomiasis 
 Two main form of this protozoal disease are recognised: 
1.  African trypanosomiasis (sleeping sickness) and  
2. American trypanosomiasis (Chagas' disease)  
1. African trypanosomiasis , or sleeping sickness   
 Two forms of African trypanosomiasis , or sleeping sickness , are seen:

1) Trypanosoma brucei gambiense  in West Africa  
 West African trypanosomiasis has a slower course. Symptoms start 
several weeks or even months after the tsetse fly bite. 
2) Trypanosoma brucei rhodesiense  in East Africa.  
 Trypanosoma rhodesiense  tends to follow a more acute course. 
 progression is more rapid - starting within days of infection. Death may 
occur within weeks or months.  1322

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   86 
  Rash is a more prominent feature and lymphadenopathy is less 
frequently present.  
 Both types are spread by the tsetse fly.   
 Clinical features  include: 
 Trypanosoma chancre - painless subcutaneous nodule at site of infection 
 intermittent fever  
 enlargement of posterior cervical lymph nodes

 enlargement of posterior cervical lymph nodes 
 later: central nervous system involvement e.g. somnolence, headaches, 
mood changes, meningoencephalitis 
 The reversal of the sleep wake cycle is typical and can be accompanied by 
behavioural changes. 
 Stages  
 The first stage  of disease is haematolymphatic spread and is accompanied 
by fever, and lymphadenopathy (discrete, rubbery, non-tender nodes). A 
rash sometimes occurs and mild hepatosplenomegaly may develop.

 The second stage  is the meningoencephalitic stage. This occurs months or 
years after the acquisition of infection. Manifestations include personality 
change and progressive indifference with daytime somnolence. 
Extrapyramidal signs and ataxia are common. 
 early disease: IV pentamidine or suramin  
 later disease or central nervous system involvement: IV melarsoprol  
2. American trypanosomiasis , or Chagas' disease  
 caused by the protozoan Trypanosoma cruzi .

 caused by the protozoan Trypanosoma cruzi .  
 Transmitted by triatomine bug bite.  
 Features:  
 acute phase:  
 asymptomatic (95%)  
 chagoma (an erythematous nodule at site of infection)  
 periorbital oedema 
 Chronic Chagas' disease mainly affects the h eart, gastrointestinal tract and 
CNS . 
 Cardiac feature  myocarditis may lead to dilated cardiomyopathy 
(with apical atophy) and arrhythmias. 
 Cardiac involvement is the leading cause of death in

patients with Chagas' disease  
 GIT feature: 
 Mega-oesophagus (causing dysphagia )  
 Mega-colon (causing constipation) 
 CNS feature  meningoencephalitis  
 treatment is most effective in the acute phase using azole or nitroderivatives 
such as benznidazole  or nifurtimox 
 chronic disease management involves treating the complications e.g., heart 
failure . 
Tuberculosis 

 Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis  that most 
commonly affects the lungs.  
 Mycobacterium tuberculosis   is a small aerobic non-motile bacillus. It is classified as a 
Gram positive organism 
 the key of pathophysiology is to differentiate between primary and secondary disease. 
Primary tuberculosis  1323

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   87 
  A non-immune host who is exposed to M. tuberculosis may develop primary infection of 
the lungs. A small lung lesion known as a Ghon  focus develops. The Ghon focus is 
composed of tubercle-laden macrophages. The combination of a Ghon focus and hilar 
lymph nodes is known as a Ghon complex

lymph nodes is known as a Ghon complex 
 In immunocompotent  people the intially lesion usually heals by fibrosis.  
 Those who are immunocompromised  may develop disseminated disease (miliary 
tuberculosis).  
 Primary TB is usually asymptomatic  
 Bacilli are transported via lymphatics early in the disease process to regional lymph 
nodes to cause marked lymphadenopathy. 
 Pleural and pericardial infectio ns (which can result in effusions) occur at or shortly after 
primary infection.

primary infection. 
 Positive tuberculin test occurs between three weeks and three months after primary 
 Mycobacterium avium  causes disseminated infection in patients with advanced 
HIV, t ypically when the CD4 count is less than 50 cells/mm3. 
 Positive tuberculin test occurs between three weeks and three months after 
primary infection . 
 
Secondary (post-primary) tuberculosis  
 If the host becomes immunocompromised the initial infection may become reactivated.

 Reactivation generally occurs in the apex of the lungs and may spread locally or to more 
distant sites.  
 Possible causes of immunocomprise include: 
 immunosuppressive drugs including steroids 
 HIV 
 The lungs remain the most common site for secondary tuberculosis.  
 Extra -pulmonary infection may occur in the following areas: 
 central nervous system (tuberculous meningitis - the most serious complication) 
 vertebral bodies (Pott's disease)

 vertebral bodies (Pott's disease) 
 cervical lymph nodes (scrofuloderma) 
 renal 
 gastrointestinal tract 
 tuberculosis may be associated with an inflammatory polyarthritis that may follow 
a similar pattern to rheumatoid arthritis 
 
Miliary tuberculosis 
  
Scanning electron micrograph of Mycobacterium 
tuberculosis bacteria, which cause TB.  
 
1324

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   88 
 Patients should be routinely screened for TB exposure before treatment with Etanercept 
with the tuberculin skin test 
 
 Non-sputum producing patients are non- infectious  . Only untreated smear-positive 
pulmonary TB is likely to be infectious. 
Screening

Screening 
 The Mantoux test  is the main technique used to screen for latent tuberculosis.  
 The most commonly used screening test for contacts of a patient with 
recently diagnosed TB  
 It measures the T cell -mediated immune response to TB antigen. Immune 
complexes are not involved (these result from antibody mediated immune 
responses). 
 
  In recent years the interferon-gamma blood test has also been introduced. It is used in a 
number of specific situations such as:

number of specific situations such as: 
 the Mantoux test is positive or equivocal 
 people where a tuberculin test may be falsely negative (see below) 
 Tuberculin skin tests are an example of type IV (delayed) hypersensitivity reactions. 
These are largely mediated by interferon- Ȗ secreted by T h1 cells  which in turn 
stimulates macrophage activity. 
 
Mantoux test  (tuberculin test) ( purified protein derivative ( PPD) test) 
 It is a cell mediated immune response.

 It is a cell mediated immune response.   
 measures the T cell-mediated immune response to TB antigen  
 Memory TH1 cells previously formed against M. tuberculosis recognize peptide: 
MHC class II complexes on the surface of antigen presenting cells 
  It is a type IV , hypersensitivity reaction. 
 0.1 ml of 1:1,000 purified protein derivative (PPD) injected intradermally 
 result read 2-3 days later 
 The left forearm is typically used.

 The left forearm is typically used. 
  Only the induration, not surrounding erythema, is used in the measurement and the 
longest diameter is measured in millimetres:  
 
Diameter of 
induration  Positivity Interpretation  
< 6mm Negative - no 
significant 
hypersensitivity to 
tuberculin protein  Previously unvaccinated individuals may be given the 
BCG  
6 - 15mm Positive - 
hypersensitive to 
tuberculin protein  Should not be given BCG. May be due to previous TB

infection or BCG  or atypical mycobacteria. 
However, in other contexts (e.g. immigrant screening 
and contact tracing), further investigation should and 
follow-up may be indicated. 
> 15mm Strongly positive - 
strongly 
tuberculin protein  Suggests tuberculosis infection.  do chest x-ray   
 Active disease may be indicated by grade III/IV response to tuberculin.  
 Eighty percent of individuals with history of BCG vaccination have grade I/II response.

False negative tests may be caused  by: (  ↓reaction to tuberculin protein ) 
 miliary TB 1325

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   89 
  sarcoidosis 
 immunosuppression ( HIV , corticosteroids) 
 lymphoma 
 very young age (e.g. < 6 months) 
 Viral infections,  
 live viral vaccines  
 poor nutrition.  
January 2012 exam: Which cytokines is most involved in the response of a Mantoux test?   
 Interferon -Ȗ 
 
Heaf test

Heaf test  
 The Heaf test was previously used in the UK but has been since been discontinued. 
  It involved injection of PPD equivalent to 100,000 units per ml to the skin over the flexor 
surface of the left forearm. It was then read 3-10 days later. 
 Patients who exhibited a negative reaction to the test were considered for BCG 
vaccination. 
 Heaf tes t was used to test for tuberculosis in adolescents aged around 13 –14

 Until 2005, the test was used in the United Kingdom to determine if the  BCG  vaccine was 
needed; the Mantoux test is now used instead.  
 Heaf tests are graded as follows:  
 
0 no reaction 
1 4-6 small dots 
2 dots coalesce, normal skin in centre 
3 dots coalesce, central skin filled in 
4 solid induration >10 mm, with or without vesiculation or ulceration 
 
 Interpretation of results:  
 grade 0 ,indicating no TB;

 grade 0 ,indicating no TB;  
 An HIV -positive patient without active tuberculosis would likely have a grade 
0 reaction. 
 Without prior BCG vaccination in an HIV-negative patient with no previous 
exposure to TB a grade 0 reaction would be expected. 
 Grade 2  is a normal response in the presence of a previous BCG vaccination.  
 grade 3 -4, indicating active disease. 
 
BCG  
 is a live attenuated vaccine derived from a strain of Mycobacterium. bovis .

 BCG is currently used as a form of immunotherapy for treating bladder cancer; which can 
lead to disseminated  M. bovis  infection (systemic 'BCG-it is')  
 it also has effects against leprosy  ( Mycobacterium  (M. leprae ))   (up to 80% 
protection)  
 updates now recommend that it should be given to neonates in high risk groups. 
 It should not be given to children who have a strongly positive tuberculin test.  
 A Mantoux should be documented before administration.

 In case of increased risk of HIV, NICE advises that an HIV test should be done 
prior to vaccination.  
 
Diagnosis  
 In adults induction of sputum or bronchoscopy and lavage may be used in patients who 
cannot produce sputum 1326

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   90 
  If patient is unable to produce sputum, bronchoscopy with bronchial 
washings for microscopy staining and culture is the investigation of choice.  
 Gastric lavage for AFB is unpleasant for the patient has a lower yield than 
bronchoscopy and is therefore rarely undertaken now.

 In children who are unable to cough up sputum, the gold standard is gastric washings for 
M tuberculosis culture 
 Smear -positive tuberculosis   (Patient needs treatment and isolation from casual 
contacts, his close contacts need screening ) 
 Smear -positive tuberculosis  means the patient is highly infectious to both close 
contacts (more than 8 hours spent together per day) and casual contacts, such as 
other patients on the ward and healthcare workers.

 He therefore needs to be isolated in a negative-pressure room and contacts 
should wear particulate masks until he has received anti-tuberculous therapy 
for 2 weeks. 
The sputum might remain positive after this time, but the organisms will be 
dead.  
 Culture -positive tuberculosis  means the immediate smear is negative, but 
prolonged culture has shown tuberculosis. 
 The definitive diagnosis : requires the growth of Mycobacterium tuberculosis from 
respiratory secretions.

respiratory secretions. 
 A probable diagnosis : can be based on: 
 Typical clinical and chest X-ray findings, together with either 
  sputum (or other specimens) positive for acid-fast bacilli, 
 stains very weakly on testing. When using the Ziehl-Neelsen test  it stains 
bright red  against a blue background. 
 typical histopathological findings on biopsy material  
 
 Should only be carried out in hospitals with appropriate isolation facilities.

 Smear -positive tuberculosis means the patient is highly infectious to both close 
contacts  (more than 8 hours spent together per day) and casual contacts, such 
as other patients on the ward and healthcare workers.  
 He therefore needs to be isolated in a negative-pressure room, 
 contacts should wear particulate masks until he has received anti-tuberculous 
therapy for 2 weeks . The sputum might remain positive after this time, but the 
organisms will be dead. 
 Length of treatment :

 Length of treatment : 
 All forms of pulmonary TB may be treated equally except tuberculous pleural 
effusion which may require drainage (with large effusions causing breathlessness) 
and adjunct corticosteroids to delay reaccumulation. 
  A 6-month course of treatment is adequate for all non-CNS disease.  
 Length  of treatment for other forms are: 
 bone TB – 6 months 
 Treatment for bone and joint tuberculosis is recommended to continue

for 2 months with the initial phase consisting of quadruple therapy and 
the remaining 4 months of dual therapy.  
 It is recommended no t to extend treatment for residual complications 
such as collapsed discs or bending of the spine, although there is 
some debate about this. 
 meningitis - 1 year 
 Antituberculous treatment for 12 months is recommended for TB 
meningitis.  
  
 drug resistance - 2 years. 
 Treatment must be continued for a minimum of 18 months, with at

least 9 months of treatment after the patient becomes culture -
negative.   1327

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   91 
  TB with strider: 
 If patient of TB presents with worsening breathlessness and stridor due to  
mediastinal lymph nodes compressing the carina,  the next step - after 
commencing steroid -   is urgent (CT) scan , first to confirm the degree of airway 
compression and second to assess the response to chemotherapy.

 Patients on long term steroids with TB:  
 Patients on long term  steroids should have their dose of steroids increased 
when starting antituberculous therapy. 
 The metabolism of corticosteroids is increased by rifampicin. (P450 
inducer)  
 Failing regimen in the treatment of TB: 
 reactivation of  (TB) infection during treatment course. 
 Evidence of failing treatment: 
 worsening symptoms,  
 elevated C-reactive protein,  
 progression of chest X-ray changes

 progression of chest X-ray changes 
 what is the most appropriate next treatment step? 
 Most guidelines recommend progression to five agents – rifampicin, 
pyrazinamide, isoniazid, ethambutol and streptomycin. 
TB Drug therapy 
Treatment for   active tuberculosis  is: 
 Initial phase - first 2 months (RIPE)  
1. Rifampicin 
2. Isoniazid 
3. Pyrazinamide 
4. Ethambutol

4. Ethambutol 
 (the 2006 NICE guidelines now recommend giving a 'fourth drug' such 
as ethambutol routinely - previously this was only added if drug-resistant 
tuberculosis was suspected) 
 either ethambutol or streptomycin. 
 Continuation phase - next 4 months 
 After 2 months of therapy (for a fully susceptible isolate), pyrazinamide 
can be stopped. Isoniazid plus rifampicin are continued as daily or

intermittent therapy for 4- or-more months.  
 Therapy must be extended if the patient has cavitary disease or remains 
culture positive after 2 months of treatment. 
Treatment for  latent tuberculosis   
 isoniazid alone for 6 months 
Treatment for   meningeal tuberculosis  
  treated for a prolonged period (at least 12 months )  
 4 drugs  for the first 2 months, followed by isoniazid and rifampicin 10 months.

 addition of steroids  (equivalent to prednisolone 20-40 mg) is recommended for the 
first 2-3 weeks, then with gradual reduction.  
 (use of steroids is recommended to ensure adequate brain penetration and to 
prevent cranial nerve compression by meningeal scarring.  
 
Extra-pulmonary TB  (e.g. bone, CNS)  
 requires a longer duration of treatment, usually 9-12 months.  
Directly observed therapy   1328

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   92 
  with a three times a week dosing regimen may be indicated in certain groups, 
 homeless people with active tuberculosis 
 patients who are likely to have poor concordance 
 all prisoners with active or latent tuberculosis 
 
Tuberculosis: drug side-effects and mechanism of action 
 Rifampicin

 Rifampicin 
 mechanism of action: 
 inhibits  bacterial DNA dependent RNA polymerase  preventing  
transcription  of DNA into mRNA 
 mechanism of resistance for rifampicin resistant Mycobacterium 
tuberculosis  
 Mutations in rpoB gene cause alterations in the bacterial DNA 
dependent RNA transcriptase, which prevents the binding of 
rifampicin . 
  In patients with HIV/TB co-infection: 
 Rifampicin is a potent inducer of liver enzymes (cytochrome P450) .

Furthermore, it up-regulates the expression of P-glycoprotein in the 
gastrointestinal tract.  
 Co-administration of a protease inhibitor with rifampicin therefore will 
often lead to sub-therapeutic levels of the protease inhibitor.  
 the British HIV Association suggest the substitution of rifampicin for 
an alternative rifamycin agent ( rifabutin  or rifapentine), which has 
less inducing action of cytochrome P450  
 Side effects 
 potent liver enzyme inducer 
 hepatitis,

 hepatitis,  
 orange secretions ( Red or orange discoloration of the urine and other 
body fluids ) 
 flu-like symptoms 
 Rifampicin and isoniazid can cause a relative vitamin D deficiency 
 Isoniazid 
 mechanism of action:  
 Prevents cell wall synthesis by inhibiting the synthesis of mycolic 
acid  
 Bactericidal  
 Hepatotoxicity 
 INH is the most common drug associated with toxicity.

 INH metabolites are responsible for INH hepatotoxicity  
 N-acetyltransferase 2 (NAT2) is the primary enzyme that 
contributes to INH metabolism.  
 NAT2 deficiency increases the risk of INH-induced liver injury.  
 slow acetylators are prone to develop more severe 
hepatotoxicity than rapid acetylators. 
 Peripheral neuropathy:  
 prevent with pyridoxine (Vitamin B6) 
 agranulocytosis 
 Drug-induced lupus erythematosus 
 liver enzyme inhibitor 
INH Injures Neurons and Hepatocytes

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   93 
  Pyrazinamide 
 converted by pyrazinamidase into pyrazinoic acid which in turn inhibit s 
fatty acid synthase (FAS) 
 Bactericidal 
 Streptomycin has high activity against extracellular organisms whilst 
pyrazinamide have high activity against intracellular organisms . 
 side effects

 side effects 
 hyperuricaemia causing gout 
 arthralgia, myalgia 
 the most common cause of arthralgia after starting 
antituberculous  
 Ethambutol 
 Prevents cell wall synthesis by inhibiting arabinosyltransferase  
(which polymerizes arabinose into arabinan) 
 Bacteriostatic 
 optic neuritis: check visual acuity before and during treatment  
 Ocular side-effects of ethambutol  
 Loss of acuity 
 Colour blindness

 Colour blindness 
 Restriction of visual fields 
 dose needs adjusting in patients with renal impairment 
 Ethambutol is renally excreted  and therefore dose adjustment is 
necessary to minimise the risk of toxic effects (optic neuropathy). The 
remaining drugs are mainly metabolised in the liver and can be given in 
normal doses in renal failure. 
 Anti-tuberculosis drug and LFTs : 
 All tuberculosis patients should have pre-treatment LFTs.

 rifampicin/isoniazid/pyrazinamide all are associated with liver toxicity,  but 
isoniazid are most commonly implicated (this fact are tested in MRCPI website -
part 1, sample question)  
 Up to 20% of the patients receiving isoniazid either in single or combination 
therapy develop transient asymptomatic elevation in liver enzymes , 
which settle with continued use of the drug.   
 while some patients (less than 1% –3%) develop severe liver injury and even liver 
failure

failure 
 If there is no pre-existing liver disease, LFTs are only repeated (and 
treatment stopped) if fever, malaise, vomiting , jaundice or unexplained 
deterioration occurs during treatment. 
 Regular LFTs should be performed in patients with previously known chronic 
liver disease.  
  define hepatotoxicity  rifampicin/isoniazid/pyrazinamide should be 
stopped  
 If AST/ALT levels rise by 5 times  upper limit of normal range  without 
symptoms

symptoms   
 If ALT/AST levels rise by 3 times  upper limit of normal range with 
symptoms (abdominal pain, nausea, vomiting, unexplained fatigue or 
jaundice)  1330

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   94 
  If the patient is not unwell and/or has non-infectious TB, no treatment until 
LFT returns to normal. 
 If clinically unwell or sputum smear is positive within two weeks of starting 
treatment, consider streptomycin and ethambutol until LFT returns to 
normal.

normal.  
 Once LFT is back to normal, challenge dosages can be reintroduced 
sequentially in order of isoniazid, rifampicin and pyrazinamide with daily 
monitoring of patient's condition and LFT. 
 If there is a further reaction , the offending drug should be excluded and a 
suitable alternative regimen used. 
 Immune reconstitution disease 
 Immune reconstitution inflammatory syndrome  (IRIS) (also known 
as immune recovery syndrome ) is a condition seen in some cases

of AIDS or immunosuppression, in which the immune system begins to 
recover, but then responds to a previously acquired opportunistic 
infection with an overwhelming inflammatory response that paradoxically 
makes the symptoms of infection worse 
 occurs typically 3-6 weeks after starting treatment 
 often presents with enlarging lymph nodes 
_________________________________________________ __________ 
Latent tuberculosis infection (LTBI) 

 screening tests indicating previous infection with M. tuberculosis are positive 
without any pathological findings on radiological imaging. 
Risk for developing active tuberculosis   
 The lifetime risk of reactivation TB for a person with LTBI is about 5 –10%. 
 Risk factors for developing active tuberculosis  include:  
 silicosis 
 chronic renal failure 
 HIV positive 
 solid organ transplantation with immunosuppression 
 intravenous drug use

 intravenous drug use 
 haematological malignancy 
 anti-TNF treatment 
 previous gastrectomy 
Diagnosis  
 positive Mantoux test   
 can be positive with both active and latent TB, but can also by a previous 
BCG vaccination.  
 Recommended for close contacts of a person with TB. 
 If  positive ( induration ≥ 5 mm, regardless of BCG history )  assess for 
active TB 
 Interferon gamma release assay (IGRA)  

 Quantaferon testing (interferon gamma testing) is recommended as a 
second-line test for people whose Mantoux testing may be less reliable 
- for example, BCG-vaccinated people.  
 If the Mantoux test is positive + active TB is excluded, and evidence of 
infection is needed to decide on treatment. for example:  
 if the person needs enhanced case management or  
 if there could be adverse events from treatment.  1331

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   95 
  In people with HIV and a CD4 count of less than 200 cells/mm3 an 
interferon-gamma test should be done alongside the Mantoux  as it 
will be unreliable.  
 If either test is positive a clinical assessment should be performed 
to exclude active TB,  
 if no active disease found consideration made to treating a latent

 For immunocompromised,  ( HIV and CD4 < 200 cells/mm3, or after 
transplant),  Interferon ‑gamma release assay and a concurrent 
Mantoux test: 
 If either test is positive  assess for active TB. 
 If assess for active TB is negative,  treatment for latent TB 
 Advantage 
 Quantaferon testing is not influenced by BCG vaccination status  
 A positive test would, therefore, indicate prior exposure to M. 
tuberculosis (active or latent TB) 
 Disadvantage

 Disadvantage  
 The main disadvantage of the IGRA is its inability to distinguish 
between active and latent TB. 
 NO TB-related findings on chest x-ray (e.g., hilar lymphadenopathy, upper 
lobe opacification, or cavitation),  
Treatment  
 NICE now give two choices for treating latent tuberculosis:  
 3 months of isoniazid (with pyridoxine) and rifampicin  
 For people younger than 35 years if hepatotoxicity is a concern after an

assessment of both liver function (including transaminase levels) and 
risk factors. 
 6 months of isoniazid (with pyridoxine)  
 if interactions with rifamycins are a concern, for example, in people with 
HIV or who have had a transplant. 
 
NICE advises that once a diagnosis of pulmonary TB has been made then close 
contacts should be managed as follow:  
 
 If asymptomatic  and younger than 65 years  then: 
  test for latent TB.

  test for latent TB.  
 If Mantoux-negative and unvaccinated then offer vaccination.  
 If at risk of HIV then test for HIV first (HIV testing and if 
negative then BCG vaccination).  
 If asymptomatic  and older than 65 years  then assess with a chest X-ray. 
 
Ref: NICE guidelines 2016 
www.nice.org.uk   
Miliary TB 
Overview 
 miliary TB most likely  occur in young children. 
Features

Features 
 presents with a gradual onset of vague ill health, loss of weight and then fever.  
 TB meningitis  1332

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   96 
  15 - 20% of patients who have miliary TB also have TB meningitis at the time of 
presentation.  
 33% of patient with TB meningitis have concomitant miliary TB. 
 Hepatosplenomegaly is seen in advanced disease. 
 Choroidal tubercles can be seen in the eyes. 
 tuberculin test is often negative.

 tuberculin test is often negative.  
 negative in up to half of patients with severe disease 
 chest x ray  
 may be normal in up to one third of patients. 
 The classic millet seed nodules are small measuring about 1-2 mm. 
 Not all patients will be sputum  positive and with evidence supporting a diagnosis of 
tuberculosis treatment should be commenced swiftly.  
 Transbronchial biopsy – positive at an early stage.  
 Biopsy of liver and bone marrow might be required.

Non-tuberculous mycobacterial infections 
Opportunistic mycobacteria  
 Mycobacterium kansasii 
 Mycobacterium malmoense 
 Mycobacterium xenopi 
 Mycobacterium avium intracellular( The presence of acid fast bacilli (AFB) and absence of 
TB (Mycobacterium tuberculosis  negative on culture.) suggests an atypical AFB such 
as M. avium .) 
 The presence of AFB yet absence of TB suggests an atypical AFB such as M. 
avium .

avium . 
 Mycobacterium avium  causes disseminated infection in patients with advanced 
HIV, typically when the CD4 count is less than 50 cells/mm3. 
Mycobacterium malmoense   
 is a non -tuberculous mycobacterium  
 most commonly causes pulmonary infection in middle-aged and older adults with pre-
existing lung disease or immunodeficiency and can also cause local invasion from a skin 
lesion.  
 It causes nonspecific symptoms, such as malaise and weight loss, or chest sym ptoms

that take an atypical course.  
 they can colonise structurally abnormal lung, for example in patients with: 
 Cavitary disease 
 Chronic obstructive pulmonary disease  
 Such patients might not always require treatment. However, if treatment is 
required, then it is usually for longer than the standard 6 months needed to treat 
pulmonary tuberculosis 
 'atypical' mycobacteria differ from M. tuberculosis  in that they are ubiquitous organisms

and have no person- to-person spread.  
 Mycobacterium marinum  infection  
 It is an uncommon atypical mycobacterium infection  
 The skin is the most common site of infection, where it usually produces a solitary 
indolent granulomatous lesion - the 'fish tank granuloma'.  
 usually seen in patients who handle fish  or swim in freshwater or saltwater.  
 occurs when contaminated water is exposed to skin that has experienced open 
trauma.  1333

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   97 
  
fish tank granuloma'  caused by 
Mycobacterium marinum   
  
Diagnosis   
 A single isolate from a non -sterile site might not be significant and can just represent 
contamination.  More than two isolates from a non-sterile site are required to 
establish disease.

establish disease.   
 Chest X -ray => (like other mycobacterium) upper-zone fibrosis and cavitation. 
Treatment 
 No need to isolate patients or notify public health authorities.  
Multidrug-resistant tuberculosis (MDR-TB). 
 Defined  as resistance to rifampicin and isoniazid, with or without resistance to other 
anti-TB drugs. 
 defined as positive cultures after 4 months of therapy . 
 Epidemiology

 Rare  in previously untreated white patients born in the UK(< 2%).  
 Higher levels of resistance occur in Indian subcontinent and black, with isoniazid 
resistance occurring in 4-6% of such patients. 
 Poor compliance (the most common reason) 
 Previous anti-TB treatment 
 Contact with a known case of drug -resistant TB 
 Birth in a foreign country, particularly high-incidence countries 
 HIV infection  
 Residence in London

 Residence in London 
 Age profile, with highest rates between ages 25 and 44,  
 Male gender. 
 Homelessness 
 Intravenous drug use 
 Infection acquired in institutions (eg prison)  
 Directly observed therapy is recommended 
 should be treated with an injectable agent such as amikacin, kanamycin or 
capreomycin, in combination with a fluoroquinolone and at least three other agents. 
 At least 5 drugs, one of which is a quinolone, is the recommended

 Ideally the injectable  agent is administered daily for the first 6-8 months , 
forming an intensive phase of treatment, with other drugs then continued for a total 
of 18-24 months.  
 In practi ce, unwanted effects may lead to intravenous therapy being discontinued 
early. 
 
1334

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   98 
Vaccinations 
Live attenuated vaccines 
 BCG  
 measles, mumps, rubella 
(MMR ) 
 oral polio  
 oral rotavirus  
 oral typhoid  influenza (intranasal)  
 yellow fever 
 
 Live attenuated vaccines are contraindicated in

Live attenuated vaccines are contraindicated in 
all HIV positive and immunocompromised 
patients.  
 *whole cell typhoid vaccine is no longer used in the UK 
 
Inactivated preparations 
 rabies 
 influenza (intramuscular) 
 
Detoxified exotoxins  
 tetanus  
Extracts of the organism/virus (sometimes termed fragment) ( may also be produced using 
recombinant DNA technology) 
 pertussis ('acellular' vaccine) 
 hepatitis B  
 meningococcus, pneumococcus, haemophilus

 meningococcus, pneumococcus, haemophilus 
 
Notes  
 influenza:  
 different types are available, including whole inactivated virus, split virion (virus 
particles disrupted by detergent treatment) and sub-unit (mainly haemagglutinin 
and neuraminidase) 
 cholera:  
 contains inactivated Inaba and Ogawa strains of Vibrio cholerae together with 
recombinant B-subunit of the cholera toxin 
 hepatitis B:  
 contains HBsAg adsorbed onto aluminium hydroxide adjuvant and is prepared from

yeast cells using recombinant DNA technology 
 
contraindications to pertussis immunisation include: 
 Acute illness - until recovered 
 Previous reaction to pertussis: 
1. Local:  an extensive area of redness and swelling which becomes indurated, 
involving most of the anterolateral surface of the thigh or a major part of the 
circumference of the upper arm 
2. General:  fever equal to or more than 39.5°C within 48 hours of vaccine ,

anaph ylaxis, bronchospasm, laryngeal oedema, generalised collapse, prolonged 
hyporesponsiveness, prolonged inconsolable or high-pitched screaming of more 
than four hours, convulsions or encephalopathy occurring within 72 hours. 
Splenectomised patients 
 Splenectomised patients are at increased risk of infection with : 
 encapsulated bacteria  
 A popular mnemonic to remember most of the encapsulated bacteria is the

SHiNE SKiS bacteria ( S. pneumo, Hib, N. meningitidis, E. Coli, Salmonella, 
Klebsiella, Group B Strep).  
 infections that are filtered by the spleen (for example, malaria).  
 When elective splenectomy  is planned, vaccines to pneumococcus and 
meningiococcus should be given two weeks pre-surgery  to allow an antibody response 
to evolve. 1335

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   99 
  Patients who have emergency splenectomies  should be vaccinated post-operatively 
(most effective if performed at least 14 days after surgery )  
Post-exposure prophylaxis 
 
Hepatitis A

Hepatitis A  
 Human Normal Immunoglobulin (HNIG) or hepatitis A vaccine may be used depending on 
the clinical situation  
Hepatitis B  
 HBsAg positive source :  
 if the person exposed is a known responder to HBV vaccine then a booster dose 
should be given.  
 If they are in the process of being vaccinated or are a non-responder they need to 
have hepatitis B immune globulin (HBIG) and the vaccine 
 unknown source:

 unknown source:   
 for known responders the green book advises considering a booster dose of HBV 
vaccine.  
 For known non-responders   HBIG + vaccine should be given  
 those in  the process of being vaccinated should have an accelerated course of 
HBV vaccine. 
 accelerated course of HBV vaccine  given at zero, one and two months. For 
those who are at continued risk, a fourth dose is recommended at 12 months.   
 
                                   Source person

Exposed person HBsAg positive unknown  
responder to HBV vaccine  booster HBV vaccine booster HBV vaccine  
non-responder    (HBIG) + vaccine  HBIG + vaccine  
in the process of 
vaccination   (HBIG) + vaccine  accelerated course of HBV 
vaccine (given at zero, one and 
two months)  
 monthly PCR - if seroconversion then interferon +/- ribavirin 
HIV 
 Three antiretroviral agents for 1 month  
 New guidelines in 2014 recommend three-agent PEP with Truvada® (tenofovir

and emtricitabine) and raltegravir , which should both be taken for 1 month.  
 (i.e. Within 1-2 hours, but may be started up to 72 hours following exposure) for 4 
weeks 
 serological testing at 12 weeks following completion of post-exposure prophylaxis 
 reduces risk of transmission by 80% 
 
Varicella zoster  
 VZIG for IgG negative pregnant women/immunosuppressed  
 
Estimates of transmission risk for single needle stick injury  
Hepatitis B  20-30% 
Hepatitis C  0.5-2% 
HIV 0.3%

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   100 
 First line management of needle  stick injuries includes immediate washing of the 
affected area under running water. 
 
UK Guideline for the use of HIV Post-Exposure Prophylaxis Following  Sexual 
Exposure (PEPSE) 2015 
 If the source is of unknown status:  establish the HIV status of the source.

 Source individual known to be HIV -positive:  determine the HIV viral load, resistance 
profile and treatment history. 
 if the source is on antiretroviral therapy (ART) with a confirmed and sustained (>6 
months) undetectable plasma HIV viral load  PEPSE is no longer recommended 
 However, if there are any doubts about the HIV viral load history or the source ’s 
adherence to ART  PEP should be given following unprotected receptive anal 
intercourse.

intercourse.  
 Initiation of PEPSE is recommended as soon as possible after exposure, preferably 
within 24 hours of exposure but can be offered up to 72 hours. 
 The first-line regimen is Truvada and raltegravir 
 Truvada   fixed-dose combination of two antiretroviral medications: 
tenofovir disoproxil and emtricitabine (both are Nucleoside analog reverse-
transcriptase inhibitors (NRTIs)  
 Raltegravir (integrase inhibitors, a new class of HIV drugs ) targets integrase,

an HIV  enzyme that integrates the viral genetic material into human 
chromosomes, a critical step in the pathogenesis of HIV. 
 PEPSE beyond 72 hours are not recommend 
 duration of PEPSE should be 28 days 
 follow-up HIV testing at 8-12 weeks after exposure 
 pregnancy should not alter the decision to start PEPSE. Women must be 
counselled that antiretroviral agents used for PEPSE are unlicensed in pregnancy 
and risks / benefits must be carefully discussed

and risks / benefits must be carefully discussed 
 In the event of a further high -risk sexual exposure in the last two days of the 
PEPSE course the PEP should be continued for 48 hours after the last high- risk 
exposure 
 If the recip ient has missed more than 48 hours of PEPSE then the course should 
be discontinued. 
Virulence factors 
 Bacteria employ a large number of virulence factors which enable them to colonize the

host and evade/suppress the immune response.  
 The table below shows a select number of virulence factors which are important for the 
exam. 
1337

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   101 
  
Virulence factor  Example organisms 
IgA protease  Streptococcus pneumoniae  
Haemophilus influenzae  
Neisseria gonorrhoeae  
M Protein Streptococcus pyogenes  
Polyribosyl ribitol phosphate capsule Haemophilus influenzae  
Bacteriophage  Corynebacterium diphtheriae  
Spore formation Bacillus anthracis

Spore formation Bacillus anthracis  
Clostridium tetani  
Lecithinase alpha toxin  Clostridium perfringens  
D-glutamate polypeptide capsule Bacillus anthracis  
Actin rockets  Listeria monocytogenes  
 
 New Delhi metallo- beta-lactamase 1   
 is the mutation that leads to carbapenem resistance.  
 Typically found in Klebsiella pneumoniae, Escherichia Coli (E. Coli), Enterobacter 
cloacae and others.

cloacae and others.  
 First line of management is the old antibiotic colistin  and second line may be 
tigecycline. 
 
 D-alanyl-D-lactate   
 D-alanyl-D-lactate  variation leading to loss of affinity to antibiotics is the 
mechanism of VRE (vancomycin resistant enterococci).  
 Vancomycin binds to D- ala-D-ala. 
 
 MexAB-OprM efflux pumps  
 The presence of  MexAB-OprM efflux pumps is one of the mechanisms by which 
pseudomonas aeruginosa is resistant to -lactams, chloramphenicol,

fluoroquinolones, macrolides, novobiocin, sulfonamides, tetracycline, and 
trimethoprim.  
 
 penicillin binding protein 2   
 Alteration to the penicillin binding protein 2  is the mechanism behind methicillin-
resistant staphylococcus aureus.  
 Mutations in the MEC gene  which codes the penicillin binding proteins give 
staphylococcus aureus its resistance.  
Viral haemorrhagic fever

Viral haemorrhagic fever 
 The Viral Haemorrhagic Fevers describe infection by a group of RNA viruses which 
include Yellow fever, Lassa fever and Ebola virus.  
 Examples of viral haemorrhagic fever include: 
 Flaviviridae: dengue, yellow fever 
 Arenaviridae: Lassa fever 
 Filoviridae: Ebola virus 1338

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   102 
  this group of infections must be considered as a differential in returning travellers 
presenting with a fever. 
 They are characterised by initially non specific symptoms such as fever, headache, 
vomiting, sore throat, diarrhoea and myalgic muscle pains, progressing to shock, renal

failure and the presence of disseminated intravascular coagulation (DIC).  
 Investigations characteristically reveal an anaemia with thrombocytopaenia, low 
lymphocyte count, deranged liver function and the presence of DIC.  
West Nile virus 
 West Nile virus is a mosquito-borne zoonotic arbovirus belonging to the genus Flavivirus .  
 It is thought it is spread when a mosquito bites an infected bird and then bites a human.

 Few of those bitten develop symptoms and even fewer progress to severe disease. 
 West Nile virus can be spread via vertical transmission as well as blood transfusions and 
organ transplant. 
 If infected with the virus there are generally three different outcomes:  
1. Asymptomatic (estimated 90%) 
2. A mild febrile syndrome known as West Nile fever, or rarely  
3. Neuro -invasive disease termed West Nile meningitis or encephalitis.

 West Nile fever can present with several vague 'generally unwell' symptoms that tend to 
last three to six days such as: 
 Abdominal pain 
 Diarrhoea  
 Fever 
 Headache 
 Arthralgia  
 Nausea and vomiting 
 Rash  
 Sore throat, and  
 Lymphadenopathy. 
 The following symptoms are suggestive of West Nile encephalitis/meningitis and prompt 
medical attention is required: 
 Confusion and seizures 
 Loss of consciousness or coma  
 Muscle weakness 
 Stiff neck, and

 Stiff neck, and  
 Weakness of one arm or leg (a poliomyelitis-like paralysis). May be 
associated with poliomyelitis-like paralysis 
 Diagnosis can be via blood or cerebral spinal fluid serology for West Nile antibodies. 
More rapid techniques using polymerase chain reaction may be used. 
 Due to the viral nature of the infection the current best treatment is supportive. In general

it has an excellent prognosis. For those rare cases with severe infection it may lead to 
brain damage and death. Approximately 10% of patients with brain inflammation do not 
survive. 
 In 2003 there were 276 deaths attributed to Wes t Nile virus.  
 Interestingly, West Nile Virus is endemic in the avian population. The deaths of large 
numbers of birds in an area may thus herald an imminent epidemic of West Nile virus. 

Whooping cough (pertussis) 
 caused by the bacterium Bordetella pertussis .  gram-negative aerobic coccobacillus  
  Lymphocytosis is typically found.  
 it causes a profound leucocytosis by inhibiting chemokines that normally 
remove white cells from the blood stream. 1339

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   103 
  Pertussis toxin inactivates Gi, an inhibitory protein. Gi normally inhibits activation 
of adenylate cyclase. Therefore, the pertussis toxin inhibits an inhibitor leading 
to increased activity of adenylate cyclase.  
 Pertussis toxin  ↓ Gi  ↑adenylate cyclase

 Pertussis toxin  ↓ Gi  ↑adenylate cyclase  
  The pertussis vaccine is estimated to be 63% to 94% effective in the diphtheria-
pertussis-tetanus (DPT) shot  
  A rare complication is a hemiseizure-hemiplegia syndrome , which is thought to be 
related to post-immunisation hyperthermia rather than direct neurological toxicity.    
 infants under the age of 3 months who are at the highest risk of severe complications, 
hospitalisation and death.

hospitalisation and death.  
  Although it is a bacterial disease, antibiotics do not alter the clinical course once the 
disease is established.  
 Erythromycin, clarithromycin and azithromycin may be given however as they have been 
shown to reduce the period the patient is infective for.  
Yellow fever 
 Type of viral haemorrhagic fever (also dengue fever, Lassa fever, Ebola).  
Aetiology

Aetiology 
 Pathogen: yellow fever virus (genus Flavivirus)  
 linear RNA virus  
 spread by Aedes  mosquitos (primarily Aedes aegypti) 
 incubation period = 2 - 14 days 
 endemic in large parts of South America and Africa but not in Asia.  
 
Features 
 Most patients remain asymptomatic  
 In symptomatic patients: classic progression in three stages 
1. Period of infection (3 –4 days)  
 Sudden onset of fever (up to 41°C) 
 Headaches, chills 
 Nausea, vomiting

 Nausea, vomiting 
 Bradycardia may develop 
2. Period of remission (up to 2 days) 
 Easing of symptoms and decline in fever 
3. Period of intoxication (only in ∼ 15% of symptomatic patients) 
 Hemorrhage 
 Multiorgan dysfunction (e.g., acute kidney and liver failure) 
 Nausea, (bloody) vomiting, abdominal pain, severe jaundice 
 Zone  2 of the liver is most affected in Yellow fever.  
 
yellow fever is suggested by:

yellow fever is suggested by:  
1. Travel to endemic area ( West Africa and Central America ) 
2. Fever, with initial resolution 
3. Progression to jaundice and renal failure 
 
 Leukopenia 
 Thrombocytopenia, Ĺ PTT  
 Signs of organ failure ( acute liver failure, acute renal failure) 
 Virus detection  
 PCR  
 The best test to rule out yellow  fever infection is PCR 
 ELISA  
 Liver biopsy 
 Used for definitive diagnosis  (e.g., postmortem)

 Must not be done while the patient has an active yellow fever infection  1340

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   104 
  May show Councilman bodies 
 Councilman bodies (inclusion bodies) may be seen in the hepatocytes 
 For exam purposes Councilman bodies (eosinophilic inclusion in 
the liver on post mortem) are diagnostic  of yellow fever, although 
they can occasionally be seen in other Viral Haemorrhagic Fevers

such as Crimean Congo Haemorrhagic Fever, (but this is nosocomially 
spread)  
Treatment 
 Symptomatic treatment  
 No specific antiviral treatment is available 
 Yellow fever vaccine  
 the vaccination is the only intervention which could prevent death . 
 a live, attenuated vaccine  that consists of the 17D strain of the virus, grown in 
hens ’ eggs . 
 Administration  
 A single dose is provides life -long protection

 administer at least 10 days before traveling to endemic area. 
 Its us e is contraindicated in: 
 Under six months  
 With previous confirmed anaphylactic reaction to the vaccine 
 previous confirmed anaphylactic reaction to egg 
 thymus disorder 
 immunocompromised due to a congenital condition, disease process or 
Sepsis  
 A 'bundle' is a group of interventions related to a disease process that, when executed

together, result in better outcomes than when implemented individually.  
Sepsis Resuscitation Bundle:    
 Should begin immediately, but must be accomplished within the first six hours  of 
2. Blood cultures obtained prior to antibiotic administration. 
hours for ED admissions and one hour for non-ED ICU admissions.

4. in the event of hypotension and/or lactate > 4 mmol/l (36 mg/dl): 
 Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent). 
 Apply vasopressors for hypotension not responding to initial fluid resuscitation 
5. In the event of persistent hypotension despite fl uid resuscitation (septic shock) and/or 
 Achieve central venous pressure (CVP) of > 8 mm Hg.

 Achieve central venous oxygen saturation (ScvO 2) of > 70%. 
 To be accomplished as soon as possible may be completed within twenty-four hours  of 
1. Low-dose steroids administered for septic shock in accordance with a standardised 
ICU policy.  
2. Glucose control maintained > lower limit of normal, but < 150 mg/dl (8.3 mmol/L). 
3. Inspiratory plateau pressures maintained < 30 cm H 2O for mechanically ventilated 
patients  
 
 1341

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   105 
Acute epiglottitis 
 Acute epiglottitis is rare but serious infection caused by Haemophilus influenzae 
type B.  
  Prompt recognition and treatment is essential as airway obstruction may develop.

  Epiglottitis was generally considered a disease of childhood but in the UK it is now 
more common in adults due to the immunisation programme.  
 The incidence of epiglottitis has decreased since the introduction of the Hib vaccine 
 
Features  
 Rapid onset 
 High temperature, generally unwell   Stridor 
 Drooling of saliva (the most specific 
sign)  
 
Diagnosis 
 the preferred method of diagnosis  direct visualization of the epiglottis  using

nasopharyngoscopy/laryngoscopy  cherry-red epiglottis 
 No attempt should be made to visualise the epiglottis until an  anaesthetist is 
present as there is a high risk of causing acute airway obstruction by touching 
the inflamed tissue. 
 Lateral neck soft-tissue radiography 
 useful screening tool in suspected stable patient. 
 Only 79% of epiglottis cases are diagnosed by neck soft-tissue radiographs  
 The classic findings are: 
 swollen epiglottis (ie, a thumb sign),

 swollen epiglottis (ie, a thumb sign),  
 thickened aryepiglottic folds, and  
 obliteration of the vallecula  (pre-epiglottic space). (vallecula sign).  
 The vallecula is the air pocket found at the level of the hyoid bone 
just anterior to the epiglottis. 
 blood culture  
 cough is specific for croup 
 drooling is specific for epiglottitis 
 laryngomalacia improves in the prone position 
 Unstable patients  immediate airway management.

 Early intubation is essential, especially in cases where there is respiratory 
distress. 
 Stable patients 
 Patients without signs of airway compromise, respiratory difficulty, stridor, or 
drooling, and who have only mild swelling on laryngoscopy may be managed 
without immediate airway intervention by close monitoring in the intensive care 
unit (ICU). 
 Third generation cephalosporin is the treatment of choice. 
 Ceftriaxone is the antibiotic of choice for epiglottitis.

 Close contacts  of patients in whom Haemophilus influenzae  type b is isolated should 
receive rifampin prophylaxis  (20 mg/kg; not to exceed 600 mg/d for 4 d). 
 recurrent episodes of acute epiglottitis in adults is unusual and, when present, 
warrants immune system investigation 
Haemophilus influenzae  requires hemin ( factor X ) and NAD+ ( factor V ) for growth. 
Other Haemophilus  species require only NAD+ and therefore grow on blood agar. 1342

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   106 
 Haemophilus  influenzae  : culture requirements: 
  Read Hemophilus as "HemoFive": · Needs Heme with Factors Five and Ten. 
Animal bites 
 
 The majority of bites seen in everyday practice involve dogs and cats.  
 Dog bites become infected in 10% of cases.

 Dog bites become infected in 10% of cases.  
 These are generally polymicrobial but  the most common isolated organism is  
Pasteurella multocida . 
 cleanse wound 
 current BNF recommendation is co-amoxiclav 
 if penicillin -allergic then doxycycline + metronidazole is recommended 
 January 2011 exam: H/O a dog bite to right hand. What is the most 
appropriate antibiotic therapy?  Co-amoxiclav  

Rocky Mountain spotted fever 
 Rocky Mountain spotted fever (RMSF) is a systemic vasculitis  caused by infection 
with Rickettsia rickettsii , a tick-borne, gram-negative, intracellular bacterium, that 
primarily infects vascular endothelial cells. 
 It is the most common fatal tick -borne infection in the USA 
 Transmitted by bites of the dog or wood tick, which predominantly occur in spring and 
summer throughout much of the United States. 
Feature

Feature  
 Fever, headache, myalgia, rash, vomiting, and history of tick bite are commonly reported; 
however, the absence of any of these does not exclude diagnosis. A history of tick bite 
may not be elicited in up to 45% of cases. 
 The rash usually sparing the face and may involve palms and soles. 
 Signs and symptoms may be difficult to distinguish from those of common viral illnesses, 
leading to delayed diagnosis.

leading to delayed diagnosis. 
 Diagnosis should be considered in any person with a compatible clinical presentation and 
recent outdoor exposure. 
 Late-stage manifestations, such as noncardiogenic pulmonary edema (acute respiratory 
distress syndrome [ARDS])  and cerebral edema,  are consequences of microvascular 
leakage. 
 PCR (polymerase chain reaction) is the most appropriate test 
Treatment

Treatment 
 Doxycycline is the drug of choice  for adults and children and is almost always curative, 
especially if given in the first 5 days of illness. 
 Tetracyclines acts on 30S ribosomes to prevent protein synthesis in the infecting 
organism.  
 Aluminium hydroxide can complex with this antibiotic in the gastrointestinal 
tract, preventing absorption.  Dairy products ingested at the same time can also 
cause this.

cause this.  
 Aluminium hydroxide medication should be stoped till the antibiotic course 
is finished  
 Because the risk of death rises if appropriate therapy is not started before the fifth day of 
illness, doxycycline should be prescribed for suspected Rocky Mountain spotted fever 
before confirmatory diagnostic test results are available. 
 
1343

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   107 
  
Typhus (Rickettsial i nfection)  
 caused by Rickettsia typhi (endemic typhus) or Rickettsia prowazekii (epidemic typhus). 
T 
 Rickettsia prowazekii (epidemic typhus)  is transmitted via human- to-human contact 
through body lice.  
 Arthropod vectors transmit the etiologic agents to humans.

 Presented with fever and rash   
 Both forms of typhus consist of a rash that  classically begins centrally, and spreads 
outwardly  sparing the palms and soles (unlike Rocky Mountain spotted fever)  
 Rocky Mountain Spotted Fever can be distinguished from typhus because its rash 
begins peripherally, and spreads centrally to the palms, soles, and trunk. 
 Doxycycline is the drug of choice for treatment in patients of all ages. 

Histoplasmosis  
 Histoplasm osis is one of the most common systemic fungal infections in the United 
States. It is endemic to the Ohio and Mississippi river valleys  
 often associated with spelunkers ( cave divers ) or patients recently exposed to bird and 
bat droppings.  
Feature  
 The majority are asymptomatic.  
 can closely mimic tuberculosis in symptomatology and imaging. 
  dry cough, shortness of breath, fatigue, and fever

 Disseminated infection causes bilateral adrenal enlargement in 80% of  cases and it 
can result in adrenal insufficiency. 
 Diagnosis: Adrenal biopsy or FNA with Groccott stain (Groccott -stained 
adrenal biopsy ). 
 Chest X -ray often reveals a solitary lung lesion.  
 Disseminated histoplasmosis can cause systemic granulomatous inflammation and 
cavitation, which may be fatal.  
 The organisms can be visualized using methenamine silver or periodic acid- Schiff

staining.  
 On histology  Macrophages containing yeast  
 Histoplasma capsulatum  is a small intracellular yeast that is phagocytosed by 
alveolar macrophages.  
 
 Treatment 
 Itraconazole for 3 -6 months 
Actinomycosis  
Predisposing conditions  include: 
 tooth extractions,  
 fractures of the jaw,  
 periodontal abscesses,  
 foreign bodies penetrating the mucosal barrier (bone splinters, fish bones) or

 suppurating tonsillar crypts.  
 impaired immunity  
Features 
 cervicofacial  actinomycosis 
 the most common manifestation of infection with Actinomyces spp.  
 Initially, cervicofacia l actinomycosis presents either as an acute, usually odontogenic, 
abscess or cellulitis of the floor of the mouth, or as a slowly developing hard, painless, 
reddish or livid swelling.  1344

Notes & Notes for mrcp                                                                                     by  Dr. Yousif Abdallah Hamad   108 
  Small, acute actinomycotic abscesses may heal after surgical drainage a lone. More 
often, however, the acute initial stage is followed by a subacute to chronic course if no 
specific antimicrobial treatment is administered.  
 Chronic disease is characterised by regression of central suppurative foci while the

infection progresse s peripherally; it can spread to involve other parts of the head and 
neck, including the meninges.  
 A quick and comparatively reliable diagnosis is possible microscopically, when sulphur 
granules are present; this is not conclusive, however, as nocardiosis may present 
similarly and has a similar appearance on microscopy.  
 One way to differentiate Actinomyces spp. from Nocardia spp. is through culture: the 
former grow in anaerobic conditions and the latter do not.

Malignant otitis externa 
 Malignant otitis externa is a necrotizing infection of the ear that is commonly 
caused by Pseudomonas aeruginosa .  
 Pseudomonas species are often found swimming pools and hot tubs, and can also 
cause “hot tub folliculitis ”. 
 Susceptible individuals include diabetics and other immunosuppressed patients. 
 Feature  
 Physical exam may reveal discharge from the ear

 severe pain, out of proportion to physical findings, on manipulation of the ear.  
 The disease can affect surrounding bony architecture and cause cranial 
nerve palsies. Such involvement suggests poor prognosis.  
 Treatment  for suspected Pseudomonas infections  anti- pseudomonal 
penicillin such as piperacillin-tazobactam, which is a penicillin paired with a 
beta-lactamase inhibitor. 
Parotid swelling

Parotid swelling  
 causes of bilateral parotid swelling include: 
 Infection with viruses, including mumps, parainfluenza virus type 3, Coxsackie 
viruses and influenza A virus 
 Metabolic diseases, such as: 
 diabetes mellitus  
 uraemia 
 Drugs, such as : 
 phenylbutazone  
 thiouracil 
 Other conditions associated with chronic parotid swelling  include:  
 Alcoholic liver disease  
 Sjögren syndrome 
 Lymphoma 
 Infection with HIV  
 1345

Dermatology 
 
Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  1 
  
By
 
Dermatology
 
updated
 
Contains: 
1/ Passmedicine 2017 (white & black fields) 
2/ on examination 2016 (green fields) 
3/ pastest 2016 (yellow fields) 
5/ other colours: updated UK sources 
 
 1346

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  2 
 Epidermis 
 
 The epidermis is the outermost layer of the skin and is composed of a stratified squamous 
epithelium with an underlying basal lamina 
 It may be divided in to five layers:  
Layer Description 
Stratum corneum Flat, dead, scale-like cells filled with keratin 
Continually shed 
Stratum lucidum Clear layer - present in thick skin only

Stratum granulosum Cells form links with neighbours 
Stratum spinosum Squamous cells begin keratin synthesis  
Thickest layer of epidermis 
Stratum germinativum  The basement membrane - single layer of columnar epithelial cells 
Gives rise to keratinocytes  
Contains melanocytes 
Definitions  
 plaque is a descriptive term for a skin lesion that is raised and greater than 1 cm in 
diameter.

diameter. 
 macule  An area of altered skin colour is irrespective of the size. 
 papule  is a raised lesion less than 1 cm in diameter. 
 ulcer  is a discontinuity of the skin with complete loss of the epidermis and often portions of the 
dermis and subcutaneous fat. 
 vesicle  is a fluid-filled, well-circumscribed raised lesion. 
 Pustule  are small elevation of the skin containing cloudy or purulent material, usually 
consisting of necrotic inflammatory cells .

consisting of necrotic inflammatory cells . 
 Bulla are large vesicle containing serous fluid. 
 Fissure  are cracks in the skin that are narrow but deep. 
 Telangiectasia  are collection of enlarged capillaries visible on the skin or mucous 
1347

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  3 
  Lichenification of the skin is due to epidermal thickening characterised by visible and 
palpable thickening of the skin with accentuation of skin markings. 
 Atrophy  of the skin may be due to loss of epidermis, dermis or subcutaneous tissue. Thinning 
of the epidermis presents as skin that appears thin and translucent. Thinning of the  dermis and

subcutaneous tissue leads to a depression in the skin. 
Acanthosis nigricans 
Describes symmetrical, brown, velvety plaques that are often found on the neck, axilla an d groin 
Causes  
 paraneoplastic phenomenon 
(usually tumours of the GI tract, 
especially adenocarcinoma of the 
stomach ). 
 obesity 
 polycystic ovarian syndrome 
 acromegaly  Cushing's disease 
 familial

 familial 
 Prader-Willi syndrome 
 drugs: oral contraceptive pill, nicotinic acid 
 
Acne rosacea is a chronic skin disease of unknown aetiology 
Features  
 typically affects nose, cheeks and forehead 
 flushing is often first symptom 
 telangiectasia are common 
 later develops into persistent erythema with papules and pustules 
1348

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  4 
  rhinophyma 
 ocular involvement: blepharitis 
 
 topical metronidazole may be used for mild symptoms (i.e. Limited number of p apules and 
pustules, no plaques) 
 more severe disease is treated with systemic antibiotics e.g. Oxytetracycline 
 recommend daily application of a high-factor sunscreen

 camouflage creams may help conceal redness 
 laser therapy may be appropriate for patients with prominent telangiectasia 
Acne vulgaris 
 Acne vulgaris is a common skin disorder which usually occurs in adolescence.  
 It typically affects the face, neck and upper trunk  
 characterised by the obstruction of the pilosebaceous follicle with keratin plugs which results in 
comedones, inflammation and pustules. 
 
 affects around 80-90% of teenagers, 60% of whom seek medical advice 
 acne may also persist beyond adolescence, with 10-15% of females and 5% of  males over 25 
years old being affected 
Pathophysiology  is multifactorial 
 follicular epidermal hyperproliferation  formation of a keratin plug  obstruction of 
pilosebaceous follicle.  
 hormonal activation of sebaceous glands  
 Activity of sebaceous glands may be controlled by androgen,

 although levels are often normal in patients with acne 
 Acne accompanying polycystic ovarian syndrome is caused by modestly raised 
circulating androgen levels. 
 Acne presenting at beyond aged 20 years should always prompt investigation of a 
possible secondary cause.  
 colonisation by the anaerobic bacterium  Propionibacterium acnes 
 inflammation 
 
Classification: Acne may be classified into mild, moderate or severe:

 mild acne : open and closed comedones with or without sparse inflammatory lesion s 
 moderate acne: widespread non-inflammatory lesions and numerous papules and pustules 
 severe acne: extensive inflammatory lesions, which may include nodules, pitting, and scarring 
Features 
 
1349

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  5 
  
Management: A simple step-up management scheme often used in the treatment of acne is as 
follows: 
 single topical therapy (topical retinoids, benzyl peroxide) 
 topical combination therapy (topical antibiotic, benzoyl peroxide, topical retinoid) 
 oral antibiotics: e.g. Oxytetracycline, doxycycline. 
 Improvement may not be seen for 3-4 months.

 Improvement may not be seen for 3-4 months.  
 Minocycline is now considered less appropriate due to the possibility of irreversible 
pigmentation.  
 Gram negative folliculitis may occur as a complication of long-term antibiotic use   
 high-dose oral trimethoprim is effective if this occurs 
 Oral erythromycin may be used for acne in pregnancy . The other drugs are 
 oral isotretinoin: only under specialist supervision

 Ethinylestradiol with cyproterone acetate (Dianette) is useful in some female patients with acne 
unresponsive to standard treatment. 
 There is no role for dietary modification in patients with acne 
 
Weight loss is the most important intervention. 
 
Isotretinoin 
 Isotretinoin is an oral retinoid used in the treatment of severe acne. Two-thirds of patien ts have 
a long term remission or cure following a course of oral isotretinoin  

 teratogenicity: females should ideally be using two forms of contraception (e.g. Com bined oral 
contraceptive pill and condoms) 
 dry skin, eyes and lips: the most common side-effect of isotretinoin 
 low mood 
 raised triglycerides 
 hair thinning 
 nose bleeds (caused by dryness of the nasal mucosa) 
 benign intracranial hypertension: isotretinoin treatment should not be combined with 
tetracyclines for this reason 
 photosensitivity

Alopecia divided into scarring (destruction of hair follicle) and non-scarring (preservation of hair 
follicle) 
Scarring alopecia  
 trauma, burns 
 radiotherapy 
 lichen planus 
 discoid lupus 
 tinea capitis* 
 *scarring may develop in untreated tinea capitis if a kerion develops 1350

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  6 
 Non-scarring alopecia 
 male-pattern baldness 
 drugs: cytotoxic drugs, carbimazole, heparin, oral contraceptive pill, colchicine 
 nutritional: iron and zinc deficiency 
 autoimmune: alopecia areata 
 telogen effluvium (hair loss following stressful period e.g. surgery) 
 trichotillomania

 trichotillomania 
  psychological disorder where patients are compelled to pull their own hair, resulting in 
alopecia.  
 It is typically encountered in teenage females and children 
Cicatricial alopecia (also known as scarring alopecia)  
 
 inflammation injures hair follicles resulting in permanent bald patches with no visib le follicles.  
 inflammation can be seen as redness, scaling and crusting.  
 Common causes include:

 Common causes include: 
 discoid lupus erythematosus, and  
 lichen planopilaris (a variant of lichen planus).  
 Treatment is dependent on the underlying causes but often requires topical corticosteroi ds.  
Alopecia areata 
 Alopecia areata is a presumed autoimmune condition causing localised, well demarcate d 
patches of hair loss.  
Feature 
 localised patches of non-scarring hair loss.

 localised patches of non-scarring hair loss.  
 Remaining hairs have a characteristic 'exclamation mark' appearance, and are tapered 
towards the base.  
 small, broken hairs at the edge of the hair loss 
 More severe involvement may present as alopecia totalis (total loss of scalp hair) or alopecia 
universalis (total loss of all body hair).  
Treatment 
 Hair will regrow in 50% of patients by 1 year, and in 80-90% eventually. Careful ex planation is

therefore sufficient in many patients.  
 Other treatment options include : 
 topical or intralesional corticosteroids 
 the most appropriate treatment for area of hair loss  Intra-lesional 
triamcinolone  
 topical minoxidil 
 phototherapy 
 dithranol 
 contact immunotherapy 
 wigs 
 Androgenetic alopecia   1351

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  7 
  presents after puberty as a more diffuse slow hair loss with characteristic loss over the 
temporal regions and vertex in males. 
 Discoid lupus erythematosus (DLE)   
 presents as scarring alopecia. 
 Areas of alopecia are usually atrophic with visible loss of hair follicles.  
 Patients may have DLE lesions elsewhere.

 Patients may have DLE lesions elsewhere.  
 If not treated early, hair loss is usually irreversible. 
 Telogen effluvium   
 presents with diffuse hair loss and usually presents one to three months after a stressful 
episode, for example, viral illness, surgery, childbirth, emotional stress.  
 Hair loss is never complete and usually stops after three to five months.  
 Subsequent hair regrowth is usually complete. 
 Trichotillomania

 Trichotillomania 
 more commonly seen in children compared to adults.  
 Patients also present with localised hair loss but in a bizarre pattern.  
 Hairs of differing lengths are usually seen within and at the edges of the patches.   
 Patients may or may not volunteer a history of hair pulling. 
Pemphigus vulgaris 
 
 Pemphigus vulgaris is an autoimmune disease caused by antibodies (IgG) directed against

desmoglein 3 , a cadherin-type epithelial cell adhesion molecule.  
 The binding of autoantibodies results in a loss of cell- to-cell adhesion, a process termed 
acantholysis. 
 It is more common in the Ashkenazi Jewish population 
 seen predominantly in patients ages 50-60, but can affect many ages. 
Features 
 mucosal ulceration is common and often the presenting symptom.  Oral involvement is 
seen in 50-70% of patients 
 skin blistering - flaccid, easily ruptured vesicles and bullae.

  Blisters are thin-walled and rupture easily (intact blisters are rarely seen).  
 Lesions are typically painful but not itchy. These may develop months after the initial m ucosal 
symptoms.  
 Nikolsky's describes the spread of bullae following application of horizontal, tange ntial 
pressure to the skin 
 Immunofluorescent staining of a biopsy sample shows deposition of immunoglobulin (IgG) 
directed against to keratinocyte desmosomes and to desmosome-free areas of the

keratinocyte cell membrane, resulting in a 'chicken wire' appearance.  
 acantholysis on biopsy 
1352

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  8 
  
Mucosal ulceration is common with pemphigus  
 steroids 
 immunosuppressants 
Bullous pemphigoid 
 Pemphigoid, erythema multiforme, and herpes are the commonest causes of a bli stering rash.

 Bullous pemphigoid is an autoimmune condition causing sub-epidermal blistering  of the skin. 
  This is secondary to the development of  antibodies against hemidesmosomal proteins 
BP180 and BP230  
 caused by (IgG) autoantibodies against components of the basement membrane. 
 Bullous pemphigoid is more common in elderly patients (over 60 years) .  
 Features  include 
 itchy, tense blisters typically around flexures 
 the blisters usually heal without scarring

 the blisters usually heal without scarring 
 mouth is usually spared* 
 *in reality around 10-50% of patients have a degree of mucosal involvement. It would however be 
unusual for an exam question to mention mucosal involvement as it is seen as a classic 
differentiating feature between pemphigoid and pemphigus. 
 Skin biopsy: immunofluorescence shows IgG and C3 at the dermoepidermal junction  

 Blistering in pemphigoid occurs at the sub-epidermal level - deeper than th e blisters of 
pemphigus vulgaris (which occur at the dermal-epidermal junction); hence the ten se 
blisters seen in pemphigoid. Blisters are thin-walled and fragile in pemphigus - few 
intact blisters are ever seen. 
 In pemphigus vulgaris, mucous membrane involvement is more common, an d intact 
bullae are rare. Skin biopsy for routine and direct immunofluorescence is needed to

differentiate from bullous pemphigoid. 
 referral to dermatologist for biopsy and confirmation of diagnosis 
 oral corticosteroids are the mainstay of treatment 
 topical corticosteroids, immunosuppressants and antibiotics are also used 
1353

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  9 
  Topical corticosteroids may be attempted in patients with mild, localised bullous 
pemphigoid. 
  
Dermatitis herpetiformis  
 autoimmune blistering skin disorder associated with coeliac disea se and gluten sensitivity.  
 it is caused by deposition of IgA in the dermis. 
 
Features

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  10 
  itchy, vesicular skin lesions on the extensor surfaces (e.g. elbows, knees, buttocks) 
Diagnosis 
 
 skin biopsy:  
 direct immunofluorescence shows deposition of IgA  in a granular pattern  in the upper 
dermis  ( in the dermal papillae )(Granular IgA deposits at the basement membrane 
zone) 
 gluten-free diet 
 dapsone

 dapsone  
 
Discoid lupus erythematous 
Pathology 
 it is a chronic type of Cutaneous lupus erythematosus (CLE)  
 characterised b y follicular keratin plugs  
 characterised by a well-demarcated macular rash with erythema, scales, and plaques that 
often results in scarring and atrophy .  
Aetiology  
 thought to be autoimmune in aetiology 
Association

 may occur in the absence  or in association with systemic SLE. 
 Approximately 10% of patients may have signs of SLE. 
1355

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  11 
  generally seen in younger females.  
 occurs 2-3 times more frequently in women than in men 
 more common in African –Caribbean female.   
 
Features 
 erythematous, raised rash, sometimes scaly 
 may be photosensitive 
 more common on face, neck, ears and scalp

 more common on face, neck, ears and scalp 
 lesions heal with atrophy, scarring (may cause scarring alopecia), and pigmentation 
Diagnosis 
 made by biopsy of the lesion.  
 
 1st line  topical potent steroid cream 
 2nd line  oral antimalarials e.g. hydroxychloroquine 
 other options 
 Topical calcineurin inhibitors 
 Intralesional corticosteroids 
 Oral corticosteroids. 
 avoid sun exposure 
Prognosis

Prognosis 
 The risk of progression to SLE  in patients with DLE was demonstrated to be higher than 
previously reported ( 16.7% progression within 3 years of diagnosis,  as compared with 
previous data indicating that <5-10% of patients with DLE progress to SLE). 
  children  with DLE seem to have a higher early rate of progression to SLE (up to 25%) 
indicating that the age at onset might influence disease severity

According to a recent epidemiologic study, approximately 16% of patients with discoid 
lupus erythematosus (DLE) may develop systemic involvement within 3 years of 
 
Ref: emedicine.medscape.com .Updated: May 10, 2017  
https://emedicine.medscape.com/article/1065529-clinical  
 
1356

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  12 
 Discoid lupus erythematous affecting the scalp  
Discoid lupus erythematous affecting the 
face  
 
Contact dermatitis There are two main types of contact dermatitis  
1. Irritant contact dermatitis :  
 common  
 non-allergic reaction due to weak acids or alkalis (e.g. detergents).

 Often seen on the hands.  
 Erythema is typical, crusting and vesicles are rare 
2. Allergic contact dermatitis :  
 type IV hypersensitivity reaction.  
 Uncommon 
  often seen on the head following hair dyes.  
 Presents as an acute weeping eczema, which predominately affects the margins of the  
hairline rather than the hairy scalp itself.  
 Topical treatment with a potent steroid is indicated

Cement is a frequent cause of contact dermatitis. The alkaline nature of cemen t may cause an irritant 
contact dermatitis whilst the dichromates in cement also can cause an allergic contact derma titis 
The main difference between allergic contact dermatitis and irritant contact de rmatitis: 
 The rash caused by allergic contact dermatitis confined to contacted area , whereas in irritant 
contact dermatitis, the rash is more widespread .

In  allergic contact dermatitis the rash usually appears after a day or two  after exposure to the 
allergen, unlike irritant contact dermatitis that appears immediately after the contact with the 
trigger. 
 
1357

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  13 
Pruritus 
The table below lists the main characteristics of the most important causes of pruritus 
Liver disease History of alcohol excess 
Stigmata of chronic liver disease: spider naevi, bruising, palmar erythema, 
gynaecomastia etc

gynaecomastia etc 
Evidence of decompensation: ascites, jaundice, encephalopathy 
Iron deficiency 
anaemia  Pallor 
Other signs: koilonychia, atrophic glossitis, post-cricoid webs, angular stomatitis 
Polycythaemia  Pruritus particularly after warm bath 
'Ruddy complexion' 
Gout 
Peptic ulcer disease 
Chronic kidney 
disease  Lethargy & pallor 
Oedema & weight gain 
Lymphoma  Night sweats 
Splenomegaly, hepatomegaly 
Fatigue 
 
Other causes:

Fatigue 
 
Other causes: 
 hyper- and hypothyroidism 
 diabetes 
 'senile' pruritus 
 Urticaria 
 Uritcaria can be classified into idiopathic, immune, or non-immune.  
 Up to 50% of cases are idiopathic , and no trigger is readily identifiable. 
 skin disorders: eczema, scabies, psoriasis, pityriasis rosea 
Eczema herpeticum

Eczema herpeticum 
 Eczema herpeticum describes a severe primary infection of the skin by herpes simplex virus 1 
or 2. 
Features 
  It is more commonly seen in children with atopic eczema.  
 Typically, the child has a high fever for seven days,  and recurrent attacks can occur. 
 It may affect any site but is most often seen on face and neck. 
Treatment 
 Eczema herpeticum is considered as one of the few dermatological emergencies. 1358

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  14 
  As it is potentially life threatening children should be admitted for IV acyclovir 
 Death can result from physiological disturbances (loss of fluid electrolytes and protein through  
the skin) or dissemination of the virus to brain and other organs or from secondary bacterial 
sepsis.

sepsis. 
 may be further complicated by secondary staphylococcal infection. This is treated by  adding 
oral antibiotics, for example, flucloxacillin 500 mg q.i.d. 
Eczema: topical steroids 
 
Use weakest steroid cream which controls patients symptoms 
 
The table below shows topical steroids by potency  
 
Mild Moderate Potent Very potent 
Hydrocortisone 
0.5-2.5% Betamethasone valerate 
0.025% (Betnovate RD)

0.025% (Betnovate RD) 
 
Clobeta sone  butyrate 
0.05% (Eumovate) Fluticasone propionate 
0.05% (Cutivate) 
 
Betamethasone valerate 
0.1% (Betnovate) Clobeta sol propionate 
0.05% (Dermovate) 
 
Finger tip rule 
 1 finger tip unit (FTU) = 0.5 g, sufficient to treat a skin area about twice that of the flat of  an 
adult hand 
 
Topical steroid doses for eczema in adults 
 
Area of skin Fingertip units per dose 
Hand and fingers (front and back) 1.0 
A foot (all over) 2.0

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  15 
 Area of skin Fingertip units per dose 
Back and buttocks 7.0 
Face and neck 2.5 
An entire arm and hand 4.0 
An entire leg and foot 8.0 
 
The BNF makes recommendation on the quantity of topical steroids that should be pre scribed for an 
adult for a single daily application for 2 weeks: 
 
Area Amount 
Face and neck 15 to 30 g 
Both hands 15 to 30 g

Both hands 15 to 30 g 
Scalp 15 to 30 g 
Both arms 30 to 60 g 
Both legs 100 g 
Trunk 100 g 
Groin and genitalia 15 to 30 g 
 
Pompholyx 
Pompholyx is a type of eczema which affects both the hands (cheiropompholyx) and t he feet 
(pedopompholyx). It is also known as dyshidrotic eczema 
 
Features  
 small blisters on the palms and soles 
 pruritic, sometimes burning sensation

 pruritic, sometimes burning sensation 
 once blisters burst skin may become dry and crack 
 cool compresses 
 emollients 
 topical steroids 
___________________________________________________________ 1360

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  16 
 Nickel dermatitis 
 Nickel is a common cause allergic contact dermatitis and is an example of a type IV 
hypersensitivity reaction. It is often caused by jewellery such as watches 
 It is diagnosed by a skin patch test 
Erythema ab igne

Erythema ab igne 
 Erythema ab igne is a skin disorder caused by over exposure to infrared radiation.  
 It classically presents on the front of the legs due to the patient sitting too close to a  fire or 
heater. It may also arise as a response to chronic hot water bottle use. 
 Characteristic features include reticulated, erythematous patches with hyperpigmentation  and 
telangiectasia.  
 A typical history would be an elderly women who always sits next to an open fire.

 Hypothyroidism can make patients feel cold and hence more likely to sit next a heater / 
fire. 
 If the cause is not treated then patients may go on to develop  squamous cell skin 
cancer.  
 
Erythema ab igne  
Erythema  multiforme  
 
Herpes simplex  virus infection is the commonest cause of Erythema multiforme

 mucocutaneous inflammatory condition, characterised by target lesions that resem ble a bull's 
eye. These usually erupt over 24 to 48 hours and last for 1 to 2 weeks. 
 considered to be a type IV hypersensitivity reaction 
 Typically presents in a symmetrical distribution of lesions over the dorsal surfaces of the 
extensor extremities with minimal mucous membrane involvement. 
Causes  
1361

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  17 
  viruses: herpes simplex virus ( the most common cause ), Orf 
 bacteria: Mycoplasma , Streptococcus  
 drugs: penicillin, sulphonamides, sulphonylureas, barbiturates, carbamazepine, allop urinol, 
NSAIDs, oral contraceptive pill, nevirapine 
 connective tissue disease e.g. Systemic lupus erythematosus, inflammatory bowel disease

 Classification  
 Erythema multiforme minor  (typical targets or raised oedematous papules, with acral 
distribution, without involvement of mucosal sites, and involving <10% total body su rface area) 
 Erythema multiforme major  (typical targets or raised oedematous papules, with acral 
distribution, plus involvement of 1 or more mucosal sites, and involving <10% total body 
surface area) 
Features  
 target lesions

Features  
 target lesions 
 initially seen on the back of the hands / feet before spreading to the torso 
 upper limbs are more commonly affected than the lower limbs 
 pruritus is occasionally seen and is usually mild 
 If symptoms are severe and involve blistering and mucosal involvement the term Stev ens-
Johnson syndrome is used. 
 
Treatment 
 Supportive care and treatment of underlying infection. 
 
Prognosis

Prognosis 
 usually mild and self-limiting disease with the lesions healing within 2 to 3 weeks w ithout 
scarring.  
 
1362

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  18 
  
Related dermatitides 
 Stevens-Johnson syndrome : severe macular (atypical target) lesions that coalesce, resulting 
in epidermal blistering, necrosis, and sloughing. No typical targets. Less than 10% tota l body 
surface area affected. May present with only mucosal involvement..

 Toxic epidermal necrolysis : severe macular (atypical target) lesions that coalesce, resulting 
in epidermal blistering, necrosis, and sloughing. No typical targets. More than 30% total b ody 
surface area affected. 
 Stevens-Johnson/toxic epidermal necrolysis overlap : severe macular (atypical target) 
lesions that coalesce, resulting in epidermal blistering, necrosis, and sloughing. No typical 
targets. Between 10% and 30% total body surface area affected.\

Erythema  multiforme  Stevens-Johnson syndrome  
lesions begin on the extremities Lesions typically begin on the face and trunk.  
Commonly related to infectious diseases 
and not drug exposure.  More than 50% of cases are due to medications 
typical targets. No typical targets. 
Histology  high density of cell infiltrate 
rich in T-lymphocytes. Histology  poor infiltrate of macrophages and 
dendrocytes with strong tumor necrosis factor (TNF)

Stevens-Johnson syndrome   
 severe form of erythema multiforme associated with mucosal involvement and systemic 
symptoms  
 It is now known also as erythema multiforme major 
Features  
1363

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  19 
  rash is typically maculopapular with target lesions being characteristic. May develop into 
vesicles or bullae 
 mucosal involvement 
 systemic symptoms: fever, arthralgia 
Causes 
 bacteria: Mycoplasma, Streptococcus  
 viruses: herpes simplex virus, Orf

 viruses: herpes simplex virus, Orf 
 drugs: penicillin, sulphonamides, carbamazepine, allopurinol, NSAIDs, oral contraceptive pill  
 connective tissue disease e.g. SLE 
Toxic epidermal necrolysis (TEN) 
 TEN is a severe mucocutaneous exfoliative disease with an uncertain pathogenesis and a high 
mortality rate.

mortality rate. 
 TEN is a potentially life-threatening skin disorder that is most commonly seen secondary to a  
drug reaction.  
 In this condition the skin develops a scalded appearance over an extensive area.  
 Some authors consider TEN to be the severe end of a spectrum of skin disorders which 
includes erythema multiforme and Stevens-Johnson syndrome 
 It is often idiopathic but may be associated with: 
 Viral infections 
 Leukaemia 
 Lymphoma, and

 Lymphoma, and 
 Drugs (in particular sulphonamides and anticonvulsants). 
Features 
 systemically unwell e.g. pyrexia, tachycardic 
 positive Nikolsky's sign: the epidermis separates with mild lateral pressure 
Drugs known to induce TEN 
 sulphonamides 
 allopurinol  penicillins 
 NSAIDs 
 
 stop precipitating factor  
 is most likely to improve prognosis 
 supportive care, often in intensive care unit

 supportive care, often in intensive care unit 
 intravenous immunoglobulin has been shown to be effective and is now comm only used first-
line 
 other treatment options include: immunosuppressive agents (ciclosporin and 
cyclophosphamide), plasmapheresis 
Prognosis 
 The risk of death in patients with toxic epidermal necrolysis can be accurately predicted by th e 
toxic epidermal necrolysis-specific severity- of-illness score (SCORTEN).  1364

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  20 
  Each of the following independent prognostic factors  is given a score of one: 
 Age of greater than 40 years;  
 Heart rate of greater than 120 beats per minute;  
 Cancer/hematologic malignancy;  
 Involved body surface area of greater than 10%;  
 Serum urea level of more than 10 mmol/L;  
 Serum bicarbonate level of less than 20 mmol/L;

 Serum glucose level of more than 14 mmol/L.  
 A score of 0-1 indicates a mortality risk of 3.2%;  
 score of 2, 12.1%;  
 score of 3, 35.3%;  
 score of 4, 58.3%;  
 score of 5 or more, 90%.  
Always do a chest x-ray on a patient with erythema nodosum, to exclude sarcoidosis 
Overview 
 inflammation of subcutaneous fat 
 Histology of these lesions shows a vasculitis of small venules and panniculitis.

 typically causes tender, erythematous, nodular lesions 
 usually occurs over shins, may also occur elsewhere (e.g. forearms, thighs) 
 usually resolves within 6 weeks 
 lesions heal without scarring 
Causes 
 infection: streptococci, TB, brucellosis 
 The commonest cause is streptococcal infection. 
 systemic disease: sarcoidosis, inflammatory bowel disease  (ulcerative colitis ), Behcet's , SLE 
 malignancy/lymphoma

 malignancy/lymphoma 
 Drugs (oral contraceptive, sulfonamides, penicillins,  antipyretics, montelukast, Hep B 
vaccination, omeprazole).  
  
1365

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  21 
Erythema induratum (EI)  
 EI is a form of panniculitis characterised by chronic, recurrent, tender, subcutaneous, and  
sometimes  ulcerated  nodules on the lower legs that may also appear elsewhere. 
 (Erythema nodosum also commonly associated with TB but do not ulcerate )

 Females are more frequently affected, with a female: male ratio of 7:1 and it is more frequent 
in younger females. 
 It is found in association with tuberculosis. 
Erythrasma  
 Erythrasma is a generally asymptomatic, flat, slightly scaly, pink or brown rash usually found in  
the groin or axillae.  
 It is caused by an overgrowth of the diphtheroid Corynebacterium minutissimum

 Examination with Wood's light reveals a coral-red fluorescence.  
 Topical miconazole or antibacterial are usually effective. Oral erythromycin may be used for 
more extensive infection 
Erythroderma 
 Erythroderma is a term used when more than 95% of the skin is involved in a rash of any kind  
 Mechanism  
 The mechanism behind erythroderma is most likely from cutaneous thermal 
dysregulation.

dysregulation. 
 Increased blood flow to the skin  leads to heat and fluid loss, and increased 
rate of skin cell turnover and skin sloughing.   
 Causes  of erythroderma 
 Eczema (40%) 
 Psoriasis ( 25%) 
 drugs e.g. gold 
 lymphoma, leukaemia 
 pityriasis rubra pilaris 
 idiopathic 
  often accompanied with fever, shivering and malaise. 
 Erythrodermic psoriasis 
 may result from progression of chronic disease to an exfoliative phase with plaques

covering most of the body. Associated with mild systemic upset 
 more serious form is an acute deterioration. This may be triggered by a variety of 
factors such as withdrawal of systemic steroids. Patients need to be admitted to hospital 
for management 
 1366

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  22 
  
This image shows the generalised 
erythematous rash seen in patients 
with erythroderma, sometimes 
referred to as 'red man syndrome'  
Note the extensive exfoliation 
seen in this patient 
 
Polymorphous light eruption  
 presents most commonly in young females.

 presents most commonly in young females.  
 commonly occurs a few hours after sun-exposure and resolves after a few days, without 
scarring. 
 Various morphologies have been described, for example, macules, papules, patches or 
plaques .  
Fungal nail infections 
Onychomycosis  is fungal infection of the nails. This may be caused by 
 dermatophytes - mainly Trichophyton rubrum, accounts for 90% of cases

 yeasts - such as Candida  
 non-dermatophyte moulds 
Features 
 'unsightly' nails are a common reason for presentation 
 thickened, rough, opaque nails are the most common finding 
 nail clippings 
 scrapings of the affected nail 
 Wood ’s lamp 
 useful, rapid and easy way to confirm the diagnosis  
 Yellow to yellow-green fluorescence is characteristic of fine scales taken from active 
fungal lesions

fungal lesions  
 the sensitivity of this procedure is reduced when patients have taken a recent shower 
1367

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  23 
  
 treatment is successful in around 50-80% of people 
 diagnosis should be confirmed by microbiology before starting treatment 
 dermatophyte infection:  
 first-line: oral terbinafine  
 alternative: oral itraconazole .  
 Treatment duration: 
 for fingernail infections  6 weeks - 3 months  
 for toenails  3 - 6 months

 for toenails  3 - 6 months 
 Candida  infection: mild disease should be treated with topical antifungals (e.g. Amorolfine) 
whilst more severe infections should be treated with oral itraconazole for a period of 12 weeks  
Beau's lines 
 Beau's lines is a benign nail condition that presents as a jagged transverse groove  on the nail 
plate corresponding to an episode of nail growth arrest, which can occur during an episode

of severe medical illness . It usually affects several nails. 
 
Beau's lines  
 
Nail conditions 
 Fungal nail infections  present with thickening and discolouration of the nail plate with 
prominent subungual debris. It usually only affects one or several nails. 
 Nail psoriasis  presents with pitting, onycholysis, subungual debris and yellowish nail 
discolouration. 
 
1368

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  24 
Granuloma annulare 
Basics 
 Granuloma annulare is a benign inflammatory condition of unknown aetiology  
 characterised by dermal papules which can coalesce to form annular plaques.  
 papular lesions that are often slightly hyperpigmented and depressed centrally

 typically occur on the dorsal surfaces of the hands and feet, and on the extenso r aspects of the 
arms and legs 
 Histology reveals foci of degenerative collagen surrounded by areas of granulomatous  
 A number of associations have been proposed to conditions such as diabetes mellitus  but 
there is only weak evidence for this 
 Treatment  Observation  (The eruption should disappear spontaneously.) 
 Locally delivered steroids are effective in resolving the condition.

There are two strains of the herpes simplex virus (HSV) in humans: HSV-1 and HSV-2. Whilst it was 
previously thought HSV-1 accounted for oral lesions (cold sores) and HSV-2 for genital herpes it is 
now known there is considerable overlap 
 
Features  
 primary infection: may present with a severe gingivostomatitis 
 painful genital ulceration 

 gingivostomatitis: oral aciclovir, chlorhexidine mouthwash 
 cold sores: topical aciclovir although the evidence base for this is modest 
1369

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  25 
  genital herpes: oral aciclovir. Some patients with frequent exacerbations may benefit fro m 
longer term aciclovir 
Pregnancy 
 elective caesarean section at term is advised if a primary attack of herpes occurs during 
pregnancy at greater than 28 weeks gestation 
Molluscum contagiosum

Molluscum contagiosum 
 common skin infection caused by molluscum contagiosum virus (MCV), a member of the 
Poxviridae family (DNA) pox virus. 
 The majority of cases occur in children (often in children with atopic eczema), with the 
maximum incidence in preschool children aged 14 years. 
 occurs directly by close personal contact, or  
 indirectly via fomites (contaminated surfaces) such as shared towels and flannels.

 may be spread following scratching to other sites.  
 Typically presents with characteristic pinkish or pearly white papules with a central 
umbilication, which are up to 5 mm in diameter.  
 Lesions appear in clusters in areas anywhere on the body (except the palms of the ha nds and 
the soles of the feet). 
 In children, lesions are commonly seen on the trunk and in flexures, but anogenital lesion s 
may also occur.

may also occur.  
 In adults, sexual contact may lead to lesions developing on the genitalia, pubis, th ighs, and 
lower abdomen.  
 Rarely, lesions can occur on the oral mucosa and on the eyelids. 
 seen in patients with advanced HIV/AIDS (CD4 count less than 200 cells/mm3).  HIV 
antibody test hould be performed  
 
Self-care advice: 
 Reassure people that molluscum contagiosum is a self-limiting condition. 
 Spontaneous resolution usually occurs within 18 months

 Explain that lesions are contagious, and it is sensible to avoid sharing towels, clothing, and  
baths with uninfected people (e.g. siblings) 
 Encourage people not to scratch the lesions. If it is problematic, consider treatment to a lleviate 
the itch 
 Exclusion from school, gym, or swimming is not necessary 
 
Treatment   
 usually not recommended  Watchful waiting  (especially in children) 
 for troublesome lesions  use simple trauma or cryotherapy, depending on the parents'

wishes and the child's age: 
 simple trauma  
 Squeezing (with fingernails) or piercing (orange stick) lesions may be tried, 
following a bath.  
 Treatment should be limited to a few lesions at one time 1370

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  26 
  Cryotherapy may be used in older children or adults, if the healthcare professional is 
experienced in the procedure 
 topical imiquimod  
 topical cantharidin.  
 Oral cimetidine may be attempted in some patients with widespread lesions. 
 Eczema or inflammation can develop around lesions prior to resolution.  
 Treatment may be required if:

 Treatment may be required if: 
 → Itching is problematic; prescribe an emollient and a mild topical corticosteroid 
(e.g. hydrocortisone 1%) 
 → The skin looks infected (e.g. oedema, crusting); prescribe a topical antibiotic 
(e.g. fusidic acid 2%) 
Referral may be necessary in some circumstances: 
 HIV-positive with extensive lesions  urgent referral to a HIV specialist 
 eyelid-margin or ocular lesions and associated red eye  urgent referral to an ophthalmologist

 ano-genital lesions  should be referred to genito-urinary medicine, for screening for other 
sexually transmitted infections 
Impetigo 
 
Impetigo is a superficial bacterial skin infection usually caused by either Staphylcoccus 
aureus  or Streptococcus pyogenes . 
 
Features  
 'golden', crusted skin lesions typically found around the mouth 
 very contagious 
Limited, localised disease

Limited, localised disease 
 topical fusidic acid is first-line 
 topical retapamulin is used second-line if fusidic acid has been ineffective or is not tolerated  
 MRSA is not susceptible to either fusidic acid or retapamulin. Topical mupirocin (Bactroban) 
should therefore be used in this situation 
Extensive disease 
1371

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  27 
  oral flucloxacillin 
 oral erythromycin if penicillin allergic 
  
Erysipelas  
 Erysipelas is a Streptococcus pyogenes  (a group A streptococcal bacterium) infection of the 
deep dermis and subcutis. 
Feature

Feature 
 It is a tender, intensely erythematous, indurated plaque with a sharply demarcated borde r.  
 Its well-defined margin can help differentiate it from other skin infections (eg, ce llulitis). 
Treatment  
 IV antibiotics such as benzylpenicillin and erythromycin. 
 In a penicillin allergic patient a macrolide is the drug of choice  .There is a 10% cross 
allergy between cephalosporins and penicillins. 
 sepsis  
 cerebral abscess

 sepsis  
 cerebral abscess 
 venous sinus thrombosis. 
 
1372

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  28 
  
Well-demarcated, erythematous plaque of 
erysipelas .  
 
Leprosy 
 Leprosy is a granulomatous disease primarily affecting the peripheral nerves and skin.  
 It is caused by Mycobacterium leprae . 
 Features

 Features 
 patches of hypopigmented skin typically affecting the buttocks, face, and extensor 
 sensory loss 
 The degree of cell mediated immunity determines the type of leprosy a patient will d evelop. 
 Low degree of cell mediated immunity → lepromatous leprosy ('multibacillary')  
 symmetrical nerve involvement 
 High degree of cell mediated immunity → tuberculoid leprosy ('paucibacillary')  
 limited skin disease

 limited skin disease 
 Management: WHO-recommended triple therapy: rifampicin, dapsone and clofazimine  
Koebner phenomenon  describes skin lesions which appear at the site of injury. It is seen in:  
 vitiligo 
 warts 
 lichen sclerosus 
 molluscum contagiosum 
1373

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  29 
Lichen planus 
 
Lichen planus is a skin disorder of unknown aetiology, most probably being immune mediated . 
 
Features  
 itchy, papular rash most common on the palms, soles, genitalia and flexor surfa ces of arms

 rash often polygonal in shape, 'white-lace' pattern on the surface (Wickham's striae) 
 Koebner phenomenon may be seen (new skin lesions appearing at the site of traum a) 
 oral involvement in around 50% of patients 
 nails: thinning of nail plate, longitudinal ridging 
 Fibrin deposits at the basement membrane zone  are found in cases of lichen planus , 
although immunofluorescence studies are uncommonly done to diagnose it. 
 
Lichenoid drug eruptions - causes:

Lichenoid drug eruptions - causes: 
 gold 
 quinine 
 thiazides 
1374

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  30 
 topical steroids are the mainstay of treatment 
 extensive lichen planus may require oral steroids or immunosuppression 
Lichen sclerosus 
 Lichen sclerosus was previously termed lichen sclerosus et atrophicus.

 It is an inflammatory condition which usually  affects the genitalia and is more common in 
elderly females.  
 Lichen sclerosus leads to atrophy of the epidermis with white plaques forming 
 
Features 
 itch is prominent 
Diagnosis 
 usually made on clinical grounds but a biopsy may be performed if atypical featu res are 
present* 
 topical steroids and emollients 
Follow- up 
 increased risk of vulval cancer 
*the RCOG advise the following

*the RCOG advise the following  
 
 Skin biopsy is not necessary when a diagnosis can be made on clinical examination. Biopsy is 
required if the woman fails to respond to treatment or there is clinical suspicion of VIN or 
cancer.  
and the British Association of Dermatologists state the following: 
 
 A confirmatory biopsy, although ideal, is not always practical, particularly in children. It is not

always essential when the clinical features are typical. However, histological examination is 
advisable if there are atypical features or diagnostic uncertainty and is mandatory if there is 
any suspicion of neoplastic 
change. 
  Patients under routine follow-up will need a biopsy if:  
(i) there is a suspicion of neoplastic change, i.e. a persistent area of hyperkeratosis, 
erosion or erythema, or new warty or papular lesions; 
(ii) the disease fails to respond to adequate treatment;

(iii) there is extragenital LS, with features suggesting an overlap with morphoea; 
(iv) there are pigmented areas, in order to exclude an abnormal melanocytic 
proliferation; 
(v) second-line therapy is to be used. 
 
 1375

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  31 
Lichen simplex chronicus (LSC)  
 LSC presents with hyperpigmented, scaly, lichenified plaques.  
 Patients may volunteer a history of chronic scratching or manipulation, especially during times 
of stress.  
 The ankles are common sites for LSC.

 The ankles are common sites for LSC. 
 
Lichen amyloidosis 
 Lichen amyloidosis is a primary, localised cutaneous amyloidosis (amyloid deposition in the 
skin).  
 It results in intensely itchy shiny or hyperkeratotic, pigmented macules and occurs most 
commonly in South East Asia.  
 It appears that itching drives further amyloid deposition, and treatments are therefore directed

at reducing the sensation of itching - for example, with the use of antihistamines and intra-
lesional/topical corticosteroids. 
 
1376

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  32 
Onycholysis 
Onycholysis describes the separation of the nail plate from the nail bed 
Causes  
 trauma e.g. Excessive manicuring 
 infection: especially fungal 
 skin disease: psoriasis, eczema, dermatitis 
 impaired peripheral circulation e.g. Raynaud's

 impaired peripheral circulation e.g. Raynaud's 
 systemic disease: hyper- and hypothyroidism 
 Tetracycline  
Parvovirus B19 
Parvovirus B19 is a DNA virus which causes a variety of clinical presentations. It was identifie d in the 
1980's as the cause of erythema infectiosum 
Erythema infectiosum  (also known as fifth disease or 'slapped-cheek syndrome') 
 most common presenting illness

 most common presenting illness 
 systemic symptoms: lethargy, fever, headache 
 'slapped-cheek' rash spreading to proximal arms and extensor surfaces 
Other presentations 
 pancytopaenia in immunosuppressed patients 
 aplastic crises e.g. in sickle-cell disease (parvovirus B19 suppresses erythropoiesis for about a 
week so aplastic anaemia is rare unless there is a chronic haemolytic anaemia) 
Pityriasis rosea

Pityriasis rosea  
 describes an acute, self-limiting rash which tends to affect young adults. occurs most 
commonly in people between the ages of 10 and 35 years. 
 The aetiology is not fully understood but is thought that herpes hominis virus 7 (HHV- 7) may 
play a role.   does not appear to be contagious;  
 aetiology is unknown 
Features 
 herald patch (usually on trunk) 
 followed by erythematous, oval, scaly patches  which follow a characteristic distribution with

the longitudinal diameters of the oval lesions running parallel to the line of Langer. Th is may 
produce a 'fir-tree' appearance 
 can be pruritic or asymptomatic 
 self-limiting, usually disappears after 4-12 weeks 
  moisturisers can help the pruritus 
 1377

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  33 
  
On the left a typical herald patch is seen. After a few days a more generalised 'fir-tree' rash appears 
Pityriasis versicolor also called tinea versicolor, is a superficial cutaneous fungal 
infection caused by Malassezia furfur (formerly termed Pityrosporum ovale) 
 
Features

Features  
 most commonly affects trunk 
 patches may be hypopigmented, pink or brown (hence versicolor) 
 scale is common 
 mild pruritus 
Predisposing factors 
 occurs in healthy individuals 
 immunosuppression 
 malnutrition 
 Cushing's 
 topical antifungal. NICE Clinical Knowledge Summaries advise ketoconazole shampoo a s this 
is more cost effective for large areas 
 Topical selenium sulphide

 Topical selenium sulphide 
 if extensive disease or failure to respond to topical treatment then consider oral itraconazole 
200 mg once a day for seven days. 
Psoriasis 
 Psoriasis is a chronic relapsing inflammatory skin disorder most commonly characterised by 
erythematous, sharply demarcated papules and rounded plaques covered by silvery scales.   
 prevalence around 2%.

 prevalence around 2%. 
 there are two peaks of incidence at 16-22 years and 57-60 years.  
 Males and females are equally affected. 
1378

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  34 
 multifactorial and not yet fully understood 
 genetic:  
 polygenic inheritance 
 associated HLA-B13, -B17, and -Cw6.  
 European populations are commonly affected, 
 Strong concordance (70%) in identical twins 
 immunological:  
 abnormal T cell activity stimulates keratinocyte proliferation.

 may be mediated by T helper cells producing IL-17. 
 IL-17 is a pro-inflammatory cytokine which is expressed at high levels in 
psoriasis lesions. 
 Ixekizumab is an anti- IL-17 antibody which binds to IL-17, it is effective in 
treating active psoriasis and in reducing the risk of recurrence. 
 environmental: 
 psoriasis may be worsened (e.g. Skin trauma, stress), triggered (e.g. 
Streptococcal infection) or improved (e.g. Sunlight) by environmental factors

  increase in mitotic activity of the cells in the malpighian layer of the epidermis 
 The Malpighian layer  of the skin is generally defined as both the stratum 
basalis and stratum spinosum as a unit. 
Recognised subtypes of psoriasis 
 plaque psoriasis : the most common sub-type resulting in the typical well demarcated red, 
scaly patches affecting the extensor surfaces, sacrum and scalp 
 flexural psoriasis : in contrast to plaque psoriasis the skin is smooth

 guttate psoriasis : transient psoriatic rash frequently triggered by a streptococcal infection. 
Multiple red, teardrop lesions appear on the body 
 pustular psoriasis : commonly occurs on the palms and soles 
 
Features 
 Salmon colored skin plaques with silvery scales 
 Psoriasis may occur in hidden sites , such as the scalp (where psoriasis frequently is mistaken 
for dandruff), perineum, intergluteal cleft, and umbilicus

 The scalp is often involved in psoriasis. Most commonly, it causes a telogen effluvium, 
that is, the hair follicles are forced into the telogen resting stage.  
1379

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  35 
  nail signs: pitting, onycholysis 
 New lesions often appear at sites of injury or trauma (Koebner phenomenon), which typically 
occurs one to two weeks after the skin has been damaged.  
 Auspitz sign: small bleeding spots when psoriasis scales are scraped off. 
 Psoriasis can be associated with an anterior uveitis  

 psoriatic arthropathy (around 10%) 
 This can range from mild distal interphalangeal joint involvement with nail pitting to 
severe arthritis mutilans. 
 increased incidence of metabolic syndrome 
 increased incidence of cardiovascular disease 
 increased incidence of venous thromboembolism 
 psychological distress 
 
Diagnosis  
 usually clinical  
 skin biopsy is rarely required to confirm psoriasis.

 Hyperkeratosis (described as an increased thickness of the stratum corneum) ,  
 Parakeratosis, defined as hyperkeratosis with retention of nuclei in the stratum 
corneum,  
 Munro's microabscess  ( or neutrophils ) in the stratum corneum  of the epidermis are 
a cardinal sign   
 
Exacerbating factors 
 
 trauma 
 alcohol 
 drugs:  
 beta blockers ,  
 lithium ,  
 antimalarials (chloroquine and hydroxychloroquine),   
 gold salts,  
 NSAIDs,  
 ACE inhibitors,  
 infliximab

 NSAIDs,  
 infliximab 
 antibiotics such as tetracycline and penicillin  
 withdrawal of systemic steroids 
 Notes 
 Reactions may occur from less than one month to one year after the medication is 
 the effect of antimalarials on trans-glutaminase activity leads to stimulation of ep idermal 
proliferation 
1380

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  36 
  beta blockers  is more common than ACEi 
 
Topical potent corticosteroid + vitamin D analogue is first-line for chronic plaque psoriasis 
 
Management of chronic plaque psoriasis ( NICE guidelines 2012 ) 
 regular emollients may help to reduce scale loss and reduce pruritus 
 First-line :

 First-line :  
 potent corticosteroid applied once daily plus vitamin D analogue applied once 
daily  (applied separately, one in the morning and the other in the evening) for up to 4 
weeks as initial treatment 
 Second-line :  
 if no improvement after 8 weeks then offer a vitamin D analogue twice daily 
 Third-line :  
 if no improvement after 8-12 weeks then offer either: a potent corticosteroid applied

twice daily  for up to 4 weeks or a coal tar preparation applied once or twice daily 
 short-acting dithranol can also be used 
 
Using topical steroids in psoriasis 
 as we know topical corticosteroid therapy may lead to skin atrophy, striae and rebound 
symptoms 
 systemic side-effects may be seen when potent corticosteroids are used on large areas e.g . > 
10% of the body surface area 
 NICE recommend that we aim for a 4 week break before starting another course of topical

 they also recommend using potent corticosteroids for no longer than 8 weeks at a time and 
very potent corticosteroids for no longer than 4 weeks at a time 
What should I know about vitamin D analogues? 
 examples of vitamin D analogues include calcipotriol (Dovonex), calcitriol and tacalcitol 
 they work by reducing cell division and differentiation 
 adverse effects are uncommon 
 unlike corticosteroids they may be used long-term

 unlike coal tar and dithranol they do not smell or stain 
 they tend to reduce the scale and thickness of plaques but not the erythema 
 they should be avoided in pregnancy 
 the maximum weekly amount for adults is 100g 
 
 1381

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  37 
  
A 'before and after' image showing the effect of 6 weeks of calcipotriol therapy on a l arge plaque. 
Note how the scale has improved but the erythema remains 
Steroids in psoriasis 
 topical steroids are commonly used in flexural psoriasis and there is also a role for mild

steroids in facial psoriasis. If steroids are ineffective for these conditions vitamin D analogues 
or tacrolimus ointment should be used second line 
 patients should have 4 week breaks between course of topical steroids 
 very potent steroids should not be used for longer than 4 weeks at a time. Poten t steroids can 
be used for up to 8 weeks at a time 
 the scalp, face and flexures are particularly prone to steroid atrophy so topical steroids should

not be used for more than 1-2 weeks/month 
Scalp psoriasis 
Scalp psoriasis - first-line treatment is topical potent corticosteroids 
 
 potent topical corticosteroids used once daily for 4 weeks 
 if no improvement after 4 weeks go to second line 
 use different formulation of the potent corticosteroid (for example, a shampoo or 
mousse) and/or   
 topical agents to remove adherent scale (for example, agents containing salicy lic acid,

emollients and oils) before application of the potent corticosteroid 
 
1382

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  38 
 Face, flexutal and genital psoriasis 
 
 mild or moderate potency corticosteroid applied once or twice daily for a maximum of 2 we eks 
eg: clobetasone butyrate once a day  
 
Secondary care management  
 
Phototherapy 
 narrow band ultraviolet B-light is now the treatment of choice. If possible th is should be given 3 
times a week

times a week 
 photochemotherapy is also used - psoralen + ultraviolet A light (PUVA) 
 adverse effects: skin ageing, squamous cell cancer (not melanoma) 
Systemic therapy 
 topical are not effective  and 
 person is impacted physically, psychologically, or socially by the problem and 
 one or more of the following apply: 
 extensive psoriasis ( eg, > 10% of body surface area affected or a PASI score of 
> 10) or

> 10) or 
 localised psoriasis and associated with significant functional impairment and/or 
high levels of distress (for example severe nail disease or involvement at high-
impact sites) or 
 phototherapy has been ineffective, cannot be used or has resulted in rapid 
relapse (rapid relapse is defined as greater than 50% of baseline disease 
severity within 3 months). 
 Methotrexate  
 Oral methotrexate is used first-line.  It is particularly useful if there is associated joint 
disease

disease 
 Ciclosporin 
 Offer ciclosporin as the first choice in patients who need rapid or short-term disease 
control (for example a  
 psoriasis flare  
 palmoplantar pustulosis 
  or considering conception (both men and women) and systemic therapy cannot 
be avoided. 
 Consider changing from methotrexate to ciclosporin (or vice-versa) when response to 
the first-choice systemic treatment is inadequate. 
 Systemic retinoids (acitretin)

 Systemic retinoids (acitretin) 
 if methotrexate and ciclosporin are not appropriate or have failed or 
 for people with pustular forms of psoriasis. 
 biological agents: infliximab, etanercept and adalimumab 
 In situation with uncontrolled psoriasis and psoriatic arthritis , early instigation of a 
biological is recommended.  
1383

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  39 
  TNF alpha is a pro-inflammatory cytokine closely linked to the severity of psoriasis, and 
etanercept , a TNF alpha antagonist is the most appropriate intervention .  
 Tuberculosis and viral hepatitis should be ruled out prior to starting therapy.  
 Brodalumab is an anti-IL17 monoclonal antibody which has completed registration trials

for psoriasis. It's likely to be reserved however for patients who fail to gain control on 
other interventions.  
 ustekinumab  (IL-12 and IL-23 blocker) is showing promise in early trials 
 it is not an anti- TNF agent (so did not  reactivate TB) 
 common  dental infection  
 uncommon  depression and injection site reaction  
Mechanism of action of commonly used drugs: 
 coal tar: probably inhibit DNA synthesis

 coal tar: probably inhibit DNA synthesis 
 calcipotriol: vitamin D analogue which reduces epidermal proliferation and restores a normal 
horny layer 
 dithranol: inhibits DNA synthesis, wash off after 30 mins, SE: burning, staining 
Contra-indication: 
 Oral steroids are contraindicated in psoriasis and although one may see an initial 
improvement, a very serious rebound effect may be seen.  
Question:

Question: 
An elderly man with learning difficulties, is admitted to hospital with an acute exacerbation of 
congestive cardiac failure and severe raised plaques of psoriasis covering his chest, elbows, knees 
and scalp. he has been treating it with topical creams for years but has seen no improvem ent. What 
treatment would you recommend for his psoriasis? 
 Refer for PUVA  
 The safest treatment - that which produces the best clinical effect with minimal

side effects in this patient - would be psoralen and ultraviolet light (PUVA).  
 Emollients, baths and use of methotrexate require a fair amount of input fro m the 
patient in order to be effective and safe, which may not be the best option in this 
man.  
 
MRCPUK -part-1-sep 2017 : Which medication is of most concern with respect to worsening of 
psoriasis? 
 Atenolol  
 
Psoriasis: guttate 
 Guttate psoriasis is more common in children and adolescents.

 It may be precipitated by a streptococcal infection 2-4 weeks prior to the lesions appearing 
 
Features  
 tear drop 'drop-like' papules on the trunk and limbs 
 1384

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  40 
   
 if lesions are not widespread (<10% body surface area) and the person is not impacted 
physically, psychologically, or socially by the problem: 
 No treatment required  
 most cases resolve spontaneously within 2-3 months 
 If the lesions are not widespread (<10% body surface area) and treatment is desired:

 topical agents as per psoriasis. 
 If lesions are widespread (>10% body surface area ):  
 refer urgently to a dermatologist  as phototherapy (UVB phototherapy) can be 
 with recurrent episodes  referral to ENT should be considered   tonsillectomy may 
be necessary  
 Although guttate psoriasis can be triggered by an acute sore throat, it is not recommend ed to 
treat guttate psoriasis with anti-streptococcal antibiotics. 
 
1385

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  41 
  
Differentiating guttate psoriasis and pityriasis rosea  
 
Guttate psoriasis Pityriasis rosea 
Prodrome  Classically preceded by a 
streptococcal sore throat 2-4 weeks Many patients report recent respiratory tract 
infections but this is not common in questions 
Appearance  'Tear drop', scaly papules on the

Appearance  'Tear drop', scaly papules on the 
trunk and limbs Herald patch followed 1-2 weeks later by multiple 
erythematous, slightly raised oval lesions with a fine 
scale confined to the outer aspects of the lesions.  
 
May follow a characteristic distribution with the 
longitudinal diameters of the oval lesions running 
parallel to the line of Langer. This may produce a 
'fir-tree' appearance 
Treatment /  
natural 
history  Most cases resolve spontaneously 
within 2-3 months

within 2-3 months 
Topical agents as per psoriasis 
UVB phototherapy Self-limiting, resolves after around 6 weeks 
 
 Guttate psoriasis   
 A 46-year-old man presents with an 
extensive pruritic rash shown in 
picture A. 
 Two weeks previously he had a 
sore throat with the appearance 
shown in picture B. 
 
1386

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  42 
  
Overview  
 Pyoderma gangrenosum typically is an expanding ulcer with a polycyclic or serpiginous outline 
and a characteristic undermined bluish edge. 
 The pathogenesis is unknown, and is presumed to be immunological. 
Features 
 typically on the lower limbs

Features 
 typically on the lower limbs 
 It is most common on the lower limb and in scars or sites of previous trauma. 
 initially small red papule 
 later deep, red, necrotic ulcers with a violaceous border 
 may be accompanied systemic symptoms e.g. Fever, myalgia 
Causes* 
 idiopathic in 50% 
 inflammatory bowel disease: ulcerative colitis , Crohn's 
 Estimates of the prevalence in inflammatory bowel disease (IBD) range between 2% 
and 5%.

and 5%.  
 It tends to be associated with colonic involvement and is perhaps slightly more 
common in patients with UC.  
 rheumatoid arthritis, SLE 
 myeloproliferative disorders 
 lymphoma, myeloid leukaemias 
 monoclonal gammopathy (IgA) 
1387

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  43 
  
*note whilst pyoderma gangrenosum can occur in diabetes mellitus it is rare and is generally not  included in a 
differential of potential causes   
 
 the potential for rapid progression is high in most patients and most doctors advocate oral 
steroids as first-line treatment

steroids as first-line treatment 
 other immunosuppressive therapy, for example ciclosporin and infliximab, have a  role in 
difficult cases 
Scabies 
 
 Scabies is caused by the mite Sarcoptes scabiei and is spread by prolonged skin contact.  
 The scabies mite burrows into the skin, laying its eggs in the stratum corneum.

 The intense pruritus associated with scabies is due to a delayed type IV hypersensitivity  
 
Features 
 Scabies can present with an itchy dermatitic-looking rash on the body, but the 
clues are at certain sites (soles, genitalia, buttocks) 

 Burrows (linear crusted lesions of a few millimetres in length) are pathognomonic 
  It has a predilection for the web-spaces and around the nipples.  
 permethrin 5% is first-line 
 malathion 0.5% is second-line 
 pruritus persists for up to 4-6 weeks post eradication

1388

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  44 
  permethrin cream doesn't have any direct effect on the pruritis itself but helps to sett le 
symptoms indirectly by killing the mite, which is the root cause.  
 You should counsel your patients that it may take longer for the itching to settle as the  allergic 
reaction to the mite abates

reaction to the mite abates  
 the cream should be applied everywhere below the neck, not merely where there is rash  
present. 
 avoid close physical contact with others until treatment is complete 
 all household and close physical contacts should be treated at the same time, ev en if 
 launder, iron or tumble dry clothing, bedding, towels, etc., on the first day of treatme nt to kill off 
mites.

mites. 
The BNF advises to apply the insecticide to all areas, including the face and scalp, contrary to t he 
manufacturer's recommendation.  
Patients should be given the following instructions: 
 pay close attention to areas between fingers and toes, under nails, armpit area,  creases of the 
skin such as at the wrist and elbow 
 allow to dry and leave on the skin for 8-12 hours for permethrin, or for 24 hou rs for malathion,

before washing off 
 reapply if insecticide is removed during the treatment period, e.g. If wash han ds, change 
nappy, etc 
 Crusted scabies is seen in patients with suppressed immunity, especially HIV.  
 The crusted skin will be teeming with hundreds of thousands of organisms.  
 Ivermectin is the treatment of choice and isolation is essential  

Seborrhoeic dermatitis  
 Seborrhoeic dermatitis in adults is a chronic dermatitis thought to be caused by an 
inflammatory reaction related to a proliferation of a normal skin inhabitant, a fungus calle d 
Malassezia furfur  (formerly known as Pityrosporum ovale). 
  It is common, affecting around 2% of the general population 
 
Features  
 eczematous lesions on the sebum-rich areas: scalp (may cause dandruff), periorbital, auric ular 
and nasolabial folds

and nasolabial folds 
 otitis externa and blepharitis may develop 
Associated conditions  include 
 HIV 
  in patients with HIV the prevalence of seborrheic dermatitis may be as high as 
80%.  
 the most useful next step  HIV testing 
Scalp disease management 1389

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  45 
  Dandruff is an uninflamed form of seborrheic dermatitis and presents as scaly patches  
scattered within hair-bearing areas of the scalp.  
 over the counter preparations containing zinc pyrithione ('Head & Shoulders') and tar 
('Neutrogena T/Gel') are first-line 
 the preferred second-line agent is ketoconazole

 selenium sulphide and topical corticosteroid may also be useful 
Face and body management 
 
 topical antifungals: e.g. Ketoconazole 
 topical steroids: best used for short periods 
 difficult to treat - recurrences are common 
Shin lesions 
The differential diagnosis of shin lesions includes the following conditions: 
 erythema nodosum 
 pretibial myxoedema 
 pyoderma gangrenosum 
 necrobiosis lipoidica diabeticorum

 necrobiosis lipoidica diabeticorum 
Below are the characteristic features: 
 
Erythema nodosum  
 symmetrical, erythematous, tender, nodules which heal without scarring 
 most common causes are streptococcal infections, sarcoidosis, inflammatory bowel disease 
and drugs (penicillins, sulphonamides, oral contraceptive pill) 
Pretibial myxoedema 
 symmetrical, erythematous lesions seen in Graves' disease 
 shiny, orange peel skin 
 initially small red papule

 idiopathic in 50%, may also be seen in inflammatory bowel disease, connective tissue 
disorders and myeloproliferative disorders 
Necrobiosis lipoidica diabeticorum 
 shiny, painless areas of yellow/red skin typically on the shin of diabetics 
 often associated with telangiectasia 
Skin disorders associated with diabetes

Skin disorders associated with diabetes 
Note whilst pyoderma gangrenosum can occur in diabetes mellitus it is rare and is often not included 
in a differential of potential causes 
 
Necrobiosis lipoidica  
1390

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  46 
  a disorder of collagen degeneration with a granulomatous response, thickening of blood  vessel 
walls, and fat deposition. 
 It is usually related to diabetes, but can also occur in patients with rheumatoid arthritis 
 The exact cause of necrobiosis lipoidica is unknown, but the leading theory of necro biosis

lipoidica in diabetes has focused on diabetic microangiopathy. 
 shiny, painless areas of yellow/red/brown skin typically on the shin 
 often associated with surrounding telangiectasia 
 Necrobiosis is often mistaken for eczema, but rather than responding to steroids it may 
actually deteriorate. 
 Occasionally ulceration of the lesion may occur. 
 Necrobiosis is typically painless. 
Infection 
 candidiasis 
 staphylococcal 
 
Neuropathic ulcers 
 
Vitiligo 
 
Lipoatrophy

Vitiligo 
 
Lipoatrophy  
 
Granuloma annulare*  
 papular lesions that are often slightly hyperpigmented and depressed centrally 
 *it is not clear from recent studies if there is actually a significant association between diab etes mellitus 
and granuloma annulare, but it is often listed in major textbooks 
Polymorphic eruption of pregnancy

Polymorphic eruption of pregnancy 
 
 also known as Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP) 
 pruritic condition associated with last trimester 
 lesions often first appear in abdominal striae 
 management depends on severity: emollients, mild potency topical steroids and oral st eroids 
may be used 
1391

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  47 
  
Polymorphic eruption of pregnancy  
 
Pemphigoid gestationis  
 pruritic blistering lesions 
 often develop in peri-umbilical region, later spreading to the trunk, back, buttocks and arms  
 usually presents 2nd or 3rd trimester and is rarely seen in the first pregnancy

 oral corticosteroids are usually required 
 
Pemphigoid gestationis 
 
Melasma   
 Melasma is a benign but relatively common skin condition which can appear in pregnancy.  
 it may resolve a few months after delivery. 
1392

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  48 
 Chloasma 
 Chloasma is a hormonally stimulated increase in melanogenesis that mainly appears on t he 
face.  
 The pigment is augmented by sunlight 
 On testing, levels of melanocyte-stimulating hormone are normal  
 more likely to occur in women with darker skin tones 
Causes 
 Pregnancy  
 combined oral contraceptive pill  

 The pigmentation may take many months to resolve after parturition or pill discontinu ation  
 avoid prolonged sunlight exposure or to use a sunblock 
Skin disorders associated with tuberculosis 
Possible skin disorders 
 lupus vulgaris (accounts for 50% of cases) 
 scarring alopecia 
 scrofuloderma: breakdown of skin overlying a tuberculous focus

 verrucosa cutis 
 gumma 
Lupus vulgaris  
 the most common form of cutaneous TB seen in the Indian subcontinent.  
 Cutaneous TB usually occurs due to spread from an endogenous source  
 It generally occurs on the face and is common around the nose and mouth.   
 more than 80% of cases occur on the face and neck. 
 The initial lesion is an erythematous flat plaque which gradually becomes eleva ted and may 
ulcerate later

ulcerate later 
 Diagnosis:  On diascopy, it shows characteristic "apple-jelly" color. Biopsy will reveal 
tuberculoid granuloma with few bacilli. Mantoux test is positive.  
 Treated with combination of drugs used for tuberculosis, such 
as Rifampicin, Isoniazid and Pyrazinamide (with either streptomycin or ethambutol)  
Spider nevi  
 most common on the face and upper chest.  
 typically asymptomatic

 typically asymptomatic 
 usually resolve spontaneously.  
 Causes 
 chronic liver disease  
 the presence of more than five lesions is likely to be due to chronic liver disease. 
  may resolve when liver function increases or when a liver transplant is 
performed. 1393

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  49 
  the cause of the spider nevi  patients cannot metabolize 
circulating  estrogen  
 may resolve after childbirth.  
 oral contraceptives,  
 may resolve after stopping the contraceptives.  
 
forehead lesion (spider nevus (nevus araneus)) 
Tinea

Tinea 
 Tinea is a term given to dermatophyte fungal infections.  
 Three main types of infection are described depending on what part of the body  is infected 
1. tinea capitis - scalp 
2. tinea corporis - trunk, legs or arms 
3. tinea pedis - feet 
Tinea capitis  (scalp ringwor m) 
 a cause of scarring alopecia mainly seen in children 
 if untreated a raised, pustular, spongy/boggy mass called a kerion may form 
 Causes

 Causes 
 most common cause is Trichophyton tonsurans  in the UK and the USA  (>90% of 
cases)  
 may also be caused by Microsporum canis  acquired from cats or dogs 
 the most useful investigation is scalp scrapings 
 lesions due to Microsporum canis  green fluorescence under Wood's lamp ( but do not 
fluoresce if caused by Trichophyton tonsurans .)*.  
 *lesions due to Trichophyton  species do not readily fluoresce under Wood's lamp

 Management  (based on CKS guidelines): oral antifungals:  
 Terbinafine for Trichophyton tonsurans  infections  
 Although not licensed in young children, a four-week  course of the fungicidal 
drug terbinafine is often preferred. 
 griseofulvin for Microsporum  infections.  
1394

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  50 
  Griseofulvin is fungistatic , so a prolonged course of 2-4 months  is required.  
 Topical ketoconazole shampoo should be given for the first two weeks to reduce 
transmission 
 
Image showing a kerion 
 
griseofulvin  
The enzyme that is most likely induced by griseofulvin requires which of the following 
cofactors? 
 Vitamin B 6

 Vitamin B 6 
 Griseofulvin is a microtubule poison that is used to treat skin and nail dermatophytose s  
 strong inducer of cytochrome P450 enzymes. 
 CYP450 enzymes require heme for proper function, and thus inducers of CYP450 
increase heme synthesis.   
 
Tinea corporis  (ringworm) 
 causes include Trichophyton rubrum  and Trichophyton verrucosum  (e.g. From contact with 
cattle) 
 well-defined annular, erythematous lesions with pustules and papules

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  51 
  
Image showing tinea corporis  
 
Image showing tinea corporis. Note the well 
defined border 
 
Tinea pedis  (athlete's foot) 
 characterised by itchy, peeling skin between the toes 
 common in adolescence 
 
Tinea incognito 
 What is the cause for tinea incognito? 
 Inappropriate treatment with steroid cream

 Inappropriate treatment with steroid cream 
 Tinea incognito is the name given to tinea when the clinical appearance has been a ltered by 
inappropriate treatment, usually a topical steroid cream  
 The result is that the original infection slowly extends Often the patient and/ or their doctor 
believe they have a dermatitis, hence the use of a topical steroid cream  
 The steroid cream dampens down inflammation so the condition feels less irritable But w hen

the cream is stopped for a few days the itch gets worse, so the steroid cream is promptly u sed 
again  
 The more steroid applied, the more extensive the fungal infection becomes 
Vitiligo 
 Vitiligo is an autoimmune condition which results in the loss of melanocytes and consequent 
depigmentation of the skin.  
 It is thought to affect around 1% of the population

 symptoms typically develop by the age of 20-30 years. 
 
Features 
 well demarcated patches of depigmented skin 
 the peripheries tend to be most affected 
 trauma may precipitate new lesions (Koebner phenomenon) 
1396

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  52 
 Associated conditions 
 type 1 diabetes mellitus 
 autoimmune thyroid disorders 
 alopecia areata 
Diagnosis 
 Diagnosis is made clinically 
 anti-melanocyte antibodies 
 can be confirmed using a skin biopsy. 
 sun block for affected areas of skin 
 camouflage make- up

 camouflage make- up 
 topical corticosteroids may reverse the changes if applied early 
 there may also be a role for topical tacrolimus and phototherapy, although cau tion needs to be 
exercised with light-skinned patients 
  
Yellow nail syndrome Slowing of the nail growth leads to the characteristic thickened and 
discoloured nails seen in yellow nail syndrome. 
 
 pleural effusions

Atopic dermatitis (AD) 
1397

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  53 
  Cyclosporin is a well used drug in the treatment of atopic dermatitis (AD). It is usually at dose s 
of 2-5 mg/kg. 
 The pathophysiology of AD is complex but the T lymphocytes are involved and it is kno wn that 
there is an increased production of cytokines particularly IL- 4.

 Cyclosporin is a suppressor of T cells and in that respect works very well in atopic dermatitis 
and psoriasis. The side effects of hypertension and renal toxicity limit its use. 
 These patients are seen monthly to have their blood pressure and urea and electrolytes 
checked. 
Angular stomatitis  
 Angular stomatitis describes erythema and fissuring of the skin adjacent to the  angle of the mouth.

 The most common cause is Candida  infection,  
 also associated with:  
  allergy,  
 seborrhoeic dermatitis,  
  vitamin B deficiencies,  
  iron deficiency.  
leg ulcers  
 Diuretics may reduce oedema but have not been demonstrated per se to reduc e healing time. 
 Gravitational ulcers are not usually painful. 
 If there are no obvious features of surrounding cellulitis, antibiotic therapy is usually

unnecessary and has not been shown to improve healing in superficial infection which is 
common in ulceration.  
 In diabetic ulcers, the dressing should be left in situ for no more than one week  
Venous ulceration   
 Venous ulcers are secondary to venous stasis and chronic stretching of the walls of the 
superficial veins. These eventually become thinner and ulcerate. 
 typically seen above the medial malleolus

 typically seen above the medial malleolus  
The incidence of venous leg ulceration is higher in: 
  obese patients  
 history of varicose veins  
 history of deep vein thrombosis  1398

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  54 
 Ulcers occur owing to:  
 venous stasis  
 secondary increase in capillary pressure  
 fibrosis  
 poorly nourished skin particularly over areas such as the medial malleolus 
 
 ankle-brachial pressure index (ABPI)  is important in non-healing ulcers to assess for poor 
arterial flow which could impair healing

arterial flow which could impair healing 
 a 'normal' ABPI may be regarded as between 0.9 - 1.2.  
 Values below 0.9 indicate arterial disease.  
 Interestingly, values above 1.3 may also indicate arterial disease, in the form of false-
negative results secondary to arterial calcification (e.g. In diabetics) 
 
 compression bandaging, usually four layer (only treatment shown to be of real benefit)

 The mainstay of treatment of venous ulceration is compression therapy , which aims to 
improve venous return and thereby reduce venous hypertension.  
 The patient should always have their Doppler's and ABPI (ankle brachial pressure index) prior 
to compression. The ABPI should be greater than 1 before compression bandaging is used 
(this excludes significant arterial disease.  
 oral pentoxifylline, a peripheral vasodilator, improves healing rate

 small evidence base supporting use of flavinoids 
 little evidence to suggest benefit from hydrocolloid dressings, topical growth factors, ultrasou nd 
therapy and intermittent pneumatic compression 
Pressure ulcers 
 
 Pressure ulcers develop in patients who are unable to move parts of their body due to illn ess, 
paralysis or advancing age.

paralysis or advancing age.  
 They typically develop over bony prominences such as the sacrum or heel. The foll owing 
factors predispose to the development of pressure ulcers: 
 malnourishment 
 incontinence 
 lack of mobility 
 pain (leads to a reduction in mobility) 
1399

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  55 
  The Waterlow score  is widely used to screen for patients who are at risk of developing 
pressure areas. It includes a number of factors including body mass index, nutritional status, 
skin type, mobility and continence. 
Grading of pressure ulcers  
the following is taken from the European Pressure Ulcer Advisory Panel classification system.

Grade Findings 
Grade 
1 Non-blanchable erythema of intact skin. Discolouration of the skin, warmth, oedema, induration or 
hardness may also be used as indicators, particularly on individuals with darker skin 
Grade 
2 Partial thickness skin loss involving epidermis or dermis, or both. The 
ulcer is superficial and presents clinically as an abrasion or blister 
Grade 
3 Full thickness skin loss involving damage to or necrosis of subcutaneous tissue that may extend

down to, but not through, underlying fascia. 
Grade 
4 Extensive destruction, tissue necrosis, or damage to muscle, bone or 
supporting structures with or without full thickness skin loss 
 
 a moist wound environment encourages ulcer healing. Hydrocolloid dressings and hydrogels 
may help facilitate this. The use of soap should be discouraged to avoid drying the  wound 
 wound swabs should not be done routinely as the vast majority of pressure ulcers are

colonised with bacteria. The decision to use systemic antibiotics should be taken on a clinica l 
basis (e.g. Evidence of surrounding cellulitis) 
 consider referral to the tissue viability nurse 
 surgical debridement may be beneficial for selected wounds 
Keloid scars 
 
Keloid scars are tumour-like lesions that arise from the connective tissue of a scar and exten d beyond 
the dimensions of the original wound

the dimensions of the original wound 
 
 ethnicity: more common in people with dark skin 
 occur more commonly in young adults, rare in the elderly 
1400

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  56 
  common sites (in order of decreasing frequency): sternum, shoulder, neck, face, extens or 
surface of limbs, trunk 
 Keloid scars are less likely if incisions are made along relaxed skin tension lines* 
 *Langer lines were historically used to determine the optimal incision line. T hey were based on

procedures done on cadavers but have been shown to produce worse cosmetic results than 
when following skin tension lines 
 
Treatment  
 early keloids may be treated with intra-lesional steroids e.g. triamcinolone 
 excision is sometimes required 
Increased skin fragility  
 Increased skin fragility is seen in a number of disorders and is used as a clinical test in bu llous 
disorders (Nikolsky's sign). 
 Other causes include:

 pemphigus vulgaris 
 drug reactions (especially pseudoporphyria). 
 Other causes of increased skin fragility (not associated with bullae) include: 
  long term corticosteroid therapy,  
 Ehlers-Danlos syndrome  
 curvy (vitamin C deficiency). 
Basal cell carcinoma (BCC)  
 Basal-cell carcinomas are the most common malignant skin tumour and are re lated to

excessive sun exposure 
 most commonly occurs in elderly patients with sun-damaged skin. 
 
 Lesions are also known as rodent ulcers  
 characterised by slow-growth and local invasion . Metastases are extremely rare.  
 BCC is the most common type of cancer in the Western world.  
 BCC is more commonly seen on the upper lip. 
 
Genetics 
 environmental and genetic factors are believed to predispose patients to B CC

 Basal cell carcinoma is associated with mutations in the Hedgehog signaling pathway.  
 Up to 70% of people with sporadic BCC without Gorlin syndrome have patched PTCH1 gene  
mutations as a result of UV radiation exposure.  
Features  
 many types of BCC are described. The most common type is nodular BCC. 
 sun-exposed sites, especially the head and neck account for the majority of lesions  
 initially a pearly, flesh-coloured papule with telangiectasia 1401

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  57 
  may later ulcerate leaving a central 'crater' 
 characterized histologically by palisading nuclei .  
 Palisading nuclei consist of parallel rows of elongated nuclei. 
Management  options: 
 surgical removal 
 Mohs surgery for is useful for minimizing the amount of safety margin excised. 
 curettage 
 cryotherapy

 cryotherapy 
 topical cream: imiquimod, 5- fluorouracil  
 
(BCC) VS (SCC) 
Basal cell carcinoma  Squamous cell carcinoma  
Most common  2nd most common  
Present in upper part of face Present in lower part of face 
(appear most often on the lower lip, ear, 
and nose.) 
Does not metastasize and kill by local 
invasion(rodent ulcer) Can metastasize 
presents as a “pearly ” papule or nodule that 
grows slowly with  shiny  appearance with

grows slowly with  shiny  appearance with 
telangiectasias and an umbilicated center or ulcer usually hyperkeratotic  scaly  lesion with crusting 
and ulceration. 
often well-defined , superficial, discrete, and hard 
lesions arising from an indurated, rounded, and 
elevated base 
1402

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  58 
  
Basal  cell nevus  syndrome (Gorlin syndrome) 
 
Consider nevoid basal cell carcinoma syndrome (NBCCS) in any young patient with multiple 
basal-cell carcinomas (BCC), or with BCC and palmar pitting.  
overview 
 autosomal dominant condition caused by the loss of the tumor suppressor gene PTCH  on 
chromosome 9q22. 
Feature 
 broad forehead,

Feature 
 broad forehead,  
 palmar pits  
 multiple basal cell carcinomas under the age of 20,  
 calcified falx cerebri, an odontogenic keratocyte, or polyostotic bone cyst located in the jaw.  
Diagnosis 
 Diagnosis of NBCCS is a clinical determination, based on the presence of two major or one 
major and two minor criteria.   
 Major criteria:  
 More than 2 instances of basal cell carcinoma (BCCs), or 1 BCC in a patient younger 
than 20 years old

than 20 years old 
 Odontogenic keratocysts of the jaw 
 Three or more palmar or plantar pits 
 Bilamellar calcification of the falx cerebri 
 Bifid, fused, or markedly splayed ribs 
 First-degree relative with NBCCS 
 Minor criteria:  
 Macrocephaly 
 Ovarian fibroma or medulloblastoma 
 Congenital malformations – cleft lip or palate, frontal bossing, etc 
 Skeletal abnormalities 
 Radiological abnormalities 
 
 Management of this condition depends on the manifestations of the disease, in the particular 
individual affected.  
 It may include chemotherapy, resection of meduloblastoma in a child, and/or removal of  basal 
cell carcinomas and jaw cysts in patients in adolescence and adulthood. 
Squamous cell carcinoma (SCC) 
Overview

Overview 
 SCC is the second most common non-melanoma skin cancer worldwide (after basal cell  
cancer). 
 SCC is the most common oral cancer. 
 More common in elderly males. 1403

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  59 
  It is possible to get SCC on any part of the body, including the inside of the mouth, lips, a nd 
genitals.   
 Women frequently get SCC on their lower legs. 
Precursor and variants of SCC:   
 Actinic keratosis  presents as hyperkeratotic grey-white plaques and is a precursor lesion 
to squamous cell carcinoma of the skin.

to squamous cell carcinoma of the skin. 
 Precursor lesions for SCCs are called actinic (or sun-damage) keratosis 
 Keratoacanthoma  is a cup-shaped form of squamous cell carcinoma of the skin that develops 
rapidly and resolves spontaneously. 
 photo-exposed skin such as face and lower lips. 
 often caused by ultraviolet B -light , which can mutate DNA  via the formation 
of pyrimidine dimers.  
 exposure to ultraviolet radiation (UV), especially UVB    Mutations in the

p53 tumour suppression gene 
 commonly affects the lower lip. 
 The incidence of skin cancer has been increasing among Caucasians but remains relatively 
low in people of color.  
  Light-skinner, non-Hispanic white populations experience higher rates of S CC than 
darker people of color. 
 Low incidence in darker skins due to photo-protection provided by increased epidermal 
melanin, which filters twice as much ultraviolet (UV) radiation

 When skin cancer occurs in people of color , patients often present with an advanced 
stage, and thus, worse prognosis  in comparison to Caucasian patients 
 Chronic  immunosuppression   
 more common in patients who have received an organ transplant . 
 old scars  or burns   
 may arise from areas of Bowen ’s disease and sometimes in the margin of a chronic leg 
ulcer. 
 (SCC) arising on a scar is termed a Marjolin ulcer .

 Marjolin ulcer is typically aggressive  and associated with a poor prognosis. 
 arsenic exposure 
 ionizing radiation 
 HPV infection  
 chronic infections, particularly those associated with chronically draining sinuses. 
 actinic keratoses and Bowen's disease 
 Inherited syndromes: eg:  xeroderma pigmentosum and albinism 
 smoking 
Features 
 usually appears as a  scaly  or crusty area of skin, with a red, inflamed base. 
Diagnosis

Diagnosis 
 Excision biopsy is essential for accurate diagnosis.  
 shows keratin pearl appearance. 1404

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  60 
  The presence of keratin pearls  indicates that the tumor is well-differentiated and 
carries  a better prognosis . 
 undifferentiated tumor would contain almost entirely atypical cells that have lost 
their keratin producing function and thus keratin pearls would be absent.   
Treatment

Treatment 
 Treatments include non-surgical destruction (e.g., using cryotherapy), topical chemotherapy, 
traditional surgical excision, and Mohs micrographic surgery. 
 Surgical excision with 4mm margins if lesion <20mm in diameter. If tumour >20mm then 
margins should be 6mm. 
 Mohs surgery is the best surgical treatment to minimize the loss of normal tissue. 
 Radiotherapy is the treatment of choice in patients who are poor surgical candidates.

 Chemotherapy is used as adjuvant therapy in high risk patients 
 Sunscreen is used to minimize risk of developing SCC. 
Prognosis  
 
Good Prognosis Poor prognosis 
Well differentiated tumours Poorly differentiated tumours 
<20mm diameter >20mm in diameter 
<2mm deep >4mm deep 
No associated diseases Immunosupression for whatever reason 
 
Keratoacanthoma(KA)  
 
1405

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  61 
  
 Keratoacanthoma (KA) is a relatively common low-grade malignancy that originates in the 
pilosebaceous glands and resembles squamous cell carcinoma (SCC) pathologically. 
 Some experts support classifying KA as a variant of invasive SCC. 
 Keratoacanthoma is a benign epithelial tumour.  
 It is believed to develop from the hair follicle,

 more common in males.  
 They are more frequent in middle age and do not become more common in old age  (unlike 
basal cell and squamous cell carcinoma) 
 KA is characterised by rapid growth over a few weeks to months, followed by spontaneous 
resolution over four to six months in most cases. 
 Lesions typically are solitary and begin as firm, roundish, skin-coloured or reddish papule s that 
rapidly progress to dome-shaped nodules with a smooth shiny surface and a central

crateriform ulceration or keratin plug that may project like a horn. 
Features - said to look like a volcano or crater  
 initially a smooth dome-shaped papule 
 rapidly grows to become a crater centrally-filled with keratin 
Treatment  
 The most suitable management  Urgent referral to dermatology  
 Spontaneous regression of keratoacanthoma within 3 months is common, often resulting in a  
scar.

scar. 
 Should be urgently excised as it is difficult clinically to exclude squamous cell carcinoma. 
Removal also may prevent scarring . 
Actinic keratoses 
 Actinic, or solar, keratoses (AK) is a common premalignant skin lesion that develops as a 
consequence of chronic sun exposure 
 Less than 10% of actinic keratoses progress to invasive squamous cell carcinoma. 
 
Features 
 small, crusty or scaly, lesions

Features 
 small, crusty or scaly, lesions 
 may be pink, red, brown or the same colour as the skin 
 typically on sun-exposed areas e.g. temples of head 
 multiple lesions may be present 
 
 prevention of further risk: e.g. sun avoidance, sun cream 
 fluorouracil cream : typically a 2 to 3 week course. The skin will become red and inflamed - 
sometimes topical hydrocortisone is given following fluorouracil to help settle the inflammation

 topical diclofenac: may be used for mild AKs. Moderate efficacy but much fe wer side-effects 
 topical imiquimod: trials have shown good efficacy 
 curettage and cautery 1406

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  62 
Malignant melanoma :  
 Melanocytes are positioned in the basal layer of the epidermis  
 Melanoma is the third most common skin cancer, but is the most common cause of skin 
cancer-related death. 
 Up to 20% of patients develop metastatic disease.

The mnemonic of ABCDE  regarding characteristics of a melanoma are as follows: 
 A - Asymmetry - one half of the lesion does not match the other half 
 B - Border irregularity 
 C - Colour variegation - pigmentation is not uniform 
 D - Diameter- a diameter 7 mm warrants investigation although changes in size are also  
important 
 E - Evolution - evolving size or changes in characteristics such as nodules. 
Prognostic factors

Prognostic factors 
 
The invasion depth of a tumour (Breslow depth) is the single most important factor in 
determining prognosis of patients with malignant melanoma  
 
Breslow Thickness Approximate 5 year survival 
< 1 mm 95-100% 
1 - 2 mm 80-96% 
2.1 - 4 mm 60-75% 
> 4 mm 50% 
Treatment 
 Vemurafenib is a small molecule inhibitor of BRAF  oncogene that can be found in melanoma. 
As such, Vemurafenib is used to treat metastatic melanoma. 
 
Lentigo maligna

Lentigo maligna 
 Lentigo maligna is a type of melanoma in-situ.  
 It typically progresses slowly but may at some stage become invasive causing lentigo maligna 
melanoma. 
1407

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  63 
  Lentigo maligna melanoma occurs on the sun-exposed skin areas (usually the face) of elderly 
patients  
 
Acral lentiginous melanoma 
 The acral lentiginous melanoma is normally seen on the sole of the foot , and 
occasionally on the palm of the hand  
 It is characterised by a raised darker area surrounded by a paler macular (lentiginous)

area that may extend for several centimetres around the raised area 
 Periungual melanomas occur in the area of the nailbed  
 Hutchinson ’s sign (brown pigmentation on the nailfold) is an important pointer to malignant 
melanoma  
 Superficial spreading melanoma is the commonest type, consisting of an irregular b rown, black 
or blue –black lesion with some intermingled inflammation  
 Nodular melanoma is the most rapidly growing and aggressive variant and may contain

relatively little melanin pigment 
 
Moles 
 Uniform pigmentation is not in itself a suspicious feature of a mole, but colour 
variegation and irregular border are two of many suspicious features. 
Systemic mastocytosis  results from a neoplastic proliferation of mast cells 
Features  
 flushing 
Diagnosis

Diagnosis 
 urinary histamine 
Angiosarcoma  
 Angiosarcomas are malignant vascular tumours most commonly seen in elderly men.  
 most commonly occur on the scalp and forehead.  
 present an infiltrative vascular patch or plaque with super-imposed nodules which may blee d 
with minor trauma.  
 poor prognosis.

 poor prognosis.  
 Angiosarcomas can also occur in areas of chronic lymphoedema.  
 1408

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  64 
  
Pyogenic granuloma  
 
overview 
  relatively common benign skin lesion 
 benign vascular lesion of the skin and mucosa. 
 The name is a double misnomer - the lesion is neither pyogenic nor a granuloma.

 There are multiple alternative names but perhaps 'eruptive haemangioma' is the most useful.  
 Pathologically, it is an inflammatory lesion composed of granulation tissue and chronic 
inflammatory cells. 
Etiology:  
 unknown,  
 associated with trauma and pregnancy 
 more common in women and young adults 
Features 
1409

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  65 
  initially soft, round, bright red spot 
 usually solitary lesions, 
 Lesions often grow rapidly ( over weeks ),  
 tender and bled easily when touched. 
Localization:  
 The most common location are: 
 fingers (commonly involve the digits)  
 mucosal surfaces of the mouth  
 inner surfaces of the nose. 

 lesions associated with pregnancy often resolve spontaneously post-partum 
 other lesions usually persist.  
 surgical excision 
 Removal methods include curettage and cauterisation, cryotherapy, excision 
 
Skin disorders associated with malignancy 
Paraneoplastic syndromes associated with internal malignancies: 
 
Skin disorder Associated malignancies

Skin disorder Associated malignancies 
Acanthosis nigricans Gastric cancer 
Acquired ichthyosis Lymphoma 
1410

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  66 
 Skin disorder Associated malignancies 
Acquired hypertrichosis lanuginosa Gastrointestinal and lung cancer 
Dermatomyositis Ovarian and lung cancer 
Erythema gyratum repens Lung cancer 
Erythroderma Lymphoma 
Migratory thrombophlebitis Pancreatic cancer 
Necrolytic migratory erythema Glucagonoma 
Pyoderma gangrenosum (bullous

Pyoderma gangrenosum (bullous 
and non-bullous forms) Myeloproliferative disorders 
Sweet's syndrome Haematological malignancy e.g. Myelodysplasia - tender, purple 
plaques 
Tylosis Oesophageal cancer 
 
Acrokeratosis paraneoplastica  
 
A widespread psoriatic-type rash involving the ears is suggestive of acrokeratosis 
paraneoplastica. 
 
 Most acrokeratosis paraneoplastica cases are associated with squamous cell carcinoma  of

the upper one third of the respiratory or GI tract, i.e. the oropharynx, larynx, lungs or 
oesophagus.  
 The symptoms of indigestion and food sticking fit best with a diagnosis of oesopha geal 
Cellulitis  see infectious diseases  
Otitis externa 
Otitis externa is a common reason for primary care attendance in the UK. 
Causes  of otitis externa include:

Causes  of otitis externa include: 
 infection: bacterial ( Staphylococcus aureus ,Pseudomonas aeruginosa ) or fungal 
 seborrhoeic dermatitis 
 contact dermatitis (allergic and irritant) 
Features 
 ear pain, itch, discharge 1411

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  67 
  otoscopy: red, swollen, or eczematous canal 
The recommend initial management  of otitis externa is: 
 topical antibiotic or a combined topical antibiotic with steroid 
 if the tympanic membrane is perforated aminoglycosides are traditionally not used* 
 *many ENT doctors disagree with this and feel that concerns about ototoxicity are 
unfounded

unfounded 
 if there is canal debris then consider removal 
 if the canal is extensively swollen then an ear wick is sometimes inserted 
Second line options include 
 consider contact dermatitis secondary to neomycin 
 oral antibiotics if the infection is spreading 
 taking a swab inside the ear canal 
 empirical use of an antifungal agent 
 
Malignant otitis externa  
 more common in elderly diabetics.

 more common in elderly diabetics.  
 In this condition there is extension of infection into the bony ear canal and the soft tissues d eep 
to the bony canal.  
 Intravenous antibiotics may be required. 
Drugs causing photosensitivity 
 tetracyclines, sulphonamides, ciprofloxacin 
 NSAIDs e.g. piroxicam 
 psoralens 

Livedo reticularis  
 Livedo reticularis is due to superficial capillary dilatation, resulting in characteristic 
mottling of the skin.  
 appears as a lace-like purplish discoloration of the skin  
 It is mainly idiopathic. (primary livedo reticularis is the most common cause) 
 occur more in women than in men and usually in the 3rd decade of life.   
 It is thought to be due to spasms of the blood vessels or an abnormality of the  local circulation.

 It may be aggravated by exposure to cold,  
 occurs most often in the lower extremities 
 idiopathic livedo reticularis may improve with warming the area. 
 bath PUVA is a therapeutic option with the possibility of some success. 
 Exercise is the best remedy. Increased circulation helps to dilate the blood vessels th roughout 
the body. 1412

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  68 
   
Causes Secondary Livedo reticularis: 
 Obstruction / vasculopathy  
 Antiphospholipid syndrome  
 Cryoglobulinaemia  
 Polycythaemia rubra vera  
 Multiple myeloma 
 Cold agglutinin disease 
 Protein C and S deficiency 
 Disseminated intravascular coagulation 
 Haemolytic uraemic syndrome

 Haemolytic uraemic syndrome 
 Emboli (DVT , cholesterol emboli  and septic emboli) 
 Hypercalcaemia (calcium deposits) 
 Infections (syphilis, tuberculosis, Lyme disease) 
 Autoimmune / vasculitis / connective tissue disease 
 Small, medium and large vessel vasculitis. 
 SLE 
 Dermatomyositis 
 Rheumatoid arthritis 
 Polyarteritis nodosa 
 Drugs 
 Amantadine (dopamine agonist used to treat Parkinson disease) causes livedo thro ugh

arteriolar vasospasm associated with depletion of catecholamines.  
 Minocycline   
Reactions to drugs 
 Psoriatic-type reactions are most commonly caused by beta-blockers  
 Antibiotics may cause lupus-type reactions, erythema multiforme, Stevens –Johnson syndrome 
and erythroderma  
 Warfarin is associated with alopecia, as are cytotoxic agents and antithyroid agents  
 Phenytoin may cause both acne and gingival hyperplasia

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  69 
  
Hyperhidrosis  describes the excessive production of sweat 
 
Management  options include  
 topical aluminium chloride preparations are first-line. Main side effect is skin irritation 
 iontophoresis: particularly useful for patients with palmar, plantar and axillary hyperhidrosis

 botulinum toxin: currently licensed for axillary symptoms 
 surgery: e.g. Endoscopic transthoracic sympathectomy. Patients should be made aware o f the 
risk of compensatory sweating 
Mycosis fungoides 
 
 a cutaneous T cell lymphoma. 
 The disease presents as a pruritic eczematous rash (the pre-malignant stage) and develops 
telangiectasias and areas of 'cigarette paper' atrophy.

 As malignancy develops, nodular lesions appear and proceed to become necrotic. 
Narrow-band phototherapy (NBUVB) 
 skin disorders can be treated with narrow-band phototherapy ( NBUVB ) includes: 
 Psoriasis  
 Mycosis fungoides patch stage   (NOT tumor stage) 
 Vitiligo  
 Eczemas 
 
1414

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  70 
  
Seborrheic keratosis 
 Seborrheic keratoses are the most common benign tumor in older individuals.  
 and they develop from the proliferation of epidermal cells.  
 No specific etiologic factors have been identified.  
 Typical features include a warty and waxy surface with surface crypts and a stuck on 
appearance.

 They typically have an appearance of being stuck on the skin surface.  
 Because they begin at a later age and can have a wart-like appearance, se borrheic keratoses 
are often called the “barnacles of aging.  
 Most commonly they are  several  
 Can growths anywhere on the skin, except the palms and soles. Most often on th e chest, back, 
head, or neck.  
 Commonly used treatments include Curettage and cautery (C&C), and cryotherapy (for thinner 
lesions).  
 
1415

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  71 
  
multiple seborrheic keratoses in an autosomally dominant mode of inheritance. 
Solar keratosis  
 hyperkeratotic lesion with underlying erythema.  
 blee d when scratched  
 Progression of these lesions to squamous cell skin cancer is slow,

 Topical 5-FU cream  used twice a day for 3 –4 weeks usually achieves clearance of the lesion. 
 Diclofenac gel requires a more prolonged treatment period (up to 12 weeks), meani ng that it is 
the second-choice option for compliance reasons. It is useful where coverage of a larg er area 
of skin is required. 
 
1416

Notes & Notes for MRCP                                                                         By Dr. Yousif Abdallah Hamad  72 
  
solar keratosis (on scalp of elderly) 
Xeroderma pigmentosum  
 inherited skin disorder  
Aetiology 
 defect in nucleotide excision repair (NER),  leading to deficient repair of DNA damaged by 
UV radiation, and chromosome breakage.  
Features

Features 
 photosensitivity with severe sunburn in infancy,  
 numerous pigmented spots resembling freckles,  
 larger atrophic lesions associated with telangiectasis and multiple solar keratosis.  
  multiple malignant cutaneous neoplasms at an early age,  
 severe ophthalmic and neurological abnormalities. 
Diagnosis 
 Cellular hypersensitivity to UV radiation studies 
 chromosomal breakage studies 
Treatment 
 Avoidance of sun exposure 
 
1417

Ophthalmology 
 
Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     1 
  
By
 
Ophthalmology
  
Updated 
 
2017
 
Contains: 
 
 1418

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     2 
  
Acute angle closure glaucoma 
 
 Glaucoma  is a group disorders characterised by optic neuropathy due, in the majority of 
patients, to raised intraocular pressure (IOP).  It is now recognised that a minority of patients 
with raised IOP do not have glaucoma and vice versa

 In acute angle closure glaucoma (AACG) there is a rise in IOP secondary to an impairment of 
aqueous outflow. 
1419

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     3 
  Factors predisposing to AACG include:  
 hypermetropia (long-sightedness) 
 pupillary dilatation (Mydriatic drops are a known precipitant of acute angle closure glaucoma) 
 lens growth associated with age 
 Drugs which may precipitate acute glaucoma include anticholinergics and tricyclic 
antidepressants  
Features

Features 
 severe pain: may be ocular or headache 
 decreased visual acuity 
 symptoms worse with mydriasis (e.g. watching TV in a dark room) 
 hard, red eye 
 haloes around lights 
 semi-dilated non-reacting pupil. The oval shape is due to the iris sphincter ischaemia from the 
high intraocular pressure.  
 corneal oedema results in dull or hazy cornea 
 systemic upset may be seen, such as nausea and vomiting and even abdominal pa in 

 urgent referral to an ophthalmologist 
 management options include reducing aqueous secretions with acetazolamide and ind ucing 
pupillary constriction with topical pilocarpine 
Primary open-angle glaucoma 
 Primary open-angle glaucoma (POAG), is the most common type of glaucoma .  
 Primary open-angle glaucoma (POAG, also referred to as (chronic simple glaucoma) is

present in around 2% of people older than 40 years. 
 POAG may present insidiously and for this reason is often detected during routine optome try 
appointments.  
Risk factors  (Other than age) include: 
 black patients 
 myopia  hypertension 
 
Features : 
 peripheral visual field loss - nasal scotomas progressing to 'tunnel vision' 
 Loss of nasal visual field is the most consistent feature with POAG 
 decreased visual acuity

 ophthalmoscopic exam  optic disc cupping  management  
 Most patients are managed with eye drops. 
 These aims to lower intra-ocular pressure which in turn has been shown to prevent 
progressive loss of visual field. 
 A prostaglandin analogue (e.g. Latanoprost) should be used first-line in patients with a 
history of asthma.  
1420

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     4 
 Medication Mode of action Notes 
Prostaglandin analogues (e.g. 
Latanoprost) Increases uveoscleral 
outflow Once daily administration 
SE: brown pigmentation of the iris 
Beta-blockers (e.g. Timolol) Reduces aqueous 
production Should be avoided in asthmatics and patients 
with heart block 
Sympathomimetics (e.g. 
brimonidine, an alpha2-

adrenoceptor agonist) Reduces aqueous 
production and increases 
outflow Avoid if taking MAOI or tricyclic 
antidepressants 
Adverse effects include hyperaemia 
Carbonic anhydrase inhibitors 
(e.g. Dorzolamide) Reduces aqueous 
production Systemic absorption may cause 
sulphonamide-like reactions 
Miotics (e.g. pilocarpine, a 
muscarinic receptor agonist) Increases uveoscleral 
outflow Adverse effects included a constricted pupil,

headache and blurred vision 
 
Rubeosis iridis  
What is the most important preventative intervention to reduce the risk of glaucoma? 
 Pan-retinal photocoagulation 
 An important part of the work-up of rubeosis iridis is with fluorescein 
angiography to assess the extent of retinal ischaemia, and ultrasound.  
 Once eye disease has progressed to rubeosis, the mainstay of therapy is 
pan-retinal photocoagulation to reduce the area of viable retina.

 Anti-VEGF agents and topical steroids may also be of value, but ultimately 
the prognosis is poor because of late stage at presentation. 
 
Surgery in the form of a trabeculectomy may be considered in refractory cases. 
Age related macular degeneration 
 
 Age related macular degeneration is the most common cause of blindness in the UK.

 Degeneration of the central retina (macula) is the key feature with changes usually bilateral.  
 Traditionally two forms of macular degeneration are seen: 
1. dry (geographic atrophy) macular degeneration: characterised by drusen  - yellow 
round spots in Bruch's membrane 
2. wet (exudative, neovascular) macular degeneration: characterised by choroidal 
neovascularisation. Leakage of serous fluid and blood can subsequently result in a

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     5 
  Recently there has been a move to a more updated classification: 
- early age related macular degeneration (non-exudative, age related maculopa thy): 
drusen and alterations to the retinal pigment epithelium (RPE) 
- late age related macular degeneration (neovascularisation, exudative) 
 
 age: most patients are over 60 years of age 
 smoking

 smoking 
 family history  more common in Caucasians 
 high cumulative sunlight exposure 
Features 
 
 reduced visual acuity: 'blurred', 'distorted' vision, central vision is affected first  
 central scotomas 
 fundoscopy: drusen, pigmentary changes 
 optical coherence tomography: provide cross sectional views of the macula 
 if neovascularisation is present fluorescein angiography is performed 
 stop smoking

 stop smoking 
 high dose of beta-carotene, vitamins C and E, and zinc may help to slow down v isual loss for 
patients with established macular degeneration. Supplements should be avoided in 
smokers due to an increased risk of lung cancer  
 Having a balanced diet, with plenty of fresh fruits and vegetables may also slow the 
progression of macular degeneration. 
Dry macular degeneration - no current medical treatments 
Wet macular degeneration 
 photocoagulation

 photocoagulation 
 photodynamic therapy 
 anti-vascular endothelial growth factor (anti-VEGF) treatments: intravitreal ranibizumab 
 
1422

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     6 
Cataracts 
 
 opacification of the lens 
Causes 
 Majority 
 age related (Senile cataracts) 
 the most common cause  
 17% of people older than 40 years  
 50% of people older than 75 years  
 UV light 
 Systemic 
 steroids

 Systemic 
 steroids  
 Inhaled steroids can cause cataracts  
 infection (congenital rubella) 
 metabolic: 
 diabetes   
 hypocalcaemia,  
 galactosaemia 
 but if the galactosaemia is treated, the cataract is reversible. 
 myotonic dystrophy,  
 Ocular  
 trauma 
 uveitis 
 high myopia 
 topical steroids 
Feature 
 Symptoms 
 painless, progressive, and slow vision loss   
1423

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     7 
  absent red reflex 
 Nuclear sclerosis : 
 the most common type  of cataract, 
 involves the central or 'nuclear' part of the lens.  
 common in old age 
 reduction of vision is the major symptom. 
 change lens refractive index,  
 often leads to an increase in refractive power of the lens  causing

nearsightedness (problems with distance vision ). 
 Polar: localized, commonly inherited, lie in the visual axis 
 Subcapsular:  
 glare is the major symptom 
 Glare  is difficulty seeing in the presence of bright light such as direct or 
reflected sunlight or artificial light such as car headlamps at night. 
(صعوبة الرؤية في الضوء الساطع ) 
 due to steroid use, just deep to the lens capsule, in the visual axis 
 Posterior subcapsular cataracts  are associated with:

  retinitis pigmentosa  
 chronic steroid  use.  
 Anterior subcapsular cataracts are associated with: 
 idiopathic or  
 secondary to trauma and iotragenic causes.  
 Dot opacities 
 common in normal lenses,  
 also seen in: 
 diabetes  
 myotonic dystrophy 
Diabetic retinopathy   See endocrinology  
Angioid retinal streaks

Angioid retinal streaks 
 Angioid retinal streaks are seen on fundoscopy as irregular dark red streaks radiating from the 
optic nerve head. They are caused by degeneration, calcification and breaks in Bruch's 
membrane .  
Causes  
A useful mnemonic for angioid retinal streak is SLAPPERS : 
 S - Sickle-cell anaemia  
 L - Lead poisoning 
 A - Abetalipoproteinaemia/acromegaly 
 P - Paget's disease  /phacomatoses (tuberous, sclerosis, neurofibromatosis, Sturge-Weber)

 P - Pseudoxanthoma elasticum  
 E - Ehlers-Danlos  syndrome 
 R - Raised calcium or phosphate 
 S - Short people (dwarfism). 1424

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     8 
  
1425

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     9 
Mydriasis 
Causes of mydriasis (large pupil) 
 Holmes-Adie pupil 
 traumatic iridoplegia 
 phaeochromocytoma 
 Drug causes of mydriasis  
 topical mydriatics: tropicamide, atropine

 topical mydriatics: tropicamide, atropine 
 sympathomimetic drugs: amphetamines, pseudoephedrine, amphetamines a nd 
cocaine ,  
 anticholinergic drugs: eg antihistamines, atropine and tricyclic antidepressants 
 Poisons (atropine, CO, ethylene glycol). 
Miosis 
Causes of small pupils include: 
 Old age 
 Pontine haemorrhage 
 Argyll Robertson pupil 
 Poisons (opiates, organophosphates).

 Poisons (opiates, organophosphates). 
___________________________________________________ ________________________ 
Holmes-Adie pupil  
 
Abnormally dilated pupil (mydriasis) which does not constrict in response to light, loss 
of deep tendon reflexes, and abnormalities of sweating .  
 Holmes-Adie pupil is a benign condition most commonly seen in women. It is one of the  differentials 
of a dilated pupil. 
Overview  
 unilateral in 80% of cases 
 dilated pupil ( tonically dilated pupil )

 dilated pupil ( tonically dilated pupil ) 
 slowly reactive to accommodation but very poorly (if at all) to light 
 once the pupil has constricted it remains small for an abnormally long time 
 associated with absent ankle/knee reflexes  and impaired sweating 
- The cause of the associated arreflexia is unknown. 
pathophysiology 
 Viral or bacterial infection causes  damage to neurons in the ciliary ganglion , located in

the posterior orbit , that provides parasympathetic control of eye constriction. 
 damage to the dorsal root ganglia of the spinal cord  problems with autonomic control of 
the body . 
Diagnosis  
1426

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     10 
  testing with low dose (1/8%) pilocarpine may constrict the tonic pupil due to cholinergic  
denervation super-sensitivity. A normal pupil will not constrict with the dilute dose of 
pilocarpine.   
Argyll-Robertson pupil

Argyll-Robertson pupil  
 the prostitute's pupil - accommodates but doesn't react.  
 Another mnemonic used for the Argyll-Robertson Pupil (ARP) is Accommodation Reflex 
Present (ARP) but Pupillary Reflex Absent (PRA)  
Features  
 small, irregular pupils 
 no response to light but there is a response to accommodate 
Causes  
 syphilis (neurosyphilis) 
Optic atrophy

Optic atrophy 
 Optic atrophy is a descriptive term, it is the optic neuropathy that results in visual loss 
 Usually bilateral and causes a gradual loss of vision. 
 On fundoscopy optic atrophy is seen as pale, well demarcated disc.  
 Causes may be acquired or congenital 
 papilloedema (longstanding) 
 raised intraocular pressure (e.g. glaucoma, tumour) 
 retinal damage (e.g. choroiditis, retinitis pigmentosa) 
 ischaemia

 toxins: tobacco amblyopia, quinine, methanol, arsenic, lead 
 nutritional: vitamin B1, B2, B6 and B12 deficiency 
Congenital causes 
 mitochondrial disorders e.g. Leber's optic atrophy 
  usually affects young men.  
 It causes sequential optic neuropathies in days to weeks.  
 It is typically painless and severe.  
 Visual acuity fails to improve. 
 Mutations in the MT-ND1, MT-ND4, MT-ND4L, and MT-ND6 genes

 These genes are contained in mitochondrial DNA. 
 Specifically, more than 50% of males with a mutation and more than 85% of fema les 
with a mutation never experience vision loss or related medical problems. 
 DIDMOAD - the association of cranial Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and 
Deafness (also known as Wolfram's syndrome) 
 
 1427

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     11 
Optic neuritis  
The patient sees nothing and the doctor sees nothing 
 Optic neuritis is a broad term which can be used to describe inflammation, degeneratio n or 
demyelination of the optic nerve.  
 Optic neuritis is very rare in people over the age of 50.

 It encompasses a number of conditions, including: 
 Papillitis (anterior optic neuritis) - the intraocular portion of the nerve is affected, and  the 
optic disc is swollen 
 It is important to note that the disc changes in papilloedema may closely 
resemble those of papillitis but visual acuity is markedly reduced in papillitis and 
not papilloedema. 
 Retrobular neuritis - the distal portion of the optic nerve is affected, and the disc is 
therefore not swollen

therefore not swollen 
 Neuroretinitis - optic disc and adjacent temporal retina are affected. 
Causes 
 diabetes 
 syphilis 
Features 
 unilateral decrease in visual acuity over hours or days 
 Visual loss typically occurs  over days rather than hours.  Sudden visual loss due to 
optic neuritis is very unusual. 
 Optic neuritis presents with a particular type of central visual loss - a central 
scotoma.

scotoma.  
 poor discrimination of colours, 'red desaturation'  - ie when red looks paler to one eye than the 
other - 
 The retrobulbar neuritis seen with ethambutol  may be unilateral or bilateral; as such 
unilateral symptoms do not preclude the diagnosis. 
 pain worse on eye movement 
 relative afferent pupillary defect  during the 'swinging flashlight test'.  
 central scotoma 
 Most cases of optic neuritis are retrobulbar and hence there are no abnormalities on 
fundoscopy.

fundoscopy. 
 the most likely finding on fundoscopy  Normal optic disc  
Diagnosis 
 MRI with gadolinium of the brain  will likely show  enhancement of the optic nerve  
 Abnormal visual evoked potentials (VEP) 
 high-dose steroids 
 Methylprednisolone pulse therapy is the standard treatment  
 slightly shortens the time of recovery but does not prevent neurodegeneration 
and persistent visual impairment.  1428

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     12 
  recovery usually takes 4-6 weeks 
 erythropoietin may have neuroprotective effects in autoimmune optic neuritis 
Prognosis 
 MRI: if > 3 white-matter lesions, 5-year risk of developing multiple sclerosis is c. 50% 
 Retrobulbar neuritis has the same systemic implications as optic neuritis, in that an

episode of optic or retrobulbar neuritis can contribute to a diagnosis of multiple sclerosis  
Relative afferent pupillary defect 
 Also known as the Marcus-Gunn pupil , a relative afferent pupillary defect is found by the 
'swinging light test'. 
 It is caused by a lesion anterior to the optic chiasm i.e. optic nerve or retina   
 
Causes  
 retina: detachment

Causes  
 retina: detachment 
 optic nerve: optic neuritis e.g. multiple sclerosis 
Pathway of pupillary light reflex 
 afferent: retina → optic nerve → lateral geniculate body → midbrain  
 efferent: Edinger- Westphal nucleus (midbrain) → oculomotor nerve  
Swinging flashlight test & Relative afferent pupillary defect RAPD  (Marcus Gunn pupil )  
 The Marcus Gunn pupil is a relative afferent pupillary defect indicating a decreased pupillary  
response to light in the affected eye

response to light in the affected eye 
  In the swinging flashlight test, a light is alternately shone into the left and right eyes.  
 A normal response would be equal constriction of both pupils, regardless of which eye the light 
is directed at. This indicates an intact direct and consensual pupillary light reflex.  
 When the test is performed in an eye with an afferent pupillary defect, ligh t directed in the

affected eye will cause only mild constriction of both pupils (due to decreased respo nse to light 
1429

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     13 
 from the afferent defect), while light in the unaffected eye will cause a normal constri ction of 
both pupils (due to an intact efferent path, and an intact consensual pupillary ref lex). Thus, 
light shone in the affected eye will produce less pupillary constriction than light shone  in the 
unaffected eye.

unaffected eye. 
 A positive  RAPD is due to retinal or optic nerve disease. 
due to the consensual response of the pupillary light reflex, shining light in the unaffected eye 
will produce bilateral miosis. 
 shining light in the affected eye will not produce miosis because the afferent limb o f the 
pupillary light reflex pathway is damaged (eg: optic neuritis)  
 However, due to the bilateral projections of nerves from the Edinger-Westphal

nucleus , light shined in the unaffected eye  will produce bilateral miosis . This 
phenomenon is called a consensual response . 
 
Herpes simplex keratitis 
 Herpes simplex keratitis most commonly presents with a dendritic corneal ulcer   
Features  
 red, painful eye 
 photophobia 
 epiphora 
 visual acuity may be decreased 
 fluorescein staining may show an epithelial ulcer (dendritic corneal ulcer)

 immediate referral to an ophthalmologist 
 topical aciclovir 
Herpes zoster ophthalmicus 
 Herpes zoster ophthalmicus (HZO) describes the reactivation of the varicella zoster virus in th e 
area supplied by the ophthalmic division of the trigeminal nerve.  
 It accounts for around 10% of case of shingles. 
Features  
 vesicular rash around the eye, which may or may not involve the actual eye itself

 Hutchinson's sign: rash on the tip or side of the nose. Indicates nasociliary involvemen t and is 
a strong risk factor for ocular involvement 
 Oral antiviral  treatment for 7-10 days, ideally started within 72 hours. Topical antiviral 
treatment is not given in HZO  
 oral corticosteroids may reduce the duration of pain but do not reduce the incidence of po st-
herpetic neuralgia 
 ocular involvement requires urgent ophthalmology review 

 ocular: conjunctivitis, keratitis, episcleritis, anterior uveitis 
 ptosis 
___________________________________________________ _________________________ 1430

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     14 
 Blepharitis 
 Blepharitis is inflammation of the eyelid margins.  
 It may due to either meibomian gland dysfunction (common, posterior blepharitis) or 
seborrhoeic dermatitis/staphylococcal infection (less common, anterior blepharitis).  
 Blepharitis is also more common in patients with rosacea

 The meibomian glands secrete oil on to the eye surface to prevent rapid eva poration of the 
tear film. Any problem affecting the meibomian glands (as in blepharitis) can he nce cause 
drying of the eyes which in turns leads to irritation 
Features  
 symptoms are usually bilateral 
 grittiness and discomfort, particularly around the eyelid margins 
 eyes may be sticky in the morning 
 eyelid margins may be red. Swollen eyelids may be seen in staphylococcal blephari tis

 styes and chalazions are more common in patients with blepharitis 
 secondary conjunctivitis may occur 
 softening of the lid margin using hot compresses twice a day 
 mechanical removal of the debris from lid margins - cotton wool buds dipped in a mixture o f 
cooled boiled water and baby shampoo is often used* 
 *an alternative is sodium bicarbonate, a teaspoonful in a cup of cooled water that has recently been 
boiled

boiled 
 artificial tears may be given for symptom relief in people with dry eyes or an abnorm al tear film 
Keratitis 
 Keratitis refers to inflammation of one or more of the three corneal layers, the most com mon of 
which is epithelial keratitis. This is characterised by dendritic ulcers . Rarer forms involve the 
stroma or endothelium.

stroma or endothelium. 
 Pseudomonas aeruginosa   is commonly associated with contact lens related infections.  
 The management must also include advising the patient to discontinue wea ring contact lenses 
and referral to a specialist ophthalmic unit.  
 Recurrence is common. 
Features 
 red eye: pain and erythema ( sharp  ocular pain ) 
 blurred vision (in many cases). 
 Microbial keratitis, causing a white corneal infiltrate   
 foreign body, gritty sensation

 foreign body, gritty sensation 
 hypopyon may be seen 
Infective 
 Viral: herpes simplex keratitis  
  Treated with topical antivirals, e.g. aciclovir 5 times per day.  
 Topical steroids or oral antivirals can be used in some cases.  
 bacterial:  
 typically Staphylococcus aureus .  
 Pseudomonas aeruginosa  is seen in contact lens wearers.   1431

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     15 
  more likely if there is a history of contact lens wear or  trauma, such as a corneal 
abrasion or a corneal foreign body.  
 first line treatment of corneal ulcer  Levofloxacin hourly   
 fungal 
 amoebic: acanthamoebic keratitis 
 parasitic: onchocercal keratitis ('river blindness') 
Enviromental 
 photokeratitis: e.g. welder's arc eye

 photokeratitis: e.g. welder's arc eye 
 exposure keratitis 
 contact lens acute red eye (CLARE) 
Acanthamoeba  keratitis   
 rare and serious keratitis associated with contact lens (CL) wear.  
 Risk factors are exposure of CL to contaminated water, for example, using tap water to clean 
CL or swimming in lenses. 
 Clinical features include pain out of proportion to clinical signs, ring infiltrates and  radial 
kerato-neuritis.   
 management  Brolene drops   
Marginal keratitis

Marginal keratitis 
 Marginal keratitis is areas of peripheral corneal infiltrates/ulcers associated with blepharitis.  
 classically causes an infiltrate near the limbal edge with an area of clear cornea. There m ay be 
limbal vessels growing towards the lesion(s). 
 caused by a hypersensitivity reaction to staphylococcal exotoxins from  Staphylococcus 
aureus  present on the lid margins in blepharitis. 
 topical steroids for the keratitis 
 lid hygiene advice

 lid hygiene advice 
 topical antibiotics to treat the underlying blepharitis.  
 In severe cases oral doxycycline can also be used. 
 
Dendritic ulcers   
 caused by  herpes simplex virus. 
 Presentation  is usually with pain, 
photophobia, blurred vision, 
conjunctivitis and chemosis. 
 Steroid eye drops are 
contraindicated as they may induce 
massive amoeboid ulceration and 
 treated with aciclovir eye drops,  
which should be continued for three

which should be continued for three 
days after the ulcer has healed.  
1432

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     16 
  
Lacrimal duct problems 
Dacryocystitis  is infection of the lacrimal sac 
 Features  
 watering eye (epiphora) 
 swelling and erythema at the inner canthus of the eye 
 systemic antibiotics.

 systemic antibiotics.  
 Intravenous antibiotics are indicated if there is associated periorbital cellulitis 
Congenital lacrimal duct obstruction   
 affects around 5-10% of newborns.  
 It is bilateral in around 20% of cases 
 Features  
 watering eye (even if not crying) 
 secondary infection may occur 
 Symptoms resolve in 99% of cases by 12 months of age 
Hypopyon

Hypopyon 
  
 Hypopyon  is the collection of pus in the 
bottom of the anterior chamber of the eye.  
 It can be clearly visualized as a fluid level and 
the sedimentation is governed by the gravity.  
 The composition of the pus would be only 
white cells or leucocytes without any 
pathogens of bacterial, fungal or even viral 
origin.  causes 
 inflammatory process in that region, mainly the 
iris and the uvea.  
 usually implies infective endophthalmitis

 usually implies infective endophthalmitis 
(eg following cataract surgery),  
 sterile hypopyon can occur in cases of 
severe iritis (eg Behcet's disease).  
 
1433

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     17 
 ___________________________________________________ _________________________
Red eye 
 
There are many possible causes of a red eye. It is important to be able to recognise the causes w hich 
require urgent referral to an ophthalmologist. Below is a brief summary of the key distingu ishing 
features  
Acute angle closure glaucoma

features  
Acute angle closure glaucoma  
 severe pain (may be ocular or headache) 
 decreased visual acuity, patient sees haloes 
 semi-dilated pupil 
 hazy cornea 
Anterior uveitis  
 
 pain 
 blurred vision and photophobia  small, fixed oval pupil, ciliary flush 
 sign on ocular examination  Hypopyon  
Iritis is associated with  conditions such as: 
 Reiter's 
  Behcet's 
  Psoriatic arthropathy (about 20%)  
 and inflammatory bowel disease.

 and inflammatory bowel disease. 
A chronic iritis is rarely described in association with Lyme disease. 
Signs of anterior uveitis  
 Keratic precipitates : (opaque aggregates of inflammatory cells deposited on the endothelium 
in anterior uveitis. They are typically located inferiorly.  
 Cells +/- flare +/- fibrin in the anterior chamber 
 Ciliary injection - localised conjunctival injection (redness) around the limbus

 Posterior synechiae - where part of the pupil margin becomes stuck to the lens 
 Hypopyon (in severe anterior uveitis). 
1434

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     18 
Scleritis 
 Scleritis : inflammation that occurs throughout the entire thickness of the sclera,   
 severe pain  (may be worse on movement) and tenderness 
 pain in scleritis is more evident and severe than episcleritis.

 Tenderness to palpation of the globe can differentiate it from episcleritis. After asking 
the patient to look down with eyelids closed, the physician gently presses the globe. 
Patients with scleritis have tenderness on palpation, while those with episcleritis do no t. 
 Unlike scleritis, patients with episcleritis do not complain of blurred vision or 
photophobia.  
 Studies have shown that patients with RA-associated scleritis have  more widespread

systemic disease and a higher mortality rate than those episcleritis. 
 50% of cases are bilateral.  
 Pain often radiates to the forehead, brow and jaw. This pain worsens with movement of the 
eye, and is classically worse at night. 
  There is associated watering, photophobia and a gradual decrease in vision (sometime s with 
diplopia).  
 Systemic symptoms such as fever, headache and vomiting can occur. 
 may be underlying autoimmune disease e.g. rheumatoid arthritis

Around 50% of patients with scleritis have an underlying disease, of which the majority are 
connective tissue disorders. Rheumatoid arthritis is the most common.  
 On examination the globe is tender, and the sclera can have a bluish tinge. 
 Application of topical phenylephrine 2.5% leads to blanching of episcleral vessels in 
episcleritis but not in scleritis.   
 Management ultimately depends on the underlying cause, but includes NSAIDs and  
prednisolone.

prednisolone. 
 The patient should be referred urgently to the ophthalmology clinic  
Scleritis is painful , episcleritis is not painful  
 Results in ocular irritation with nodules.  
 acute in onset, with mild pain  or discomfort / grittiness.  
 can be unilateral or bilateral, with localised or diffuse red eye.

 There may be mild photophobia and watering.  The lack of photophobia and discharge, 
and normal vision, makes episcleritis the most likely option  
Ocular manifestation of rheumatoid arthritis (see rheumatology )  
Conjunctivitis 
 purulent discharge if bacterial, clear discharge if viral 
 Viral conjunctivitis

 Viral conjunctivitis  
 causes redness, soreness and watering.  
 In severe cases it can cause a keratitis which may affect vision. 1435

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     19 
  It is highly contagious so patients should be advised to practise strict hand hygiene, to 
avoid sharing towels and to take time off work. 
 It is a self-limiting disease which may take several weeks to resolve. 
  Patients are treated with topical lubricants and some ophthalmologists give topical

chloramphenicol to protect against secondary bacterial infections. 
Subconjunctival haemorrhage 
 history of trauma or coughing bouts 
 adverse effect of aspirin  therapy (and other antiplatelets). 
 It usually resolves over 10-14 days. 
 If the haematoma is large it may be worth considering prophylactic antibiotic eyedrops. 

Posterior uveitis  
 Posterior uveitis describes inflammation of the choroid, which can involve the retina l vessels.  
 presents with gradual visual loss and floaters, which is often bilateral.  
  Discomfort and erythema are rare.  
 Slit light examination can demonstrate inflammatory lesions on the retina or choroid, w ith 
inflammation of the retinal vessels and oedema of the optic nerve.  
Retinitis

Retinitis  
CMV Retinitis : causes hemorrhage at the edge of the area of retinal necrosis 
 Retinitis  is inflammation of the retina in the eye, which may lead to blindness. 
 may be caused by several infectious agents, toxoplasmosis, cytomegalovirus and candida.  
 Cytomegalovirus retinitis is the most common cause of vision loss in  AIDS patients.  
 
 1436

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     20 
  
Toxocara  retinitis 
 In retinitis due to Toxocara canis , there is usually only a single, well demarcated lesion.  
 
The slide shows the typical appearance 
of Toxocara  retinitis with a lesion at the 
macula.  
 
Retinitis pigmentosa 
 
 Retinitis pigmentosa is a degenerative  disease involving retinal receptors and pigment cells. 
 degeneration of rod photoreceptor cells  in the retina  night blindness and low peripheral 
vision   
 There are two types of photoreceptors, called rods and cones.  
 Rods  are in the outer regions of the retina, and allow us to see in dim and dark 
light.  
 Died early  night blindness

light.  
 Died early  night blindness  
 Cones  reside mostly in the central portion of the retina, and allow us to perceive 
fine visual detail and color. 
 Died in the late stages 
Features  
 night blindness is often the initial sign  
 funnel vision (the preferred term for tunnel vision) 
1437

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     21 
  fundoscopy: 
 black bone spicule-shaped pigmentation in the peripheral retina,  
 mottling of the retinal pigment epithelium 
Associated diseases 
 Refsum disease:  
 cerebellar ataxia, peripheral neuropathy, deafness, ichthyosis 
 Usher syndrome 
 abetalipoproteinemia 
 Lawrence-Moon-Biedl syndrome 
 Kearns-Sayre syndrome 
 Alport's syndrome

 mitochondrial myopathy 
 drug-induced 
 Thioridazine  
 (typical antipsychotic drug belonging to the phenothiazine group and was 
previously widely used in the treatment of schizophrenia and psychosis; 
withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias,)  
 It is important to differentiate this from corneal deposits that may develop with th e 
use of chlorpromazine.

use of chlorpromazine.  
 Thioridazine  retinal  deposits ( retinitis pigmentosa ). 
 chlorpromazine   corneal deposits 
 
Fundus showing changes secondary to retinitis pigmentosa 
Deficiency of ornithine- δ-aminotransferase 
 Deficiency of ornithine-  δ-aminotransferase causes atrophy of the choroid and retina, 
 beginning as a small yellowish spot and increasing to a circular lesion edged with pigment

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     22 
  Children present with myopia  and decreased night vision , which progresses to blindness in 
middle life 
 Cataracts also develop but the optic discs, cornea and iris remain normal 
 A few patients develop mild proximal muscle weakness  

CHRPE - congenital hypertrophy of the retinal pigment epithelium .  
 These can be typical' or 'atypical'. 
  Typical CHRPE  are grey or black, with depigmented lacunas, and are found in one quadrant 
of one eye. They do not affect vision.  
 Atypical CHRPE  have a white fishtail and are bilateral. They do not affect vision, but if there 
are more than four atypical CHRPE in each eye, then familial adenosis polyposis or Gardner

syndrome might be suspected as an association.  Colonoscopy  and examination of all 
family members would therefore be appropriate. 
A referral to gastroenterology is the best next step. 
Sudden painless loss of vision 
 
An elderly patient with acute visual loss has giant cell arteritis until proved otherwise  
The most common causes  of a sudden painless loss of vision are as follows:

 ischaemic optic neuropathy (e.g. temporal arteritis or atherosclerosis) 
 occlusion of central retinal vein 
 occlusion of central retinal artery 
 vitreous haemorrhage 
 retinal detachment 
Ischaemic optic neuropathy 
 may be due to arteritis (e.g. temporal arteritis) or atherosclerosis (e.g. hypertensive, diabetic 
older patient) 
 due to occlusion of the short posterior ciliary arteries, causing damage to the optic nerve 
 altitudinal field defects are seen

 altitudinal field defects are seen 
Central retinal vein occlusion 
 
 incidence increases with age, more common than arterial occlusion  
 causes: glaucoma, polycythaemia, hypertension, DM 
 severe retinal haemorrhages are usually seen on fundoscopy 
 hypertension and diabetes are risk factors 
 In central retinal vein occlusion there are widespread dot-blot and flame hemorrhages 
throughout the fundus and disc edema. In branch vein occlusion the hemorrhages are

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     23 
 Nasal branch retinal vein occlusion  sudden blurring (not total visual loss) of 
the temporal field in the affected eye. 
 
Central retinal artery occlusion 
 due to thromboembolism (from atherosclerosis) or arteritis (e.g. temporal arteritis) 
 features include afferent pupillary defect, 'cherry red' spot on a pale retina

 Retinal artery occlusions lead to amaurosis fugax, often describes as a 'black curtain' 
descending over the vision. 
 In retinal artery occlusion, the area of retina involved is pale  and interrupted columns of 
blood may be seen in retinal arteries. If the macula is involved, the center of the macula (blo od 
supply from the intact underlying choroid) stands out as a cherry-red spot. 
Vitreous haemorrhage

Vitreous haemorrhage 
 The history of diabetes, complete loss of vision in the affected eye and inability  to visualise the 
retina point towards a diagnosis of vitreous haemorrhage.   
 causes: diabetes, bleeding disorders . the most likely source of bleeding in a diabetic patient is 
fragile neovascular tissue ( Proliferative retinopathy)  
 features may include sudden visual loss, dark spots 
Retinal detachment

Retinal detachment 
 features of vitreous detachment, which may precede retinal detachment, include flashes of 
light or floaters (see below) 
Differentiating posterior vitreous detachment, retinal detachment and vitreous haemorrhage  
Posterior vitreous 
detachment Retinal detachment Vitreous haemorrhage 
♦ Flashes of light (photopsia) 
- in the peripheral field of 
vision 
♦ Floaters, often on the 
temporal side of the central 
vision 
♦ occur in up to 50 -75% of

vision 
♦ occur in up to 50 -75% of 
the population over 65 years  ♦ Dense shadow that starts 
peripherally progresses towards the 
central vision 
♦ A veil or curtain over the field of 
vision 
♦ Straight lines appear curved 
Central visual loss ♦ Large bleeds cause sudden visual 
loss 
♦ inability to visualise the retina  
♦ Moderate bleeds may be described 
as numerous dark spots 
♦ Small bleeds may cause floaters 
 1440

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     24 
  
1441

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     25 
  
Central retinal vein occlusion  
 
Retinal artery occlusion 
 
1442

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     26 
  
1443

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     27 
  
Tunnel vision 
Tunnel vision  (also known as Kalnienk vision ) is the loss of peripheral vision with retention of 
central vision, resulting in a constricted circular tunnel-like field of vision. 
Causes  
 glaucoma 
 retinitis pigmentosa  choroidoretinitis

 retinitis pigmentosa  choroidoretinitis 
 optic atrophy secondary to tabes dorsalis 
 hysteria 
 
Keratoconus  
Keratoconus, meaning, "cone shaped," describes a condition in which th e cornea (the clear front window of 
the eye) becomes thin and protrudes. This abnormal shape can cause serious dist ortion of visual images.  
 
Retinoblastoma

Retinoblastoma  
 The incidence is 1 in 16,000 live births. 
 Genetic predisposition occurs in 20% of patients with unilateral disease, and 30% of pati ents 
with bilateral disease. 
 The gene has been localised to 13q and the inherited form is associated w ith an increased risk 
of malignancy such as osteosarcoma and pineal tumours.  
 It may be inherited as autosomal dominant. 
1444

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     28 
  The commonest presentation is leucocoria (yellowish white pupil reflex),  and there may 
be diminished or absent vision or strabismus. 
 Late symptoms are: 
 pupil irregularity 
 hyphema 
 pain  proptosis 
 signs of raised intracranial pressure. 
 The tumours have rarely metastasised before they are detected.

Ectopia lentis  
Ectopia lentis/subluxation of the lens is associated with: 
 Ehlers-Danlos syndrome 
 Marfan's syndrome 
 Weill-Marchesani syndrome (short stature, skeletal abnormalities and ectopia lentis), and 
 Refsum's disease. 
Fundoscopic features  
 Cytomegalovirus  (CMV) retinitis  
- secondary to human immunodeficiency virus (HIV)

- Fundoscopy of the left eye revealed an extensive 'brushfire-like' lesion  in the major 
superior temporal arcade with a large patch of white fluffy lesion mixed with extensive 
retinal haemorrhages.  
 Ocular histoplasmosis and syphilitic choroiditis  would give a fundus picture of multiple 
whitish lesions . 
 Syphilitic neuroretinitis  would normally give a picture of a macular star exudation . 
 Tuberculous periphlebitis  gives a picture of  perivenous sheathing and minimal retinal

haemorrhages . 
Anisocoria  
 is a condition characterized by an unequal size of the eyes' pupils.  
 Affecting 20% of the population,  
 it can be an entirely harmless condition or a symptom of more serious medical problems  
 The history of anisocoria, with headaches and diplopia should ring alarm bells, in that a 
life-threatening posterior communicating artery aneurysm /berry aneurysm needs to be 
excluded urgently .

excluded urgently . 
Eye signs in Systemic diseases  
 Lisch nodules  of the iris are golden nodules occurring bilaterally in the teenage 
years onwards in Neurofibromatosis type 1 (NF-1).  Axillary freckles  appear at 10 
years of age, while cafe au lait spots increase in size and number throughout childhood. 
 Brushfield spots  of the iris are found in people with Down syndrome.  1445

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     29 
  Kayser-Fleischer rings  are due to copper deposition in Descemet's membrane of the 
cornea.  
 Band keratopathy  is caused by calcium deposition in Bowman's layer of the 
cornea.  Patients who present with band keratopathy should have a serum calcium 
and phosphate level 
 Ectopia lentis  with aortic regurgitation  Marfan syndrome  (Lens dislocation

(classically upwards )). 
 Inferior  dislocated lens  consistent with a diagnosis of homocytinstinuria. 
 Roth's spots  haemorrhages in the retina  associated with subacute bacterial 
endocarditis.  also, seen in leukaemia.  
 'black sunburst' - a chorioretinal scar, which is one of the commoner retinal manifesta tions of 
Sickle cell disease (SCD) and  pathognomonic.  
Immune reconstitution uveitis

Immune reconstitution uveitis 
associated with recovery of the CD4 count in HIV . In this condition a granulomatous uveitis 
appears as the immune system recovers as a result of autoimmune mechanisms.  
Hyphaema 
 Occurs when bleeding from iris vessels fills the anterior chamber with blood and if there is 
enough blood  
 the main risk in the acute stage is of raised intraocular pressure (IOP).

 It is usually caused by trauma - often small objects (champagne corks, squash balls) hitting 
the eye. 
Treatment 
 Strict rest is vital if a hyphaema is present, as there is an increased risk of a second bleed 
in the initial period.   
 Intravenous carbonic anhydrase inhibitors  is the most appropriate 
treatment  
 Aspiration may be required to prevent loss of vision. 
 avoid drops that dilate  the pupil (such as anticholinergics) the iris remains stable and a

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     30 
  
The slide shows hyphaema: blood in the anterior chamber. 
Acute corneal hydrops  
 Acute corneal hydrops occurs in advanced keratoconus, which is the most common cause of  
corneal ectasia. 
 The cornea is made of three main layers: 
 Epithelium 
 Stroma 
 Endothelium

 Stroma 
 Endothelium 
 The transparency of the cornea is maintained by the endothelium which constantly pu mps 
water out from the stroma. 
 Descemet's membrane is a specialised basement membrane which lies between the 
endothelium and stroma, which helps to provide structural integrity to the cornea. 
  In acute corneal hydrops the endothelium and Descemet's membrane split which allows 
aqueous to enter the corneal stroma.

aqueous to enter the corneal stroma. 
 Stromal and epithelial oedema results in corneal opacification and formation of epithelia l 
bullae. 
 Patient present with painful loss of vision  
  cornea is opaque and appears to be protruding  
 Keratoconus is associated with atopic conditions (for example, asthma, hay feve r, eczema) 
and Down syndrome. 
 
1447

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     31 
Subtarsal foreign body 
 history of 'gritty pain' in the eye with pain on blinking.  
 The appropriate management would be to  examine underneath the lid to search for and 
remove a foreign body.  
 Further management would involve topical chloramphenicol ointment three to four times a d ay

for five days. 
 Physical examination shows a white pupillary reflex in both eyes .  
 The responsible gene, RB1, coding for pRb, is located on chromosome 13.  
 malignancy of the retina of the eye 
 often presents in children less than 3 years of age 
 Genetics 
 60% are sporadic.  
 There is no significant family history of disease. 
 40% are heritable.

 40% are heritable.  
 Rb is a tumor suppressor gene located on chromosome 13 
 loss of heterozygosity 
 both alleles must be deleted/mutated before the development of cancer and 
expression of disease ("two-hit hypothesis") 
 as opposed to oncogenes which require just one mutation 
 mutation in a tumor suppressor gene leads to increased cancer risk 
 inhertied loss of Rb protein results in bilateral disease 
 regulates cell growth and repair damage

 regulates cell growth and repair damage 
 see Tumor suppressor gene topic  
 see Cell cycle topic 
 associations 
 familial retinoblastoma is a predisposing factor to the development of osteosarcoma 
 Presentation   
 Symptoms 
 visual loss 
 leukocoria  
 absence of red-light reflex 
 unilateral exophthalmos 
 strabismus 
 Evaluation   
 Referral to opthamologist if seen in general pediatric screening 
 1448

Notes & Notes for MRCP                                                             By Dr. Yousif Abdallah Hamad     32 
 Treatment   
 Surgical 
 enucleation of the eye 
 
 1449

Psychiatry 
 
Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    1 
  
By
 
Updated 
 
2017
 
Contains: 
 
 1450

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    2 
 Unexplained symptoms 
 
There are a wide variety of psychiatric terms for patients who have symptoms for which  no organic 
cause can be found:  
Somatisation disorder  
 multiple physical SYMPTOMS  present for at least 2 years 
 patient refuses to accept reassurance or negative test results 
Hypochondrial disorder

Hypochondrial disorder 
 persistent belief in the presence of an underlying serious DISEASE , e.g. cancer 
 patient again refuses to accept reassurance or negative test results 
 more common in those who have lost a close family member to a serious illness. 
Conversion disorder 
 typically involves loss of motor or sensory function  
 the patient doesn't consciously feign the symptoms (factitious disorder) or seek material gain 
(malingering)

(malingering) 
 patients may be indifferent to their apparent disorder - la belle indifference - a lthough this has 
not been backed up by some studies 
Dissociative disorder 
 dissociation is a process of 'separating off' certain memories from normal consciousness 
 in contrast to conversion disorder involves psychiatric symptoms e.g. Amnesia, fugue, 
stupor  
 dissociative identity disorder (DID) is the new term for multiple personality disorder as is the

most severe form of dissociative disorder 
Munchausen's syndrome 
 also, known as factitious disorder 
 the intentional production of physical or psychological symptoms 
Malingering 
 fraudulent simulation or exaggeration of symptoms with the intention of finan cial or other gain 
Anorexia nervosa 
  
1451

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    3 
 Anorexia nervosa is the most common cause of admissions to child and adolescent 
psychiatric wards.  
 
 90% of patients are female 
 predominately affects teenage and young-adult females 
 prevalence of between 1:100 and 1:200 
Features  
 Reduced body mass index 
 Phobic avoidance of normal weight 
 Relentless dieting

 Relentless dieting 
 Self-induced vomiting 
 Laxative use 
 Excessive exercise 
 Amenorrhoea 
 enlarged salivary glands  Lanugo hair 
 Denial 
 Concealment 
 Over-perception of body image 
 Enmeshed families. 
 
Physiological abnormalities 
 Hypokalaemia   
 (it is the most likely abnormality to be seen on routine laboratory testing with both 
induced vomiting and abuse of diuretics). 
 low FSH, LH, oestrogens and testosterone

 low FSH, LH, oestrogens and testosterone 
 raised cortisol and growth hormone 
 ↑↑ Cortisol,  
 ↑↑ growth hormone (due to GH resistance) 
 impaired glucose tolerance 
 ↑↑ glucose (impaired glucose tolerance)  
 hypercholesterolaemia 
 hypercarotinaemia 
 low T3 
 though thyroxine (T4) and TSH may be normal. 
 hypoalbuminaemia,  
 anaemia, 
 Ferritin levels are low in a state of malnutrition. 
 leukopaenia, 
Diagnosis (based on the DSM-IV criteria)

Diagnosis (based on the DSM-IV criteria) 
 person chooses not to eat - BMI < 17.5 kg/m^2, or < 85% of that expected 
 intense fear of being obese 
 disturbance of weight perception 
 amenorrhoea = 3 consecutive cycles 
Investigation 1452

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    4 
  Use of laxatives to drive weight loss is common, and a  purgative screen  is therefore a 
logical next step.  
Prognosis 
 remains poor 
 Up to 10% of patients will eventually die because of the disorder. 
Bulimia nervosa 

 Bulimia nervosa is a type of eating disorder characterised by episodes of binge eating 
followed by intentional vomiting  to prevent weight gain. 
 Most common in women in their 20s and 30s. 
 usually appear physically normal,  
 low self-esteem 
 depressive thoughts,  
 lack of confidence. 
 Parotid hypertrophy  and erosion of the teeth  are the most common physical signs 
and may prompt diagnosis. 
 Lab Features

 Lab Features  
 hypokalaemic metabolic alkalosis  
 Hyponatraemia. 
 Hypocalcaemia.  
 Alkaline phosphatase is often raised , due to bone loss resulting from nutritional 
deficiencies.  
 first-line treatment   Cognitive behavioural therapy (CBT) is considered the optimal 
primary treatment  
 pharmacological treatments have a limited role   
 Selective serotonin-reuptake inhibitors (SSRIs) or serotonin-norepinephrine

reuptake inhibitors (SNRIs) (used adjunctively to CBT, or as an alternative when 
CBT is not available).  
 a trial of  high-dose fluoxetine is currently licensed for bulimia but long-term data 
is lacking  
 
 1453

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    5 
Hypomania vs. mania 
The presence of psychotic symptoms differentiates mania from hypomania 
Mania  Psychotic symptoms 
 mania and hypomania  
 delusions of grandeur Mood   predominately elevated 
 irritable 
 auditory hallucinations 
 Speech and

 Speech and 
thought   pressured 
 flight of ideas 
 Behaviour   insomnia 
 loss of inhibitions: 
 sexual promiscuity, 
 overspending,  
 risk-taking 
 increased appetite 
 
Antipsychotics 
 
 Antipsychotics act as dopamine D2 receptor antagonists , blocking dopaminergic 
transmission in the mesolimbic pathways.

transmission in the mesolimbic pathways.  
 Conventional antipsychotics are associated with problematic extrapyramidal side-effects which 
has led to the development of atypical antipsychotics such as clozapine 
Extrapyramidal side-effects 
 Parkinsonism 
 acute dystonia (e.g. torticollis, oculogyric crisis) 
 affects about 2% of patients. 
 Administer procyclidine 
 akathisia (severe restlessness) 
 tardive dyskinesia (late onset of choreoathetoid movements, abnormal, involuntary) ,

 may occur in 40% of patients,  
 may be irreversible,  
 most common is chewing and pouting of jaw 
 Specific warnings when antipsychotics are used in elderly patients: 
 increased risk of stroke (especially olanzapine and risperidone) 
 increased risk of venous thromboembolism 
Other side-effects 
 antimuscarinic: dry mouth, blurred vision, urinary retention, constipation 
 sedation,  
 weight gain 
 raised prolactin : galactorrhoea,  
1454

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    6 
  block dopamine D2 receptors  block dopamine's action on the pitutary reduces 
inhibition of prolactin secretion  hyperprolactinaemia. 
 Amenorrhoea, infertility 
 loss of libido, and erectile dysfunction. 
 neuroleptic malignant syndrome: pyrexia, muscle stiffness

 reduced seizure threshold (greater with atypicals) 
 prolonged QT  interval (particularly haloperidol ) 
 
Typical antipsychotics 
 
Typical Antipsychotics  
High Potency 
(in Descending 
Order) 
 Advantages  Disadvantages  Unique Features  
  Fewer side 
effects of 
sedation and 
hypotension 
  High association with 
extrapyramidal symptoms  Able to use as long-
acting depot injections

acting depot injections 
 Can be given IM in 
acute situations 
 Fluphenazine 
 
Perphenazine 
 
Chlorpromazine  
  Lower 
frequency of 
extrapyramid
al side 
effects 
  Greater incidence of 
anticholinergic side-effects, 
hypotension, sedation  Corneal  deposits 
Thioridazine   Retinal deposits 
 QT prolongation 
 
Atypical antipsychotics

Atypical antipsychotics 
 
atypical antipsychotics such as olanzapine/risperidone/clozapine have been associated with 
hyperglycaemia and insulin resistance. 
 
 Atypical antipsychotics should now be used first-line in patients with schizophrenia, a ccording 
to 2005 NICE guidelines.  
1455

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    7 
  The main advantage of the atypical agents is a significant reduction in extra-pyram idal side-
effects. 
Adverse effects of atypical antipsychotics 
 clozapine is associated with agranulocytosis (see below) 
Examples of atypical antipsychotics 
 clozapine  
 olanz apine  
 queti apine  
 risperidone 
 amisulpride

 amisulpride 
 
Atypical Antipsychotics  
Medication  Unique features and side effects  
Risperidone  High potency 
 Usually first line 
 Hyperprolactinemia 
 Weight gain 
 
Olanzapine  Severe weight gain 
 Very sedating 
Ziprasidone   Minimal to no weight gain 
 Increased QTc 
 
Quetiapine  Low potency 
 Sedating 
 Useful in bipolar depression and augmentation of major 
depression therapy 
 
Lurasidone   Minimal weight gain

Lurasidone   Minimal weight gain 
 Useful in bipolar depression 
 
Clozapine   Weight gain 
 Most effective anti-psychotic 
 Decreased suicide risk 
 Agranulocytosis 
 Myocarditis 
 Sialorrhea 
 Orthostatic hypotension 
 Increased seizures 
 
Aripiprazole  D2 partial agonist 
 Augmentation of major depression therapy 1456

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    8 
  
Clozapine    
 should only be used in patients resistant to other antipsychotic medication  (due to significant 
risk of agranulocytosis ) 
Adverse effects of clozapine  
 agranulocytosis (1%), neutropenia (3%) 
 reduced seizure threshold - can induce seizures in up to 3% of patients

Monitoring:  (full blood count monitoring is therefore essential during treatment) 
 A white cell count with differential is checked prior  to treatment , 
 then weekly  for the first 18 weeks,  
 then two weekly  from week 18 to 52, 
 then four weekly  after one year of clozapine with stable blood results.  
 then checked for four weeks after discontinuation of treatment.  
 
Risperidone 
 Risperidone is a novel antipsychotic belonging to the benzisoxazole derivative class

 It is a high-affinity D2 and 5- HT-2 receptor antagonist 
 To a lesser extent, risperidone is also an antagonist at α -p adrenergic receptors, H1-
histaminergic and α2 - adrenergic receptors 
 Common adverse effects include: 
 Insomnia 
 Anxiety 
 Headache 
 Risperidone may also lead to impaired glucose tolerance, although the incidence of 
abnormalities in glucose metabolism is less than that seen with other antipsychotics

Neuroleptic malignant syndrome 
 Neuroleptic malignant syndrome is a rare but dangerous condition seen in patients taking 
antipsychotic medication.  
 It carries a mortality of up to 10% 
 can also occur with atypical antipsychotics.  
 It may also occur with dopaminergic drugs (such as levodopa) for Parkinson's disease, 
usually when the drug is suddenly stopped or the dose reduced.

 Concomitant treatment with lithium or anticholinergics may increase the risk of NMS. 
 
1457

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    9 
  
A patient with P/H/O parkinson's disease, deteriorate 1 – 2 days after admission to hospital for other 
condition  neuroleptic malignant syndrome (NMS) as a result of not taking her parkinson's 
medication  do Creatine kinase to confirm the diagnosis   
 
Features 
 more common in young male patients

Features 
 more common in young male patients 
 onset usually in first 10 days of treatment or after increasing dose 
 pyrexia 
 rigidity 
 Renal failure may occur secondary to rhabdomyolysis 
 Raised creatine kinase  in most cases.  
  the most important investigation to be performed  
 always elevated (>1000 IU/L−1), reflecting myonecrosis secondary to intense muscle 
contracture. 
 leukocytosis may also be seen 
 
differential diagnosis 
 serotonin syndrome

 serotonin syndrome  
 Myoclonus is the distinguishing feature of serotonin syndrome (found only in 
serotonin syndrome).  All the other features can be present in both conditions.  
 Features of both NMS and serotonin syndrome.  
 Severe muscular rigidity 
 Hyperthermia (temperature >38°C) 
 Autonomic instability 
 Changes cognition or in the level of consciousness 
 Rhabdomyolysis 
 Recent commencement or change of dose of a medication

 Causes of Serotonin syndrome  
 in those taking therapeutic doses of SSRIs, as part of drug-drug interaction  
(e.g. the addition of: 
 ondansetron,  
 amphetamine, cocaine, meperidine(Pethidine),  
 dextromethorphan, fentanyl, buspiron, ergot alkaloids, lithium, L-dopa, 
LSD, St. John ’s Wort),  
 or following intentional self-poisoning  with SSRI.  
 treatment  for serotonin syndrome: 
 stopping any serotinergic agents,  
 using benzodiazepines for agitation

 using benzodiazepines for agitation 
 consideration of use of serotonin antagonists such as cyproheptadine  if 
there is severe autonomic disturbance. 
 stop antipsychotic 
 IV fluids to prevent renal failure 
 dantrolene may be useful in selected cases 1458

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    10 
  thought to work by decreasing excitation-contraction coupling in skeletal muscle by 
binding to the ryanodine receptor, and decreasing the release of calcium from the 
sarcoplasmic reticulum 
 bromocriptine , dopamine agonist, may also be used 
 levodopa preparations may be beneficial 
 
Neuroleptic malignant syndrome Serotonin syndrome

 develops over days to weeks.  develops over 24 hours. 
 characterized by sluggish neuromuscular 
responses (rigidity, bradyreflexia).  characterized by neuromuscular 
hyperreactivity ( tremor,  hyperreflexia , 
myoclonus ). 
 resolution typically requires an average of 
nine days.  resolution typically requires less than 24 
hours . 
 
Hunter's Decision Rules for Diagnosis of Serotonin Toxicity 
 
1459

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    11 
Antidepressants  
 Classes 
1. selective serotonin reuptake inhibitors ( SSRIs ),  
2. selective serotonin-norepinephrine reuptake inhibitors (SS NRIs),  
3. Serotonin antagonist and reuptake inhibitors ( SARIs ) 
4. monoamine oxidase inhibitors ( MAOIs ),

4. monoamine oxidase inhibitors ( MAOIs ), 
5. tricyclic antidepressants ( TCAs ).  
6. Atypical antidepressants 
 Most of these drugs work by increasing the levels of serotonin, norepinephrine, 
or dopamine within the synaptic cleft.  
 SSRIs are the first-line treatment for the vast majority of patients with depression 
  MAOIs and TCAs are similarly efficacious but are rarely used today due to their large n umber 
of potentially severe adverse effects.

of potentially severe adverse effects. 
Selective serotonin reuptake inhibitors ( SSRIs)  
 
 Mechanism of action   
 inhibition of serotonin reuptake in synaptic cleft ĺ  Ĺ serotonin levels 
 primarily act at the 5HT transporter protein 
 Drugs  
 Fluoxetine  
 Paroxetine  
 Sertraline 
 Citalopram 
 Escitalopram 
 First-line treatment for major depressive disorder  
 Generalized anxiety disorder

 Generalized anxiety disorder  
 Obsessive-compulsive disorder 
 Post-traumatic stress disorder 
 Somatic symptom disorder 
 Panic disorder 
 Gambling disorder 
 Premature ejaculation 
 Premenstrual dysphoric disorder 
 Binge-eating disorder 
 Side effects  
 Sexual disorders (anorgasmia, erectile or ejaculatory dysfunction, Ļ libido)  
 Diarrhea, nausea, vomiting  
 gastrointestinal symptoms are the most common side-effect 
1460

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    12 
  Sleep disorders 
 Headache 
 Increased risk of bleeding  
 proton pump inhibitor should be prescribed if a patient is also taking a NSAID 
 Serotonin syndrome 
 patients should be counselled to be vigilant for increased anxiety and agitation after 
starting a SSRI  
 Contraindications

 risk of serotonin syndrome if given concomitantly within 14 days of MAOIs , linezolid , 
or methylene blue  use 
 Additional information  
 must usually be taken for 4 –6 weeks before symptom reduction is seen 
 citalopram (although Ĺ QT interval) and fluoxetine are currently the preferred SSRIs 
 sertraline is useful post myocardial infarction  as there is more evidence for its safe 
use in this situation than other antidepressants

use in this situation than other antidepressants 
 nice advice 2017  For people who also have a chronic physical health problem, 
consider using citalopram or sertraline  as these have a lower propensity for 
interactions.  
 SSRIs should be used with caution in children and adolescents. Fluoxetine is the drug 
of choice when an antidepressant is indicated 
 
 Citalopram and the QT interval 
 citalopram and escitalopram are associated with dose-dependent QT interval

prolongation and should not be used in those with: congenital long QT syndrome; 
known pre-existing QT interval prolongation; or in combination with other medicines that 
prolong the QT interval 
 the maximum daily dose is now 40 mg for adults; 20 mg for patients older than 65 
years; and 20 mg for those with hepatic impairment 
 Interactions 
 NSAIDs: NICE guidelines advise 'do not normally offer SSRIs', but if given co-prescribe 
a proton pump inhibitor

a proton pump inhibitor 
 warfarin / heparin:  NICE guidelines recommend avoiding SSRIs and considering 
mirtazapine  
 the SSRIs least likely to cause drug interactions with warfarin appear to be 
sertraline and citalopram . 
 aspirin: see above 
 triptans: avoid SSRIs 
 fluoxetine and paroxetine have a higher propensity for drug interactions 
 
 Antidepressant Follow- up 
 After initiation of antidepressant therapy patients should normally be reviewed by a 
doctor after 2 weeks.

doctor after 2 weeks.  
 For patients under the age of 30 years or at increased risk of suicide they should be 
reviewed after 1 week.  1461

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    13 
  If a patient makes a good response to antidepressant therapy they should continu e on 
treatment for at least 6 months after remission as this reduces the risk of relapse.  
 
 Selective serotonin reuptake inhibitor discontinuation syndrome  
 
 When stopping a SSRI the dose should be gradually reduced over a 4 week period (th is

is not necessary with fluoxetine). This not necessary with fluoxetine due to its l onger 
half-life. 
 Paroxetine has a higher incidence of discontinuation symptoms. 
 Discontinuation symptoms 
 increased mood change 
 restlessness 
 difficulty sleeping 
 unsteadiness 
 sweating 
 gastrointestinal symptoms: pain, cramping, diarrhoea, vomiting 
 paraesthesia  
 
while not as selective as the SSRIs, drugs of abuse such as cocaine, fenfluramine, an d

(3,4-methylenedioxy) methamphetamine ( MDMA  or ecstasy) are inhibitors of serotonin uptake . 
__________________________________________________________________
Selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) 
 Mechanism of action  
  inhibition of serotonin and norepinephrine reuptake in synaptic cleft 
ĺ Ĺ serotonin and norepinephrine levels 
 Drugs  
 Venlafaxine 
 Duloxetine 
 Major depressive disorder ( second-line therapy )

 Generalized anxiety disorder 
 Duloxetine: stress incontinence in women  
 Similar profile to SSRIs (see “Selective serotonin reuptake inhibitors ” above) 
 Increased blood pressure 
 Contraindications : risk of serotonin syndrome if given concomitantly within 14 
days of MAOIs, linezolid, or methylene blue use 
 Additional information :  
 Blood pressure should be controlled before initiating SSNRI therapy. 
 
1462

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    14 
 __________________________________________________________________
Serotonin antagonist and reuptake inhibitors (SARIs) 
 Inhibition of serotonin reuptake ĺ  Ĺ serotonin levels 
 Antagonist of H 1- and α1-receptors 
 Drugs 
 Trazodone 
 Nefazodone 
 Indications :

 major depressive disorder, especially in patients with insomnia 
 Priapism 
 Sedation (due to H 1 antagonism) 
 Orthostatic hypotension 
 Contraindications:  
 Additional information 
 Mainly used as adjunct to other antidepressants for treatment of insomnia associated 
with depression

with depression  
 Off-label use: insomnia in patients without depression 
Monoamine oxidase inhibitors (MAOIs) 
  inhibition of monoamine oxidase ĺ  Ļ breakdown of epinephrine, norepinephrine, 
and serotonin ĺ Ĺ levels of epinephrine, norepinephrine, and serotonin 
 Drugs 
 Tranylcypromine 
 Phenelzine 
 Selegiline 
 Isocarboxazid 

 Major depressive disorder ( third- or fourth-line therapy ) 
 due to its potentially severe side effects, interaction with foods containing 
tyramine, and numerous drug interactions 
 particularly effective for treating atypical symptoms of depression (Ĺ appetite  and weight 
gain, Ĺ sleep, leaden paralysis)  
 Selegiline: Parkinson's disease (as an adjunct to carbidopa-levodopa)

 For the treatment of depression, Selegiline  is available as a transdermal patch  
 (oral form is only used for Parkinson's disease) 
 Hypertensive crisis with ingestion of foods containing tyramine  (e.g. aged cheeses, 
smoked/cured meats, alcoholic beverages, dried fruits)  
 Serotonin syndrome  
 Contraindications  1463

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    15 
  risk of serotonin syndrome if given concomitantly within 14 days of MAOIs, linezolid , 
or methylene blue use 
Tricyclic antidepressants (TCA)  
 
  inhibition of serotonin and norepinephrine reuptake in synaptic cleft

 Drugs  
Tertiary amines  Secondary amines 
Amitriptyline 
Clomipramine 
Doxepin 
Imipramine 
Trimipramine Nortriptyline 
Desipramine 
Protriptyline 
 
 less commonly now for depression due to their side-effects and toxicity in overdo se.  
 used widely in the treatment of neuropathic pain, where smaller doses are typically 
required. 
 prophylaxis of headache (both tension and migraine)

 Neuropathy (diabetic neuropathy, post-herpetic neuralgia, etc.) 
 Chronic pain (including fibromyalgia) 
 Sedation and delirium 
 Anticholinergic symptoms 
 Cardiovascular symptoms:  
 wide QRS complex, tachycardia,  arrhythmia (including ventricular 
fibrillation),  
 hypotension  
 CNS symptoms: drowsiness , confusion, hallucinations, sedation, coma, seizures

 Gastrointestinal symptoms: intestinal ileus, constipation  
 Genitourinary symptoms: urinary retention  
 General:  
 Xerostomia (dry mouth) 
 blurred vision  
 mydriasis,  
 hyperthermia/dry skin 
 
1464

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    16 
  
More sedative Less sedative 
Dosulepin  
Trazodone ( is technically a 'tricyclic-related)  Imipramine 
Lofepramine  
Nortriptyline 
 
 Overdose  
 
 lofepramine has a lower incidence of toxicity in overdose 
 amitriptyline and dosulepin  (dothiepin) are considered the most dangerous in overdose

 Clinical features:  caused by anticholinergic effects  
 Secure airways, oxygenation, monitoring, fluid resuscitation 
 ECG: cardiac arrhythmia (e.g., tachycardia, QRS prolongation) 
 Urine immunoassay: detection of TCA in the body  
 Activated carbon in first 2 hours after ingestion as soon as the airways are 
secured 
 Sodium bicarbonate for cardiac arrhythmia  (QRS ≥ 100 ms  or ventricula 
arrhythmias)  
 Benzodiazepines for seizures 

 Risk of serotonin syndrome if given concomitantly within 14 days of MAOIs, linezolid , 
 Tertiary amines are high-risk medications in the elderly population as they can 
cause confusion due to sedative and anticholinergic side effects. 
 Rarely used as a first- or second-line antidepressant today due to extensive side effect 
profile and risk of lethal overdose (ingestion of a one week supply can be fa tal)

 Physostigmine should not be given to patients with suspected TCA overdose because  it 
can precipitate cardiac arrest 
 Antimuscarinic side-effects are more common with  imipramine  than other types 
of tricyclic antidepressants.  
Atypical antidepressants 
 Mirtazapine 
 α2-adrenergic antagonist ĺ  Ĺ serotonin and norepinephrine release

 5-HT2 and 5- HT3 receptor antagonist ĺ  Ĺ effect  of serotonin on free 5- HT1 receptor 
ĺ likely responsible for antidepressant effects  
 H1 antagonist 
 major depressive disorder, especially in underweight and insomniac patients  
1465

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    17 
  Side effects 
 Ĺ appetite  and weight gain 
 Contraindications 
 risk of serotonin syndrome if given concomitantly within 14 days of MAOIs, linezolid , 
Bupropion 
 not fully understood, but thought to increase dopamine and norepinephrine levels

via reuptake inhibition  
 Smoking cessation :  
 used in conjunction with counseling and nicotine replacement 
 Major depressive disorder 
 Depressive disorders with seasonal pattern 
 Reduction of seizure threshold 
 Tachycardia, palpitations, agitation 
 Neuropsychiatric symptoms (including depression, mania, psychosis, and paranoia) 

 Patients with Ĺ risk  for seizure (epilepsy, anorexia/bulimia, alcohol or benzodiazepine 
withdrawal, etc.) 
 Bupropion has no sexual side effects , which makes it a viable alternative 
to SSRIs or SSNRIs for patients who experience sexual dysfunction. 

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    18 
  
Action: 
 Benzodiazepines (lorazepam, diazepam, chlordiazepoxide) enhance the effect of  the inhibitory 
neurotransmitter gamma-aminobutyric acid (GABA).  
 Sedation 
 Hypnotic 
 Anxiolytic  Anticonvulsant 
 Muscle relaxant 
 
Prescription

Prescription 
 Patients commonly develop a tolerance and dependance to benzodiazepines a nd care should 
therefore be exercised on prescribing these drugs.  
 The Committee on Safety of Medicines advises that benzodiazepines are only prescrib ed for a 
short period of time (2-4 weeks). 
Benzodiazepine withdrawal  
 The BNF  gives advice on how to withdraw a benzodiazepine :

 The dose should be withdrawn in steps of about 1/8 (range 1/10 to 1/4) of th e daily dose every 
fortnight(أسبوعين  .) 
 A suggested protocol for patients experiencing difficulty is given: 
 Switch patients to the equivalent dose of diazepam 
 Reduce dose of diazepam every 2-3 weeks in steps of 2 or 2.5 mg 
 Time needed for withdrawal can vary from 1 month to 1 year or more 
benzodiazepine withdrawal syndrome:

benzodiazepine withdrawal syndrome:  
 If patients withdraw too quickly from benzodiazepines they may  experience benzo diazepine 
withdrawal syndrome, a condition very similar to alcohol withdrawal syndrome.  
 This may occur up  to 3 weeks after stopping a long-acting drug.  
 Features include:  
 Insomnia 
 Irritability 
 Anxiety 
 Tremor 
 Loss of appetite  Tinnitus 
 Perspiration 
 Perceptual 
disturbances 
 Seizures 
 
Flumazenil

 Seizures 
 
Flumazenil 
 Flumazenil, a benzodiazepine antagonist, is used to reverse the central sedative 
effects of benzodiazepines after anaesthetic and similar procedures  
 Flumazenil has a shorter half-life than that of diazepam and midazolam and  there is a 
risk that patients may become re-sedated - in which case a repeat dose of flum azenil 
should be given 
1467

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    19 
  
 Diazepam has a long half-life, principally because of its active metabolites.  
 Midazolam is short-acting but is only used intravenously.  
 Promethazine is an antihistamine with a 12-hour half-life and may cause daytime sed ation.  
 Clomethiazole is less safe in overdose, has dependence potential and is only licensed for

sedation in the elderly.  
 Loprazolam is sho rt-acting (half-life 6 –12 hours) .  
Post-traumatic stress disorder 
 Post-traumatic stress disorder (PTSD) can develop in people of any age following a traumatic 
event, for example a major disaster or childhood sexual abuse.  
 It encompasses what became known as 'shell shock' following the first world war.

 One of the DSM- IV diagnostic criteria is that symptoms have been present for more than one 
month 
 the onset of symptoms is usually delayed and it tends to run a prolonged course 
Features  
 re-experiencing: flashbacks, nightmares, repetitive and distressing intrusive images 
 avoidance: avoiding people, situations or circumstances resembling or associated with the 
event 
 hyperarousal: hypervigilance for threat, exaggerated startle response, sleep problems,

irritability and difficulty concentrating 
 emotional numbing - lack of ability to experience feelings, feeling det ached from other people 
 drug or alcohol misuse 
 anger 
 unexplained physical symptoms 
 following a traumatic event single-session interventions (often referred to as debriefing) are n ot 
recommended 
 watchful waiting may be used for mild symptoms lasting less than 4 weeks

 military personnel have access to treatment provided by the armed forces 
 trauma-focused cognitive behavioural therapy (CBT) or eye movement desensitisation and 
reprocessing (EMDR) therapy may be used in more severe cases 
 drug treatments for PTSD should not be used as a routine first-line treatment f or adults.  If drug 
treatment is used then paroxetine or mirtazapine  are recommended  
Post-concussion syndrome

Post-concussion syndrome 
Post-concussion syndrome is seen after even minor head trauma 
 
Typical features include  
 headache 
 fatigue 
 anxiety/depression 
 dizziness 1468

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    20 
Grief reaction 
 It is normal for people to feel sadness and grief following the death of a lo ved one and this 
does not necessarily need to be medicalised.  
 
 Grief stages:  One of the most popular models of grief divides it into 5 stages.

1. Denial: this may include a feeling of numbness and also pseudohallucinations of the 
deceased, both auditory and visual. Occasionally people may focus on physical objects 
that remind them of their loved one or even prepare meals for them 
2. Anger: this is commonly directed against other family members and medical 
professionals 
3. Bargaining 
4. Depression 
5. Acceptance 
 It should be noted that many patients will not go through all 5 stages.

 risk factors of Abnormal, or atypical, grief reactions 
 more likely occur in women 
 if the death is sudden and unexpected. 
 problematic relationship before death  
 if the patient has not much social support. 
 Features of atypical grief  reactions include: 
 delayed grief: sometimes said to occur when more than 2 weeks passes before grieving 
begins 
 prolonged grief: difficult to define. Normal grief reactions may take up to and  beyond 12 
months

months 
Depression: screening and assessment 
Screening  
The following two questions can be used to screen for depression 
 'During the last month, have you often been bothered by feeling down, d epressed or 
hopeless?' 
 'During the last month, have you often been bothered by having little interest or pleasu re in 
doing things?' 
A 'yes' answer to either of the above should prompt a more in depth assessment.

Assessment  
 
There are many tools to assess the degree of depression including the Hospital Anxiety and 
Depression (HAD) scale and the Patient Health Questionnaire (PHQ-9). 
 
Hospital Anxiety and Depression (HAD) scale  
 consists of 14 questions, 7 for anxiety and 7 for depression 
 each item is scored from 0-3 1469

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    21 
  produces a score out of 21 for both anxiety and depression 
 severity: 0-7 normal, 8- 10 borderline, 11+ case 
 patients should be encouraged to answer the questions quickly 
Patient Health Questionnaire (PHQ- 9) 
 asks patients 'over the last 2 weeks, how often have you been bothered by any of the  following 
problems?'

problems?' 
 9 items which can then be scored 0-3 
 includes items asking about thoughts of self-harm 
 depression severity: 0-4 none, 5-9 mild, 10-14 moderate, 15-19 moderately se vere, 20- 27 
severe 
NICE  use the DSM- IV criteria to grade depression: 
 1. Depressed mood most of the day, nearly every day 
 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, 
nearly every day

nearly every day 
 3. Significant weight loss or weight gain when not dieting or decrease or increase in ap petite 
 4. Insomnia or hypersomnia nearly every day 
 5. Psychomotor agitation or retardation nearly every day 
 6. Fatigue or loss of energy nearly every day 
 7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day 
 8. Diminished ability to think or concentrate, or indecisiveness nearly every day

 9. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide 
attempt or a specific plan for committing suicide 
 
Subthreshold 
depressive symptoms Fewer than 5 symptoms 
Mild depression  Few, if any, symptoms in excess of the 5 required to make the 
diagnosis, and symptoms result in only minor functional impairment 
Moderate depression  Symptoms or functional impairment are between 'mild' and 'severe'

Severe depression  Most symptoms, and the symptoms markedly interfere with 
functioning. Can occur with or without psychotic symptoms 
 Psychotic symptoms such as delusions and hallucinations may occur in depression, and when they  do, 
treatment with both an antidepressant and an antipsychotic is indicated.  
Psychotic depression  
 Psychotic depression: severe depression accompanied by psychotic features  
  is uncommon but important due to high risk of suicide.

 The history of low mood predating the psychotic symptoms, also the fact that the 
auditory hallucinations and delusions are consistent with the depressive feelings of 
guilt, distinguish this from schizophrenia.  
 
 1470

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    22 
  
Electroconvulsive therapy (ECT) 
• Electroconvulsive therapy (ECT) would usually be avoided if he had a recent 
cerebrovascular accident.  Most guidelines state that a recent CVA (within 1 to 3 months) is a 
contraindication.  
Early morning waking  is a classic somatic symptom of depression and often develops 
earlier than general insomnia.

earlier than general insomnia.  
_____________________________________________________________ _____  
Suicide 
 
Factors associated with risk of suicide  following an episode of deliberate self-harm: 
 efforts to avoid discovery 
 planning 
 leaving a written note 
 final acts such as sorting out finances 
 violent method 
These are in addition to standard risk factors for suicide  
 male sex 
 advancing age 
 unemployment or social isolation 
 divorced or widowed

 divorced or widowed 
 history of mental illness (depression, schizophrenia) 
 history of deliberate self harm 
 alcohol or drug misuse 
 
Treatment 
 In an Emergency Department the suicidal patient who declines to be admitted fo r observation 
and treatment should be managed as follows: 
 Ensure that a member of staff stays with them at all times 
 Call the duty psychiatrist 
 If they attempt to abscond before or during psychiatric assessment, the staff of

the Emergency Department have a duty under Common Law to restrain the 
patient 
A suicidal patient became agitated and insisted that she wanted to go home immediately. 
How should you proceed?  
 Call the duty psychiatrist, and with other staff in the Emergency Department attempt 
to restrain her until they arrive  
 
 1471

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    23 
Depression in older people  
 Older patients are less likely to complain of depressed mood  
 Depression in elderly can depress cognitive function, hence cognition may be inaccurately 
depressed on measurement scales.

depressed on measurement scales.  
 In elderly patients, geriatric depression scale (GDS) is more appropriate than Becks 
depression scale, as the latter focuses heavily on somatic symptoms that frequen tly under-
score depression in elderly patients.  
Features  
 physical complaints (e.g. hypochondriasis) 
 agitation 
 insomnia 
 SSRIs are first line (adverse side-effect profile of TCAs more of an issue in the elderly)

Mood disorder  
cyclothymic disorder   
 characterised by the presence of numerous periods of both depression (but not ma jor 
depressive episodes) and hypomania for at least two years. 
 The crucial feature of a major depressive disorder is a severe dysphoric mood and persistent 
loss of interest or pleasure in all usual activities. 
dysthymic disorder

dysthymic disorder  
 In dysthymic disorder, the patient's mood is chronic depression with never a manic or 
hypomanic episode, for at least two years. 
Bipolar I disorder  
 characterised by severe alterations in mood ( mania and depression ) that are usually episodic 
and recurrent.  
 Sodium valproate and carbamazepine are efficacious as first line treatment in th e 
prophylaxis of manic and depressive episodes in bipolar I disorder. Lithium may be

used if these anticonvulsants are ineffective. 
 However, in the initial stages of manic episodes, the addition of drugs with potent 
sedative effects are often required, for example, clonazepam, lorazepam and 
haloperidol. 
 These drugs can be tapered and then discontinued as soon as the initial phase 
of the manic episode has subsided and the effects of the anticonvulsants or 
lithium are seen clinically. 
Bipolar II disorder

Bipolar II disorder 
 characterised by one or more major depressive  episodes, at least one hypo manic episode 
and NO manic  episodes. 
 
 1472

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    24 
Cognitive behavioural therapy 
Main points 
 useful in the management of depression and anxiety disorders 
 usually consists of one to two hour sessions once per week 
 should be completed within 6 months 
 patients usually get around 16-20 hours in total

Seasonal affective disorder 
 Seasonal affective disorder (SAD) describes depression which occurs predominately around 
the winter months.  
 Bright light therapy has been shown to be more effective than placebo for p atients with SAD   
Body dysmorphic disorder 
 Body dysmorphic disorder (sometimes referred to as dysmorphophobia) is a mental disord er

where patients have a significantly distorted body image 
 Diagnostic and Statistical Manual (DSM) IV criteria: 
 
 Preoccupation with an imagine defect in appearance. If a slight physical anomaly is 
present, the person's concern is markedly excessive 
 The preoccupation causes clinically significant distress or impairment in social, 
occupational, or other important areas of functioning 
 The preoccupation is not better accounted for by another mental disorder (e.g.,

dissatisfaction with body shape and size in Anorexia Nervosa) 
____________________________________________________________ ______  
Post-partum mental health problems 
 
Post-partum mental health problems range from the 'baby-blues' to puerperal psych osis. 
 
The Edinburgh Postnatal Depression Scale  may be used to screen for depression: 
 10-item questionnaire, with a maximum score of 30 
 indicates how the mother has felt over the previous week

 score > 13 indicates a 'depressive illness of varying severity' 
 sensitivity and specificity > 90% 
 includes a question about self-harm 
 
1473

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    25 
  
'Baby-blues' Postnatal depression Puerperal psychosis 
Seen in around 60-70% 
of women 
 
Typically seen 3-7 days 
following birth and is 
more common in 
primips 
 
Mothers are 
characteristically 
anxious, tearful and 
irritable Affects around 10% of women 
 
Most cases start within a month and 
typically peaks at 3 months

typically peaks at 3 months 
 
Features are similar to depression seen 
in other circumstances Affects approximately 0.2% 
of women 
 
Onset usually within the first 
2-3 weeks following birth 
 
Features include severe 
swings in mood (similar to 
bipolar disorder) and 
disordered perception (e.g. 
auditory hallucinations) 
Reassurance and 
support, the health 
visitor has a key role As with the baby blues reassurance and 
support are important 
 
Cognitive behavioural therapy may be

Cognitive behavioural therapy may be 
beneficial. Certain SSRIs such as 
sertraline and paroxetine* may be used 
if symptoms are severe** - whilst they 
are secreted in breast milk it is not 
thought to be harmful to the infant Admission to hospital is 
usually required 
 
There is around a 20% risk 
of recurrence following 
future pregnancies 
 
*paroxetine is recommended by SIGN because of the low milk/plasma ratio 
**fluoxetine is best avoided due to a long half-life

 Sleep paralysis is a common condition characterized by transient paralysis of skeletal muscles 
which occurs when awakening from sleep or less often while falling asleep.  
 It is thought to be related to the paralysis that occurs as a natural part of REM (rapid eye 
movement) sleep.  
 Sleep paralysis is recognised in a wide variety of cultures 
 
Features

Features  
 paralysis - this occurs after waking up or shortly before falling asleep 
 hallucinations - images or speaking that appear during the paralysis 
 if troublesome clonazepam may be used 
 
 1474

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    26 
Alcohol - problem drinking: management 
 Alcohol is a common cause of hypoglycaemia , and can be rapidly life-threatening if not 
recognised. Common initial symptoms are tachycardia and sweating.

 patients who abuse alcohol often are relatively hypotensive as they are often relat ively 
dehydrated and are thin due to minimal food intake.  
deficient' 
Drugs used 
 Disulfram : promotes abstinence - alcohol intake causes severe reaction due to inhibition of

 acamprosate : reduces craving, known to be a weak antagonist of NMDA receptors, improves 
 is derived from taurine 
 increases the γ -aminobutyric acid (GABA) level, which inhibits CNS activity 
 has relatively few side-effects

 has relatively few side-effects 
 Naltrexone:  reduces the pleasure that alcohol brings and craving when it is withdrawn, and 
can halve the relapse rates; however, it is associated with a number of adverse effects, 
including:  
 nausea, vomiting, anxiety, nervousness, insomnia, lethargy, arthralgia, increased 
sweating and lacrimation, diarrhoea or constipation, increased thirst and liver and 
kidney dysfunction

kidney dysfunction 
 particularly the Gl symptoms recognised with naltrexone may discourage use in a 
patient with a previous 
history of IBS  
Alcohol withdrawal 
Alcohol withdrawal is the most common cause of paranoid psychosis with visual hallucination  
 Mechanism  
 chronic alcohol consumption enhances GABA  mediated inhibition in the CNS  (similar to 
benzodiazepines) and inhibits NMDA-type glutamate receptors

 alcohol withdrawal is thought to be lead to the opposite (decreased inhibitory GABA and 
increased NMDA glutamate transmission) 
Features 
 symptoms start at 6-12 hours 
 peak incidence of seizures at 36 hours 
 peak incidence of delirium tremens is at 72 hours 1475

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    27 
  if patients continue to abstain from alcohol they usually peak after about 72 hours and 
may last a week or more, but usually have resolved by 3 weeks. 
 
 Minor Withdrawal  Alcoholic 
Hallucinosis  Withdrawal 
Seizure  Delirium Tremens  
Time Since Last 
Drink  6-12 hours  12-24 hours  24-48 48-72 hours 
 
Features  Insomnia 
 Tremor

 Tremor 
 Anxiety 
 Nausea 
 Vomiting 
 Headache 
 Sweating 
 Palpitations visual, auditory 
and tactile 
hallucinations.   generalised 
tonic-clonic 
seizures.   Autonomic 
instability  
(tachycardia, 
hypertension, 
and pyrexia), 
 Disorientation 
 Hallucinations 
 Agitation 
 
 Withdrawal Seizure   
 Most patients will have single or few fits, and complete spontaneous disappeara nce is 
anticipated within 6-12 hours.

anticipated within 6-12 hours.  
 The presence of focal fits, more than six fits, a prolonged post-ictal phase or 
development of status epilepticus should suggest another diagnosis.  
 Around 30% of patients will go on to develop delirium tremens and prophylactic do ses 
of diazepam or chlodiazepoxide are indicated. 
 Delirium tremens  
 the most severe form of alcohol withdrawal.  
 Onset is typically three to seven days after cessation of chronic alcohol ingestion. 
 characterised by

 characterised by  
 visual hallucinations,  
 autonomic instability (tachycardia, hypertension, pyrexia),  
 obtundation and confusion.  
 Sweating, tremors and agitation are also features.  
 
 In hepatic impairment benzodiazepines with a shorter half-life (e.g. lorazepam and 
oxazepam) are preferred 
 carbamazepine also effective in treatment of alcohol withdrawal 
 at a starting dose of 800 mg per 24 hours

 at a starting dose of 800 mg per 24 hours 
 phenytoin is said not to be as effective in the treatment of alcohol withdrawal seizures 
 best avoided because of the risk of causing hypotension. 
 Thiamine is also indicated in chronic alcoholism but is not as immediately important as 
diazepam. 
 1476

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    28 
Schizophrenia 
Risk of developing schizophrenia  
 monozygotic twin has schizophrenia = 50% 
 parent has schizophrenia = 10-15% 
 sibling has schizophrenia = 10% 
 no relatives with schizophrenia = 1% 
 Schizophrenia is more common in social classes IV and V.

 Temporal lobe epilepsy 
 Amphetamines may cause a state resembling hyperactive paranoid schizophrenia with 
hallucinations. 
Schizophrenia: features 
Schneider's first rank symptoms may be divided into auditory hallucinations, thoug ht disorders, 
passivity phenomena and delusional perceptions: 
 
Auditory hallucinations of a specific type:  
 two or more voices discussing the patient in the third person 
 thought echo 
 voices commenting on the patient's behaviour

 voices commenting on the patient's behaviour 
Thought disorder: occasionally referred to as thought alienation 
 thought insertion 
 thought withdrawal 
 thought broadcasting 
Passivity phenomena:  
 bodily sensations being controlled by external influence 
 actions/impulses/feelings - experiences which are imposed on the individual or influenced by  
others 
Delusional perceptions 
 a two stage process) where first a normal object is perceived then secondly there is a sudde n

intense delusional insight into the objects meaning for the patient e.g. 'The traff ic light is green 
therefore I am the King'. 
Other features of schizophrenia include 
 impaired insight 
 incongruity/blunting of affect (inappropriate emotion for circumstances) 
 decreased speech 
 neologisms: made-up words 
 catatonia 
 Concrete thinking where a patient cannot use abstraction to understand the meaning of 
a sentence.  It is more common in schizophrenia.

a sentence.  It is more common in schizophrenia. 
 negative symptoms: incongruity/blunting of affect, anhedonia (inability to derive  pleasure), 
alogia (poverty of speech), avolition (poor motivation) 
Prognostic indicators 
Factors associated with poor prognosis 
 strong family history 1477

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    29 
  gradual onset 
 low IQ 
 premorbid history of social withdrawal 
 lack of obvious precipitant 
Schizophrenia: management 
Key points : (NICE guidelines 2009)  
 oral atypical antipsychotics are first-line 
 cognitive behavioural therapy should be offered to all patients

 close attention should be paid to cardiovascular risk-factor modification due to the  high rates of 
cardiovascular disease in schizophrenic patients (linked to antipsychotic medication and high 
smoking rates) 
Electroconvulsive therapy 
 Electroconvulsive therapy is a useful treatment option for patients with severe depression 
refractory to medication or those with psychotic symptoms.

 The only absolute contraindications is raised intracranial pressure. 
 
Short-term side-effects  
 headache 
 nausea 
 short term memory impairment 
 memory loss of events prior to ECT 
 cardiac arrhythmia 
Long -term side-effects 
 some patients report impaired memory 
Charles Bonnet syndrome 
 Charles Bonnet syndrome (CBS) is characterised by persistent or recurrent complex

hallucinations (usually visual or auditory), occurring in clear consciousness.   
 This is generally against a background of visual impairment (although visual impairment is not 
mandatory for a diagnosis).  
 Insight is usually preserved.  
 Well-formed complex visual hallucinations are thought to occur in 10-30 percent of ind ividuals 
with severe visual impairment.  
 Around a third find the hallucinations themselves an unpleasant or disturbing expe rience.

 This must occur in the absence of any other significant neuropsychiatric disturbance. 
 
 CBS is equally distributed between sexes and does not show any familial predisposition.  
 Prevalence of CBS in visually impaired people is thought to be between 11 and 15 p ercent.  
 
 Advanced age 
 Peripheral visual impairment 1478

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    30 
  Social isolation 
 Sensory deprivation 
 Early cognitive impairment 
 
Associated conditions  
 The most common ophthalmological conditions associated with this syndrome are age-related 
macular degeneration, followed by glaucoma and cataract.  
Prognosis

Prognosis  
 In a large study published in the British Journal of Ophthalmology, 88% had  CBS for 2 years or 
more, resolving in only 25% at 9 years (thus it is not generally a transient experience).  
Treatment 
 Reassurance is usually the best treatment  
 
Aphonia 
 Aphonia describes the inability to speak.  
 recurrent laryngeal nerve palsy (e.g. Post-thyroidectomy) 
 psychogenic

 psychogenic 
De Crambault's syndrome 
 De Crambault's syndrome, also known as erotmania, is a form of paranoid delusion with an  
amorous quality.  
 The patient, often a single woman, believes that a famous person is in love with her.  
 
Bouffée délirante  is an acute psychotic disorder in which hallucinations, delusions or perceptual

disturbances are obvious but markedly variable, changing from day to day or even from hour to hour. 
Fregoli delusion  is the mistaken belief that some person currently present in the deluded person's 
environment (typically a stranger) is a familiar person in disguise. 

Capgras delusion  is the belief that significant others have been replaced by impostors, robots or 
aliens. 
Couvade  is the common but poorly understood phenomenon whereby the expectant  father 
experiences somatic symptoms during the pregnancy for which there is no recognised ph ysiological 
basis.  
 
 1479

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    31 
 __________ ________________________________________________________  
Delusions 
Cotard syndrome 
 Cotard syndrome is a rare mental disorder where the affected patient believes that they (or 
in some cases just a part of their body) is either dead or non-existent.

 This delusion is often difficult to treat and can result in significant problems due to patients 
stopping eating or drinking as they deem it not necessary. 
 
Othello syndrome is a delusional belief that a patients partner is committing infidelity despite no 
evidence of this. It can often result in violence and controlling behaviour. 
 
De Clerambault syndrome  (otherwise known as erotomania), is where a patient believes that

a person of a higher social or professional standing is in love with them. Often this presents 
with people who believe celebrities are in love with them. 
 
Ekbom syndrome  is also known as delusional parasitosis and is the belief that they are 
infected with parasites or have 'bugs' under their skin. This can vary from the classic psychosis 
symptoms in narcotic use where the user can 'see' bugs crawling under their skin or can be a patie nt 
who believes that they are infested with snakes.

who believes that they are infested with snakes. 
 
Capgras delusion  is the belief that friends or family members have been replaced by an identical 
looking imposter. 
Personality disorders 
Disorder Features 
Antisocial  Failure to conform to social norms with respect to lawful behaviors as 
indicated by repeatedly performing acts that are grounds for arrest;

 Deception, as indicated by repeatedly lying, use of aliases, or conning 
others for personal profit or pleasure; 
 Impulsiveness or failure to plan ahead; 
 Irritability and aggressiveness, as indicated by repeated physical fights 
or assaults; 
 Reckless disregard for safety of self or others; 
 Consistent irresponsibility, as indicated by repeated failure to sustain 
consistent work behavior or honor financial obligations;

 Lack of remorse, as indicated by being indifferent to or rationalizing 
having hurt, mistreated, or stolen from another 
Avoidant  Avoidance of occupational activities which involve significant 
interpersonal contact due to fears of criticism, or rejection. 
 Unwillingness to be involved unless certain of being liked 1480

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    32 
 Disorder Features 
 Preoccupied with ideas that they are being criticised or rejected in social 
situations 
 Restraint in intimate relationships due to the fear of being ridiculed 
 Reluctance to take personal risks due to fears of embarrassment 
 Views self as inept and inferior to others

 Views self as inept and inferior to others 
 Social isolation accompanied by a craving for social contact 
Borderline  Efforts to avoid real or imagined abandonment 
 Unstable interpersonal relationships which alternate between 
idealization and devaluation 
 Unstable self image 
 Impulsivity in potentially self damaging area (e.g. Spending, sex, 
substance abuse) 
 Recurrent suicidal behaviour 
 Affective instability 
 Chronic feelings of emptiness 
 Difficulty controlling temper

 Difficulty controlling temper 
 Quasi psychotic thoughts 
 
Borderline - think nightmare girlfriend/boyfriend 
Dependent  Difficulty making everyday decisions without excessive reassurance 
from others 
 Need for others to assume responsibility for major areas of their life 
 Difficulty in expressing disagreement with others due to fears of losing 
support 
 Lack of initiative 
 Unrealistic fears of being left to care for themselves

 Urgent search for another relationship as a source of care and support 
when a close relationship ends 
 Extensive efforts to obtain support from others 
 Unrealistic feelings that they cannot care for themselves 
Histrionic  Inappropriate sexual seductiveness 
 Need to be the centre of attention 
 Rapidly shifting and shallow expression of emotions 
 Suggestibility 
 Physical appearance used for attention seeking purposes 
 Impressionistic speech lacking detail 
 Self dramatization

 Self dramatization 
 Relationships considered to be more intimate than they are 
Narcissistic  Grandiose sense of self importance 
 Preoccupation with fantasies of unlimited success, power, or beauty 1481

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    33 
 Sense of entitlement 
 Taking advantage of others to achieve own needs 
 Lack of empathy 
 Excessive need for admiration 
 Chronic envy 
 Arrogant and haughty attitude 
 
Narcissistic - Steve Jobs's ex-wife thought he had this  
Obsessive-

compulsive  Is occupied with details, rules, lists, order, organization, or agenda to the 
point that the key part of the activity is gone 
 Demonstrates perfectionism that hampers with completing tasks 
 Is extremely dedicated to work and efficiency to the elimination of spare 
time activities 
 Is meticulous, scrupulous, and rigid about etiquettes of morality, ethics, 
or values 
 Is not capable of disposing worn out or insignificant things even when

they have no sentimental meaning 
 Is unwilling to pass on tasks or work with others except if they surrender 
to exactly their way of doing things 
 Takes on a stingy spending style towards self and others; and shows 
stiffness and stubbornness 
 
Paranoid  Hypersensitivity and an unforgiving attitude when insulted 
 Unwarranted tendency to questions the loyalty of friends 
 Reluctance to confide in others 
 Preoccupation with conspirational beliefs and hidden meaning

 Unwarranted tendency to perceive attacks on their character 
Schizoid  Indifference to praise and criticism 
 Preference for solitary activities 
 Lack of interest in sexual interactions 
 Lack of desire for companionship 
 Emotional coldness 
 Few interests 
 Few friends or confidants other than family 
 
Schizoid - think Bruce Wayne/Batman from recent Christopher Nolan 
films 
 
 1482

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    34 
Schizotypal  Ideas of reference (differ from delusions in that some insight is retained) 
 Odd beliefs and magical thinking 
 Unusual perceptual disturbances 
 Paranoid ideation and suspiciousness 
 Odd, eccentric behaviour 
 Lack of close friends other than family members 
 Inappropriate affect

 Inappropriate affect 
 Odd speech without being incoherent 
 
Borderline personality disorder is marked out by instability in moods, behaviour and relationships. 
 
Diagnosis is confirmed by the presence of at least 5 of the following symptoms; 
 
1) Extreme reactions including panic, depression, rage, or frantic actionsto abandonment, whe ther 
real or perceived 
 
2) A pattern of intense and stormy relationships with family, friends, and loved o nes, often veering

from extreme closeness and love to extreme dislike or anger 
 
3) Distorted and unstable self-image or sense of self, which can result in sudden chang es in feelings, 
opinions, values, or plans and goals for the future (such as school or career choices). 
 
4) Impulsive and often dangerous behaviours, such as spending sprees, unsafe sex, substance 
abuse, reckless driving, and binge eating. 
 
5) Recurring suicidal behaviours or threats or self-harming behaviour, such as cutting

Intense and highly changeable moods, with each episode lasting from a few hours to  a few days. 
 
6) Chronic feelings of emptiness and/or boredom. 
 
7) Inappropriate, intense anger or problems controlling anger 
 
8) Having stress-related paranoid thoughts or severe dissociative symptoms, such as feeling cut off 
from oneself, observing oneself from outside the body, or losing touch with rea lity.

There are no features consistent with endogenous depression, such as early morning wake ning or 
loss of appetite, and no features consistent with hypomania such as pressure of speech , flight of 
1483

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    35 
 ideas, or over exuberant behaviour. We are given no indication of drug abuse which may  indicate 
drug induced psychosis. Anti-social personality disorder is characterised by a failure to conform to  
social norms, and repeated law breaking. There is consistent irresponsibility, impulsivity and

disregard for both their own safety and that of others. 
Panic disorder  
 The patient is suffering from panic disorder - sudden, discrete attacks of intense anxiety or 
fear accompanied by physical symptoms, for example, palpitations and a feeling of 
suffocation.  
 Abnormal discharge from the  locus caeruleus in the midbrain has been implicated in

panic attacks.  The locus caeruleus is the origin of most brain noradrenergic pathways.  
 To distinguish it from a specific phobia, some of the attacks must occur without an  
environmental trigger. 
Acute confusional state (delirium) (NICE 2014)  
  A sudden change in the mental state or sudden onset of behaviour that is out o f character in

an older person is most likely to be due to an acute confusional state (delirium).  
 Recent changes in behavior  (within hours or days)  
 Older people (≥ 65  ) 
 cognitive impairment or dementia  
 severe illness  
 20–30% of people on medical wards  in hospital have delirium,  
 10% - 50% of people who have  surgery  develop delirium  
 Current hip fracture 
delirium vs dementia

delirium vs dementia  
 It can be difficult to distinguish between delirium and dementia because symptoms overlap, 
and some people may have both conditions.  
 Dementia tends to develop slowly, whereas delirium is characterised by sudden changes.  
 Dementia is generally a chronic, progressive disease for which there is no cure. Delirium is a 
potentially reversible condition if the causes are identified and they are treatable.

 If clinical uncertainty exists over the diagnosis, initial management should be for delirium. 
Diagnosis  
 By clinical assessment based on: 
 Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)  criteria or  
 short Confusion Assessment Method (short CAM)  to confirm the diagnosis.  
 In critical care or in the recovery room after surgery, CAM-ICU  should be used.  
 1484

Notes & Notes for MRCP                                                                               By Dr. Yousif Abdallah Hamad    36 
  
Treatment 
 the first intervention  Interview the patient, take a history, assess mental state and try 
to reassure the patient.  
 Adults with delirium who are distressed or are a risk to themselves or others are not prescribed 
antipsychotic medication unless de-escalation techniques (Communication approaches) a re

ineffective or inappropriate.  
 Sedation should only be used as a last resort and preferably only once the cau se of the 
delirium has been established. 
 short-term (usually for 1 week or less) haloperidol or olanzapine 
 avoid antipsychotics in patients Parkinson's disease or dementia with Lewy bodies.  
 Mirtazapine , which enhances both noradrenergic and serotinergic transmission, would 
be a good antidepressant choice for an emaciated agitated elderly patients. (medical-

masterclass.com 2017 mrcp part 2)  
 Mirtazapine blocks alpha-2, 5-HT2A and 5-HT3 receptors, thus increasing the amounts 
of both noradrenaline and serotonin in the synaptic gap. It also has a high affinity  for H1 
receptors so it tends to cause weight gain and drowsiness, a good choice for a thin 
agitated patient. 
Chronic fatigue syndrome

Chronic fatigue syndrome  
 also been called myalgic encephalomyelitis (ME) and, more recently, systemic exertion 
intolerance disease (SEID).  
 extreme fatigue that can't be explained by any underlying medical condition. 
 The fatigue may worsen with physical or mental activity, but doesn't improve with rest. 
 The cause is unknown, although there are many theories — ranging from viral infections to 
psychological stress.  

 Age (most commonly affects people in their 40s and 50s) 
 Sex (more common in female ) 
 stress 
Diagnosis  
 rule out other conditions with similar symptoms. 
  
Treatment 
 Graded exercise programmes  and cognitive-behavioural therapy are the only two treatments 
shown to be of definite benefit.  
 
 1485

Basics – Cell biology  
 
  1    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
By
 
Basic sciences
 
Cell biology  
 
Updated 
 
2017
 
Contains:

Updated 
 
2017
 
Contains: 
 
 1486

  2    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
 Membrane receptors 
 
There are four main types of membrane receptor: 
1. ligand-gated ion channels,  
2. tyrosine kinase receptors,

2. tyrosine kinase receptors,  
3. guanylate cyclase receptors and  
4. G protein-coupled receptors  
Ligand-gated ion channel receptors  
 generally mediate fast responses 
 e.g. nicotinic acetylcholine , GABA-A & GABA-C, glutamate receptors 
Tyrosine kinase receptors  
 intrinsic tyrosine kinase: insulin, insulin-like growth factor (IGF), epidermal growth factor 
(EGF) 
 receptor-associated tyrosine kinase: growth hormone, prolactin, interferon, interleukin 
Guanylate cyclase receptors

Guanylate cyclase receptors  
 contain intrinsic enzyme activity 
 e.g. atrial natriuretic factor, brain natriuretic peptide 
G protein-coupled receptors  
 located on Cell membrane 
 generally mediate slow transmission and affect metabolic processes 
 activated by a wide variety of extracellular signals e.g. Peptide hormones, biogenic a mines, 
lipophilic hormones, light 
 7-helix membrane-spanning domains 
 consist of 3 main subunits: alpha, beta and gamma

 the alpha subunit is linked to GDP  (guanine diphosphate). Ligand binding causes 
conformational changes to receptor, GDP is phosphorylated to GTP ( Ligand binding 
leads to GDP replacement by GTP) , and the alpha subunit is activated 
 The muscarinic acetylcholine receptor is an example of a G protein-coupled receptor 
 G proteins are named according to the alpha subunit (G s, Gi, Gq) 
 
 1487

  3    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
Gs Gi Gq 
Mechanism  Stimulates adenylate 
cyclase → increases 
cAMP → activates 
protein kinase A Inhibits adenylate 
cyclase → decreases 
cAMP → inhibits

cAMP → inhibits 
protein kinase A Activates 
phospholipase C → 
splits PIP 2 to IP 3 & 
DAG → activates 
protein kinase C 
Examples  • Beta-1  receptors 
(epinephrine, 
norepinephrine, 
dobutamine) 
• Beta-2  receptors 
salbuterol) 
• H2 receptors 
(histamine) 
• D1 receptors 
(dopamine) 
• V2 receptors 
(vasopressin) 
• Receptors for ACTH, 
LH, FSH, glucagon, 
PTH, calcitonin, 
prostaglandins • M2 receptors 
(acetylcholine) 
• Alpha-2  receptors

• Alpha-2  receptors 
norephinephrine) 
• D2 receptors 
(dopamine)  
• GABA -B receptor • Alpha-1  receptors 
(epinephrine , 
norepinephrine) 
• H1 receptors 
• V1 receptors 
• M1, M3  receptors 
Adenosine interact with  G protein-coupled receptor 
 
1488

  4    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
 G protein-coupled receptors 
Gs B1, B2 , H2, D1, V2 , prostaglandins, (ACTH, LH, FSH), PTH, Calcitonin 
Gi M2, α2, D2, Adenosine in nodal tissue

Gi M2, α2, D2, Adenosine in nodal tissue  
Gq α1, H1, V1, M1, M3, Adenosine in bronchial smooth muscle  
 
Nucleus receptors:   
The nucleus is the site of RNA transcription and DNA replication. Active vitamin D  and steroid 
hormones  such as cortisol, estrogen, and progesterone act by binding receptors that localize 
to the nucleus   and alter gene transcription.  
 
Cell signalling 
 Phosphorylation of specific tyrosine residues is often a key event in the activation of

the Cell signalling pathways 
 
Intracellular signalling proteins (Ras protein) 
 The Ras family of oncogenes are important intracellular signalling proteins which transmit 
signals from receptor tyrosine kinase proteins in the cell membrane down to the nucleus . 
 Ras is controlled by the activity of a GTPase binding site; when guanosine triphosphate 
(GTP) is bound Ras is active and it slowly hydrolyses the GTP to guanosine 
diphosphate (GDP) resulting in an inactive state.

 Mutations in codon 12 result in decreased GTPase activity and a Ras protein which is 
'always on' resulting in increased proliferation of the cell. 
 Mutation in codon 12 of the Ras oncogene often results in   Decreased GTP 
hydrolysis   increased proliferation of the cell. 
 
G proteins 
 
 1489

  5    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
 Diseases caused by GPCR loss- of-function mutations 
Receptor Disease Inheritance 
Cone opsins Color blindness X-linked; autosomal recessive

Rhodopsin Retinitis pigmentosa Autosomal dominant; 
recessive 
V2 vasopressin Nephrogenic diabetes 
insipidus X-linked 
Ca2+ sensing Familial hypocalciuric 
hypercalcemia Autosomal dominant 
Melanocortin 4 Extreme obesity Codominant 
TRH Central hypothyroidism Autosomal recessive 
 
GPCR Gene Gain- of-Function Mutations 
 gain- of-function mutations in the LH and TSH receptor genes may mimic states of hormone

excess, familial male precocious puberty, and familial nonautoimmune hyperthyroidism , 
 Women inheriting gain- of-function mutations in the LH receptor gene do not show 
precocious puberty because, unlike in males,  the combined action of LH and FSH is 
required for female pubertal development.  
 
Diseases caused by GPCR gain- of-function mutation 
Rhodopsin Congenital night blindness Autosomal dominant 
LH Familial male precocious

LH Familial male precocious 
puberty Autosomal dominant 
LH Sporadic Leydig cells 
tumors Somatic 
TSH Familial nonautoimmune 
hyperthyroidism Autosomal dominant 
Ca2+ sensing Familial hypocalcemia Autosomal dominant 
 
 1490

  6    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
 _________________________________________________________
Adrenoceptors 
 
 Agonists  Antagonists  Pathways 
Alpha-1 
  vasoconstriction 
 relaxation of GI

Alpha-1 
 relaxation of GI 
smooth muscle 
 salivary secretion 
 hepatic 
glycogenolysis Doxazosin (α -1) 
( for HTN & BPH) 
Tamsulosin  (α-1a) 
(acts mainly on 
urogenital tract) activate 
IP3 → DAG  
Alpha-2  
  mainly presynaptic: 
inhibition of 
transmitter release  
 inhibits insulin 
 platelet aggregation yohimbine inhibit adenylate 
cyclase 
Beta-1 
  mainly located in the 
heart 
 increase heart rate + 
force atenolol stimulate adenylate

force atenolol stimulate adenylate 
cyclase 
Beta-2 
  vasodilation 
 bronchodilation 
  stimulate adenylate 
cyclase 
Beta-3  
  lipolysis 
cyclase 
 
Alpha antagonists  
 non-selective: phenoxybenzamine (previously used in peripheral arterial disease) 
Beta antagonists  
 non-selective: propranolol 
 Carvedilol and labetalol are mixed alpha and beta antagonists   
 
 1491

  7    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
 _________________________________________________________ 
Second messengers 
Overview 
 many different types 
 allow amplification of external stimulus

 allow amplification of external stimulus 
 
cAMP system Phosphoinositol 
system cGMP 
system Tyrosine 
kinase system 
Ligand: 
Neurotransmitters 
(Receptor)  Epinephrine (α2, β1, β2)  
Acetylcholine (M2) Epinephrine (α1)  
Acetylcholine (M1, 
M3) - - 
Ligand: 
Hormones  ACTH, ADH, calcitonin, 
FSH, glucagon, hCG,LH, 
MSH, PTH , TSH, GHRH* angiotensin II, GnRH, 
GHRH*, Oxytocin, 
TRH ANP, 
Nitric 
oxide  insulin, growth 
hormone, I GF, 
PDGF, 
prolactin

PDGF, 
prolactin 
Primary effector  Adenylyl cyclase Phospholipase C Guanylate 
cyclase Receptor 
tyrosine kinase 
Secondary 
messenger  cAMP (cyclic adenosine 
monophosphate) IP3 (inositol 1,4,5 
trisphosphate) and 
DAG (Diacylglycerol) cGMP Protein 
phosphatase 
*the cAMP pathway is the most important 
 
Molecules that freely pass through the cell membrane  include: 
 cholesterol,  
 steroid hormones  (progesterone, testosterone, oestradiol and cortisol) , and

 vitamin D.   
other ionic hormones such as the following are unable to pass the plasma membrane 
 Act through cyclic adenosine monophosphate (cAMP) as the second messenger : 
 adrenaline 
 growth hormone-releasing hormone (GHRH) 
 glucagon 
 luteinising hormone (LH) 
 follicle stimulating hormone (FSH) 
 parathyroid hormone (PTH), and 
 thyroid-stimulating hormone (TSH). 
Acts through mitogen-activated protein (MAP) kinase pathway  
 Insulin 
 growth hormone (GH)  
 prolactin. 1492

  8    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
 Act through calcium/phosphoinositide : 
 Thyroid releasing hormone (TRH) 
 gonadatrophin-releasing hormone (GnRH), and 
 antidiuretic hormone (ADH).

 antidiuretic hormone (ADH). 
Act through cyclic guanosine monophosphate (cGMP). 
 Nitric oxide  
 atrial natriuretic peptide (ANP) 
Acts by binding to intracellular receptors. 
 Triiodothyronine (T3) 
 
 1493

  9    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad               
                                                                                                                                                                   
Cell organelles 
The table below summarises the main functions of the major cell organelles:  
Organelle/macromolecule Main function

Organelle/macromolecule Main function 
Endoplasmic reticulum Rough endoplasmic reticulum (RER) 
 translation and folding of new proteins 
 manufacture of lysosomal enzymes 
 site of N-linked glycosylation 
 Hydroxylation of proline and lysine residues in 
procollagen chains occurs in the RER and requires 
vitamin C   
 examples of cells with extensive RER include 
pancreatic cells, goblet cells, plasma cells 
Smooth endoplasmic reticulum (SER) 
 steroid, lipid synthesis

 steroid, lipid synthesis 
 SER is the site of drug detoxification  
 examples of cells with extensive SER include those 
of the adrenal cortex , hepatocytes , testes , ovaries 
 Drugs such as barbiturates can increase the amount 
of SER in cells 
Golgi apparatus Modifies, sorts, and packages these molecules that are 
destined for cell secretion 
Site of O-linked glycosylation 
Mitochondrion Aerobic respiration. Contains mitochondrial genome as

circular DNA . has its own self-replicating DNA  
Nucleus DNA maintenance and RNA transcription 
Lysosome  Breakdown of large molecules such as proteins and 
polysaccharides.   breakdown of oligopeptides  
Nucleolus Ribosome production 
Ribosome Translation of RNA into proteins 
Peroxisome Catabolism of very long chain fatty acids and amino acids  
Results in the formation of hydrogen peroxide 
Proteasome  Along with the lysosome pathway involved in degradation of

protein molecules that have been tagged with ubiquitin 
( degradation of polypeptides)  
 
 1494

  10    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
Tumour suppressor genes  
 
Basics  
 genes which normally control the cell cycle 
 loss of function results in an increased risk of cancer

 both alleles must be mutated before cancer occurs 
 
Examples  
 
Gene Associated cancers 
p53 Common to many cancers, Li-Fraumeni syndrome 
APC Colorectal cancer 
BRCA1 Breast and ovarian cancer 
BRCA2 Breast and ovarian cancer 
NF1 Neurofibromatosis 
Rb Retinoblastoma 
WT1 Wilm's tumour 
Multiple tumor suppressor 1 (MTS-1, 
p16) Melanoma 
 
p53 
 p53 is a tumour suppressor gene located on chromosome 17p.  
  It is the most commonly mutated gene in breast, colon and lung cancer

 p53 is thought to play a crucial role in the cell cycle, preventing entry into the S phase until 
DNA has been checked and repaired.  
  It may also be a key regulator of apoptosis  
 Li-Fraumeni syndrome is a rare autosomal dominant disorder characterised by the early 
onset of a variety of cancers such as sarcomas and breast cancer. It is caused by 
mutation in the p53 gene  
1495

  11    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
Eukaryotic cell cycle 
 
Eukaryotes (higher organisms) vs prokaryotic cells  
 nuclear membranes

 nuclear membranes  
 Eukaryotes have muliple chromosomes in the genome, which is separated from the 
rest of the cell by nuclear membranes. 
 Prokaryotes lack a membrane bound nucleus, and their DNA occurs in a circular 
form. 
 Transcription  
 Transcription of eukaryotic genes requires non-coding sequences (introns) in the 
mRNA to be spliced out before translation at the ribosome. 
 Ribosomes  
 Ribosomes are found in eukaryotic and prokaryotic cells

 Both eukaryotes and prokaryotes have a ribosome, though the  ribosome is 
significantly larger in eukaryotes.  
 
Phases of cell cycle  
 The cell cycle is regulated by proteins called cyclins which in turn control cyclin-dependent 
kinase (CDK) enzymes. 
Phase Notes Regulatory proteins 
G0  'resting' phase 
 quiescent cells such as hepatocytes 
and more permanently resting cells 
such as neurons  
G1  Gap 1, cells increase in size 
 determines length of cell cycle

 determines length of cell cycle 
 under influence of p53 Cyclin D / CDK4, Cyclin D / CDK6 and 
Cyclin E / CDK2: regulates transition from 
G1 to S phase. determine the length of the 
cell cycle  
S  Synthesis of DNA, RNA and 
histone 
 centrosome duplication Cyclin A / CDK2: active in S phase 
G2  Gap 2, cells continue to increase in 
size Cyclin B / CDK1: regulates transition from 
G2 to M phase 
M  Mitosis - cell division 
 the shortest phase of the cell cycle  1496

  12    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
G0 phase 
 G0 is a resting stage with non-dividing cells

 G0 is a resting stage with non-dividing cells 
 Cells can enter the G0 phase  from G1 if they are not preparing for cell division. This may 
occur if the cell has reached its final differentiation  
G1 phase 
 G1 and G2 are gap phases 
 G1 is a gap phase under the influence of the p53 gene 
 G1 phase determines the variability of the cycle length  
 In normal tissues, cells with significant damage to their DNA are arrested at the G1 phase  
S phase

S phase  
 During the S phase the cell prepares itself for division by duplicating the chromosomes.   
 DNA is synthesised in the S phase 
M phase  
 Mitosis  occurs during the M phase of the cell cycle.  
1497

  13    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
  Mitosis describes the process in which somatic cells divide and replicate producing

genetically identical diploid daughter cells. This allows tissue to grow and renew itself.  
 
Radio-sensitivities during phases of the cell cycle. 
 
 Normal and cancerous cells exhibit different radiosensitivities during different phase s of the 
cell cycle. 
 They are most sensitive in G2-M phase  when the cell is preparing to and actively dividing 
due to the fragile nature of the intracellular structure during this event.

 Cells are most resistant in G0, early G1 and the late S phase of the cell cycle .  
 Resistance in S phase is thought to be due to elevated levels of glutathione, as w ell as 
rapid DNA synthesis and repair enzymes.  
Cell division 
There are two types of cell division; mitosis and meiosis.  
The table below demonstrates the key differences:  
 
Mitosis Meiosis 
Occurs in somatic cells Occurs in gametes

Occurs in somatic cells Occurs in gametes 
Results in 2 diploid daughter 
cells Results in 4 haploid daughter cells 
Daughter cells are genetically 
identical to parent cell Daughter cells contain one homologue of each 
chromosome pair and are therefore genetically different 
 
Remember:  
 somatic cells have 22 pairs of autosomes and 1 pair of sex chromosomes, i.e. 4 6XY or 
46XX 
 cells with a normal chromosome complement are known as diploid cells

 gametes (ova or spermatozoa) have a single copy of each chromosome and are know n as 
haploid cells 
 
 1498

  14    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
Mitosis 
 
The table below shows the phases of mitosis: 
 
Prophase Chromatin in the nucleus condenses

Prophase Chromatin in the nucleus condenses 
Prometaphase  Nuclear membrane breaks down allowing the microtubules to attach to 
the chromosomes  
Metaphase  Chromosomes aligned at middle of cell 
Anaphase  The paired chromosomes separate at the kinetochores and move to opposite 
sides of the cell 
Telophase  Chromatids arrive at opposite poles of cell 
Cytokinesis  Actin-myosin complex in the centre of the cell contacts resulting in it being 
'pinched' into two daughter cells

  15    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
 Meiosis 
  
 Meiosis is the form of cell division that produces gametes.  
 It is divided into two parts, meiosis 1 and meiosis 2.

 Deoxyribo nucleic acid (DNA) replication occurs before meiosis 1, and the cell begins 
division with twice the normal cellular amount of DNA. 
 In meiosis 1, each daughter cell gets one of the duplicated chromosomes of each pa ir.  
 At the beginning of meiosis 2, each cell contains 23 chromosomes each with a duplicated  
pair of chromatids. 
 In meiosis 2, the duplicated pair separate and each daughter cell ends up with one of  each 
of the 23 chromosomes (4 hapolid daughter cells).

 Two common errors of cell division occurring during meiosis are: 
1. non-disjunction  (2 chromosomes fail to separate, so both copies of the 
chromosome go to one of the daughter cells);  
 In Down's syndrome, non-disjunction accounts for 94% of cases. The 
incidence of this increases with increasing maternal age.  
 5% of cases are due to translocation, and 1% to mosaicism. 
 Non-disjunction at mitosis (meisois 2) results in mosaicism.

2. anaphase lag  in which a chromatid is lost because it fails to move quickly enough 
during anaphase to become incorporated into one of the new daughter cells. 
Matrix metalloproteinases (MMPs)  
 Matrix metalloproteinases (MMPs) are a group of enzymes responsible for the degradation 
of most extracellular matrix proteins during organogenesis, growth and normal tissue 
turnover.

turnover.  
  (MMPs) are calcium-dependent zinc-containing endopeptidases  
 They are distinguished from other endopeptidases by their dependence on metal ions 
as cofactors , their ability to degrade extracellular matrix , and their specific 
evolutionary DNA sequence.  
1500

  16    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
  All are involved in normal remodelling processes, such as embryonic development,

postpartum involution of the uterus, bone and growth-plate remodelling, ovulation an d 
wound healing 
 The activity of MMPs in adult tissues is normally quite low.  
 ↑ activity of MMPs unwanted tissue destruction (inflammatory diseases & tumours)  
 ↑MMPs  degrade the structural proteins of the aortic wall Aortic Aneurysm.  
 ↑collagenases, especially MMP- 8  periodontitis and peri-implantitis  
 ↑MMP -2 and MMP -9  metastasis.

 ↑MMP -2 and MMP -9  metastasis.  
 ↑MMP -1  rheumatoid arthritis and osteoarthritis.  
 Disregulation of the balance between MMPs and TIMPs  (Tissue Inhibitor of Metallo-
Proteinases) is also a characteristic of acute and chronic cardiovascular diseases.  
 A range of MMP inhibitors is currently under development for the treatment of solid 
tumours.   
 Doxycycline, at sub-antimicrobial doses, inhibits MMP activity, and has been used in

various experimental systems for this purpose, such as for recalcitrant recurrent 
corneal erosions. It is used clinically for the treatment of periodontal disease and is 
the only MMP inhibitor that is widely available clinically.  
Normal wound healing 
 Phase 1 : hemostasis (1 – 24 h) 
 The initiating factor originate from platelets activated by mature collagen exposed 
in the wound

in the wound 
 Platelets first  aggregate  then release a variety of active agents including 
lysosomal enzymes, ATP, serotonin and wound cytokines 
 A fibrin clot develops, which completes haemostasis and provides strength and 
support to the wound 
 platelets are integral to initiating wound healing  release cytokines that cause 
leukocyte migration and chemotaxis into the wound 
 Phase 2 : inflammation (1 – 5 days)  
 native cells initiate the inflammatory phase

 native cells initiate the inflammatory phase 
 secrete cytokines that cause vasodilation and increase vascular 
permeability 
 allows influx of neutrophils and macrophages to the wound bed 
 neutrophils 
 present early in inflammatory phase 
 clear intralesional pathogens 
 prepare the wound bed by removing damaged cells 
 secrete cytokines that stimulate infux of macrophages 
 macrophages  
 present late in inflammatory phase

 present late in inflammatory phase 
 secrete cytokines and growth factors that drive fibroblast proliferation  
and angiogenesis 
 Phase 3:  proliferation (3 – 7 days) 
 fibroblasts lay down type III collagen 1501

  17    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
  myofibroblasts  (fibroblasts with contractile filaments) initiate wound 
 macrophages become active as the main agents of demolition, removing

unwanted fibrin, dead cells and bacteria and creating fluid-filled spaces for 
granulation tissue   
 Which cell initiates granulation of the wound?   Macrophages  
 Macrophages also release factors that stimulate the formation of new capillary 
buds  during this phase, and later they initiate and control fibroblast activity 
during repair  
 angiogenesis and vasculogenesis lay down new blood vessels 
 granulation tissue (newly laid collagen with neovascularization) forms

 epithelialization occurs from surrounding basal keratinocytes and hair follicle 
basal cells 
 Within the connective tissue, randomly orientated collagen  begins to form after 
a few days, reaching a peak of activity after 5-7 days  
 Phase 4 : maturation and remodeling  (up to 1 year) 
 the phase of maturation and remodeling lasts for up to 12 months . 
 type III collagen remodeled to type I collagen 
 
1502

  18    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
Molecular biology techniques 
 
 SNOW ( South - NOrth - West)

 SNOW ( South - NOrth - West) 
 DROP ( DNA - RNA - Protein) 
 
The following table shows a very basic summary of  molecular biology techniques  
 
Technique Description 
Southern blotting Detects DNA 
Northern blotting Detects RNA 
Western blotting Detects proteins 
Uses gel electrophoresis to separate native proteins by 3-D structure 
Examples include the confirmatory  HIV test 
commonly used as a confirmatory test following a positive ELISA.

Enzyme-linked immunosorbent assay (ELISA)  
 a type of biochemical assay used to detect antigens and antibodies 
 a colour changing enzyme is attached to the antibody if looking for an antigen and to an 
antigen if looking for an antibody 
 the sample therefore changes colour if the antigen or antibody is detected 
 an example includes the initial  HIV test  
 the first step in screening for HIV in adults.

 the first step in screening for HIV in adults. 
 It can detect antibodies against HIV, but not the genetic material. 
 
1503

  19    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
 initial  HIV test  ELISA  
 confirmatory  HIV test  Western blotting 
 Polymerase chain reaction (PCR) is the only technique that would allow for the

detection of the genetic material from HIV . 
 Maternal antibodies usually cross the placenta during pregnancy, therefore any 
test that detects antibodies to HIV could give a false positive reading. 
 
Polymerase chain reaction (PCR) 
 
the main action of PCR  DNA amplification  
 
 Polymerase chain reaction (PCR) is a molecular genetic investigation technique.  
 Used  in: 
 prenatal diagnosis

 Used  in: 
 prenatal diagnosis  
 Pre-implantation diagnosis uses IVF and genetic analysis of 3- day-old 
embryos before selective transfer of unaffected embryos to uterus. 
 detection of mutated oncogenes 
 diagnosis of infections 
 PCR is used to determine viral load 
 forensics. 
 The main advantage of PCR is its sensitivity: only one strand of sample DNA is neede d to 
detect a particular DNA sequence.

detect a particular DNA sequence.  
 Prior to the procedure it is necessary to have two DNA oligonucleotide primers . These 
are complimentary to specific DNA sequences at either end of the target DNA.  To do this 
the DNA double helix must first be split into two strands by Heating to nearly 100°C.  
 Initial prep  
 sample of DNA is added to test tube along with two DNA primers 
 a thermostable DNA polymerase (Taq) is added 
 The following cycle then takes place

 The following cycle then takes place  
 mixture is heated to almost boiling point causing denaturing (uncoiling) of DNA 
 mixture is the allowed to cool: complimentary strands of DNA pair up, as there is an 
excess of the primer sequences they pair with DNA preferentially 
 The above cycle is then repeated, with the amount of DNA doubling each time 
 
 advantages of PCR over ELISA in HIV testing: 
 PCR becomes positive earlier in disease course

 PCR becomes positive earlier in disease course 
 Positive ELISA result is dependent on antibody formation 
 PCR does not require that the patient have a competent immune system  
 ELISA requires the host to make antibodies 
 important specific cases when PCR should always be used 
 a newborn whose mother is HIV+ 
 will have antibodies even if not infected, so ELISA does not work 
 when earliest possible detection is required 1504

  20    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
Reverse transcriptase PCR  
 used to measure the amount of RNA present in a sample 
 used to amplify RNA

 used to amplify RNA 
 RNA is converted to DNA by reverse transcriptase 
 gene expression in the form of mRNA (rather than the actually DNA sequence) can  
therefore be analyzed 
 Using the enzyme reverse transcriptase, the cDNA (complementary (cDNA) is then 
amplified by conventional polymerase chain reaction (PCR). 
 Reverse transcriptase-PCR (RT-PCR) is able to identify the transcripts of a given 
gene by detecting the messenger(m) RNA coding for the gene

MRCPUK-part-1-sep 2017: what is the function of reverse transcriptase?  
 Generation of cDNA from an RNA template 
 
Positron Emission Tomography (PET) 
 
Positron Emission Tomography (PET) is a form of nuclear imaging which uses  
fluorodeoxy glucose  (FDG) as the radiotracer. This allows a 3D image of metabolic activity to 
be generated using glucose uptake as a proxy marker. The images obtained are the n combined

with a conventional imaging technique such as CT to decide whether lesions are metaboli cally 
active.  
 
Uses  
 evaluating primary and possible metastatic disease 
 cardiac PET: not used mainstream currently 
 
 1505

  21    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
 ___________________________________________________________________  
Oncogenes and proto-oncogenes

Oncogenes and proto-oncogenes  
 
Illustration of how a normal cell is converted to a cancer cell, when an oncogene bec omes 
activated  
 
 oncogene  is a gene that has the potential to cause cancer. 
 Oncogenes are endogenous human deoxyribonucleic acid (DNA) sequences that ari se 
from normal genes called proto-oncogenes. 
 Proto-oncogenes are normally expressed in many cells, particularly during fetal 
development, and are thought to play an important regulatory role in cell growth and

development. 
 Alterations in the proto-oncogene can activate an oncogene, which produces unregulat ed 
gene activity, contributing directly to tumourogenesis. 
 myc is an oncogene which encodes a transcription factor 
 The bcr-abl fusion protein is the proto-oncogene from the Philadelphia chromosome fou nd 
in CML. It is a potent tyrosine kinase  which stimulates signal transduction and hence 
mitosis. 
 
Oncogene alterations are important causes of: 
 Rhabdomyosarcomas (ras oncogene)

 Rhabdomyosarcomas (ras oncogene) 
 Burkitt's lymphoma (C-myc is translocated intact from its normal position on chromosome 8 
to chromosome 14) 
 Neuroblastoma (N-myc proto-oncogene is seen in a proportion of patients with poor 
prognosis). 
They should be contrasted with tumour suppressor genes. In this situation, the genes n ormally 
down regulate cell growth, and require inactivation to allow malignant growth. Exa mples include 
retinoblastoma. 
 
1506

  22    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
In situ hybridisat ion

In situ hybridisat ion 
 gene mapping technique, denatured (DNA) from metaphase chromosomes is 
hybridised with a radioactively labelled probe. This DNA is then exposed to film to 
reveal the approximate chromosomal location of the DNA in the probe.  
 It uses a labelled complementary DNA or RNA probe to localise a specific sequence within 
a tissue.  
 Firstly, the tissues are treated to fix the target, then the probe is added. This then

hybridises to the target, following which, excess probe is washed away.  
 In the classical form, the probe is labelled with radio-labelled bases, which can then be 
identified using plain film.   
FISH (fluorescence in situ hybridization)  
 FISH  is a form of in situ hybridisation in which the probe is labelled with fluorescent bases, 
which can then be visualised under a fluorescent microscope.  
 Gene amplifications and chromosomal translocations are best detected

by FISH (fluorescence in situ hybridization),  a technique that employs the use of DNA 
probes linked to fluorescent markers to visualize chromosomes.  
 eg : Detection of Her2/neu  
 HER2/neu encodes human epidermal growth factor receptor protein, a 
transmembrane receptor tyrosine kinase that participates in cellular growth signaling.  
 HER2/neu is often amplified in breast cancer.  
 
 DNA amplification  is used to detect deletions and insertions in single genes.

 Metaphase karyotype analysis  is often used for the detection of large chromosomal 
abnormalities including a trisomy like Down syndrome or Patau syndrome. 
Recombination   
 Recombination is the production of genetic combinations not found in either of the 
parents.  
 In humans, this is predominantly created by crossing-over between homologous 
chromosomes during meiosis.

chromosomes during meiosis. 
 The maximum possible recombination distance between two genes (or any two markers on  
a chromosome) is 50%, because they may be inherited together at random on  50% of 
occasions. If two genes (or markers) have a recombination fraction of 50%, then they  either 
lie on different chromosomes, or a long distance apart on the same chromosome 
 
Ref: medical-masterclass.com 2017 mrcp part 1 
  
 1507

  23    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
Protein synthesis 
In DNA, Adenine is paired with Thymine  and Cytosine with Guanine.

messenger RNA produced in the nucleus, matures in the cytoplasm, 
binds to the ribosome and initiates protein synthesis 
 
 Protein synthesis consists of two phases. 
 Transcription  is where one strand of the deoxyribonucleic acid (DNA) double helix 
is used as a template by ribonucleic acid (RNA) polymerase to synthesise 
messenger RNA from RNA nucleotides.The mRNA then migrates into the cytoplasm 
maturing, for example, by the splicing of non-coding sequences.

 Translation  occurs when the ribosome binds to mRNA at the start codon and 
transfer RNA brings amino acids into position along the mRNA template. 
  Ribosomal RNA interacts with transfer RNA during translation by providing peptidyl 
transferase activity.The ribosome moves from codon to codon along the mRNA 
producing a polypeptide sequence. 
 Transfer RNA (tRNA) binds to messenger RNA (mRNA) codons  by the specific

area called (anticodons)  during translation of protein synthesis. ((mRNA)  has 
acodon & (tRNA)  has anticodon ) 
 Each type of RNA consists of nucleotides, which are made up of phosphate, ribose su gar 
and nitrogen bases. 
 RNA polymerase is the enzyme which is responsible for synthesing RNA molecules . 
 A purine always pairs with a pyrimidine (adenine with thymine; guanine with cytosine). 
 DNA is much more stable than RNA. This property is exploited in forensic pathology

 The bases in RNA and DNA differ. RNA contains uracil in place of thymidine; they are 
structurally similar. In RNA ribose is hydroxylated at the 2 ’ and 3 ’ positions ; in DNA only 
at the 3 ’ position (hence ‘deoxyribonucleic ’). 
 
1508

  24    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
 Other notes about protein synthesis 
 codon  is a three-base sequence (three 
nitrogen bases in a row) on mRNA . It calls

nitrogen bases in a row) on mRNA . It calls 
for a specific amino acid to be brought to 
the growing polypeptide.  
 anticodon is a three-base sequence on 
Transfer RNA (tRNA) . 
 mRNA has codons which are bound 
by the anticodons on tRNA during 
translation of protein synthesis. 
 
 RNA splicing  
 Removal of the introns in 
RNA transcript 
modification is called 
RNA splicing. 
Splicing occurs in the 
nucleus  before transport 
to the cytoplasm. 
 
 Telomere

 Telomere  
 telomere  is a DNA sequence at the end of each chromosome which becomes 
progressively shorter with each division the cell undergoes. 
 When it is reduced to a critical length the cell is not capable of dividing.  
 The enzyme telomerase is able to lengthen the telomere thus preventing this 
occurring. 
 The level of cellular telomerase activity will affect  The number of cell 
divisions 
 Exons  are coding sequences in the mRNA

 Exons  are coding sequences in the mRNA  
 introns  are areas of unknown function. 
 Transposons  are genetic sequences that have been transposed from one part of DNA to 
another. 
 Cyclins  are key regulators of the cell cycle; different cyclins are expressed at different 
stages of the cell cycle . 
1509

  25    Notes & Notes for MRCP                                                                            By Dr. Yousif Abdallah Hamad            
                                                                                                                                                                      
 Restriction enzymes  cut DNA  at sequences specific for each restriction enzyme.

 They are vital tools for molecular biology and molecular genetic research. 
Apoptosis   
 Apoptosis is a physiological process of programmed cell death (in contrast to necrosis 
which is pathological). 
 A key event in the initiation of apoptosis is the activation of a cascade of cysteine-asp artate 
specific proteases known as caspases . (Apoptosis is induced by Activation of 
caspases )

caspases )  
 A mediator of this process is p53 a tumour suppressor gene  that inhibits mitosis and 
promotes apoptosis  
 BCL-2 is an inhibitor of apoptosis. 
 Fas is a cell receptor and caspases are present in all cells; both promote apoptosis but are 
not tumour suppressor genes. 
 1510

Basics – Biochemistry & metabolism 
 
Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  1 
  
By
 
Biochemistry & metabolism
 
Updated 
 
2017
 
Contains: 
 
1511

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  2 
 Anion gap (AG) 
 
 The anion gap allows for the differentiation of 2 groups of metabolic acidosis.  
1. Metabolic acidosis with a high AG  is associated with the addition  of endogenously 
or exogenously generated acids .

or exogenously generated acids .  
2. Metabolic acidosis with a normal AG  is associated with the  loss  of HCO 3 or the 
failure to excrete H+ from the body.  
 The anion gap is calculated by: (sodium + potassium) - (bicarbonate + chloride) 
 A normal anion gap is 8-14 mmol/L  
 It is useful to consider in patients with a metabolic acidosis: 
 Causes of a normal anion gap or hyperchloraemic metabolic acidosis  
 gastrointestinal bicarbonate 
loss: diarrhoea, uretero-

sigmoidostomy, fistula 
 renal tubular acidosis   drugs: e.g. acetazolamide 
 ammonium chloride injection 
 Addison's disease 
 
 Causes of a raised anion gap metabolic acidosis  
 lactate: shock, hypoxia 
 ketones: diabetic 
ketoacidosis, alcohol  urate: renal failure 
 acid poisoning: salicylates, 
methanol 
 
mnemonic of high anion gap acidosis: 
 DR. MAPLES: D-DKA; R-renal; M-methanol; A-alcoholic ketoacidosis; P-paraldehyde ,

phenformin; L-lactic (ie, CO, HCN); E-ethylene glycol; S-salicylates 
 
Remember the mnemonic MUDPILES  high anion gap acidosis 
M Methanol 
U Uremia 
D Diabetic ketoacidosis 
P Paraldehyde  
I Infection 
L Lactic acidosis 
E Ethylene glycol 
S Salicylates 
 
1512

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  3 
  
Metabolic acidosis associated with bladder reconstruction (e.g: for carcinoma of the bladder).   
 Hyperchloraemic metabolic acidosis is a documented complication of neobladder formation. 
However, it usually improves with time and is mild.

 Severe and persistent metabolic acidosis may manifest when patients undergo further surgery 
for other reasons, as is the case in this patient.  
 Neobladder formation following radical cystectomy or cystoprostatectomy is becoming 
increasingly more common, and medical staff treating patients with neobladders should 
recognise and treat metabolic acidosis with intravenous fluids and bicarbonate .  
 
____________________________________________________________________  
Metabolic alkalosis

Metabolic alkalosis 
Overview 
 Metabolic alkalosis may be caused by a loss of hydrogen ions  or a gain of bicarbonate .  
 It is due mainly to problems of the kidney  or gastrointestinal tract  
 The initial disturbance of metabolic alkalosis is an increased HCO 3- concentration, followed by 
a compensatory response of increased Pco 2. 
 Hypoventilation is an immediate compensatory response to metabolic alkalosis.

 All renal tubular defects result in metabolic alkalosis, except for Fanconi syndrome. 
Causes  
 vomiting / aspiration (e.g. peptic ulcer 
leading to pyloric stenos, nasogastric 
suction) 
 liquorice, carbenoxolone 
 Bulimia nervosa  primary hyperaldosteronism  
 Liddle syndrome 
 Con syndrome  
 Bartter's syndrome 
 congenital adrenal hyperplasia 
Mechanism of metabolic alkalosis

Mechanism of metabolic alkalosis 
 the main mechanisms of metabolic alkalosis in the setting of vomiting are increased H+ 
excretion in the distal tubule and increased bicarbonate reabsorption in the proximal 
tubule. 
 activation of renin-angiotensin II-aldosterone (RAA) system is a key factor 
 ECF depletion (vomiting, diuretics) ĺ Na+ and Cl- loss ĺ activation of RAA system ĺ raised 
aldosterone levels  reabsorption of Na+ in exchange for H+ in the distal convoluted tubule

 in hypokalaemia, K+ shift from cells ĺ ECF, alkalosis is caused by shift of H+ into cells to 
maintain neutrality 
 
A patient with liver cirrhosis develops metabolic alkalosis. What  is the most likely 
pathological mechanism?   Reduced urea synthesis  
 
A patient in the intensive care unit following liver transplant surgery has a metabolic alkalosis. 1513

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  4 
 What is the most likely cause? 
 Diuretic-induced volume depletion 
 Cirrhosis  hypoalbuminaemia  low colloid osmotic pressure  Relative 
volume depletion  Ĺaldosterone, (which is not adequately metabolised by an 
impaired liver).

impaired liver). 
 Furosemide use in the post-operative period further exacerbates alkalosis 
driven by hyperaldosteronism . 
Prognosis 
 plasma pH of 8.0 is incompatible with life 
 when the pH is greater than 7.65  mortality rate is 80% 
 
Treatment 
 Acetazolamide is a diuretic used to alkalinize the urine or treat metabolic alkalosis as it 
inhibits carbonic anhydrase. 
Buffering agents in plasma

Buffering agents in plasma 
 Buffers are substances or solutions that accept a proton or hydroxyl group with very little 
change in overall pH.  
 Blood buffers include: 
1. bicarbonate,  
2. haemoglobin   
 Haemoglobin is a protein and has imidazole side chains which can buffer 
H+ ions.  
 Along with bicarbonate, it is one of the most important buffering agents in 
plasma.  
 Haemoglobin is a much more effective buffer in its deoxygenated form;

this contributes to the Haldane effect where carbon dioxide is offloaded 
more easily at the lungs (when haemoglobin is oxygenated) but is easily 
picked up and transported from the tissues when haemoglobin has been 
deoxygenated. 
 Deoxyhaemoglobin is a much more effective buffer than oxyhaemoglobin 
which accounts for some proportion of the Haldane effect (the effect of 
oxygen on haemoglobin, reducing its ability to transport carbon dioxide). 
3. protein.  
4. phosphate

4. phosphate  
 Technically is also a serum buffer but so little of it is present in the plasma 
that it has no significant contribution to the body ’s acid-base balance 
mechanisms. 
 
 1514

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  5 
 _____________________________________________________________________  
Arterial blood gas interpretation 
The Resuscitation Council (UK) advocate a 5 step approach to arterial blood gas interpretation. 
 
1. How is the patient? 
 
2. Is the patient hypoxaemic? 
 the Pa0 2 on air should be >10 kPa

 the Pa0 2 on air should be >10 kPa 
3. Is the patient acidaemic (pH <7.35) or alkalaemic (pH >7.45) 
 
4. Respiratory component: What has happened to the PaCO 2? 
 PaCO 2 > 6.0 kPa suggests a respiratory acidosis (or respiratory compensation for a metabolic 
alkalosis) 
 PaCO 2 < 4.7 kPa suggests a respiratory alkalosis (or respiratory compensation for a metabolic 
acidosis) 
5. Metabolic component: What is the bicarbonate level/base excess?

 bicarbonate < 22 mmol/l (or a base excess < - 2mmol/l) suggests a metabolic acidosis (or 
renal compensation for a respiratory alkalosis) 
 bicarbonate > 26 mmol/l (or a base excess > + 2mmol/l) suggests a metabolic alkalosis (or 
renal compensation for a respiratory acidosis) 
 
1515

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  6 
 _____________________________________________________________________________
Calcium metabolism  see endocrinology  
Hypercalcaemia  see endocrinology  
Hypocalcaemia  see endocrinology  
Vitamin D  see endocrinology  
_____________________________________________________________________________

Hyperkalaemia  
 Plasma potassium levels are regulated by a number of factors including: 
  Aldosterone 
 acid-base balance  
 insulin levels.  
 Metabolic acidosis is associated with hyperkalaemia as hydrogen and potassium ions compete 
with each other for exchange with sodium ions across cell membranes and in the distal tubu le.  
 
Causes of hyperkalaemia: 
 Chronic kidney disease alone generally will not cause hyperkalemia until the eGFR is

less than 20-25 mL/min. 
 drugs*: Can be due to:  
 Potassium being shifted out of cells, for example:  
 β-blockers 
 *beta-blockers interfere with potassium transport into cells and can 
potentially cause hyperkalaemia in renal failure patients - remember beta-
agonists, e.g. Salbutamol, are sometimes used as emergency treatment 
 acidosis 
 Reduced renal excretion, for example: 
 potassium sparing diuretics : spironolactone, 
 angiotensin converting enzyme (ACE) 
inhibitors

 angiotensin 2 receptor blockers 
  ciclosporin 
 lithium 
 heparin** 
 
**both unfractionated and low-molecular weight heparin can cause hyperkalaemia.  This 
is thought to be caused by inhibition of aldosterone secretion ĻĻrenal potassium 
excretion, particularly in patients with diabetes or those who are acidotic  
 Other causes, for example: 
 fluoride 
 digoxin  
 Addison's 
 rhabdomyolysis 
 massive blood transfusion

Foods that are high in potassium: 
 salt substitutes (i.e. Contain potassium rather than sodium) 1516

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  7 
  bananas, oranges, kiwi fruit, avocado, spinach, tomatoes 
 
Features 
 Weakness and fatigue are the most common complaints 
 May be asymptomatic 
 Cardiac: Palpitations, Chest pain, Dyspnea 
 Neuromuscular: Frank muscle paralysis, Depressed or absent deep tendon reflexes, 
Paresthesias

Paresthesias 
 Nausea or vomiting 
 ECG changes seen in hyperkalaemia include: 
 Early changes  (typically seen at a serum potassium level of 5.5-6.5 mEq/L) 
 tall, peaked T waves 
 shortened Q T interval 
 ST-segment depression. 
 At a serum potassium level of 6.5-8.0 mEq/L, in addition to peaked T waves: 
 Decreased or disappearing P wave 
 Prolonged PR interval 
 Widening of the QRS 
 Amplified R wave 
 
Treatments  
Immediate treatment principles include:

Immediate treatment principles include:  
1. Providing calcium salts to reduce the risk of arrhythmia ( ‘protect the heart ’);  
2. Administering intravenous glucose and insulin ( ‘shift potassium into cells ’);  
3. Reducing intake and increasing output of potassium ( ‘remove potassium from the body ’). 
Untreated hyperkalaemia may cause life-threatening arrhythmias.  
 Precipitating factors should be addressed (e.g. acute renal failure) and aggravating drugs 
stopped (e.g. ACE inhibitors).

stopped (e.g. ACE inhibitors).  
 Mild chronic hyperkalaemia (eg: 5.6 mmol/l) is well tolerated and not a cause for 
concern.  If serum potassium  rise to >6.0 mmol/l, standard practice would be to stop the ACEi 
and - if K >6.0 mmol/l were to persist - to advise a low potassium diet.  
 Management may be categorised by the aims of treatment : 
 Stabilisation of the cardiac membrane  
 intravenous 10 ml 10% calcium gluconate (or calcium chloride) 
1517

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  8 
  The effects of intravenous calcium occur within 1 to 3 minutes but last for only 30 
to 60 minutes.  
 Short-term shift in potassium from extracellular to intracellular fluid compartment 
 combined insulin/dextrose infusion 
 the most effective agent

 the most effective agent  
 In hyperglycaemic patients (serum glucose >15 mmol/L) insulin may be 
given without additional intravenous glucose 
 The dose: 10 units of soluble insulin   
 nebulised salbutamol 
 salbutamol is not recommended as monotherapy for hyperkalaemia but is 
a useful adjunct to intravenous insulin and glucose. 
 ineffective in up to 40% of patients with end-stage renal disease. 
 Patients prescribed beta blockers may be ‘resistant ’ to the hypokalaemic

effects of salbutamol. 
 Sodium bicarbonate  has little use in the routine treatment of hyperkalemia 
unless severe metabolic acidosis is present. 
 Sodium bicarbonate  Ĺ blood pH  H+ shift out of the cell to buffer the 
alkalinizing units. In exchange, K  will move from the blood into the cell.  
 Removal of potassium from the body 
 calcium resonium (orally or enema) 
 loop diuretics 
 dialysis

 dialysis  
May 2012 exam: H/O muscle weakness and lethargy. K+ = 6.3 mmol/l. What is the most appropriate 
initial treatment to lower the serum potassium level? Insulin/dextrose infusion  
 
Pseudohyperkalaemia 
 
 Pseudohyperkalaemia is a rise in serum potassium that occurs due to excessive leakage of 
potassium from cells, during or after blood is taken.

 It is a laboratory artefact and does not represent the true serum potassium concentration .  
 The majority of potassium is intracellular and thus leakage from cells can significantly impact 
serum levels.  
Causes  include: 
 haemolysis during venepuncture (excessive vacuum of blood drawing or too fine a needle  
gauge) 
 delay in the processing of the blood specimen 
 abnormally high numbers of platelets, leukocytes, or erythrocytes (such as myeloproliferative 
disorders)

disorders)  
 essential thrombocytosis 
 familial causes 
 Re-check a fresh sample at the hospital  
1518

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  9 
  Measuring an arterial blood gas will give a quick and accurate measure of true serum 
potassium.  
 For obtaining a lab sample, using a lithium heparin tube, requesting a slow spin (on the lab 
centrifuge) and walking the sample to the lab should ensure an accurate result.

Hypokalaemia and acid-base balance 
 
 Potassium and hydrogen can be thought of as competitors.  
 Hyperkalaemia tends to be associated with acidosis because as potassium levels rise fewer 
hydrogen ions can enter the cells  
Causes  
Hypokalaemia with alkalosis 
 Vomiting 
 Diuretics  Cushing's syndrome 
 Conn's syndrome (primary 
hyperaldosteronism) 
Hypokalaemia with acidosis 
 Diarrhoea

 Diarrhoea 
 Renal tubular acidosis  Acetazolamide 
 Partially treated diabetic ketoacidosis 
Drug induced hypokalaemia  
 Intracellular shifts of potassium with normal total body potassium, for example: 
 theophylline 
 ȕ-agonists  caffeine 
 insulin 
 Loss of potassium stores, for example: 
 chronic diuretic use 
Magnesium deficiency  may also cause hypokalaemia. In such cases, normalizing the potassium

level may be difficult until the magnesium deficiency has been corrected  
 
Features 
symptoms associated with hypokalaemia of less than 3.0 mmol/L include: 
 Tiredness 
 General weakness 
 Muscle pain, and 
 Constipation. 
ECG changes : When potassium falls below 3 mmol/l, the ECG often demonstrates: 
 Flattening of the T waves 
 ST depression 
 QT prolongation, and 
 Prominent U waves. 
 
1519

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  10 
 Treatment 
 if K>2.5 with no symptoms or ECG changes  oral potassium 
 if K<2.5 with symptoms or ECG changes  IV potassium 
 in life-threatening cases  1L IV 0.9% NaCL with 40 mmol/l KCl infused over four hours  
 Cardiac monitoring . 
 Potassium should be given in NaCl.

 Potassium should be given in NaCl.  
 Concentration should not exceed 40 mmol/l  
 No more than 10-20 mmol/hour should be given.  
 
Daily maintenance requirements   
amounts prescribed for patients on maintenance fluids (NICE guidelines): 
 Water  1500-2500 ml/ day 
 25-30 ml/kg/day  
 Potassium, Sodium and Chloride   1 mmol/kg/day   
 Sodium   70 mmol   
 potassium  (40-80 mmol/day)  In the absence of kidney disease or hyperkalaemia 
(around 1 mmol/kg per day)

(around 1 mmol/kg per day)  
 
Estimation of total body potassium loss: 
 a drop in 1 mmol /L K+ of serum potassium in approximately equivalent to a 200 
mmol K+ total body loss.  
Hypernatraemia 
Causes  
 excess of hypertonic fluids (IV saline, enteral or parenteral nutrition); 
 excessive free water loss: 
 renal ( diabetes insipidus , diuretics, osmotic diuresis as with hyperglycaemia),

 GI (diarrhoea, vomiting),  
 skin (sweating, burns) 
 reduced thirst - seen in very old and very young patients. 
Treatment 
 Treatment is aimed at the underlying cause.   
 Hypernatraemia should be corrected with great caution.  
 Although brain tissue can lose sodium and potassium rapidly, lowering of other osmolytes (and 
importantly water) occurs at a slower rate, predisposing to cerebral oedema, resulting in 
seizures, coma and dea th.

seizures, coma and dea th.  
  acute hypernatraemia can be corrected quickly but if chronic (>24hours) then it should b e 
corrected at <0.5mmol/L/hr.  
 Fluid resuscitation should involve oral water, 0.45% saline or 5% dextrose IV.  1520

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  11 
  
Free water deficit in litres  = (Serum sodium - 140)/ 140) x total body water  
 
______________________________________ _______________________________
Hyponatraemia  
 Hyponatraemia may be caused by water excess or sodium depletion.

 Causes of pseudohyponatraemia include hyperlipidaemia (increase in serum volume) or a 
taking blood from a drip arm.  
 Urinary sodium and osmolarity levels aid making a diagnosis. 
 
Cause of hyponatraemia 
Urinary sodium > 20 mmol/l  Urinary sodium < 20 mmol/l  
Sodium depletion, renal 
loss (patient often  
hypovolaemic ) Patient often euvolaemic  Sodium depletion, 
extra-renal loss 
(hypovolaemic ) Water excess (patient often 
hypervolaemic  and 
oedematous) 
 Addison's

 diuretic stage of 
  SIADH (urine 
osmolality > 500 
mmol/kg) 
  diarrhoea, 
vomiting, 
sweating 
 burns, 
adenoma of 
rectum 
  secondary 
hyperaldosteronism
: heart failure, 
cirrhosis 
 reduced GFR: renal 
failure 
 IV dextrose, 
psychogenic 
 
Nice guidelines 2013  
 Additional monitoring of urinary sodium may be helpful in patients with high -volume 
gastrointestinal losses.

gastrointestinal losses. 
  (Reduced urinary sodium excretion [less than 30 mmol/l] may indicate total body sod ium 
depletion even if plasma sodium levels are normal. 
  Urinary sodium may also indicate the cause of hyponatraemia, and guide the achievem ent 
of a negative sodium balance in patients with oedema.  
However, urinary sodium values may be misleading in the presence of renal impairmen t or 
diuretic therapy.) 
Features  
 Fatigue 
 Muscle weakness 
 Gait disturbance 
 Falls

 Falls 
 Cerebral oedema 1521

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  12 
  Seizures 
 And death if untreated. 
 
 It is important with hyponatraemia to ascertain volume status as this will determine 
 The management of each is as follows:  
 
 Hypovolaemic hyponatraemia

 Hypovolaemic hyponatraemia  
 Diagnosis may supported by an elevated urea suggesting dehydration.   
 rehydration with sodium chloride 0.9%  or a balanced crystalloid (Hartmann's) 
 avoid rapid correction of sodium in order to reduce the risk of osmotic 
complications such as central pontine myelinolysis 
 Euvolaemic hyponatraemia  
 check urine and serum osmolality. Does the patient meet the criteria for SIADH? 
 treat the underlying cause where possible in SIADH

 fluid restriction (500-750mls/day) 
 monitor fluid balance and perform daily weights 
 consider demeclocycline or tolvaptan (under specialist supervision). Both inhibit 
the action of antidiuretic hormone. 
 Hypervolaemic hyponatraemia  
 fluid and salt restriction 
 consider diuretics 
 treat the underlying cause (e.g. cardiac failure) 
 
Hyponatraemia: correction 
 
Acute hyponatraemia  
 predisposing factors to acute hyponatraemia:  
 Over consumption of fluids,

 Over consumption of fluids,  
 prolonged race duration and inadequate training  
 When hyponatraemia develops over a short duration the ability of the brain to a dapt is 
exceeded and cerebral oedema can result which may lead to confusion, seizures and  
coma. As a result patients may die from brain herniation.  
 The correct treatment to give is hypertonic saline.  
 Decompressive craniotomy would help alleviate raised intracranial pressure due to

cerebral oedema however is not an appropriate first line treatment.  
1522

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  13 
  A small, quick increase in the serum sodium is required in order to decrease intracranial 
pressure. Hypertonic saline (3%) boluses are the most appropriate treatment to 
improve neurological status in such patients.  
 
Central pontine demyelinolysis

Central pontine demyelinolysis 
 demyelination syndrome caused by rapid correction of chronic hyponatraemia  
 Pathological changes are not confined to the pons (despite the name of the condition ). 
 In 10%, demyelination also occurs in extrapontine regions, including the mid brain, thala mus, 
basal nuclei, and cerebellum.  
 Occur more frequently in females than in males. 
 Risk factors  for central pontine myelinolysis  
 alcoholism,  
 malnutrition, and

 malnutrition, and  
 hyponatremia. 
 Risk factors for central pontine myelinolysis in the hyponatremic patient: 
 Serum sodium of less than 120 mEq/L for more than 48 hours 
 Aggressive IV fluid therapy with hypertonic saline solutions 
 Development of hypernatremia during treatment 
 Features 
 Consciousness is usually impaired. 
 quadriparesis and bulbar palsy 
 The most consistent examination findings are those of pseudobulbar palsy  and

spastic quadriplegia caused by demyelination of corticospinal and corticobulbar 
tracts within the pons.  
 Delirium is extremely common. 
 Lesions within the pons cause horizontal gaze paralysis . 
 locked-in syndrome 
 includes paralysis of lower cranial nerves and limb musculature.  
 Vertical eye movements, blinking, breathing, and alertness may remain intact in 
these patients. 
 Diagnosis : MRI brain 
 MRI is the imaging modality of choice

 MRI is the imaging modality of choice  
 (MRI) usually shows changes within the pons, however the appearances are not 
diagnostic. 
 Typically, T2-weighted MRI images demonstrate hyperintense or bright areas where 
demyelination has occurred and has been caused by relatively increased water co ntent 
in those regions.  
 Treatment is supportive only.   
 Avoid hypernatremia 
 Many authorities recommend that increases in serum sodium of <12 mmol/24

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  14 
  Certain patients with hypokalaemia, liver disease, poor nutritional state or burns 
are at higher risk of demyelination and should have a rate of sodium correction of 
<8 mmol/24 hours.  
 
Which fluid should be used to resuscitate a patient with diuretic-induced hyponatraemia and 
dehydration?

dehydration?  
 Hartmann's solution  
"Saline depletion, for example due to excessive diuretic exposure, is best managed 
with a balanced electrolyte solution such as Hartmann's." 
 
Fluid resuscitation in other clinical situations: 
 Losses from diarrhoea/ileostomy/small bowel fistula/ileus/obstruction should be rep laced 
volume for volume with Hartmann's or Ringer's lactate/acetate type solutions.

 Excessive losses from gastric aspiration/vomiting should be treated pre-operatively w ith an 
appropriate crystalloid solution which includes an appropriate potassium supplemen t. 
 Hypochloraemia is an indication for the use of 0.9% saline, with appropriate additions o f 
potassium and care not to produce sodium overload. 
 
Osmolar gap  
 Osmolar gap is the difference between the calculated osmolarity and the measured 
osmolality .

osmolality .  
 The normal value is 10-15 but may be increased in the presence of unmeasured 'a bnormal' 
osmotically active ions in the plasma. 
 An elevated osmolar gap provides indirect evidence for the presence of an abnorma l solute 
that may be present in significant amounts.  
 To have much effect on the osmolar gap, this substance needs to have a low molecu lar weight 
and be uncharged so it can be present in a form and in a concentration (mea sured in mmol/l)

sufficient to elevate the osmolar gap. 
 Ethanol, ethylene glycol (anti-freeze), acetone and methanol are solutes that wil l cause 
elevation of the osmolar gap in this way. 
 Osmolarity is the measure of solute concentration, defined as the number of osmoles (Osm) of 
solute per litre (l) of solution (Osmol/l). 
 Calculated osmolarity = 2 (Na + K) + Glucose + Urea (all in mmol/L). 
 Normal serum osmolarity is 285-295 mOsm/L.

 Normal serum osmolarity is 285-295 mOsm/L.  
 Osmolarity can be affected by temperature and pressure and for a given solution, this 
calculated variable is less than the osmolality. 
 Osmolality is also a measure of solute concentration but is defined as the number of osmoles 
(Osm) of solute per kilogram (Osm/Kg).The value is independent of temperature and pressure. 
It is measured in the laboratory using an osmometer . Osmometers use the colligative

properties of a solution such as depression of freezing point or vapour pressure. 
 1524

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  15 
  
Magnesium (Mg):  
 99% of total body magnesium is intracellular or bone-deposited, with only 1% present in th e 
extracellular space.  
 Normal plasma magnesium  (0.7-0.9 mmol)

 Normal plasma magnesium  (0.7-0.9 mmol) 
 magnesium homeostasis: The main controlling factors in magnesium homeostasis  GIT 
absorption and renal excretion. 
 Renal absorption 
 Unlike most ions, the majority of magnesium is not reabsorbed in the proximal 
convoluted tubule (PCT). the thick ascending limb (TAL) of the loop of Henle 
is the major site of reabsorption  (60-70%).   
 In the TAL, magnesium is passively  reabsorbed  with calcium through 
paracellular tight junctions

paracellular tight junctions 
 Claudins are the major components of tight-junction strands in the TAL, where 
the reabsorption of magnesium occurs 
 In the distal convoluted tubule (DCT), magnesium is reabsorbed via an active, 
transcellular process that is thought to involve TRPM6  
 The TRPM6 channel is embedded in the membrane of epithelial cells of 
large intestine, distal convoluted tubules, lungs, and testes. 
 
Hypomagnesaemia  
 Low magnesium  (below 0.7 mmol/L)

 Low magnesium  (below 0.7 mmol/L)  
Uses for magnesium include: 
 polymorphic ventricular tachycardia (torsade de pointes),  
 acute asthma  
 prevention/treatment of seizures in pre-eclampsia. 
 Magnesium salts can be given as laxatives 
Causes of low magnesium 
 Inadequate intake: 
 Malnutrition, and 
 Alcohol dependence. 
 hypomagnesemia is the most common electrolyte abnormality observed in 
alcoholic patients 
 total parenteral nutrition 
 Malabsorption:

 Malabsorption: 
 Inflammatory bowel disease 
 Long term PPI therapy 
 Gluten enteropathy 1525

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  16 
  Intestinal bypass, and 
 Radiation enteritis. 
 Renal tubular disease: 
 Hyperaldosteronism 
 Hyperparathyroidism 
 Obstructive uropathy 
 Potassium depletion, and 
 Drugs (including diuretics, amphotericin, cisplatin, ciclosporin, amikacin, gentamicin, 
laxatives, and tacrolimus).

laxatives, and tacrolimus). 
 Intracellular shift: 
 Post myocardial infarction 
 Post parathyroidectomy 
 Recovery from diabetic ketoacidosis (K+ and PO 4- also enter cells) 
 Refeeding syndrome (PO 4- also enters cells), 
 Acute pancreatitis. 
 
 Drugs:  
 cisplatin,  
 diuretics,  
 cyclosporine  
 cardiac glycosides  
 Colorectal cancer treatment with cetuximab/panitumumab (EGF receptor 
inhibitors)  Ļ TRPM6  hypomagnesemia.

inhibitors)  Ļ TRPM6  hypomagnesemia.  
 Omeprazole   hypomagnesaemia   hypoparathyroidism  hypocalcaemia.  
 The reasons for this are unclear, but it may be due to reduced uptake of 
Mg2+ ions in the gut.  
 Omeprazole reduces acid production and raises stomach pH.  
 An acid environment can aid release of metal ions from their binding sites 
in food molecules which facilitate absorption.  
 Metabolic acidosis

 Metabolic acidosis 
 Chronic metabolic acidosis   Ļrenal TRPM6 expression in the DCT  Ļ Mg 
reabsorption Ļ serum Mg.  
 Hypercalcaemia 
 Hypercalcemia  activation of calcium-sensing receptor (CaSR)  Ļ Mg 
 hypokalaemia, hypocalcaemia 
 Genetic diseases  
 Hypomagnesemia with secondary hypocalcemia (HSH): 
 autosomal recessive 
 caused by mutations in the TRPM6 gene  ↓↓ intestinal magnesium

reabsorption  ↓↓ serum magnesium  ↓↓ (PTH)  ↓↓ serum  calcium levels 
(hypocalcemia). 1526

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  17 
  manifests in early infancy with generalized convulsions refractory to 
anticonvulsant treatment or with other symptoms of increased neuromuscular 
excitability, such as muscle spasms or tetany.  
 Laboratory evaluation reveals extremely low serum magnesium and serum 
calcium levels.

calcium levels. 
 familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)  
 Mutations in the claudin-16 and claudin-19 genes 
 excessive renal magnesium and calcium wasting,  
 polyuria,  
 recurrent urinary tract infections,  
 bilateral nephrocalcinosis,  
 progressive renal failure. 
 autosomal-dominant hypocalcemia with hypercalciuria (ADHH),  
 due to activating mutations of the CaSR  
 (CaSR),  is a G-protein –coupled receptors.

 (CaSR),  is a G-protein –coupled receptors.  
 The CaSR is expressed in TAL.  
 characterized by hypocalcemia, hypercalciuria, and hypomagnesemia and by 
low, but detectable, levels of PTH. 
 
Features 
 General  
 lack of appetite. 
 Lethargy 
 fatigue 
 neuromuscular  hyper-excitability  
 muscle weakness including 
 changes in personality 
 tetany 
 seizures  cardiac 
 arrhythmias 
 ECG features similar to those of 
hypokalaemia

hypokalaemia 
 The ECG change most typically 
associated with hypomagnesaemia is QT 
prolongation. 
 exacerbates digoxin toxicity 
 decreased PTH secretion ĺ 
hypocalcaemia 
 Hypokalemia ( in 40-60%) 
 Associations with hypomagnesemia  
 hypoparathyroidism  
 Ļ Mg Ļ magnesium-dependent adenyl cyclase generation of cyclic adenosine 
monophosphate (cAMP)   ĻPTH  hypoparathyroidism  
 DM ( Ļ Mg Ļ insulin sensitivity and secretion) 
 Cardiac: 
 CAD

 Cardiac: 
 CAD 
 Hypertension (Mg plays a role in BP regulation).  
 cardiac arrhythmia  
 prolongation of the QT interval  
 Torsade de pointes 1527

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  18 
 Investigation 
 blood magnesium levels can guide but do not accurately reflect total body magnesium status. 
Attempts to find a marker of cellular magnesium status include measuring eryth rocyte or 
monocyte Mg but these are not generally available.

 Urine Mg excretion is a useful guide. When there is inadequate intake or malabsorption, the  
kidneys would normally conserve Mg, giving urine Mg concentrations <7 mmol/24 hours. The 
reference range is around 2-7 mmol/24 hours. 
 
Treatment  
 <0.4 mmol/l  
 intravenous replacement is commonly given. An example regime would be 40 mmol of 
magnesium sulphate over 24 hours 
 >0.4 mmol/l 
 oral magnesium salts (10-20 mmol orally per day) 
 diarrhoea can occur with oral magnesium salts

Hypermagnesaemia  
 Hypermagnesaemia is much less common than hypomagnesaemia and is often ia trogenic in 
cause. 
Causes of hypermagnesaemia: 
 Iatrogenic : 
 Treatment with magnesium sulphate to prevent/treat seizures in patients with eclampsia 
or pre-eclampsia 
 Treatment with Mg containing antacids 
 Use of citrate-glucuronic acid solutions to dissolve renal calculi either through bladder

irrigation or via a nephrostomy tube 
 Over-zealous IV treatment of hypomagnesaemia 
 Chronic use of Mg-containing enemas. 
 Other causes: 
 Acute or  chronic renal failure  
 release of Mg from tissues,  
 Mg in dialysate,  
 Mg in phosphate binding drugs 
 Familial hypocalciuric hypercalcaemia. 
Lithium can cause hyper magnesaemia  
 
Interpretation of serum Mg results: 
 0.7-1.5 mmol/L: reference range 
 1.5-2.5 mmol/L: mild hypermagnesaemia - symptoms uncommon

 2.5-5.0 mmol/L: moderate hypermagnesaemia - symptoms develop including h ypotension, 
prolonged PR and QRS intervals on ECG, arreflexia 
 >5.0 mmol/L: severe hypermagnesaemia - at risk of respiratory paralysis through inhibition of 
acetylcholine release and cardiac arrest. 1528

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  19 
 Features 
 Signs of hypermagnesaemia include: 
 Nausea 
 Vasodilatation, and 
 Hypotension (myocardial depression + vasodilatation). 
 In severe cases it can also include: 
 Double vision 
 Drowsiness 
 Loss of deep tendon reflexes 
 Respiratory depression 
 Bradycardia 
 Coma, and

 Coma, and 
 Cardiac arrest. 
 
• if mild/moderate and iatrogenic, often it is enough to identify and stop the cause .  
• In an emergency, dialysis or administration of IV calcium glucuronate (10 ml of 10%) will 
reduce the effects of hypermagnesaemia. 
_________________________________________ ____________________________ 
Hypophosphataemia 
 serum phosphate level of less than 2.5 mg/dL (0.8 mmol/L).  
 
Causes Consequences 
 alcohol excess

 acute liver failure 
 diabetic ketoacidosis 
 refeeding syndrome 
 primary 
hyperparathyroidism 
 osteomalacia  
 Hyperventilation   red blood cell haemolysis 
 white blood cell and platelet 
dysfunction 
 muscle weakness and rhabdomyolysis 
 central nervous system dysfunction 
 
 The three major mechanisms of hypophosphataemia are: 
1. Redistribution of extracellular phosphate into cells

 hyperventilation  respiratory alkalosis   activating phosphofructokinase  
moves phosphate into cells   stimulates intracellular glycolysis.  
 Glycolysis leads to phosphate consumption as phosphorylated glucose 
precursors are produced.  
 Any cause of hyperventilation (eg, sepsis, anxiety , pain, heatstroke, alcohol 
withdrawal, diabetic ketoacidosis [ DKA ], hepatic encephalopathy, salicylate 1529

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  20 
 toxicity, neuroleptic malignant syndrome [NMS]) can precipitate 
hypophosphatemia.  
2. Decreased intestinal absorption, 
 chronic diarrhea,  
 malabsorption syndromes,  
 severe vomiting, 
 nasogastric (NG) tube suctioning.  
3. Depletion due to increased urinary loss.

3. Depletion due to increased urinary loss. 
  the most common cause of hypophosphatemia  
 primary and secondary hyperparathyroidism.  
 Osmotic diuresis, such as seen in hyperosmolar hyperglycemic 
syndrome (HHS)  
  Fanconi syndrome (proximal tubule dysfunction)   
 X linked hypophosphataemic rickets 
 Oncogenic hypophosphataemic osteomalacia 
 
Sep 2017 part 1 : what is the mechanism of Hypophosphataemia during  treatment of DKA?

 Shift from extracellular to intracellular space  
 
Sep 2017 part 1 : what is the mechanism of Hypophosphataemia  in alcoholic patients  after 
hospital admission ?  
 The alcoholic patient often has chronic phosphate depletion, and, after admissi on 
to the hospital, is prone to severe hypophosphatemia resulting from redistribution 
of extracellular phosphate into the cells.  
 Two factors may contribute to this shift:

 Two factors may contribute to this shift: 
1. I.V therapy with dextrose-containing solutions or refeeding  ↑Glucose  
↑ insulin release  ↑ phosphate uptake by the cells  
2. alcohol withdrawal  hyperventilation acute respiratory alkalosis 
intracellular alkalosis  stimulates intracellular phosphofructokinase ↑ 
glycolysis  movement of phosphate into cells 
Ref: uptodate.com 2017  
Hyperphosphataemia

Hyperphosphataemia 
 
 The healthy adult usually ingests about 8400 mg per week of phosphate through their diet  
 Absorption occurs mainly in the jejunum 
 Renal absorption 
 The majority  (70%) of filtered phosphate is reabsorbed by type 2a sodium phosphate  
cotransporters  located on the apical membrane of the renal proximal tubule .  1530

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  21 
  expression of these cotransporters is increased by: 
 low dietary phosphate intake  
 several growth factors to enhance phosphate absorption.  
 expression is decreased by: 
 high dietary phosphate intake,  
 parathyroid hormone (PTH),  
 FGF23, and  
 dopamine.

 dopamine.  
 Impaired expression or function of these transporters is associated with 
nephrolithiasis.  
 absorption in the remainder of the nephron  is generally mediated by type 3  sodium 
phosphate cotransporters.  
 The normal adult range for phosphorus is 2.5-4.5 mg/dL (0.81-1.45 mmol/L).  
 Levels are 50% higher in infants and 30% higher in children, because of growth 
hormone effects. 
 Renal excretion

 Renal excretion  
 About 5400 mg of phosphate is excreted per week through the kidneys.  
 
 increased phosphate intake, 
 decreased phosphate excretion,  
 disorder that shifts intracellular phosphate to extracellular space.  
 Tumor lysis 
Foods that are characteristically rich in phosphate include: 
 dairy products , (Cheddar cheese ) 
 fibre rich foods,  
 chocolate, and  
 processed meats. 
Causes  
 usually iatrogenic

Causes  
 usually iatrogenic 
 Ļcalcium + Ĺ phosphate levels seen in: 
 hypoparathyroidism, and pseudohypoparathyroidism 
 Ĺcalcium + Ĺphosphate seen in: 
 vitamin D intoxication ( ĻPTH + Ĺ vitamin D) 
 milk-alkali syndrome ( ĻPTH + Ļvitamin D) 
 Laxative (Phospho-soda) abuse 
 
Features 1531

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  22 
   most are asymptomatic 
 hypocalcemic symptoms, such as muscle cramps, tetany, and perioral numbness or tingling.  
 Other symptoms include bone and joint pain, pruritus, and rash. 
 heart block 
 soft tissue calcification 
 24-hour measurement of urinary phosphate

 24-hour measurement of urinary phosphate  
 Fractional renal excretion > 15%:  Suggests: 
 massive phosphate ingestion (eg, laxative [Phospho-soda] abuse) or  
 lysis of tissue and resulting release of intracellular phosphate 
 Fractional renal excretion > 15%: Suggests that renal excretion is impaired because of:  
 renal failure or  
 hypoparathyroidism 
 Phosphate level is important to control in patients with chronic renal failure. 
 Decrease dietary phosphorous

 Decrease dietary phosphorous 
 Aluminum hydroxide 
 Hydration and acetazolamide 
 Dialysis  
 1532

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  23 
  
1533

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  24 
Collagen synthesis  
 Collagen synthesis starts with the synthesis of preprocollagen, which is the same process as 
translation of alpha chains. This process occurs in the rough endoplasmic reticulum.

 Hydroxylation of proline and lysine residues is the second step of collagen synthesis. It al so 
occurs in the rough endoplasmic reticulum, and this process is impaired in Vitamin C 
deficiency leading to scurvy. 
 Glycosylation of pro-alpha-chain hydroxylysine residues and formation of procollag en, via 
hydrogen and disulfide bonds, yielding a triple helix. Problems in this step of collag en I 
synthesis leads to osteogenesis imperfecta .

synthesis leads to osteogenesis imperfecta . 
 The final step of collagen synthesis occurs extracellular and includes the  cross-
linking  of lysine-hydroxylysine residues in collagen by lysyl oxidase. This creates collagen 
fibrils and is impaired in diseases like Ehlers-Danlos syndrome or Menkes disease. 
 
Collagen Types   
Type I   
 strongest tensile form of collagen 
 majority of collagen in the body (approx. 90%) 
 found in bone, fascia, tendons, teeth (dentin), cornea, skin

 type III of early wound repair converted to type I in late wound repair  
 defective in osteogenesis imperfecta (OI) type I   
 defective in various forms of Ehlers-Danlos syndrome 
Type II 
 spongy collagen to absorb shock 
 found in cartilage (including hyaline), vitreous body of the eye, nucleus pulposus of ve rtebral 
disc 
Type III 
 web-like fibers 
 found in skin, blood vessels, uterus, fetal tissue 
 granulation tissue

 granulation tissue 
 type III of early wound repair converted to type I in late wound repair 
 defective in Ehlers-Danlos type IV 
 associated with joint dislocation, berry aneurysms, organ rupture 
Type IV 
 basement membrane, especially kidney, ears, eyes, skin 
 defective in Alport's syndrome 
 kidney ĺ progressive hereditary nephritis  
 ears ĺ deafness  
 eyes ĺ ocular disturbances  
 one of the causes of epidermolysis bullosa 
 weak union of dermis and epidermis of the skin

 weak union of dermis and epidermis of the skin 
 easily formed blisters 
 Goodpasture's syndrome involves an auto-antibody against collagen type IV in pu lmonary and 
glomerular capillaries 
 presents with hemoptysis and glomerular disease 
 1534

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  25 
 ______________________________________ _______________________________  
Vitamin B3 (Niacin) deficiency  
Basics 
 Niacin is present in two forms - nicotinamide and its precursor molecule, nicotinic acid. 
Causes   
 poor diets (diets low in tryptophan or niacin) or malabsorption

  niacin is  present in a wide range of plant and animal foodstuffs. However, sometimes 
the form of the vitamin is not readily absorbable in humans - such as occurs in m aize.  
 Deficiency can occur in places where maize constitutes the main dietary carbohydrate. 
(corn staple diets) 
 more common in alcoholics.  
 Diseases affecting the availability of tryptophan (Niacin is manufactured via metabolism 
of tryptophan) 
 Hartnup disease

 Hartnup disease 
 autosomal recessive ↓ tryptophan absorption in kidneys and small intestine   
Niacin deficiency  
 ↑ tryptophan in urine.  
 also known as "pellagra-like dermatosis" 
 treatment 
 high-protein diet 
 protection from sunlight 
 avoid other aggravating factors, such as photosensitizing drugs, 
 carcinoid tumor .  
 Tryptophan is used by carcinoid tumours to produce 5-hydroxytryptamine.

 As the carcinoid tumour mass increases  more and more of the available 
tryptophan is consumed, and less is available for niacin production.   
 isoniazid therapy  
 isoniazid inhibits the conversion of tryptophan to niacin  
 ↓ vitamin B6 leading to ↓ niacin synthesis  
Presentation   
 severe deficiency leads to pellagra 
 
Atrophic glossitis  
 the tongue is pink or red 
 appears glossy and smooth due to the atrophy of papillae.  
 can be painful. 
 
 1535

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  26 
 Pellagra  
The classical features are the 3 D's - Dermatitis, Diarrhoea and Dementia 
Causes 
• Pellagra is a caused by nicotinic acid (niacin) deficiency .  
Features  
 Initially non-specific features such as nausea, fatigue, reduced appetite, gastrointestina l 
 Dermatitis

 Dermatitis 
 bilateral, symmetric and typically on sun-exposed areas (neck, arms).  
 progresses to hyperpigmented, dry, rough skin. 
 brown scaly rash  on sun-exposed sites  - termed Casal's necklace if around neck 
 aggravated by exposure to sunlight  (photosensitivity dermatitis) 
 dementia, depression 
 death if not treated 
Vitamin C (ascorbic acid) (scurvy)

Vitamin C (ascorbic acid) (scurvy) 
• Vitamin C is a water soluble vitamin. 
• Dehydroascorbic acid, the oxidative product of ascorbic acid metabolism, passively penetrates 
cellular membranes and is the preferred form for erythrocytes and leukocytes.  
Functions  
 Antioxidant ( Ascorbic acid provides electrons needed to reduce molecular oxygen. These anti-
oxidant capabilities also stabilize vitamin E and folic acid.  )

 It is a cofactor for reduction of folate to dihydro- and-tetrahydrofolate. 
 Therefore macrocytic anaemia  in scurvy may occur due to two reasons:  
 oxidative hemolysis and  
 folate metabolism defects. 
 collagen synthesis: acts as a cofactor for enzymes that are required for the hydroxy lation 
proline and lysine in the synthesis of collagen 
 Vitamin C deficiency (scurvy) leads to defective synthesis of collagen resulting in

capillary fragility (bleeding tendency) and poor wound healing 
 facilitates iron absorption 
 cofactor for norepinephrine synthesis 
 cofactor for reduction of folate to dihydro-and-tetrahydrofolate. 
Causes 
 occurs in people with poor dietary intake, who eat little or no fruit and vegetables, comm only 
alcoholics and elderly people existing on a ‘tea and toast ’ diet.  
 Pregnancy, lactation and thyrotoxicosis increase ascorbic acid requirements and may 
precipitated scurvy.

precipitated scurvy. 
Features vitamin C deficiency  
 gingivitis, loose teeth 
 poor wound healing 1536

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  27 
  bleeding from gums, haematuria, epistaxis 
 general malaise 
 anaemia   
 macrocytic anaemia in scurvy may occur due to two reasons: oxidative 
hemolysis and folate metabolism defects.  
 normochromic, normocytic anaemia reflects bleeding into tissues 
Continued deficiency leads to: 
 Anaemia

 Anaemia 
 Myalgia 
 Bone pain 
 Bruising 
 Petechial and perifollicular 
haemorrhages 
 Corkscrew hairs 
 Mood changes  Fragility 
 scleral icterus (late, probably secondary to 
haemolysis), and 
 pale conjunctiva. 
 Fractures, dislocations and tenderness of 
bones are common in children. 
 Bleeding into muscles and joints may be 
seen 
Late stages can lead to: 
 Generalised oedema 
 Severe jaundice 
 Haemolysis 
 Haemorrhage  Neuropathy

 Haemorrhage  Neuropathy 
 Convulsions, and 
 Death. 
 
The classical skin manifestations of scurvy are: 
 perifollicular hyperkeratotic papules 
 perifollicular haemorrhages 
 purpura, and 
 ecchymoses. 
Treatment 
 vitamin C supplementation,  
 recovery is usually complete within three months.  
Vitamin B12 deficiency

Vitamin B12 deficiency 
• Vitamin B12 is mainly used in the body for red blood cell development and also maintenance 
of the nervous system. 
• It is absorbed after  binding to intrinsic factor  (secreted from parietal cells in the stomach) 
and is actively absorbed in the terminal ileum .  
• A small amount of vitamin B12 is passively absorbed without being bound to intrinsic factor. 
 Approximately 1 percent of a large oral dose of vitamin B 12 is absorbed by this second

mechanism. This pathway is important in relation to oral replacement. 
  Once absorbed, vitamin B 12 binds to transcobalamin II  and is transported throughout the 
body.  
• Exhaustion of vitamin B12 stores usually occurs after 12 to 15 years of absolute vitamin B12 
deficiency.  
Causes of vitamin B12 deficiency  
 pernicious anaemia (the most common cause) 1537

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  28 
  post gastrectomy 
 poor diet eg: vegetarians and vegans (sources of vitamin B12 are limited to anima l foods) 
 disorders of terminal ileum (site of absorption): Crohn's, blind-loop etc 
 Atrophic gastritis (affect10% –30% of older adults)  Ļ HCL   Ļ absorption of vit B12.

 Ļ HCL  Ĺ growth of normal intestinal bacteria that use vitamin B12  Ļ  vit B12  
 They are unable to absorb the vitamin B12 that is naturally present in food. howe ver, 
they can absorb the synthetic vitamin B12. 
 metformin  (rare) 
 Chronic metformin use results in vitamin B12 deficiency in 30% of patients. 
 macrocytic anaemia 
 sore tongue and mouth 
 neurological symptoms: e.g. Ataxia

 neurological symptoms: e.g. Ataxia 
 include paresthesias, peripheral neuropathy, and demyelination of the corticospina l tract 
and dorsal columns (subacute combined systems disease).  
 The neurological symptoms can occur without anemia 
  psychiatric disorders symptoms: including impaired memory, irritability, depression, deme ntia 
and, rarely, psychosis 
 cardiovascular effect: 
 Similar to folic acid deficiency, vitamin B 12 deficiency produces hyperhomocysteinemia,

which is an independent risk factor for atherosclerotic disease.  
 Serum high concentrations of homocysteine and low levels of folic acid and vitamin 
B12 are significantly correlated with the categories of coronary artery diseases  
investigations 
 Serum cobalamin levels are the initial test 
  A normal serum cobalamin level does not exclude cobalamin deficiency. 
 Diagnosis of vitamin B 12 deficiency is typically based on measurement of serum vitamin

B12 levels; however, about 50 percent of patients with subclinical disease have normal 
B12 levels.  
 A more sensitive method of screening for vitamin B 12 deficiency is measurement of 
serum methylmalonic acid and homocysteine levels, which are increased early in 
vitamin B 12deficiency.  
 elevated methylmalonic acid level is more specific for vitamin B 12 deficiency than 
an elevated homocysteine level.

an elevated homocysteine level.  
 Vitamin B 12 or folic acid deficiency can cause the homocysteine level to rise, so folic 
acid levels also should be checked in patients with isolated hyperhomocysteinemia.  
 two enzymatic reactions are known to be dependent on vitamin B 12. 
1.  methylmalonic acid is converted to succinyl-CoA using vitamin B 12 as a cofactor. 
Vitamin B 12 deficiency, therefore, can lead to  increased levels of serum 
methylmalonic acid.

methylmalonic acid.  
2. homocysteine is converted to methionine by using vitamin B 12 and folic acid as 
cofactors. In this reaction, a deficiency of vitamin B 12 or folic acid may lead to 
increased homocysteine levels.  1538

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  29 
 if no neurological involvement 1 mg of IM hydroxocobalamin 3 times each wee k for 2 weeks, 
then once every 3 months 
 oral vitamin B 12 has been shown to have an efficacy equal to that of injections  in 
the treatment of pernicious anemia and other B 12 deficiency states.

 Although the daily requirement of vitamin B 12 is approximately 2 mcg, the initial 
oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg.  
 This high dose is required because of the variable absorption of oral vitamin 
B12 in doses of 500 mcg or less. 
 This regimen has been shown to be safe, cost-effective, and well tolerated by  
patients. 
 if a patient is also deficient in folic acid then it is important to treat the B12 deficiency  first to

avoid precipitating subacute combined degeneration of the cord 
 Large amounts of folic acid can mask the damaging effects of vitamin B12 
deficiency  by correcting the megaloblastic anemia caused by vitamin B12 deficiency 
without correcting the neurological damage that also occurs 
 
Schedule for Vitamin B 12 Therapy 
ROUTE OF 
ADMINISTRATION  INITIAL DOSAGE  MAINTENANCE DOSAGE  
Oral 1,000 to 2,000 mcg per day for one to two weeks 1,000 mcg per day for life

Intramuscular 100 to 1,000 mcg every day or every other day for 
one to two weeks 100 to 1,000 mcg every one to 
three months 
 
Sep 2017 part 1:  Which structure in the body are able to synthesize vitamin B12? 
  gut bacteria   
 It is synthesized by gut bacteria in humans, but humans cannot absorb the 
B12 made in their guts, as it is made in the colon which is too far from the small 
intestine, where absorption of B 12 occurs 
 Therefore  diet is the only source of vit B12.

Vitamin B1 (Thiamine) deficiency  
 the biologically active form of this vitamin is thiamine pyrophosphate  (TPP)  
 Thiamine function 
 the most important biochemical reactions requiring the availability of thiamine includes  
 glycolysis and  
 tricarboxylic acid (TCA) cycle.   
 There are three enzymes that require the presence of thiamine pyrophosphat e as a co-
factor:

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  30 
 2. branched chain amino acid dehydrogenase , and  
3. pyruvate dehydrogenase . 
 Causes of thiamine deficiency 
 chronic alcoholism due to inadequate dietary intake or impaired absorption 
 diet mainly composed of polished rice (non-enriched rice) 
 mainly by history

 mainly by history  
 can be made by measuring increased transketolase activity after thiamine 
administration  
 mechanism 
 thiamine is a cofactor necessary for the function of transketolase 
 Wernicke's encephalopathy 
 Wernicke's encephalopathy is a result of thiamine deficiency.  
 Most cases occur in those with a history of chronic alcohol ingestion however 
malnutrition of any cause is a risk factor.  
 The classic triad of features is

 The classic triad of features is 
1. Encephalopathy 
2. Ataxia and 
3. Oculomotor dysfunction ((usually nystagmus but also lateral rectus palsies 
or conjugate gaze palsies  (ophthalmoplegia) ). 
 Korsakoff's psychosis  
 Korsakoff's psychosis is a chronic condition resulting from untreated thiamine 
 characterised by: 
 both anterograde and retrograde amnesia with confabulation. 
 psychosis,  
 mammillary body hemorrhage 
 Beriberi: can be divided into  
 wet beriberi

 wet beriberi 
 high-output cardiac failure ( dilated cardiomyopathy ) 
 edema 
 dry beriberi 
 resulting in symmetrical peripheral neuropathy  due to demyelination 
 symmetrical muscle wasting  
 no fluid retention 
 
 1540

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  31 
  
What happens if you do not give the thiamine first before starting an intravenous glucose 
infusion? 
 ATP failing to be adequately generated,  
 The inability of pyruvate to enter the TCA cycle causes the cell to convert the py ruvate to

lactate (or lactic acid) in order to be able to maintain glycolysis. 
 pyruvate is accumulating   Ĺacidosis.  
 The reason the cell converts pyruvate to lactate is to regenerate the NAD+ 
required for the process of glycolysis to continue and to generate a net balance 
of at least 2 ATP. 
 inability of the pentose phosphate pathway to protect the cell from reactive oxygen 
species  that damage cellular structures, results in either cell death or activation of 
apoptosis .

apoptosis .  
 
Vitamin function as a co-factors: 
 Biotin for carboxylase reactions.  
 Thiamine for dehydrogenase reactions  
 B9 (folate) for transferases.  
 Vit C for hydroxylases.  
 
Vitamin E 
 Forms and Sources of Vit E: 
1. Ȗ-tocopherol:  
 the most common form. 
 found in corn oil, soybean oil, margarine, and dressings.  
2. α-tocopherol:

2. α-tocopherol: 
 the most biologically active form of vitamin E, 
 the second-most common form of vitamin E in the diet.  
 found  in wheat germ oil, sunflower, and safflower oils 
 The nutritional content of vitamin E is defined by α -tocopherol activity.  
 consumption of more than 1,000 mg (1,500 IU) of tocopherols per day may 
cause hypervitaminosis E,   interfere with vitamin K metabolism   vitamin K deficiency 
  increased tendency to bleed. 
 Function:

 Function:  
 lipid-soluble antioxidant in the glutathione peroxidase pathway  removes the free 
radical intermediates   protects cell membranes from oxidation by reacting with lipid 
radicals produced in the lipid peroxidation chain reaction.  1541

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  32 
Vitamin K Deficiency  
 Disruption of all vitamin K-dependent factors 
 II, VII, IX, X, protein C, protein S 
 See Vitamin  topic     
 Deficiency most commonly seen in 
 newborns

 newborns 
 lack gut colonization by bacteria that produce vitamin K 
 newborns are given IM vitamin K shot at birth for prophylaxis 
 malabsorptive conditions 
 long-term antibiotic therapy 
 kills gut bacteria that produce vitamin K 
 Symptoms  
 bleeding  
 Labs  
 ↑ PTT, PT 
 normal bleeding time 
 Administer vitamin K 
 
 1542

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  33 
Vitamin deficiency 
The table below summarises vitamin deficiency states 
Vitamin Chemical name Deficiency state 
A Retinoids Night-blindness (nyctalopia). dry skin. 
B1 Thiamine Beriberi 
 polyneuropathy, Wernicke-Korsakoff syndrome

 polyneuropathy, Wernicke-Korsakoff syndrome 
 heart failure (dilated cardiomyopath) 
B2  (riboﬂavin)  Angular stomatitis, cheilosis, corneal vascularization 
B3 Niacin Pellagra 
 dermatitis 
 dementia 
B6 Pyridoxine Anaemia, irritability, seizures 
B7 Biotin Dermatitis, seborrhoea 
B9 Folic acid Megaloblastic anaemia, deficiency during pregnancy - neural tube defects 
B12 Cyanocobalamin Megaloblastic anaemia, peripheral neuropathy 
C Ascorbic acid Scurvy 
 gingivitis

 gingivitis 
 bleeding 
 poor wound healing  
D Ergocalciferol, 
cholecalciferol Rickets, osteomalacia 
E Tocopherol, tocotrienol ↑ fragility of RBCs. Mild haemolytic anaemia in newborn infants, ataxia, 
peripheral neuropathy 
K Naphthoquinone Haemorrhagic disease of the newborn, bleeding diathesis 
Selenium Selenium Keshan disease (cardiomyopathy). 
 
 1543

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  34 
Vitamin A 
 Which substances in vitamin A is most likely to be maximally involved in correcting the 
visual disturbance? 
 Retinaldehyde  
 
 Retinaldehyde is derived from the oxidation of retinol

 light causes retinaldehyde to change to its trans isomer, and this leads to 
changes in membrane potentials that are transmitted to the brain 
 Retinol and retinoic acid are involved in the control of cell proliferation and 
differentiation 
 Retinyl phosphate is a cofactor in the synthesis of most glycoproteins containing 
mannose 
 What would you give the patient who taking long term steroids to help his wound heal 
faster? 
 Vitamin A

faster? 
 Vitamin A  
 
 Vitamin A is believed to counteract the effect of steroids on slowing wound 
healing by stimulating TGF-beta and IGF-I, as well as collagen production.  
 However, high levels (which can accumulate because vitamin A is fat soluble) 
can also be toxic and inhibit collagen synthesis, such as in the skin. 
 β-Carotene is the main carotenoid found in green vegetables, carrots and other yellow  and red 
fruits

fruits 
 Its conversion to retinol in humans is inefficient - 6 mg of beta-carotene is equiv alent to 1 mg of 
preformed retinol  
Zinc deficiency  
Features 
 perioral dermatitis : red, crusted lesions 
  (rough and dry skin) 
 acrodermatitis 
 alopecia 
 short stature (dwarfism) 
 hypogonadism 
 geophagia (ingesting clay/soil) 
 cognitive impairment

 cognitive impairment 
Zn supplementation has been shown to improve neuropsychological function in Chinese children. 
Zn deficiency is associated with adverse pregnancy outcomes. 
 1544

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  35 
 ____________________________ ________________________________
Pyruvate kinase 
 Pyruvate kinase is the rate-limiting step in glycolysis  and gluconeogenesis 
 It catalyses the transfer of a phosphate group from phosphoenolpyruvate t o ADP, yielding a 
molecule of pyruvate and a molecule of ATP

molecule of pyruvate and a molecule of ATP 
 Deficient pyruvate kinase activity may result in the development of hereditary 
haemolytic anaemias 
 
Which biochemical processes is likely to contribute most to energy creati on in long distance running? 
 Fatty acid oxidation  
 
Daily requirement 
• daily intake  of calories   
 for a man  10,500kJ (2,500kcal) a day .  
 for a woman  8,400kJ (2,000kcal) a day.

 for a woman  8,400kJ (2,000kcal) a day.  
 These values can vary depending on age, metabolism and levels of physical activity, 
among other things.  
• Normal daily fluid and electrolyte  requirements (nice):  
 25 –30 ml/kg/d water  
 1 mmol/kg/day sodium, potassium, chloride  
 50 –100 g/day glucose (e.g. glucose 5% contains 5 g/100ml). 
• FDA state that  In general, Americans should limit daily sodium consumption to 2,300

milligrams, but this is an upper safe limit, not a recommended daily allowance. Even active  
people who lose lots of sodium through sweating require no more than 1,500 milligrams of 
sodium per day.  
 
Essential amino acids  
Humans can synthesise 11 of the basic set of 20 amino acids. The rest m ust be obtained from the diet: 
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, thre onine, tryptophan and valine are 
therefore known as ͚essential ͛ amino acids.

therefore known as ͚essential ͛ amino acids. 
Carnitine  
 Carnitine is a naturally occurring hydrophilic amino acid derivative,  
 produced endogenously in the kidneys and liver and derived from meat and  dairy products in 
the diet.  
 Function 
 transfer of long-chain fatty acids into the mitochondria for beta-oxidation.  
 Carnitine binds acyl residues and helps in their elimination.

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  36 
  Primary carnitine deficiency  is caused by a deficiency in the plasma membrane 
carnitine transporter, with urinary carnitine wasting causing systemic carnitine 
depletion.  
 intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the

mitochondrial matrix. Consequently, long-chain fatty acids are not available for beta-
oxidation and energy production, and the production of ketone bodies (which are used  
by the brain) is also impaired. 
 The 3 areas of involvement include: 
1. the cardiac muscle, which is affected by progressive cardiomyopathy (by far, the 
most common form of presentation), 
2. the CNS, which is affected by encephalopathy caused by hypoketotic 
hypoglycemia,

hypoglycemia,  
3. the skeletal muscle, which is affected by myopathy. 
 Feature 
 hypoketotic hypoglycemic encephalopathy, accompanied by  
 hepatomegaly, elevated liver transaminases, and hyperammonemia. 
 Cardiomyopathy  
 secondary carnitine deficiency: caused by:  
 other metabolic disorders (eg, fatty acid oxidation disorders, organic acidemias),  
 secondary to the formation of acylcarnitine adducts and the inhibition of carnitine

transport in renal cells by acylcarnitines.  
  drugs associated with secondary carnitine deficiency (eg, valproate , pivampicillin, 
emetine, zidovudine).  
 Valproic acid  secondary carnitine deficiency by directly impairing renal tubular 
reabsorption of carnitine.  
 Zidovudine   ↓carnitine uptake in muscle   ↓muscle carnitine levels  
Muscle mitochondrial impairment. 
Carnitine deficiency will cause significant impairment of B-oxidation

why hypoglycemia? --> because B-oxidation provides energy for gluconeogenesis in the liver. 
why hypoketosis? --> because the primary source of ketone bodies is acetyl CoA from B-oxidation.  
 
 Deferential diagnosis 
 A good way to differentiate between Myophosphorylase deficiency (McArdle) 
and Carnitine deficiency, is by remembering that in McArdle you have difficulty in the 
beginning of the exercise  while in myopathic carnitine acyl transferase deficiency

you have a problem after a prolonged exercise. 
 The explanation for this is that glycogen is utilized first by muscles as a source of 
energy so in McArdle (Muslce glycogen phosphorylase deficiency) you have a problem 
in the beginning and patients will have muscle cramps after few seconds of starting the 
exercise. However once the beta oxidation kicks in they will experience the classical 
"second wind". 
 While in Muslce carnitine deficiency you have a problem later on when Fatty acids

oxidation is needed. 
 Both conditions may have myoglobinuria 1546

Notes & Notes  for MRCP                                                                                                    By Dr. Yousif Abdallah Hamad  37 
  In muscle carnitine you'll see accumulated triglycerides in biopsy while in McArdle (also 
called Type V glycogen storage disease) you will have accumulated glycogen in muscle 
biopsy. 
Acid maltase deficiency

Acid maltase deficiency 
 typically presents with insidious onset of proximal myopathy and early respiratory muscle 
weakness.  
 Respiratory failure in inflammatory myopathies (polymyositis, dermatomyositis, inclusion body 
myositis) and limb girdle muscular dystrophy are rare.  
 Muscle biopsy shows vacuolation in muscle fibres. 
 
 1547

Basics - Immunology 
 
Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  1 
  
By
 
Immunology 
 
Updated 
 
2017
 
Contains: 
 
 1548

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  2 
 human leukocyte antigen (HLA) associations 
 The human leucocyte antigen (HLA) system is the name given to the major histo compatibility complex 
(MHC) in humans.  
 HLA antigens are encoded for by genes on short arm of chromosome 6.  
 HLA A, B and C are class I antigens whilst DP, DQ, DR are class II antige ns.

 Class-I molecules (subtypes A, B and C) are expressed on all cell types except erythrocytes and 
trophoblasts  
 They interact with CD8-positive T-cells and are involved in driving cytotoxic r eactions 
  Class II matching is particularly important when it comes to transplant matching, 
 Studies in renal transplantation indicate that mismatches at the A, B, and DR loci  are associated with 
worse allograft survival.

worse allograft survival. 
 when HLA matching for a renal transplant the relative importance of the HLA antige ns are as 
follows  DR > B > A 
 Anti-HLA antibodies are typically not naturally occurring, only occur post tran splantation 
 MHC class II is only expressed on immune cells. MHC I is expressed on any cell type. 
The golden notes: 
HLA (MHC): 
 Found on chromosome  6 
 2 classes: 
 Class I  HLA  A , B, C 
 expressed on all cells, except erythrocytes and trophoblasts

 interact with CD8+ 
 class II  HLA DP, DQ, DR 
 expressed on B cells, dendritic cells, and monocytes 
 most important in transplant  (DR)  
 
 1549

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  3 
 The most important HLA associations are listed below : 
 HLA type 
Hemochromatosis  HLA- A3 
Behcet's disease HLA B51 is a split of B5 HLA- B5 
21-hydroxylase deficiency  HLA- B47 
Psoriasis HLA-CW6 
Diabetes mellitus type 1(but more with HLA-DR4)  
 HLA- DR3 + DR4 combined

HLA- DR3 + DR4 combined  
steroid-responsive nephrotic syndrome HLA- DR7  
Goodpasture's  
 hay fever,  
systemic lupus erythematosus,  
multiple sclerosis.  HLA- DR2 
Felty's syndrome  (90% )  => most common 
 Rheumatoid arthritis (70%)  
Diabetes mellitus type 1 (> DR3)  
Drug-induced SLE 
HOCM  HLA- DR4 
Ankylosing spondylitis  
Postgonococcal arthritis  
Reiter's syndrome (reactive arthritis) 
Acute anterior uveitis  HLA- B27 
Autoimmune hepatitis

Primary biliary cirrhosis    
Coeliac disease (95% associated with HLA-DQ2)  
Diabetes mellitus type 1  
Primary Sjögren syndrome  
Dermatitis herpetiformis  HLA- DR3 
 
HLA-A3101  
 Toxic epidermal necrolysis and Stevens –Johnson syndrome  are associated with HLA-A3101 in 
patients of Japanese and European descent.  
 In patients who develop SJS on carbamazepine , A3101 HLA type should be suspected. 
HLA-B1502

HLA-B1502  
 HLA-B1502 is strongly associated with the development of SJS in patients of H an Chinese and Thai 
ethnic origin. 
 
________________________________________________________________________________________  1550

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  4 
 Clusters of differentiation 
Function and usage of CDs : 
 Commonly used as cell markers in immuno-phenotyping , allowing cells to be defined based on what 
molecules are present on their surface. 
 often acting as  receptors  or ligands (the molecule that activates a receptor)

 cell signaling:  Errors in cellular information processing are responsible for diseases such 
as cancer, autoimmunity, and  DM 
 Cell adhesion :  essential for the pathogenesis of infectious organisms. Eg:  
 Plasmodium falciparum  uses adhesion molecules to bind to liver cells and RBCs.  
 Cancer metastases by mechanisms of cell adhesion.  
 Adhesion of bacteria is the first step in colonization and regulates  tropism  (tissue- or cell-specific 
interactions).

interactions).  
 Pemphigus  is the result of auto-antibodies which target desmosomal cadherins , resulting in loss of 
cell adhesion. 
 viruses also have adhesion molecules required for viral binding to host cells. For example:  
  influenza virus has a hemagglutinnin on its surface that is required for recog nition of the sugar 
sialic acid on host cell surface molecules.  
 HIV has an adhesion molecule termed gp120  that binds to its ligand CD4, which is expressed on 
lymphocyte .

lymphocyte . 
 
Leukocyte adhesion deficiency-1 (LAD- 1) is an example of genetic  diseases caused by an inability 
to express a specific adhesion molecule ( β2-integrin subunit precursor).This integrin is required 
for leukocytes to adhere to the blood vessel wall during inflammation  in order to fight infection. The 
leukocytes from LAD-I patients fail to adhere and patients exhibit serious infections. 
  
 1551

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  5 
  
The table below lists the major clusters of differentiation (CD) molecul es 
Cluster of 
differentiation Function 
CD1 MHC molecule that presents lipid molecules 
CD2 Found on thymocytes, T cells, and some natural killer cells that acts as a ligand for

CD58 and CD59 and is involved in signal transduction and cell adhesion 
CD3 The signalling component of the T cell receptor (TCR) complex 
CD4  Found on helper T cells.  
Co-receptor for MHC class II  
Used by HIV to enter T cells  
CD5 Found in the majority of mantle cell lymphomas 
CD8  Found on cytotoxic T cells. 
Co-receptor for MHC class I  
Found on a subset of myeloid dendritic cells 
CD14 Cell surface marker for macrophages 
CD15 Expressed on Reed-Sternberg cells (along with CD30)

CD28 Interacts with B7 on antigen presenting cell as costimulation signal 
CD95 Acts as the FAS receptor, involved in apoptosis 
 
The number of CD4 and CD8 T cells in blood is often used to monitor the progression of HIV  
infection . 
CD4: 
 encoded by a gene on chromosome 12 . 
 They are helper cells  send signals to other immune cells, including CD8 killer cells, which then 
destroy the infectious particle.

destroy the infectious particle.  
  If CD4 cells become depleted, (eg: HIV, immunosuppressive)  ↑ vulnerable to infections  
 .GP 41 , GP 120 fuses to CD4  receptor , this allow GP41 to penetrate  the cell membrane  (GP41 is 
the HIV peptide which play a role in initial step for HIV entry to the cells   ) (Jan 2015 exam)  
 CD4 uses its D 1 domain to interact with the ȕ 2-domain of MHC class II  molecules  
 Normal values for CD4 cells being 500-1200 cells/mm3

 The newest National Institute of Health guidelines recommend  treatment of any HIV-positive 
individuals, regardless of CD4 count.   
 PCP, disseminated fungal disease, and CMV infection almost always occur when the C D4 counts are 
very  low, usually below 200 cells/mm3. 1552

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  6 
  CD4 continues to be expressed in most neoplasm derived from T-helper cells. It is t herefore possible to 
use CD4 immunohistochemistry on tissue biopsy samples to identify most forms of peripheral T 
cell lymphoma and related malignant conditions. The antigen has also been associated with a number

of autommune diseases such as vitiligo and type I diabetes mellitus  
CD8: 
 encoded by genes on chromosome 2  
 CD8 is specific for the class I MHC protein  
 CD8+ T lymphocytes are otherwise known as cytotoxic T lymphocytes. 
 The T cell receptor on the surface of the CD8+ T cell recognises virus peptides in the  context of self 
HLA class I  molecules on the surface of virus infected antigen presenting cells. The infected cell is 
then lysed.

then lysed. 
 The CD8 co-receptor is predominantly expressed on the surface of cytotoxic T class cytotoxic T 
cells, but can also be found on natural killer cells, cortical thymocytes, and dendri tic cells.  
 
Clusters of differentiation 
 CD4   
 Found on helper T cells.  
 Co-receptor for MHC class II 
 Used by HIV to enter T cells 
 GP120  fuses to CD4  allow GP41 to 
penetrate the cell membrane  
 CD 8   
 Found on cytotoxic T cells.

 CD 8   
 Found on cytotoxic T cells. 
 Co-receptor for MHC class I  
 Found on a subset of myeloid dendritic cells  
 CD14  Cell surface marker for macrophages 
 CD18  the absence of it causes Leukocyte adhesion 
___________________________ __________________________________________ 
Complement pathways  
 Activation may occur via three pathways: 
1. Classical pathway :  
 Triggered by antigen-antibody complexes containing lgM or lgG.

 IgG and IgM are the main antibody classes that activate the classical pathway 
1553

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  7 
  C1 is the initiating protein, and after binding to an Fc is able to activate C4 and C2, 
which in turn activate multiple C3 molecules. 
 C1q binds to the Fc (Fc, crystallisable Fragment) 
 C2 is involved in activation via the classical pathway 
2. Alternative pathway :

2. Alternative pathway : 
 Initiated by certain antigens (lipopolysaccharide, endotoxin) and lgA complexes on cell 
surfaces which activate C3. 
 the alternative , (not the classical ) C3, convertase enzyme involves  C3b  
 Generates early innate response that does not require antibody for activation. 
3. Lectin pathway  :Mannose-binding lectin (MBL)  : lectin proteins bind to carbohydrates 
present on bacteria. This indirectly activates the next complement components. C2 and C 4.

A child has recurrent pyogenic infection. What is the most likely diagnosis ? 
 Mannose binding lectin deficiency  
 Mannose-binding lectin (MBL) (an acute phase protein secreted by the liver) 
 MBL deficiency is thought to be the most common complement deficiencies 
 low MBL result from mutations in MBL2 gene (3 - 5 % of population. Heterozygosity in 30 % 
of population). 
 deficiency of MBL is associated with:

 deficiency of MBL is associated with:  
 ↑pyogenic infections, especially encapsulated bacteria, due to defective o psonization.  
 ↑severity of chronic inflammatory conditions.  1554

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  8 
  
1555

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  9 
  
 All complement pathways have one final common pathway at C3.  
Complement inhibitor  
membrane bound complement inhibitor 
 CD59  
 complement receptor 1  
 decay accelerating factor 
 membrane cofactor protein.

 membrane cofactor protein. 
soluble complement inhibitors 
 factor H 
 C4 binding protein 
 C1 inhibitor 
 factor I 
 
1556

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  10 
 Hypersensitivity 
The Gell and Coombs classification divides hypersensitivity traditionally divi des reactions into 4 types: 
 
Type Mechanism Examples 
Type I - Anaphylactic  Antigen reacts with IgE 
bound to mast cells 
(IgE-mediated  ) • Anaphylaxis  
• Atopy (e.g. asthma, eczema and hayfever)

• Atopy (e.g. asthma, eczema and hayfever) 
Diagnosed by plasma tryptase  (protease released from 
mast cell).  
Type II - Cell bound  IgG or IgM binds to 
antigen on cell surface 
(antibody-mediated )   • Autoimmune haemolytic anaemia  
• ITP  
• Goodpasture's syndrome  
• Pernicious anaemia  
• Acute haemolytic transfusion reactions 
• Rheumatic fever  
• Pemphigus vulgaris / bullous pemphigoid  
Type III - Immune 
complex  Free antigen and 
antibody (IgG, IgA) 
combine 
(Immune  complex

combine 
(Immune  complex 
deposition ) • Serum sickness  
• Systemic lupus erythematosus  
• Post-streptococcal glomerulonephritis 
• Extrinsic allergic alveolitis (especially acute phase ) 
Type IV - Delayed 
hypersensitivity  T-cell mediated 
(cell-mediated  ) • Tuberculosis / tuberculin skin reaction  
• Graft versus host disease  
• Allergic contact dermatitis 
• Scabies  
• Extrinsic allergic alveolitis (especially chronic phase ) 
• Multiple sclerosis

• Multiple sclerosis  
• Guillain -Barre syndrome 
 
In recent times a further category has been added: 
Type  V Antibodies that recognise and bind to the cell surface receptors.  
This either stimulating them or blocking ligand binding • Graves' disease 
• Myasthenia gravis 
  
What is the hallmark signs of mast cell degranulation? 
 Classical wheal and flare  
 1557

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  11 
  
Anaphylaxis 
 
 Anaphylaxis may be defined as a severe, life-threatening, generalised or systemic hyper sensitivity 
reaction. 
 caused by type I hypersensitivity.

reaction. 
 caused by type I hypersensitivity. 
 Immunoglobulin E is the most common immunoglobulin involved in the pathogenesis 
of anaphylaxis. 
 mediated by histamine 1 receptor stimulation. 
 antigen production of IgE  initiates events  
 can be associated with leukotrienes B4, C4, D4 and E4 
  (B4, C4, D4 )are the mediators that make up the slow-reacting substance of an aphylaxis (SRSA) 
 Usually takes 15-30 minutes from the time of exposure to the antigen.

 Flushing, warmth and tingling are typical initial symptoms 
 At least 50% of fatalities are due to respiratory complications, and more th an 20% of patients will have 
a second episode within 8 hours 
 Mediators involved in the development of anaphylaxis  include:  
 histamine, leukotrienes, prostaglandins and platelet aggregating factor, which are generated by 
mast cell degranulation.  
 Additional factors include:  
 Tryptase  Chimase  Heparin 
 Chondroitin 
sulphate  IL4  IL13.

sulphate  IL4  IL13. 
 
 IL4 and IL13 are thought to be important in driving the onward cascade of  inflammation to other 
immune system cells and contribute to the severity of anaphylaxis. 
 Th2 CD4 positive lymphocytes are involved in the pathogenesis of anaphylaxis, via the  
production of IL-4/IL-13 that act on B cells to increase IgE production and precipitate the  
development of acute hypersensitivity.

development of acute hypersensitivity. 
 IL-4 also exacerbates anaphylaxis by acting synergistically with other vasoactive 
mediators to increase vascular permeability.  
 
Causes 
1558

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  12 
 Common identified causes of anaphylaxis.  
Mast cell mediator release can be triggered by both IgE and non-IgE-mediated factor s. Therefore, anaphylaxis 
may be termed anaphylaxis (IgE mediated) or anaphylactoid (non --IgE mediated). 
1. anaphylaxis (IgE mediated) :

1. anaphylaxis (IgE mediated) :  
 food (e.g. Nuts) - the most common cause in children 
 drugs 
 The most common IgE-mediated triggers are drugs, typically penicillin or other  beta-
lactam antibiotics .  
 Neuromuscular blocking agents (eg  vecuronium) are responsible for 60-70% of 
allergic reactions related to anaesthesia.  The antigen responsible is thought to be the 
quaternary ammonium group that is found in other drugs, foods, cosmetics and hair 
products 
 venom (e.g. Wasp sting)

products 
 venom (e.g. Wasp sting) 
2. Anaphylactoid (non --IgE mediated).  
 Anaphylactoid reactions are defined as those reactions that produce the same clinical picture  
as anaphylaxis but are not IgE mediated .’ 
 Non-IgE-mediated causes include : plasma proteins or compounds, which act directly on the 
mast cell membrane, such as  
 vancomycin,  
 quinolone antibiotics,  
 aspirin or other non-steroidal anti-inflammatory drugs  
 opiates, 
 radiographic contrast media

 opiates, 
 radiographic contrast media  
 
Anaphylaxis following a blood transfusion can be due to immunoglobulin A def iciency.  
 
anaphylaxis  VS Anaphylactoid   
Is it anaphylactic OR anaphylactoid reaction? 
 Anaphylactic 
(IgE-mediated anaphylactic 
reactions ) Anaphylactoid 
(Non IgE-mediated 
anaphylactic reactions ) 
 
Is sensitization required? Yes No 
Can reaction occur in first 
exposure?  No Yes 
How much exposure is needed to

How much exposure is needed to 
elicit reaction?  very little (dose independent)  usually more than for 
anaphylaxis  
Is reaction predicted by skin 
allergy test?  Yes No 
 
Triggers for anaphylactic reactions  
 heat, cold,  1559

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  13 
  sexual activity.  
 Anaphylaxis may be exacerbated by exercise  
 
Features 
 The most common presentation of anaphylaxis is due to involvement of the skin . 
 Dermatographism  is a physical examination sign that signifies a type I hypersensitivity

 When the examiner applies pressure to the skin of a patient and writes a wo rd, it 
remains imprinted as erythematous wheals.  
 It occurs when a patient has urticaria, otherwise known as hives. 
 
Dermatographism  
 
 Plasma tryptase  activity is the most likely investigation to confirm the nature of the reaction  
 Tryptase is a mast cell – specific protease  
 Elevated Tryptase imply mast cell degranulation

 The greater the severity of anaphylaxis, the more likely that serum tryptase le vels will be 
elevated.  
 Elevated serum  tryptase  levels demonstrate that mast cell activation with mediator release 
has occurred whether triggered by IgE-mediated anaphylaxis or non-IgE-m ediated 
anaphylactoid reactions.  
 has a half-life of 2 h, peaking at 1 h after anaphylaxis onset and return to baseline by 6 hours.  
 Both sensitivity and specificity to confirm diagnosis is  95%

 Tryptase levels, may be helpful in confirming the diagnosis  of anaphylaxis, but does not 
elucidate the cause.  
 Normal tryptase results do not exclude anaphylaxis  and can be seen in serious reactions. 
  Typically the increase is less marked in non-allergic reactions (non-IgE mediated 
anaphylaxis). 
 skin test  
 skin prick (SPT)  
 usually carried out 4 –6 weeks after a reaction to allow replenishment of histamine in 
mast cell granules. 
1560

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  14 
  Antihistamine drugs must be stopped for 5 days though steroids may be continued .  
 A wheal of >3 mm in diameter than the negative control is considered positiv e and the 
presence of a flare or itching is also significant. 
 intradermal (IDT)

 intradermal (IDT)   
 IDT is indicated if there is clinical suspicion but negative SPT.  
 A 4-mm bleb of diluted solution is injected under the skin and read after 15 min by  
measuring the wheal and flare.  
 IDT is considered positive if the bleb doubles or exceeds 8 mm.  
 IDT are more sensitive but less specific than SPT. 
 Others 
 Total serum IgE level is non-specific and unhelpful.  
 
 Adrenaline  is by far the most important drug in anaphylaxis and should be given as soon as 
possible . The recommended doses for adrenaline, hydrocortisone and chlorphenamine are as follows: 
 
Adrenaline Hydrocortisone Chlorphenamine 
< 6 months  150 micrograms (0.15ml 1 in 1,000) 25 mg 250 micrograms/kg 
6 months - 6 years  150 micrograms (0.15ml 1 in 1,000) 50 mg 2.5 mg 
6-12 years  300 micrograms (0.3ml 1 in 1,000) 100 mg 5 mg 
Adult and child > 12

Adult and child > 12 
years  500 micrograms (0.5ml 1 in 1,000) 200  10 g 
 
 Adrenaline can be repeated every 5 minutes if necessary.  
 The best site for IM injection is the anterolateral aspect of the middle third o f the thigh. 
 It is recommended to observe patients after resolution of an anaphylactic episode for 24 hours for 
possible second -phase reactivation.  
Late-phase reaction 
In IgE mediated reactions such as asthma or anaphylaxis what therapy inhibits t he important late-

phase reaction ? steroids  
 The late phase reaction is due to attraction of T cell, release of leukotri enes and prostaglandins often 
characterised by asthma 
 prevented by the administration of steroids  (Hydrocortisone ). 
 Approximately 30% of deaths related to anaphylaxis occur as a consequence of this late-phase 
reaction  
 
 1561

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  15 
Exercised induced anaphylaxis   
 a rare disorder in which anaphylaxis occurs after physical activity.  
Features  
 usually occur around 10 minutes after exercise and follow a sequence of pruritus, widespread ur ticaria

and then subsequently respiratory distress and vascular collapse.  
 may be related to endorphin release during exercise. The endorphin causes excessive histamine 
release from mast cells in susceptible individuals.  
 Co-factors such as foods, alcohol, temperature, drugs (eg, aspirin and other nonsteroida l anti-
inflammatory drugs), humidity, seasonal changes, and hormonal changes are impor tant in the 
precipitation of attacks.

precipitation of attacks.  
 most associated with wheat ingestion.  
 The foods most commonly implicated in food-dependent exercise-induced anaphylaxis are whe at, 
shellfish, tomatoes, peanuts, and corn.  
 The patients can usually eat the causative food without problems so long as they  do not exercise 
afterwards.  
Treatment  
 managed in the same manner as anaphylaxis.  
 usually resolves on stopping exercise

 usually resolves on stopping exercise  
 Reducing physical activity to a lower level may diminish the frequency of attacks. 
 Patients should be instructed on the proper use of emergency injectable epinephrine and hav e one 
available at all times.  
 Patients should wear a medical alert bracelet with instructions on the use of epinephrine . 
Anaphylactic Reactions Associated with Anaesthesia

 Neuromuscular blocking drugs and latex appear to cause anaphylaxis more commonly in female 
patients 
 Individuals with a history of atopy, asthma or allergy to some  foods appear to be at increased risk 
of latex allergy but not anaphylaxis to neuromuscular blocking drugs or antibiotics  
 Anaphylaxis associated with radiographic contrast media  appears to be associated with atopy  
 Patients with asthma or taking b-blocking drugs  may suffer a more severe reaction.

 Neuromuscular blocking agents (NMBAs)  
 60% of cases of anaesthesia-related anaphylaxis are due to neuromuscular blocking 
agents .  
 anaphylactic reactions to neuromuscular blocking agents (NMBAs) is more frequent 
 80% of NMBA reactions occur without prior exposure  
 Quaternary ammonium ions (QAI) are proposed to be the allergenic epitope s in NMBAs. 
 Common environmental chemicals such as toothpastes, washing detergents, shampoos, and

cough medicines  share these allergenic epitopes with the NMBAs , predisposed individual to 
become sensitised to QAIs and thus be at risk of developing anaphylaxis to NMBAs during 
anaesthesia.  
 succinylcholine  is the NMBA most likely  to be associated with allergic anaphylax is 
 Succinylcholine carries the highest risk because of its molecular shape and size.  
 Mivacurium  and atr acurium  are associated with non-allergic anaphylaxis 1562

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  16 
  If clinical suspicion has been raised, all types of NMBAs should be tested  by SPT ± IDT 
because of extensive cross-reactivity.  
 Future anaesthesia if allergic to one NMBA: 
 Rocuronium and vecuronium are contraindicated.

 The negative intradermal testing to atracurium and succinylcholine does not guarantee 
their safety and therefore all relaxants must be avoided because of the incidence of 
cross-reactivity.  
 If future NMBA use is clinically unavoidable , then a relaxant with negative SPT and 
IDT should be used  
 
 Latex hypersensitivity is the second most common cause of anaesthesiarelated anaphylaxis in m any 
studies (up to 20% of cases). But now decreased due to decline in the use of latex gloves.

 Approximately 15% of anaesthesia-related anaphylactic episodes are due to antibiotics . 
 Skin testing is only approximately 60% predictive of clinical hypersensitivity. Penicill ins and  
 cephalosporins which share the b-lactam ring are responsible for approximately 70% of 
antibiotic-induced anaphylaxis. 
 There is a higher rate of antibiotic allergy in smokers, 
 Anaesthetic induction agents  
 Anaphylaxis to propofol  is very uncommon.

 Anaphylaxis to propofol  is very uncommon. 
 Anaphylaxis to thiopental has become extremely uncommon, probably reflecting the decline  in 
its use. 
 Antiseptics and disinfectants  
 Reactions to chlorhexidine  have come into greater prominence in recent years. 
 Anaphylaxis has occurred when chlorhexidine was used as an antiseptic for urological 
and gynaecological procedures as well as insertion of central venous and epidural 
catheters.

catheters.  
 Allowing chlorhexidine to dry before beginning a procedure may reduce the ri sk of 
reaction. 
 Anaphylaxis to other antiseptics is rare. 
Diagnosis 
 Timings: 
 Type I reactions typically occur within seconds to minutes after i.v. exposure. A n insidious or 
delayed onset may occur (e.g. with latex, antibiotics, and colloids1and a tourniquet may delay 
onset until after surgery). 
 History of atopy and asthma has a clear link with latex allergy.

Ref: Association of Anaesthetists of Great Britain and Ireland GUIDELINES 2009 
https://www.aagbi.org/sites/default/files/anaphylaxis_2009_0.pdf  
Allergy 
 Birch-associated oral allergy syndrome  
  occurs with stoned fruits, apples, carrots and potatoes 
 However, this only happens with the raw form as cooking denatures the allergen

 The birch-tree pollen season is usually in April/May, giving the typical rhi nitis symptoms 
 Latex allergy  can be associated with certain foods such as bananas, avocado, kiwi and melon, but 
this allergen is heat-stable  
 Most apples contain a considerable amount of salicylate, which can induce urticaria in aspirin-sensit ive 
individuals; however, this is not usually associated with pharyngeal itching

 Allergic contact dermatitis  is caused by a type 4 delayed hypersensitivity reaction to a chemical in  
contact with the skin 1563

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  17 
  Initial sensitisation can occur 7-10 days after first contact with a potent all ergen 
 However, it is more usually a consequence of many months or years of exposure to s mall amounts of 
the allergen 
 Once sensitised, contact with the allergen can produce dermatitis within 24-48 h, and all areas of the

body are equally susceptib le 
 Urticaria is a common condition and usually responds very well to  systemic antihistamines which are 
the correct first line treatment. Oral steroids can be given for severe cases but only as a last resort. 
 Blood testing including allergy screening is not routinely recommended in the man agement of urticaria, 
which may occur as part of an allergic or non-allergic process.

 Cetirizine may have greater pharmacodynamic effect in certain individuals than desloratidin e. 
Allergy tests 
Skin prick test  Most commonly used test as an easy to perform and inexpensive. 
 the first line for detection of allergen-specific IgE 
  Drops of diluted allergen are placed on the skin after which the 
skin is pierced using a needle.  
 A large number of allergens can be tested in one session.

  Normally includes a histamine (positive) and sterile water 
(negative) control.  
 A wheal will typically develop if a patient has an allergy. 
 Can be interpreted after 15 minutes 
 Useful for food allergies and also pollen 
 It can induce anaphylaxis, and must therefore be done in an 
environment where resuscitation facilities are available. 
Radioallergosorbent 
test (RAST)   Determines the amount of IgE that reacts specifically with suspected or

known allergens, for example IgE to egg protein. 
  Results are given in grades from 0 (negative) to 6 (strongly positive)  
 Useful for food allergies, inhaled allergens (e.g. Pollen) and wasp/bee 
venom 
 Blood tests may be  used when skin prick tests are not suitable, for 
example if there is extensive eczema or if the patient is taking 
antihistamines  
Skin patch testing   Useful for contact dermatitis . 
  Around 30-40 allergens are placed on the back.

 Irritants may also be tested for.  
 The patches are removed 48 hours  later  with the results being read 
by a dermatologist after a further 48 hours 
 
If a history of anaphylaxis is given it would not be appropriate to perform a ski n prick test, thus 
Radioallergosorbent test (RAST) is the most appropriate first-line test to inv estigate the cause of the 
reaction  
Reasons for a false negative RAST test:

Reasons for a false negative RAST test: 
 Immediately following anaphylaxis / allergic reaction (transient drop in I gE) 1564

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  18 
  Waning of allergen-specific IgE with time following a reaction. 
 Unstable allergens in the RAST substrates (especially food allergens) 
Latex allergy

Latex allergy 
 Nearly 1 in 5 anaphylactic reactions may be due to latex allergy,  (more common than peanuts allergy) 
 NHS trusts in the UK have moved away from the routine use of latex gloves precisely because of the 
risk of allergy. As a result, latex allergy in hospital is now very rare in the UK.   
 it is very unlikely that a latex allergy would explain an anaphylaxi s during anaesthetic induction

(latex allergies typically used to commence when a surgeon began handling internal organ s). 
 Sensitivity to latex may cause a number of problems: 
 type I hypersensitivity (anaphylaxis) 
 type IV hypersensitivity (allergic contact dermatitis) 
 irritant contact dermatitis 
 Latex allergy is more common in children with myelomeningocele spina bifida. 
 Latex can induce allergy through IgE bound to mast cells

 Morphine, radiocontrast media and colloid plasma expanders induce histamine release via their di rect 
effects on mast cells  
 
Latex-fruit syndrome 
 It is recognised that many people who are allergic to latex are also allergic to f ruits, particularly 
banana , pineapple, avocado, chestnut, kiwi fruit, mango, passion fruit and straw berry.  However, 
bananas are the most commonly associated with latex/rubber allergy

MRCPUK part-1-May 2016 exam: A nurse who is known to have an allergy to latex develops a 
widespread urticarial rash and facial oedema shortly after eating lunch. Which foo d is she most 
likely to have consumed?  Banana  
Peanut allergy  
 The sensitivity of a negative skin prick test  to foods is high: that is, for all nuts, skin prick tests miss 
only 0.5% of cases, whereas specific IgE will miss 22%

 Less than 20% of individuals will grow out of peanut allergy, but they are usually those in whom the 
reactions are mild and started under 1 year of age 
 The wheal size resulting from the skin prick test is an excellent predictor of a po sitive food 
challenge to peanuts 
  Which feature is the most important predictor of anaphylaxis in  asthmatic patient with peanut 
allergy?  
 Poorly controlled asthma

allergy?  
 Poorly controlled asthma 
 Poorly controlled asthma is an important risk factor for fatal anaphy laxis in this situation. 
 Patients such as this should have their asthma well controlled and have ready access to, 
and knowledge of how to use, self-injectable adrenaline. 
 
 1565

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  19 
Serum Sickness  
 an example of immune complex mediated hypersensitivity.  
 Drugs are the most common cause .  
 Classical features are rash, fever, and polyarthralgias or polyarthritis, which  begin one to two weeks

after first exposure  to the responsible agent.  
 Symptoms resolve quickly upon discontinuation of the offending agent and progno sis is excellent.  
 Treatment is symptomatic. Short courses of steroids are used for severe arthritis. 
Immune system  
 
1566

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  20 
  
Immune system cells: innate immune response   
The following cells are mostly involved in the innate immune response: 
 
Cell type Functions and properties 
Neutrophil Primary phagocytic cell in acute inflammation 
Granules contain myeloperoxidase  and lysozyme   
Most common type of white blood cell

Most common type of white blood cell 
Multi-lobed nucleus 
Basophil Releases histamine during allergic response 
Granules contain histamine  and heparin  
Expresses IgE receptors on the cell surface 
Bi-lobed nucleus 
Mast cell Present in tissues and are similar in function to basophils but derived from different cell 
lines 
Granules contain histamine and heparin 
Eosinophil Defends against protozoan and helminthic infections 
Bi-lobed nucleus

Monocyte Differentiates into macrophages 
Kidney shaped nucleus 
Macrophage Involved in phagocytosis of cellular debris and pathogens 
Acts as an antigen presenting cell 
Major source of IL-1 
Natural killer cell Induce apoptosis in virally infected and tumour cells 
Dendritic cell Acts as an antigen presenting cell , but have no cytotoxic potential. 
 
Which cell type is the most important antigen-presenting cell during sensitisation ? 
 Dendritic cells

 Dendritic cells  
 dendritic cells is a key antigen-presenting cell.  
 After uptake of antigen, it migrates from the site of antigen up take to the regional 
draining lymph node, where it presents processed antigen to T cells, stimulating either 
proliferation of established memory cells or differentiation of naive T cells reactive to the 
antigen presented.  
 1567

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  21 
  
Innate (non-specific system)  Adaptive (acquired system)  
Components  
1. Anatomical and phys iological barriers  
2. Inflammatory response with leakage of  
antibacterial serum proteins (acute-phase 
proteins) and phagocytic cells 
3. Phagocytosis by neutrophils and 

4. Complement system  Components 
1. Cell-mediated response effected by T cells 
2. Humeral immune response effected by B cells  
 
Properties  
1. Rapid: responds within minutes to infection  
 
2. No antigenic specificity, i.e. the same 
molecules and cells respond to  
range of pathogens  
 
3. No memory, i.e. the response does not  
change after repeated exposure exposure 
 
4. Preformed or rapidly formed components  Properties

1. Slow : response over days to weeks 
2. Antigenic specificity i.e. each cell is a 
programmed genetically to respond to a single 
antigen 
3. Immunological memory , i.e. on repeated the 
response is faster, stronger and qualitatively 
different 
4. Diversity: ability to recognize and respond to 
a vast number of different antigens 
 
5. Self/non-self recognition : i.e. lack of respon se 
(tolerance) to self-antigens but response to 
foreign antigens

foreign antigens 
 Macrophages are defined as a lymphocyte that is able to phagocytose debris, toxins, cells or 
pathogens.  
 Most macrophages in the body are tissue macrophages; i.e. they are allocated to specific tissues where 
they will patrol for pathogens, or “house-keep ”, removing cellular debris.  
 Most tissue macrophages are positioned at the most likely entry points for pathog ens. 
 Types

 Types 
 Tissue macrophages are either fixed (i.e. their location is fixed in connect ive tissue) or 
wandering (able to scavenge or move in response to signalling).  
 Fixed macrophages include: 
 Kupffer cells (liver) 
 lining the sinusoids of the liver  
 they account for nearly 90% of the tissue macrophages of the body.  
 Pathogens from the intestine will first travel to the liver via the por tal 
venous system, and consequently, the Kupffer cells are positioned to

engulf bacteria, debris and endotoxins.  
 Microglial cells (CNS) 
 Mesangial cells (kidney) 1568

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  22 
  Osteoclasts 
 Macrophages of the reticuloendothelial system 
 Wandering macrophages include: 
 Macrophages of the serosal cavities (pleura, peritoneum, pericardium) 
 Alveolar macrophages 
_______________________________ _____________________________ 
Immunoglobulins

Immunoglobulins  
 
The table below summarises the characteristics of the 5 types of immunoglobulin fou nd in the body:  
Type Frequency Shape Notes 
IgG 75% Monomer • comprises the majority of circulating antibody in serum    
• the major antibody produced in the secondary  immune response.  
• Enhance pha Gocytosis of bacteria and viruses 
• half-life: 7-23 days  
• Fixes classical complement 
• can bind to NK cells for antibody-dependent cytotoxicity (ADCC).

• the only antibody that can cross the placenta and enter the fetal 
circulation   
• Most abundant isotype in blood serum  
• Gamma is the type of heavy chain found in Ig G. 
IgA 15% Monomer/ 
dimer • Found in secretions such as saliva, tears and mucous  
• made primarily in the mucosal-associated lymphoid tissues (MALT). 
• Provides localized protection on mucous membranes  
• The Fc portion of secretory IgA binds to components of mucous and

contributes to the ability of mucous to trap microbes. 
• Most commonl y produced immunoglobulin in the body (but blood 
serum concentrations lower than IgG) 
• half- life ≈ 5 days  
• Transported across the interior of the cell via transcytosis  
• can activate the alternative complement pathway. (Ig A ≈ Alternate) 
• Low levels of IgA are associated with an increased incidence of 
Coeliac Disease. 
• Alpha is the type of heavy chain found in Ig A.

IgM 10% Pentamer  • First immunoglobulins to be secreted in response to an infection  
(primary response) 
• Fixes classical complement pathway ( most efficient ) 
• Anti -A, B blood antibodies (note how they cannot pass to the fetal 
circulation, which could of course result in haemolysis) 
• Monomeric forms of IgM are found on the surface of B-lymphocytes as 
B-cell receptors or sIg. 
1569

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  23 
 Type Frequency Shape Notes 
• half-life: about 5 days 
• Mu is the type of heavy chain found in Ig M. 
IgD 1% Monomer • Involved in activation of B cells  (as a surface receptor on B cells) 
• may play a role in eliminating B-lymphocytes generating self-reactive 
autoantibodies.

autoantibodies. 
• Delta is the type of heavy chain found in Ig D. 
• Hyper-lgD is associated with periodic fever  (attacks of fever every 4-8 
weeks, with each attack lasting 3-7 days) 
IgE 0.1% Monomer • produced by plasma cells   
• Mediates type 1 hypersensitivity reactions 
• Binds  to Fc receptors found on the surface of mast cells and basophils 
• Provides immunity to parasites such as helminths  
• Least abundant isotype in blood serum  
• half-life of 2 days

• half-life of 2 days 
• IgE may protect external mucosal surfaces by promoting inflammation, 
enabling IgG, complement proteins, and leucocytes to enter the tissues. 
• Cross linking of cell-bound IgE by antigen triggers the release of 
vasodilators for an inflammatory response. 
• The Fc portion of IgE made against parasitic worms and arthropods can 
bind  to eosinophils enabling opsonization. This is a major defense 
against parasitic worms and arthropods.

against parasitic worms and arthropods. 
• Epsilon is the type of heavy chain found in Ig E. 
 
Each day an average adult produces approximately 3gm of antibodies, about two-thirds of this IgA 
 
Acute organ rejection is due to anti-IgG antibodies to the human leukocyte antigen (HLA) 
incompatible tissues with primary activation of T cells. 
 
Rhesus  antibodies are IgG , wherese ABO  antibodies are IgM 
 
Commonly recognized immunoglobulin changes in liver disease

(usually accompanied by a decrease in albumin) are: 
• lgG ↑ in: chronic active hepatitis, cryptogenic cirrhosis 
• lgM ↑ in: 1° biliary cirrhosis, alcoholic cirrhosis 
• lgA  ↑ in: alcoholic cirrhosis. 1570

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  24 
  
Which one of the immunoglobulin structure forms antigen binding site? 
 The variable region of one heavy and one light chain 
 
Complement fixation 
 IgA can fix complement via the alternative  pathway 
 IgG and IgM can fix complement via the classical  pathway through the Fc portion of the 
immunoglobulin

immunoglobulin  
Hyper-IgM syndrome 
 also known as CD40 ligand deficiency 
 an X-linked condition  
 a T-cell defect 
 presenting in a similar way to X-linked agammaglobulinaemia with recurrent sinopul monary disease 
 affected individuals are  susceptible to  
 Pneumocystis jirovecii pneumonia 
 chronic Cryptosporidial  infection, leading to sclerosing cholangitis and liver failure

 increased risk of malignancy, particularly abdominal cancers  
Hypergammaglobulinaemia 
Causes of polyclonal  hypergammaglobulinaemia: 
1. Artefactual, e.g. prolonged venous stasis before venepuncture 
2. Haemoconcentration secondary to dehydration 
3. Chronic infection, e.g. TB, infective endocarditis, leishmaniasis 
4. Autoimmune disease, e.g. SLE, rheumatoid arthritis 
5. Ulcerative colitis and Crohn's disease 
6. Sarcoidosis

6. Sarcoidosis 
7. Hepatic disease. 
 
Causes of monoclonal  hypergammaglobulinaemia 
1. Multiple myeloma, Waldenstrom's macroglobulinaemia and heavy chain diseas e  
2. Leukaemia, lymphoma or carcinoma 
3. Bence Jones proteinuria 
4. 'Benign' paraproteinaemia 
5. Amyloidosis. 
 Immunoglobulins which undergo reversible precipitation at 4 deg C, dissolve when warmed to 37 deg  
C.

C.  
 One third of cases are idiopathic 
 Type I (25%):  
 monoclonal - IgG or IgM 1571

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  25 
  associations: multiple myeloma, Waldenstr om macroglobulinaemia 
 Type II :  (25%):  
 mixed monoclonal and polyclonal: usually with RF 
 associations: hepatitis C, RA, Sjogren's, lymphoma 
 Type III(50%):  
 associations: RA, Sjogren's

Symptoms  (if present in high concentrations)   
 cutaneous: vascular purpura, distal ulceration, ulceration 
Tests 
 high ESR 
Treatment 
Immunoglobulins: therapeutics  
Basics 
 formed from large pool of donors (e.g. 5,000)

 formed from large pool of donors (e.g. 5,000) 
 IgG molecules with a subclass distribution similar to that of normal blood 
 half-life of 3 weeks 
Uses  
 primary and secondary immunodeficiency 
 idiopathic thrombocytopenic purpura 
 Kawasaki disease 
 toxic epidermal necrolysis 
 pneumonitis induced by CMV following transplantation 
 low serum IgG levels following haematopoietic stem cell transplant for malignancy 
 dermatomyositis

 chronic inflammatory demyelinating polyradiculopathy 
Leukotrienes 
 mediators of inflammation and allergic reactions 
Production 
 secreted by leukocytes 
 formed from arachidonic acid by action of lipoxygenase 1572

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  26 
  it is thought that the NSAID induced bronchospasm in asthmatics is secondary t o the express 
production of leukotrienes due to the inhibition of prostaglandin synthetase 
Function 
 cause bronchoconstriction,  
 mucous production ( an important consideration in the pathophysiology of bronchial asthma )

 increase vascular permeability, attract leukocytes 
 leukotriene D4 has been identified as the SRS-A (slow reacting substance of anaphyl axis)  which 
causes bronchial wall and intestinal smooth muscle contraction 
Acute phase proteins 
 CRP  
 procalcitonin 
 ferritin 
 fibrinogen 
 alpha-1 antitrypsin 
 caeruloplasmin 
 serum amyloid A 
 serum amyloid P component*

 serum amyloid P component* 
 *plays a more significant role in other mammals such as mice 
 haptoglobin 
 complement 
During the acute phase response the liver decreases the production of other proteins  (sometimes referred 
to as negative acute phase proteins). Examples include: 
 albumin 
 transthyretin (formerly known as prealbumin) 
 transferrin 
 retinol binding protein 
 cortisol binding protein

 cortisol binding protein 
ANCA  
 
 There are two main types of anti-neutrophil cytoplasmic antibodies (ANCA): 
1. cytoplasmic (cANCA) and  
2. perinuclear (pANCA) 
 For the exam, remember: 
 cANCA - Wegener's granulomatosis 
 pANCA - Churg-Strauss syndrome + others (see below) 
cANCA 
 most common target serine proteinase 3 (PR3)   
1573

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  27 
  some correlation between cANCA levels and disease activity 
 Wegener's granulomatosis, positive in > 90% 
 In Wegener's, the level of PR3 antibody and ANCA titre are related to disease activity  and the 
antibodies typically disappear when the disease is in remission.

 microscopic polyangiitis, positive in 40% 
pANCA 
 most common target is myeloperoxidase (MPO)  
 cannot use level of pANCA to monitor disease activity 
 associated with immune crescentic glomerulonephritis (positive in c. 80% of patients) 
 microscopic polyangiitis, positive in 50- 75% 
 Churg-Strauss syndrome, positive in 60% 
 primary sclerosing cholangitis, positive in 60-80% 
 Wegener's granulomatosis, positive in 25% 
 Other causes of positive ANCA (usually pANCA)

 Other causes of positive ANCA (usually pANCA)  
 inflammatory bowel disease (UC > Crohn's) 
 connective tissue disorders: RA, SLE, Sjogren's 
 autoimmune hepatitis  
May 2006 exam: Which one of the following statements is true regarding cytoplasmic anti-neutrophil 
cytoplasmic antibodies (cANCA)? Associated with Wegener's granulomatosis  
Rheumatoid factor  (see rheumatology)

Rheumatoid factor  (see rheumatology)  
Antibodies   
antibody  Associated condition  
Antinuclear antibodies 
(ANA)  
  Younger women often have low (ANAs)  
 increase with age  
 ANA positivity with antiphospholipid antibody syndrome (APL) suggests 
secondary APL, ie in association with a connective tissue disease. 
 The common tests used for detecting and screening ANAs are indirect

immunofluorescence and enzyme-linked immunosorbent assay (ELISA).  
 Although positive titres of 1:160 or higher are strongly associated with 
autoimmune disorders, they are also found in 5% of healthy individuals 
 Positive titres of less than 1:160 are present in up to 20% of the healthy 
population, especially the elderly.  
 
Anti-Ro (SS- A) 
 and anti- La (SS- B)  Anti- Ro 
Sjögren's syndrome (50 –70%) 
SLE with cutaneous involvement (30%)

SLE with cutaneous involvement (30%) 
anti-Ro can cross the placenta and cause neonatal lupus in babies. 
Anti-Smith (Anti-Sm)  very specific marker for SLE  (99%) 
sensitivity (20%) 
not associated with disease activity.  1574

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  28 
 Anti-nuclear 
ribonucleoprotein 
(anti-nRNP)  also known 
as anti- U1-RNP  highly associated with mixed connective tissue disease.  
SLE (30 – 40%) 
Anti-double stranded 
DNA (anti-dsDNA)  very specific marker for SLE , (nearly 100%). 
sensitivity  (85%). 
Correlate with disease activity in SLE .

Correlate with disease activity in SLE . 
also linked with lupus nephritis. 
Anti-histone  drug induced lupus (75–95%)  
idiopathic SLE (75%) 
Unlike anti-dsDNA, these antibodies do not fix complement. 
anti-glycoprotein-
210 (anti-gp210) 
and anti-nucleoporin 
62 (anti- p62) primary biliary cirrhosis (PBC) (25 –30%).  
 
Anti-centromere  limited cutaneous systemic sclerosis , also known as CREST syndrome, 
primary biliary cirrhosis 
Thyroid autoantibodies 
(microsomal and

(microsomal and 
thyroglobulin) Hashimoto's thyroiditis (70-90% microsomal: 75-95% thyroglobulin) 
Pernicious anaemia (55% microsomal)  
Anti-Scl- 70 diffuse cutaneous scleroderma (40%), 
limited cutaneous involvement (10%).  
SLE  (5%) 
The antigenic target of anti-Scl-70 antibodies is topoisomerase I  
Antireticulin Coeliac disease (37%) 
Crohn's disease (24%) 
 
Gastric parietal cell 
antibody 
 Pernicious anaemia (>90%) 
Atrophic gastritis( 60%)

Atrophic gastritis( 60%) 
Autoimmune thyroid disease (33%)  
Anti-mitochondrial 
antibody Primary biliary cirrhosis (60-94%) 
Anti-smooth muscle 
antibody Chronic active hepatitis  (40-90%) 
Primary biliary cirrhosis (30-70%) 
Idiopathic cirrhosis (25-30%) 
Viral infections (80%) 
Anti- sp100  primary biliary cirrhosis (PBC) (20 –30%). 
very specific marker of the disease.  
Anti- PM-Scl polymyositis/systemic sclerosis (PM/SSc) overlap syndrome (50%). 
 1575

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  29 
 The only two auto-antibodies which have a role in monitoring disease activity  
(there is correlation between levels and disease activity ) 
1. Anti-ds DNA antibodies in systemic lupus erythematosus (SLE)  
2. Circulating anti-neutrophil cytoplasmic antibody (cANCA) in Wegener's granul omatosis.

Interleukin   
 Interleukin are a group of cytokines (secreted proteins and signal molecules) that were first seen to be 
expressed by white blood cells (leukocytes). 
 The function of the immune system depends in a large part on interleukins,  
 The majority of interleukins are synthesized by helper CD4 T lymphocytes, as well as 
through monocytes, macrophages, and endothelial cells.

 They promote the development and differentiation of T and B lymphocytes, and  hematopoietic cells. 
 Interleukin receptors on astrocytes in the hippocampus are also known to be involved in the 
development of spatial memories in mice 
 
Mnemonic Hot T-Bone stEAk  
 IL-1: fever (Hot) 
 IL-2: stimulates T lymphocytes 
 IL-3: stimulates Bone marrow  
 IL-4: stimulates Ig E 
 IL-5: stimulates Ig A 
 
Interleukin 1 ( IL-1) (α, β)

Interleukin 1 ( IL-1) (α, β)  
 Interleukin 1 (IL-1) is a key mediator of the immune response.  
  It is secreted mainly by macrophages and monocytes  and acts as a costimulator of T cell 
and B cell proliferation. (Stimulation of acute phase response)  
 Other effects include increasing the expression of adhesion molecules on the endothelium.   
 By stimulating the release by the endothelium of vasoactive factors such as PAF (plate let-

activating factor), nitric oxide and prostacyclin it also causes vasodilation and increas es 
vascular permeability.   
 It is therefore one of the mediators of shock in sepsis.  
  Along with IL-6 and TNF, it acts on the hypothalamus causing pyrexia. 
 IL-1 β levels in the circulation are only detectable in the following situations:  
 after strenuous exercise, 
  in ovulating women, 
  sepsis, 
  acute organ rejection, 
 acute exacerbation of rheumatoid arthritis.

 acute exacerbation of rheumatoid arthritis.  
 IL-1 play a role in the formation of the atherosclerotic plaque. 
 The uptake of oxidized low-density lipoproteins (LDL) by vascular endothelial cells results in  
IL-1 expression  stimulates the production of platelet-derived growth factor. 
 1576

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  30 
 Interleukin-2 (IL- 2) 
 IL-2 is a member of a cytokine family. It is a protein that regulates the activities of wh ite blood 
cells (leukocytes, often lymphocytes) that are responsible for immunity. 
 IL-2 is part of the body's natural response to microbial infection, and in discriminating between

foreign ("non-self") and "self". 
 Through its role in the development of T cell immunologic memory, it also has a key role  in 
enduring cell-mediated immunity. 
 there is some evidence that IL-2 may be involved in itchy psoriasis 
 High-dose interleukin-2 can produce a high rate of response and durable remissions in 
patients with metastatic renal cancer. 
____________________________ _________________________________________ 
Cytokine disorders

Cytokine disorders 
Both cytokine overexpression and underexpression or their receptors 'can be 
pathogenic: 
 
1. Septic shock : production of IL-1, IL-6 and TNF due to endotoxin stimulation of macrop hages 
following Gram-negative infection. 
 
2. Toxic shock syndrome : massive release of cytokines due to super antigen stimulation of T-cells 
by TSST-1, a bacterial exotoxin. 
 
3. Chagas' disease  (T. cruzi infection): causes reduced expression of IL-2 receptor, leading to

marked immune suppression. 
Interferon 
 Interferons (IFN) are cytokines released by the body in response to viral infectio ns and neoplasia.  
 They are classified according to cellular origin and the type of receptor they bi nd to.  
 IFN-alpha and IFN-beta bind to type 1 receptors  whilst IFN-gamma binds only to type 2 receptors. 
 
IFN-alpha 
 produced by leucocytes 
 antiviral action

 antiviral action 
 useful in hepatitis B & C, Kaposi's sarcoma, metastatic renal cell cancer, hairy cell  leukaemia 
 adverse effects include flu-like symptoms and depression 
IFN-beta 
 produced by fibroblasts 
 reduces the frequency of exacerbations in patients with relapsing-remitting MS 
IFN-gamma 
 produced by T lymphocytes & NK cells 
 weaker antiviral action, more of a role in immunomodulation particularly macrophage activation

 may be useful in chronic granulomatous disease and osteopetrosis 1577

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  31 
Chemokines  
 Chemokines  are a family of small cytokines, or signaling proteins secreted by cells.  
 Their name is derived from their ability to induce directed chemotax is in nearby responsive cells; they 
are chemo tactic cyto kines .

are chemo tactic cyto kines .  
 have four cysteine residues in conserved locations that are key to forming their 3-dimensional shape.  
Types and function 
 Homeostatic chemokines:  
 responsible for basal leukocyte migration.  
 include: CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13.  
 Inflammatory chemokines: 
  Released under pathological conditions (on pro-inflammatory stimuli, such as IL-1, TNF-
alpha, LPS, or viruses)

alpha, LPS, or viruses)  
 attracting immune cells to the site of inflammation.  
 Examples are: CXCL8 (IL- 8), CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10 
 May promote wound healing. 
 promote angiogenesis (the growth of new blood vessels) 
 The major role of chemokines is to act as a chemoattractant to guide the  migration of cells. 
 CXC chemokines have two cysteine residues separated by another amino acid. They are mainl y 
chemoattractive for neutrophils.

chemoattractive for neutrophils.  
 IL-8 is an example of a CXC chemokine. 
 CC chemokines do not have the separating amino acid and mainly act on monocytes and lymphocyt es. 
 
Nitric oxide 
 Previously known as endothelium derived relaxation factor , nitric oxide (NO) has emerged as a 
molecule which is integral to many physiological and pathological processes.

 It is formed from L-arginine  and oxygen by nitric oxide synthetase (NOS).  
 An inducible form of NOS has been shown to be present in macrophages.  
 Nitric oxide has a very short half-life (seconds), being inactivated by oxyg en free radicals  
 Nitric oxide generates cyclic guanosine monophosphate (cGMP) as the second messenger 
 
Effects  
 acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decr easing Ca2+ 
levels 
 vasodilation, mainly venodilation

levels 
 vasodilation, mainly venodilation 
 inhibits platelet aggregation  
 
Clinical relevance  
 underproduction of NO is implicated in hypertrophic pyloric stenosis 
 lack of NO is thought to promote atherosclerosis 
 in sepsis increased levels of NO contribute to septic shock 1578

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  32 
  organic nitrates (metabolism produces NO) is widely used to treat cardiovascular disease (e. g. angina, 
heart failure) 
 sildenafil is thought to potentiate the action of NO on penile smooth muscl e and is used in the treatment 
of erectile dysfunctions

of erectile dysfunctions 
 N2O, also known as 'laughing gas', is often used in obstetrics and trauma for pai n relief  
Endothelin-1 
 It is a 21-amino-acid polypeptide  
 It is a highly potent vasoconstrictor and plays a part in the modulation of vascular tone 
 It may have a role in diseases such as Raynaud's phenomenon 
 Its levels increase when the endothelium is stressed, for example in trauma or oxidative stress

Other proteins activated during tissue stress 
 ICAM-1 is a cellular adhesion molecule (I = intercellular), which is increased during infl ammation and by 
IL-1, an interleukin 
 Heat-shock proteins (HSPs) are also increased during tissue stress  
Kinins 
 kinins are potent vasoactive basic peptides involved in the inflammatory response 
 Their activation leads to release of chemotactic cytokines

 Their properties including the ability to 
 increase vascular permeability 
 cause vasodilation, pain, and the contraction of smooth muscle 
 stimulate arachidonic acid metabolism 
Erythrocyte sedimentation rate (ESR) 
 
The ESR is a non-specific marker of inflammation and depends on both th e size, shape and number of red

blood cells and the concentration of plasma proteins such as fibrinogen, alpha2-glob ulins and gamma globulins 
 
Causes of a high ESR  
 temporal arteritis 
 myeloma 
 other connective tissue disorders e.g. systemic lupus erythematosus 
 other malignancies 
 other factors which raise ESR: increasing age, female sex, anaemia 
Causes of a low ESR  
 afibrinogenaemia/ hypofibrinogenaemia  
 
 1579

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  33 
Tumour necrosis factor (TNF) 
 Tumour necrosis factor (TNF) is a pro-inflammatory cytokine  with multiple roles in the immune 
system 
 TNF is secreted mainly by macrophages and has a number of effects on the immune system, acting

mainly in a paracrine fashion: 
 activates macrophages and neutrophils 
 acts as co-stimulator for T cell activation 
 key mediator of bodies response to Gram negative septicaemia 
 similar properties to IL-1 
 anti-tumour effect (e.g. phospholipase activation) 
 is a key cytokine in the pathogenesis of multi-organ failure. 
 exerts an interferon-like effect against viruses 
 Enhanced HLA class I expression 
 Stimulation of acute phase response

 Stimulation of acute phase response 
 TNF-alpha binds to both the p55 and p75 receptor. These receptors can induce apoptosis. It also cause 
activation of NFkB 
 Endothelial effects include increase expression of selectins and increased production of platelet 
activating factor, IL-1 and prostaglandins 
 TNF promotes the proliferation of fibroblasts and their production of protease and collag enase. It is 
thought fragments of receptors act as binding points in serum

 Systemic effects include pyrexia, increased acute phase proteins and disordered metabolism leading t o 
cachexia 
 TNF is important in the pathogenesis of rheumatoid arthritis - TNF blockers ( e.g. infliximab, etanercept) 
are now licensed for treatment of severe rheumatoid 
 
TNF blockers  
 infliximab: monoclonal antibody, IV administration 
 etanercept: fusion protein that mimics the inhibitory effects of naturally occu rring soluble TNF receptors, 
subcutaneous administration

subcutaneous administration 
 adalimumab: monoclonal antibody, subcutaneous administration 
 adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelinati on 
 Infliximab is also used in active Crohn's disease unresponsive to steroids 
 
Contraindications of usage of TNF- alpha antagonist:  
 Active infection  
 Active TB  
 MS (Multiple sclerosis)  
 Heart failure (NYHA grade 3-4).  
 Pregnancy and Breast feeding 
 
 1580

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  34 
Growth factors 
Transforming growth factor-beta (TGF- β) 
 Generally limits inflammatory response. 
 Enhances lgA synthesis. 
 Initiates and terminates tissue repair. 
 Undergoes autoinduction.

 Undergoes autoinduction. 
 Released by platelets at the site of tissue injury and promotes the formation of extracell ular 
matrix. 
 Implicated in diseases of tissue fibrosis such as cirrhosis and glomerulosclerosis. 
Leukocyte alkaline phosphatase 
 
 Myelofibrosis 
 Leukemoid reactions 
 Polycythemia rubra vera 
 Steroids, Cushing's syndrome

 Steroids, Cushing's syndrome 
 Pregnancy, oral contraceptive pill  Chronic myeloid leukemia 
 Pernicious anemia 
 Paroxysmal nocturnal hemoglobinuria 
 Infectious mononucleosis 
 
Monoclonal antibodies 
 
Rituximab - monoclonal antibody against CD20 
 
 manufactured by a technique called somatic cell hybridization.

 This involves the fusion of myeloma cells with spleen cells from a mouse that has been immunized with 
the desired antigen. The resulting fused cells are termed a hybridoma and act as a 'factor y' for 
producing monoclonal antibodies.  
 The main limitation to this is that mouse antibodies are immunogenic leading to the formation of human 
anti-mouse antibodies (HAMAs). This problem is overcome by combining the variable regi on from th e

mouse body with the constant region from an human antibody. 
 
 1581

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  35 
 Clinical examples of monoclonal antibodies:  
MONOCLONAL AB TYPE  USES  
Rituximab Anti-CD20 non-Hodgkin's lymphoma 
Infliximab anti-TNF  rheumatoid arthritis and Crohn's 
Cetuximab anti-epidermal growth factor receptor metastatic colorectal cancer and 
head and neck cancer

head and neck cancer 
Trast uzumab anti-HER 2, anti EGF receptor metastatic breast cancer 
Alemtuzumab anti-CD52 chronic lymphocytic leukemia 
Abciximab anti-glycoprotein IIb/IIIa receptor undergoing PCI, prevention of 
ischemic events in patients 
OKT3 anti-CD3 prevent organ rejection 
 
Monoclonal antibodies are also used for:  
 medical imaging when combined with a radioisotope 
 identification of cell surface markers in biopsied tissue 
 diagnosis of viral infections

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  36 
Diagnostic antibody testing  
AB Association  
Anti-Hu  small-cell lung cancer, neuroblastoma and prostatic cancer 
Intrinsic factor antibodies pernicious anaemia, and hence (subacute combined degeneration of the

spinal cord) secondary to vitamin B12 deficiency 
Anti- Ri neuroblastoma (children) and fallopian or breast cancer (adults), resulting 
in paraneoplastic opsoclonus myoclonus ataxia (POMA). 
Anti- Yo  gynaecological tumours and breast cancer, 
Anti- Tr Hodgkin's disease, resulting in cerebellar degeneration. 
Anti-Ta (Ma2)  testicular tumours, and can lead to limbic or brain stem encephalomyelitis. 
Anti-endomysial / gliadin /

Anti-endomysial / gliadin / 
transglutaminase  coeliac disease, and related vitamin B-1 deficiency may lead to Wernicke's 
encephalopathy and Korsakoff's psychosis 
Tissue transglutaminase 
antibody ('tTGA') 
 & Endomysial 
antibody ('EMA') The most accurate blood tests for coeliac disease 
Antimitochondrial antibodies 
(M2 pattern) primary biliary cirrhosis (PBC) 
double-stranded DNA (ds-
DNA) Anti-dsDNA  highly specific for SLE. 
Antibodies that bind single-
stranded denatured DNA (ss-

DNA)  present in 90% of patients with SLE, but also in drug-induced lupus and 
other connective tissue disorders. 
Antihistone antibody seen in SLE and drug-induced lupus. 
Anticentromere antibody present in 70% of patients with CREST and 15% of patients with diffuse 
scleroderma. 
 CREST syndrome: calcinosis, Raynaud's phenomenon, oesophageal 
dysfunction, sclerodactyly and telangiectasia. 
ASMA – Anti- smooth 
muscle antibody  Chronic active hepatitis

muscle antibody  Chronic active hepatitis  
pANCA  Ulcerative Colitis  
cANCA  Wegner ’s granulomatosis 
Anti-centromere  CREST / Scleroderma 
Anti- Ro Sjogren ’s Syndrome 
Anti- La Sjogren ’s syndrome 
Anti- Jo Polymyositis 
Rheumatoid factor  Rheumatoid arthritis , Sjogren ’s (90%), SLE (30%) 
 5% of normal population  
 
 1583

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  37 
Lymphocytes 
 B lymphocytes T lymphocytes 
Site of 
production bone marrow . 
germinal centre  of lymph nodes and 
spleen. produced in the bone marrow but 
mature in the thymus   
Paracortical region  of lymph nodes and 
spleen.

spleen. 
Functions  Humoral immunity  
 antibody production 
(immunoglobulins) 
 control of pyogenic bacteria 
prevention of blood-borne 
infections. 
 neutralization of toxins.  Cell-mediated immunity; 
  protection against intracellular 
organisms, protozoa and fungi;  
 graft rejection;  
 control of neoplasms. 
% of total 
lymphocytes:   12% 
 mainly fixed.   70-80% (the majority of 
circulating lymphocytes in 
plasma).

plasma).  
 mainly circulating;   
 long-lived memory cells.   
Thymus 
  The thymus is composed of two identical lobes and is located anatomically in the anterior 
superior mediastinum, in front of the heart and behind the sternum.  
 Histologically, each lobe of the thymus can be divided into a central medulla and a 
peripheral cortex which is surrounded by an outer capsule.

 The thymus is largest and most active during the neonatal and pre-adolescent peri ods. By the early 
teens, the thymus begins to atrophy and thymic stroma is mostly replaced by adi pose (fat) tissue. 
Nevertheless, residual T lymphopoiesis continues throughout adult life. 
 Cells in the thymus can be divided into thymic stromal cells and cells of hematopoietic origin (derived 
from bone marrow resident hematopoietic stem cells). Developing T-cells are r eferred to

as thymocytes and are of hematopoietic origin. Stromal cells include epithelial cells of t he thymic cortex 
and medulla, and dendritic cells. 
 Cortical thymocytes are immature forms, and either do not express CD4 or CD8 (doubl e negative cells) 
or express both CD4 and CD8 (double positive cells).  
 As the cells mature, they pass to the thymic medulla, where they lose expression o f either CD4 or CD8, 
to become single positive cells.

to become single positive cells. 
 Negative selection occurs at the stage when thymocytes express both CD4 and CD8, but co-
expression of these markers does not mediate negative selection.  1584

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  38 
  Negative selection occurs when a thymocyte expresses a TcR with high affinity for self antigen :MHC 
complexes in the thymic micro-environment. 
 Once a thymocyte has successfully rearranged and expressed an alpha/beta or gamma/delta TcR it is 
committed to that lineage.

committed to that lineage. 
 Thymocytes whose TcR bind with high affinity to self Ag/MHC complexes are clon ally deleted  by 
a process of negative selection. 
Immune cell antigen receptors 
 
 T and B lymphocytes express receptors on their surface that recognise antigen in a specific mann er. 
  Each individual lymphocyte expresses a single type of receptor with unique specificit y (except dual 
specificity T cells

specificity T cells  
 The receptor on the B lymphocyte is membrane bound immunoglobulin (IgM and IgD isoty pe) and 
recognises particulate antigen, whilst the TCR is a heterodimer that recogni ses peptide fragments 
presented by MHC molecules.  
 T cells with dual specificities have been reported although their function is unknown.  
B-cells and  plasma cells

B-cells and  plasma cells 
 B-cells have surface IgG and major histocompatibility complex (MHC) class II 
 B cells express immunoglobulin on their surface  
 B-cells undergo somatic hypermutation and isotype switching  (ie switching through the 
immunoglobulin classes) 
 Plasma cells are fully differentiated cells from B-cells and hence lack these features   
 Multiple myeloma  is a cause of isolated B-cell immune deficiency  
 B cells usually require T cell help for full activation.

 B cells activated in the primary immune response initially produce IgM. With continu ing T cell help B 
cells then undergo heavy chain class switching and enter germinal centres in secondary lymphoid 
organs.  
 The germinal centres are the sites of immunoglobulin affinity maturati on and memory B cell formation.  
 CD40 and CD40L are required for co-stimulation by T cells. Deficiency of eit her CD40 or CD40L 
impairs class switching.

impairs class switching.  
 Certain antigens can activate B cells in the absence of T cell help - thymus independent anti gen. T cell 
independent B cell responses are mainly to carbohydrate antigen, for example,  pneumococcal 
polysaccharide. These antigens are not processed and presented in association with MHC molecules, 
and therefore cannot activate T helper cells.  
 The influenza virus will activate T and B cells, and result in memory cell pr oduction.

 Affinity maturation of the B cell receptor is an important process initiated during the primary 
immune response 
 IgD are surface receptors of B lymphocytes 
 
Class II MHCs  are present on all antigen presenting cells, for example, 
 B cells 
 Dendritic cells 
 Macrophages 1585

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  39 
  Langerhans cells. 
They are also present on activated T cells. 
CD4 T-cells interact with B-cells via MHC class II 
 
Class I major histocompatibility complexes (MHCs) react with CD 8 on T cells to  result in immune 
system activation

system activation 
Proteins are displayed on the cell surface by MHC I  human leukocyte antigen (HLA) antigens. 
If the MHC I is presenting material recognised as foreign, then it is detec ted and destroyed by CD 8 plus T 
cells 
 
Antigen presenting cells (APCs) 
 Extracellular antigen which is not directly recognised as foreign requires processi ng by APCs to 
generate an immune response. This process involves these cells expressing antigenic peptide s in 
conjunction with MHC class II.

conjunction with MHC class II. 
 Antigen is presented via MHC class II complexes,  
 MHC class I aids in the recognition of virally infected cells. 
 Direct stimulation of an immune response may occur in the absence of APCs. 
 APCs are not required before an immune response to viral infection can be successf ully mounted. 
 T cells  
 
 Co-operation with other cell types is required for T cell recognition of antigen

 T cells recognise antigen only when presented by (self) MHC molecules on an antigen present ing cell.  
 Autoreactive T cells exist in the periphery and other mechanisms are responsible for the  protection of 
the body against autoimmunity.  
 The antigen specificity of T and B cells is generated during developm ent in the thymus (T lymphocytes) 
and in the bone marrow (B lymphocytes).  
 Patients with HIV have a deficiency of T-cells ( CD4 T-cell lymphocytes )

 T lymphocytes are involved in cell-mediated acquired immune responses, whereas B lym phocytes are 
involved in humoral immunity and produce immunoglobulins.  
 T lymphocytes compose the majority of circulating lymphocytes in plasma.  
 Within lymph nodes:  
 The paracortical areas  contain T cells and accessory cells. 
 Cortex    B cells are found within the cortex in follicles, which have c entral areas known as 
germinal centres.

germinal centres. 
 The medulla   contains large blood vessels and sinuses, and medullary cords that contai n 
plasma cells secreting antibody. 
Which is the predominant site in the lymph node that contains T cells? Paracortex  
 
 1586

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  40 
T-Helper cells  There are two major subsets of T-Helper cells: 
Th1 
 involved in the cell mediated response and delayed (type IV) hypersensitivity 
 secrete IFN-gamma, IL-2, IL-3 
Th2 
 involved in mediating humoral (antibody) immunity

 e.g. stimulating production of IgE in asthma 
 secrete IL-4, IL-5, IL-6, IL-10, IL- 13 
An increase in the Th1:Th2 ratio is associated with a reduction in the risk of allergic/hypersensit ivity reactions.  
May 2012 exam:  Which one of the following is most commonly secreted by T-helper cell s 
subset 2 (Th2 cells) ? Interleukin 4  
Mast cells

Mast cells   
Mast cells are basophilic cells in the connective and subcutaneous tissues, which are involved in inflamma tory 
and immune responses. 
They contain storage granules that contain lytic enzymes (for example, tryptase) and inflamm atory mediators, 
for example: 
 Histamine 
 Heparin 
 5-Tryptase hydroxytryptamine (5-HT) 
 Leukotrienes 
 Platelet aggregating factor 
 Leukocyte chemotactic factor 
 Hyaluronidase.

 Hyaluronidase. 
Release of these mediators occurs during mast cell degranulation, which can be tri ggered by: 
 Tissue injury 
 Drugs 
 Complement activation 
 Foreign antigenic material. 
An anaphylactic reaction occurs when a previously sensitised individual is re-exposed to t he antigen. It is an 
IgE mediated immune response. 
Mastocytosis occurs when excess mast cells are present in the circulation or as tissue infiltrates.

Degranulation releases lytic enzymes and inflammatory mediators from storage granules 
 
 1587

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  41 
Immunity to viruses 
 Natural killer cells are activated faster than cytotoxic T-cells 
 Infected non-immune cells produce interferon- α and -ȕ, whereas interferon -Ȗ is produced by T -cells

 Influenza virus mutates its surface neuraminidase and haemagglutinin to avoid antibody recognit ion 
 Enveloped viruses are susceptible to complement attack 
 IgA can offer protection at mucosal surfaces  
Immunity to bacteria 
 Cellular immunity  is essential in protection against intracellular bacteria, eg mycobacteria 
 Phagocytes interact directly but weakly with bacteria, or strongly if they  are complement-opsonised 
 Endotoxin activates macrophages by binding to CD14

 bacteria opsonised by antibodies and complement are more effectively phagocytosed 
than those opsonised by antibodies alone  
Congenital immunodeficiency disorders 
 
Types 
 B-cell immunodeficiencies 
 B-cell defects  (humoral immunity  deficiencies) account for 50–60% of all primary

immunodeficiencies. 
 Include 
 Bruton agammaglobulinemia (X-linked agammaglobulinemia) 
 Selective IgA deficiency (SIgAD) 
 Common variable immunodeficiency (CVID) 
 T-cell immunodeficiencies 
 T cell defects  (cellular immunity  deficiencies) are responsible for  5–10% of primary 
 Include: 
 DiGeorge syndrome (22q11.2 deletion syndrome) 
 mixed immunodeficiencies 
 Severe combined immunodeficiency (SCID) 
 Wiskott-Aldrich syndrome 
 Ataxia telangiectasia

 Ataxia telangiectasia 
 Congenital complement deficiencies 
 C1-esterase inhibitor deficiency (hereditary angioedema) 
 Terminal complement deficiency (C5 –C9 deficiency) 
 phagocyte deficiencies 
 Phagocytic defects are characterized by impaired ability of phagocytic cells  (e.g., monocytes, 
macrophages, granulocytes such as neutrophils and eosinophils) to kill pathogens  
 account for 10–15% of primary immunodeficiencies. 
 Include: 
 Chronic granulomatous disease (CGD)

 Chronic granulomatous disease (CGD) 
 Leukocyte adhesion deficiency type 1 
 Chediak-Higashi syndrome 1588

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  42 
  
Primary immunodeficiency   
disorders may be classified according to which component of the immune system they affect.  
Neutrophil disorders  
Disorder Underlying defect Notes 
Chronic 
granulomatous 
disease Lack of NADPH oxidase 
reduces ability of 
phagocytes to produce

phagocytes to produce 
reactive oxygen species Caused by  a failure of intracellular killing (no respiratory 
burst). 
Causes recurrent pneumonias and abscesses, particularly due 
to catalase-positive bacteria (e.g. Staphylococcus aureus  and 
fungi (e.g. Aspergillus ) 
Negative nitroblue-tetrazolium test 
Screening is by the nitroblue tetrazolium (NBT) test 
Abnormal dihydrorhodamine flow cytometry test 
Chediak-Higashi 
syndrome Microtubule 
polymerization defect

polymerization defect 
which leads to a 
decrease in phagocytosis Affected children have 'partial albinism' and peripheral 
neuropathy. Recurrent bacterial infections are seen 
Giant granules in neutrophils and platelets 
Leukocyte 
adhesion 
deficiency Defect of LFA-1 integrin 
(CD18) protein on 
neutrophils Recurrent bacterial infections.  
Delay in umbilical cord sloughing may be seen 
Absence of neutrophils/pus at sites of infection 
 
B-cell disorders

B-cell disorders 
Common variable 
immunodeficiency  CVID  Many varying causes Hypogammaglobulinemia is seen. May predispose 
to autoimmune disorders and lymphona 
Bruton's (x-linked) 
congenital 
agammaglobulinaemia Defect in Bruton's 
tyrosine kinase (BTK) 
gene that leads to a 
severe block in B cell 
development X-linked recessive.  
Recurrent bacterial infections are seen 
Absence of B-cells with reduce immunoglogulins 
of all classes

of all classes 
Selective immunoglobulin 
A deficiency Maturation defect in B 
cells  Most common primary antibody 
deficiency . 
  Recurrent sinus and respiratory infections 
 Associated with coeliac disease and may 
cause false negative coeliac antibody 
screen  
 1589

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  43 
 T-cell disorders  
DiGeorge syndrome 22q11.2 deletion, 
failure to develop 
3rd and 4th 
pharyngeal pouches Common features include congenital heart disease (e.g. 
tetralogy of Fallot), learning difficulties, hypocalcaemia, 
recurrent viral/fungal diseases, cleft palate

recurrent viral/fungal diseases, cleft palate 
 
Combined B- and T-cell disorders 
Combined B- and T-cell disorders: SCID WAS ataxic (SCID, Wiskott-Aldrich syndrome, 
ataxic telangiectasia)  
 
Severe combined 
immunodeficiency Most common (X-linked)  
due to defect in the 
common gamma chain, a 
protein used in the 
receptors for IL-2 and 
other interleukins. Other 
causes include adenosine

causes include adenosine 
deaminase deficiency  Recurrent infections due to viruses, bacteria and fungi.  
Reduced T-cell receptor excision circles 
Stem cell transplantation may be successful  
Ataxia 
telangiectasia Defect in DNA repair 
enzymes  Autosomal recessive.  
 Features include: 
1. cerebellar ataxia, 
2.  telangiectasia (spider angiomas),  
3. recurrent chest infections 
4.  and 10% risk of developing malignancy, 
lymphoma or leukaemia 
Wiskott-Aldrich

Wiskott-Aldrich 
syndrome Defect in WAS gene X-linked recessive. Features include recurrent bacterial 
infections, eczema, thrombocytopaenia. 
Low IgM levels 
Increased risk of autoimmune disorders and malignancy 
 
Antibody deficiency 
 
 The most common type of primary immunodeficiency (>50% of cases) invol ves being deficient in 
antibody production 
 Selective IgG deficiencies include the decreased production of IgA and/or the various IgG subclasses

and impaired antibody responses to polysaccharide antigens 
 Normal immunoglobulin serum levels, including subclasses, do not exclude antibody defi ciency 1590

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  44 
  Hence in patients with a good history of recurrent (proven) bacterial infection s, IgG responses to 
Haemophilus influenzae, Pneumococcus spp, and tetanus toxoid should all be assessed, as should 
postimmunisation responses if required

postimmunisation responses if required 
 Good IgG antibody responses to immunisations  excludes IgG subclass deficiency. 
 
Which disease occurring during pregnancy is most likely to lead to the neonate having l ow 
immunoglobulin levels and hence being prone to bacterial infections? 
Intestinal lymphangiectasia 
Selective IgA deficiency (SlgAD) 

  total absence or severe deficiency of IgA, serum levels are usually less than 0.05g/L (wit h a normal 
adult range of 0.9 - 4.5 g/L).  
 the most common primary antibody deficiencies  
 prevalence: 1 in 700 
 high incidence in Arab and Spanish  
Causes 
 unknown  
 occurs more frequently in first degree relatives of patients with common varia ble immunodeficiency 
(CVID).  
Features 
 Often asymptomatic,

(CVID).  
Features 
 Often asymptomatic,  
 most commonly present with otitis media, chronic rhinosinusitis and pneumonia. 
 chronic diarrhea ( Giardia ), steatorrhea 
 coeliac disease  
 10-fold increased risk of coeliac disease  
 gluten-sensitive enteropathy (GSE)  
 IgG subclass or specific antibody deficiency: 
 The possibility of lgG2 deficiency should always be investigated in IgA-defi cient

individuals with a history of recurrent bacterial infections, but Staphylococcus aureu s is 
the exception 
 pernicious anaemia and hence gastric carcinoma  
 Allergy and autoimmune conditions  
 ↑ adverse reactions to blood products . 
 Patients with selective IgA deficiency should be tested for the presence of anti-IgA antibodies 
prior to transfusion with blood products. 
 may progress to common variable immune deficiency  (involving low  levels of both IgA and IgG, and

sometimes also IgM), 
Diagnosis  
 low serum IgA level, with normal IgG and IgM levels 
 Treatment  
 no specific treatment  
 Prophylactic antibiotics 
 Intravenous infusion of IgA is not recommended  because: 
 the risk of anaphylactic reactions (caused by the production of anti-IgA antibodies).  1591

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  45 
  the short half-life of IgA and the relative paucity of IgA in commercial i mmunoglobulin 
preparations 
Ref:  
 medical-masterclass.com 2017 mrcp part 1  
 pastest part 1  
 www.amboss.com  2017 
Common variable immunodeficiency (CVID)

Common variable immunodeficiency (CVID)  
 
 The most common clinically significant primary immunodeficiency  is CVID.  
 IgA deficiency is more common, but most are asymptomatic.  
 Sex: ♀ = ♂ 
 Onset: present later than other B cell defects (usually 20 –35 years of age) 
 immunodeficiency arising from B-cell dysfunction 
 B cells are phenotypically normal but unable to differentiate into Ig-producing cells

 defect in B-cell differentiation   (cannot differentiate to plasma cells  which produces antibodies). 
 no clear pattern of inheritance 
 Can be acquired in young adulthood 
 A well-accepted definition of CVID includes three key features:  
1. the presence of hypogammaglobulinaemia of two or more immunoglobulin isotypes ( low IgG, 
IgA, or IgM),  
2. recurrent sinopulmonary infections 
3. impaired functional antibody responses.

3. impaired functional antibody responses.  
 include absent isohaemagglutinins (eg. antibodies associated with blood transfusion 
reactions),  
 poor responses to protein (diphtheria, tetanus) or polysaccharide vaccines (S 
pneumoniae), or both. 
 Features 
 Symptoms 
 recurrent sinopulmonary infections 
 persistent diarrhea 
 Giardia lamblia 
 Physical exam 
 generalized lymphadenopathy 
 Associated conditions and complications:

 Associated conditions and complications:  
 ↑risk for  autoimmune diseases (~20%) 
 (e.g., rheumatoid arthritis, autoimmune hemolytic anemia, immune 
thrombocytopenia, vitiligo) 
 alopecia areata 
 granulomatous diseases 
 ↑risk for  lymphoma 
 common cause of death in patients with CVID  lymphoma 
 especially non-Hodgkin's lymphoma [NHL], and gastrointestinal [GI] carcinoma). 
 Lymphoma occurs 300 times more frequently in women with CVID than in affected men.

 Most lymphomas are of these are of the B cell immunophenotype  1592

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  46 
  frequently associated with Epstein-Barr virus (EBV). 
 permanent damage to lungs  bronchiectasis  
 severe gastroenteropathy with severe malabsorption (20%), resembling coeliac sprue, nodul ar 
lymphoid hyperplasia, and chronic inflammatory bowel disease such as ulcerative colitis and 
Crohn's disease.

Crohn's disease. 
 Granulomas in 5-10%.  
 Granulomas are indistinguishable from those of classic sarcoidosis 
 are found in the: Lung, Liver, Spleen, and Conjunctivae. 
 Quantitative Ig levels (low levels of IgG, IgA, IgM) 
 ↓ All immunoglobulin classes, especially IgA and IgG  
 IgG is more likely to be deficient than IgM. 
 Flow cytometry shows normal B and T cell subsets 
 Lymph node biopsy – to exclude malignancy 
 reactive follicular hyperplasia 

 IVIG replacement therapy (first line) 
 the best option would best prevent recurrent chest infections  Intravenous 
immunoglobulin 
 Prophylactic antibiotics 
 Poor response to immunizations 
 Patients with common variable immunodeficiency should receive killed vaccines for p rophylaxis 
against infections. 
Question 
H/O recurrent Giardia lamblia diarrhea and multiple upper respiratory  infections  since birth. serum

analysis reveals normal levels of mature B lymphocytes . What other finding on serum analysis predisposes 
the patient to recurrent diarrheal infections? 
Answer  
 Deficiency in IgA  
 The patient has common variable immunodeficiency disorder (CVID)  
 IgA plays an important role in mucosal immunity. By its presence on the surf ace of intestinal 
mucosal cells, IgA is able to prevent the binding of pathogens to the epithel ial cells; thus,

preventing protozoa like Giardia lamblia from causing inflammation. Its absen ce, therefore, 
leads to the increased likelihood of repeat infection of the GI mucosa and repeat episod es of 
non-bloody diarrhea 
 
CVID  B-cell Cannot differentiate into plasma cells  low immunoglobulins but normal or decreased B 
cells.  
Bruton's    Pre-B lymphocytes are increased because there's a maturation defect.  

Bruton's (x-linked) congenital agammaglobulinaemia (XLA) 
 X-linked recessive  disease that causes a complete deficiency of B lymphocytes 
 Etiology  
 mutations in the gene coding for Bruton tyrosine kinase  (BTK).  
 BTK is critical to the maturation of pre –B cells to differentiating mature B cells.  1593

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  47 
  The most common genetic event is a missense mutation (substitution in one amino 
acid in a protein).  
 Males with XLA have a total or almost total absence of B lymphocytes and plasma cells.  
 appears in boys only 
 Features 
 frequent infections

 Features 
 frequent infections 
 Infections begin once transferred maternal immunoglobulin G (IgG) antibo dies have 
been catabolized, typically at about 6 months of age. (because transplacentally 
transferred maternal IgG is no longer active) 
 Recurrent, severe pyogenic infections (e.g., pneumonia, otitis media); especiall y by 
encapsulated organisms (S. pneumoniae, N. meningitidis, and H. influenzae) 
 Hepatitis viruses and enteroviruses (e.g., Coxsackie virus)

 small or absent tonsils, adenoids, lymph nodes, and Peyer patches in the intestines , due 
to absence of B lymphocytes which is normally make most of the bulk of these t issues. 
 flow cytometry  
 showing absent or low B cells and normal T cells  
 low B cell count  in the blood is the most reliable indicator of XLA 
  Quantitative Ig levels  
 immunoglobulins (IgG, IgM, and IgA) are absent or very low

 Diagnosis confirmed by absence of Bruton ’s tyrosine kinase (BTK), or by detection of an 
abnormality in the BTK gene. 
 IV immunoglobulins 
 Prophylactic antibiotics  
Severe combined immunodeficiency disease (SCID) 
 Combined B- and T-cell disorder  causing immunodeficiency 
 multiple variants found 
 most common is X-linked defective common gamma chain 
 found in IL-2, IL-4, IL-7 ,  IL-9, IL-15, and IL- 21

 autosomal recessive adenosine deaminase deficiency   
 2nd most common  
 ↑ deoxyadenosine, which is toxic to lymphocytes  
 Mutations in adenosine deaminase gene  ↓adenosine deaminase  
↑deoxyadenosine 
 ↓ DNA synthesis  
Features  
 most patients present before age 3 months. Without intervention, SCID usually results in severe 
infection and death in children by age 2 years.  
 recurrent infections, diarrhea, dermatitis, and failure to thrive.

 common cutaneous manifestations and typical infections can provide clinical clues in diagnosing this 
pediatric emergency.  
Diagnosis 
 ↓ Lymphocyte count (< 3000/μL)  
 Chest radiography with no thymic shadow 
 Flow cytometry 
 absent T-cells 1594

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  48 
  abnormal function of B-cells 
DiGeorge syndrome 
 
 DiGeorge syndrome is a primary immunodeficiency disorder caused by T-cell  deficiency and 
dysfunction.

 Results from maldevelopment of thymic epithelial elements derived from t he third and fourth pharyngeal 
pouches. (abnormal development of the 3rd and 4thbranchial pouches.)  thymic aplasia and defective 
parathyroid  
 The thymus arises from the 3rdpharyngeal pouch, 
 the parathyroid glands receive contribution from both 3rd and 4th pouches.  
 It is an example of a microdeletion syndrome. 
 The gene defect mapped to chromosome 22 q11.  
Features

Features  
 risk of viral and fungal infections 
 parathyroid gland hypoplasia ĺ hypocalcaemic tetany  
 thymus hypoplasia  T-lymphocyte deficiency/dysfunction   susceptible to opportunistic infections 
such as yeast. 
 cardiac defects  
 interrupted aortic arch,  
 truncus arteriosus  
 tetralogy of Fallot 
 isolated VSD. 
 Facial abnormalities may include abnormal ears, a shortened philtrum, micrognathia and hypertelorism  
  high and broad nasal bridge

  high and broad nasal bridge 
 Affected individuals usually have a  small , histologically  normal thymus located near the base  of the 
tongue or in the neck , allowing most patients to develop functional T-cells in numbers that may or 
may not be adequate for host defence 
 X-ray shows absence of the thymic shadow. 
  low levels of serum calcium and parathormone 
 
May 2013 exam:  In a patient having DiGeorge syndrome, which infection is he most at risk from,

secondary to his immune system dysfunction? Cryptococcus neoformans (T-cell dysfunction  ĹĹ risk 
from recurrent viral and fungal infections)  
Wiskott-Aldrich syndrome 
 recurrent bacterial infections (e.g. Chest) 
 eczema 
 thrombocytopaenia 
 
1595

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  49 
  Wiskott-Aldrich syndrome causes primary immunodeficiency due to a combined B- and T-cell  
 It is inherited in a X-linked recessive  fashion  
 and is thought to be caused by mutation in the WASP gene .( which responsible for ensuring proper

functioning of the actin cytoskeleton in haematopoietic cells)  
 Features include : 
 recurrent bacterial infections (e.g. chest),  
 eczema  
 thrombocytopenia  
 low IgM levels 
 humoral immunodeficiency, 
 
 The disease have variable penetrance , which means that life expectancy can range from 6 -  30 
years.  
Complement deficiencies

Complement deficiencies 
 
C3 deficiency is associated with recurrent bacterial infections,  
C5 deficiency is more characteristically associated with disseminated meningococcal infection  
 
 Complement is a series of proteins that circulate in plasma and are involved in the inflammator y and 
immune reaction of the body.  
 Complement proteins are involved in chemotaxis, cell lysis and opsonisation.  
 
C1 inhibitor (C1-INH) protein deficiency 
 causes hereditary angioedema

 causes hereditary angioedema 
 C1-INH is a multifunctional serine protease inhibitor 
 probable mechanism is uncontrolled release of bradykinin resulting in oedema of tissues 
C1q, C1rs, C2, C4 deficiency (classical pathway components) 
 predisposes to immune complex disease 
 e.g. SLE, Henoch-Schonlein Purpura, vasculitidies 
 complement activity is associated with clearance of circulating immune complexes

 If immune complexes are not cleared, they undergo  tissue deposition where an inflammatory 
process is triggered, leading to SLE 
C3 deficiency 
 causes recurrent bacterial infections 
 Deficiencies of C3 is more commonly associated with haemolytic uraemic syndrome  
C5 deficiency 
 predisposes to Leiner disease 
 recurrent diarrhoea, wasting and seborrhoeic dermatitis 
C5-9 deficiency 1596

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  50 
  encodes the membrane attack complex (MAC) 
 particularly prone to Neisseria meningitidis  infection 
 Absent classical and alternate pathway activity  
 
Decay-accelerating factor (DAF) deficiency is associated with  Paroxysmal nocturnal haemoglobinuria 
(PNH). 
Diagnosis 
 CH50 assay screening test

(PNH). 
Diagnosis 
 CH50 assay screening test 
 
Question 
Post splenectomy what type of immunodeficiency is occurs?  
     Humoral    . Post splenectomy there is increased susceptibility to H. Influenzae, N. Meningiti dis and 
Strep pneumonia which are encapsulated organisms  due to the loss of splenic macrophages which 
are part of the humoral response.  
 
If adenosine deaminase is absent from a cell i.e. in severe combined immunodeficiency disease, 
what does this result in?

what does this result in?  
Leads to accumulation of deoxyadenosine .  Adenosine deaminase enzyme leads to the breakdown of 
deoxyadenosine, which is a breakdown product of DNA. Deoxyadenosine is toxic to lymphocy tes, thus 
accumulation of this leads to apoptosis of lymphocytes.   
 
How to exclude antibody deficiency?  
 Presence of Specific antibodies to haemophilus and pneumococci

May 2009 exam: A 23-year-old man is admitted with sepsis. Blood cultures are reported as Neisseria gonorrhoeae  
.Which complement protein is the patient most likely to deficient in?  C5-9 
 
Membrane attack complex (MAC)  
 formed by C5b, C6, C7, C8, and multiple copies of C9 complement proteins on pathogen  cell 
membranes 
 function  lyses pathogens   
 Inhibition 
 CD59  inhibit the complex.  
 This exists on body cells to protect them from MAC.

 paroxysmal nocturnal haemoglobinuria, results in red cells that lack CD59. These  red 
cells can, therefore, be lysed by MAC. 
 
 1597

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  51 
Hereditary angioedema 
 
 Hereditary angioedema is an autosomal dominant  condition associated with low plasma levels of 
the C1 inhibitor (C1-INH) protein .  
 C1-INH is a multifunctional serine protease inhibitor  
 
 deficiency of C1 esterase inhibitor leads to persistent activation of the classical complement pathw ay 
and C4 levels are frequently low secondary to activation and consumption. 
 ↓C1 inhibitor allow C1 to act on C4 and C2 
 Mechanism of attacks : uncontrolled release of bradykinin  resulting in oedema of tissues.  
 
 C1-INH level is low during an attack 
 Low C2 and C4 levels are seen, even between attacks.

  Serum C4 is the most reliable and widely used screening tool 
Symptoms 
 painless, non-pruritic swelling of subcutaneous/submucosal tissues 
 urticaria is not usually a feature 
 attacks may be proceeded by painful macular rash 
 may affect upper airways, skin, genital or abdominal organs (can occasi onally present as abdominal 
pain and vomiting due to visceral oedema) 
 Membrane-attack complex deficiencies leave patients particularly susceptible to neisserial infectio n

 Triggers  include stress, infection and menstruation  
 acute : IV C1-inhibitor concentrate (1000-1500 units given intravenously over 20-30 m in), 
 fresh frozen plasma (FFP) if this is not available 
 prophylaxis :  
 anabolic steroid,  synthetic androgen :  Danazol may help 
 aminocaproic acid  
 
1598

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  52 
  
Other  Causes of angioedema  
 Angioedema associated with angiotensin-converting enzyme (ACE) inhibitors is the 
commonest cause of these swellings involving the face and tongue; it often begins sev eral 
years after starting an ACE inhibitor

years after starting an ACE inhibitor 
 Salicylate- and/or aspirin-associated angioedema  more likely to coexist with urticaria 
 Idiopathic angioedema  
 If treatment fails to normalise the C4 levels and they remain persistently low, these patients are 
at an increased risk of developing SLE . 
The granulomatous response

The granulomatous response 
 A granuloma is a collection of macrophages: giant cells as a nidus of chronic inflamm ation 
 The centre may necrotise to form caseation, classically in tuberculosis 
 Granuloma is seen in : 
 tertiary syphilis 
 sarcoidosis 
 Crohn's  
 Wegener's granulomatosis 
IgG deficiency  
 In IgG subclass deficiency, the overall level of IgG may be normal or sligh tly reduced

 lgG2 deficiency  increase susceptibility to infections with polysaccharide-coated bacteria, including 
Haemophilus influenzae,  multiple presentations with otitis media and respiratory tract infections 
 If these patients are vaccinated with Pneumovax, they are still unable to mou nt a response to S. 
pneumoniae antigens 
 lgG3 deficiency  increase susceptibility to infections with Moraxella catarrhalis, frequent chronic 
sinusitis

sinusitis 
 lgG1 deficiency normally occurs as part of a wider picture of common vari able immunodeficiency  
 
IgG4-related disease 
 IgG4-related disease has been described in virtually every organ system: the bili ary tree, salivary 
glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta,  breast, prostate, thyroid, 
pericardium, and skin.

pericardium, and skin.  
 The histopathological features are similar across organs, regardless of the site.  
 IgG4-related disease is analogous to sarcoidosis, in which diverse organ manifestations are li nked by 
similar histopathological characteristics.  
 Raised concentrations of IgG4 in tissue and serum can be helpful in diagnosing IgG4 disease , 
but neither is a specific diagnostic marker. 
 
Examples include: 
 Riedel's Thyroiditis 
 Autoimmune pancreatitis

 Autoimmune pancreatitis 
 Mediastinal and Retroperitoneal Fibrosis 
 Periaortitis/periarteritis/Inflammatory aortic aneurysm 1599

Notes & Notes for MRCP                                                                                                      By Dr. Yousif Abdallah Hamad  53 
  Kuttner's Tumour (submandibular glands) & Mikulicz Syndrome (salivary and lacrim al glands) 
 Possibly sjogren's and primary biliary cirrhosis 
Isolated IgD deficiency  
 No specific signs or symptoms

 No specific signs or symptoms  
 increased viral respiratory tract infections , 
 IgE deficiency leads to both viral and parasitic infections  
 IgA, IgG and IgM levels are entirely normal 
 isolated IgD deficiency has been identified amongst people of Basque ori gin, hence the link to northern 
Spain  
 not require any specific treatment 
 1600

Basics - Genetics 
 
Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 1 
  
By
 
Genetics
 
Updated 
 
2017
 
Contains: 
 
 1601

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 2 
  
Autosomal dominant conditions 
 
The following conditions are autosomal dominant:  
 Achondroplasia 
 Acute intermittent porphyria 
 Adult polycystic disease 
 Antithrombin III deficiency 
 Familial adenomatous polyposis 
 Hereditary haemorrhagic telangiectasia

 Hereditary haemorrhagic telangiectasia 
 Hereditary spherocytosis 
 Hereditary non-polyposis colorectal 
carcinoma 
 Huntington's disease 
 Hyperlipidaemia type II 
 Hypokalaemic periodic paralysis  Malignant hyperthermia 
 Marfan's syndromes 
 Myotonic dystrophy 
 Neurofibromatosis 
 Noonan syndrome 
 Osteogenesis imperfecta 
 Peutz-Jeghers syndrome 
 Retinoblastoma 
 Romano-Ward syndrome 
 Tuberose sclerosis 
 Von Hippel-Lindau syndrome 
 Von Willebrand's disease*

 Von Willebrand's disease* 
 
As an autosomal dominant condition, two affected parents can expect: 
 1 in 4 chance of an unaffected child 
 1 in 2 chance of an affected heterozygous child 
 1 in 4 chance of an affected homozygous child.  
Which disease demonstrates autosomal co-dominant inheritance?  
 Alpha-1-antitrypsin deficiency  
 
*type 3 von Willebrand's disease (most severe form) is inherited as an autosomal recessive trai t. Around 80% of patients 
have type 1 disease

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 3 
 __________________________________________________________________ 
Achondroplasia  
 
Etiology 
 Mutation in fibroblast growth factor receptor 3 gene (FGFR3) ĺ reduced endochondral 
ossification  
 The homozygous form is usually fatal. 
 
 Most common type of skeletal dysplasia and disproportionate short stature (1:40,000 ch ildren 
worldwide affected) 
 The incidence increases with  paternal  age.  
 Epiphyseal growth cartilage fails, 
 there is normal bone formation and repair .  
 Therefore NO increased risk of fracture.  
Features  
becomes obvious within the first year with disparity between a large skull, normal trunk len gth and short 
limbs. 
 short stature

limbs. 
 short stature  
 short limbs (rhizomelia) with shortened fingers (brachydactyly) 
 The fingertips may only come down to the iliac crest, and the shortness of the lim bs is 
often most marked proximally. 
 short stature due to shortening of the limbs, but spinal length is maintained. 
 The limbs appear broad with deep creases. 
 large head (Macrocephaly) with frontal bossing 
 midface hypoplasia with a flattened nasal bridge 
 'trident' hands 
 lumbar lordosis

 lumbar lordosis 
 Normal intelligence 
 Small foramen magnum  compression of the cervical medulla  
 Spinal canal stenosis and radiculopathy (of the lower back) 
 low back and leg pain,  
 paresthesias, dysesthesia,  
 Secondary scoliosis 
 Recurrent otitis media  
 Cardiopulmonary complications (due to a small chest wall) 
Diagnostics  1603

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 4 
  X-ray  
 It may be diagnosed radiographically at birth , 
 Lateral skull 
 midface hypoplasia,  
 frontal prominence 
 pelvis  
 narrow in anteroposterior diameter with deep sacroiliac notches and short iliac 
wings. 
 Spine 
 progressive narrowing of the interpedicular distance from top to bottom (reverse of

normal). 
 abnormally narrow interpedicular distance → spinal canal stenosis; scoliosis 
 Extremities 
 bones are short and broad;  
 short fingers 
 metaphyseal irregularity,  
 flaring in the long bones,  
 late-appearing irregular epiphyses.  
 medical 
 Early administration of growth hormone  (1–6 years)  
 Surgical corrections:  
 spinal stenosis, secondary scoliosis, genu varum, foramen magnum decompression

__________________________________________________________________ 
Osteogenesis imperfecta ( “brittle bone disease ”) 
 Etiology  
 rare, autosomal dominant mutation  in COL 1A1 or COL 1A2 genes;  
 results  in defective type I collagen synthesis due to decreased synthesis of pro-alpha 1  
or pro-alpha 2  collagen polypeptides.  
 Clinical features   
 Growth retardation  
 Skeletal deformities, brittle bones, and recurrent fractures  from minimal trauma

 Blue sclerae  due to visible choroidal pigment.  
 Progressive  hearing loss  secondary to otosclerosis  
 Brittle, opalescent teeth  (dental imperfections ) 
 Types 
 type 1:The most common, and milder form. 
 Type II: most severe form; lethal perinatally or within the first year  
 Diagnostics  
 DNA test 
 Ultrasonography before birth and radiographic skeletal survey afterwards (fractures,  
callus, deformities)  
 Bone or skin biopsy   type 1 collagen mutation   
 Therapy

 Therapy  
 No cure available 
 IV bisphosphonates  to increase cortical thickness 
 Surgery for functional improvement   
 
May 2009 exam: A pregnant woman is known to have polycystic kidney disease. What is the 
chance her child will also have the disease?  50% (Polycystic kidney disease is usually inherited 
in an autosomal dominant fashion and hence 50% of her children will be affecte d, regardless of 
gender)  
 
Down's syndrome (trisomy 21)   
Epidemiology and genetics 
 the most common autosomal abnormality  
Risk of Down's syndrome with increasing maternal age 
 1604

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 5 
 Age (years) Risk 
20 1 in 1,500 
30 1 in 800 
35 1 in 270 
40 1 in 100 
45 1 in 50 or greater 
 
One way of remembering this is by starting at 1/1,000 at 30 years and then dividing t he denominator by 
3 (i.e. 3 times more common) for every extra 5 years of age  
 
Cytogenetics  
Mode % of cases Risk of recurrence

Mode % of cases Risk of recurrence 
Non-disjunction 94% 1 in 100 if under mother < 35 years 
Robertsonian translocation 
(usually onto 14) 5% 10-15% if mother is translocation carrier 
2.5% if father is translocation carrier 
Mosaicism 1%  
 
 The chance of a further child with Down's syndrome is approximately 1 in 100 if the mother  is 
less than 35 years old. If the trisomy 21 is a result of a translocation the risk is much higher.  
 Down syndrome have one of the two karyotypes:

 Down syndrome have one of the two karyotypes:  
1. 47,XX,+21 (trisomy 21)  
 more common  
2. 46,XY,der(14;21).  
 characterized by the presence of two normal chromosomes 21, one normal 
chromosome 14 and a product of Robertsonian translocation between 
chromosomes 14 and 21 (der(14;21); der stands for derivative).  
 
Features  
 face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongu e, 
small ears, round/flat face

small ears, round/flat face 
 flat occiput 
 single palmar crease, pronounced 'sandal gap' between big and first toe 
 hypotonia 
 congenital heart defects (40-50%, see below) 
 duodenal atresia can be diagnosed by U/S at gestation  double bubble sign  
 Hirschsprung's disease 
 
associations 
 Children with Down syndrome are at increased risk for developing acute myeloid 
leukemia (AML)  (approximately 1-2% of children with Down syndrome develop AML, the great

majority < 5 y) rather than acute lymphoblastic leukemia (ALL), which is a more common form  of 
leukemia in children. 
 Other haematological disorders associated with Down's syndrome include: 
 Fanconi's anaemia,  
 Patients with learning disabilities may be prone to lead poisoning due to pica. 
 
Cardiac complications  
  50% of children with Down's syndrome have a cardiac defect. 
 multiple cardiac problems may be present 1605

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 6 
  endocardial cushion defect (c. 40%, also known as atrioventricular septal canal defects)  
 ventricular septal defect (c. 30%) 
 secundum atrial septal defect (c. 10%) 
 tetralogy of Fallot (c. 5%) 
 isolated patent ductus arteriosus (c. 5%) 
Later complications

Later complications  
 subfertility: males are almost always infertile due to impaired spermatogenesis.  Females are 
usually subfertile,  and have an increased incidence of problems with pregnancy and labour 
 learning difficulties 
 repeated respiratory infections (+hearing impairment from glue ear) 
 acute lymphoblastic leukaemia 
 Alzheimer's 
 atlantoaxial instability 
Diagnosis 
Screening tests

Diagnosis 
Screening tests  
 Increased nuchal translucency is a finding on ultrasound  that may suggest trisomy 21 or 
other chromosomal defects such as trisomy 18 or 45 XO, thus additional testing is required to 
confirm the diagnosis.  
 Alpha-fetoprotein (AFP),  human chorionic gonadotropin (hCG),  urine unconjugated estriol , and 
inhibin are components of the quad screen for Down syndrome.  
 Ļ AFP Ļ unconjugated estriol Ĺ hCG Ĺ inhibin is consistent with the diagnosis of

Down syndrome. 
 quad screen done between the 15th and 22nd weeks of the pregnancy.  
 In pregnancies where the fetus has Edwards syndrome (trisomy 18),  unconjugated 
estriol and hCG  levels are  low and AFP levels can be variable.  
 Anencephaly will have a low hCG and a high AFP value. 
  Beta hCG should double in value every 48-72 hours and a decreased hCG should raise  
suspicion for an ectopic pregnancy or a missed abortion.

 Elevations of AFP  are associated with neural tube defects , multiple gestations or 
abnormal dating.  
 amniocentesis 
 
Noonan ’s syndrome  
 Noonan ’s syndrome is a mutation affecting the RAS-MAPK pathway.  
 It is an autosomal dominant disorder  
feature 
 short stature,  
 learning disabilities,  
 pectus deformity and

 pectus deformity and  
 congenital cardiac defects (typically pulmonary stenosis, atrial septal defect (ASD) and 
occasionally hypertrophic cardiomyopathy). 
1606

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 7 
 Autosomal recessive conditions 
  
Two copies of the defective gene (one 
inherited from each parent) are required in order 
to be born with the disorder.  
Autosomal recessive conditions are often 
thought to be ' metabolic ' as opposed to 
autosomal dominant conditions being 'structural', 
notable exceptions:

notable exceptions: 
 some ' metabolic' conditions such as 
Hunter's and G6PD are X-linked 
recessive whilst others such as 
hyperlipidemia type II and hypokalemic 
periodic paralysis are autosomal 
dominant 
 some 'structural' conditions such as 
ataxia telangiectasia and Friedreich's 
ataxia are autosomal recessive 
 
The following conditions are autosomal recessive : 
 
 Albinism 
 Ataxia telangiectasia 
 Congenital adrenal hyperplasia 
 Cystic fibrosis 
 Cystinuria

 Cystinuria 
 Familial Mediterranean Fever 
 Fanconi anaemia 
 Gilbert's syndrome* 
 Glycogen storage disease  Haemochromatosis 
 Homocystinuria 
 Lipid storage disease: Tay-Sach's, 
Gaucher, Niemann-Pick 
 Mucopolysaccharidoses: Hurler's 
 PKU 
 Sickle cell anaemia 
 Thalassaemias 
 
*this is still a matter of debate and many textbooks will list Gilbert's as autosomal dominant

May 2012 exam: A man diagnosed as having hereditary hemochromatosis. His wife is not a carrier. 
What is the chance his child will develop haemochromatosis?  0% (Haemochromatosis is an autosomal 
recessive condition. If one of the parents has haemochromatosis (i.e. is homozygous) and the oth er is not a 
carrier/affected then all the children will inherit one copy of the gene from the affected parent an d hence will be carriers)

Pseudoxanthoma elasticum 
 inherited condition ( usually autosomal recessive *) characterised by an abnormality in elastic 
fibres 
 *there are reports of autosomal dominant inheritance in a minority of cases  
 
Features  
 retinal angioid streaks 
 'plucked chicken skin' appearance  - small yellow papules on the neck, antecubital fossa and 
axillae

axillae 
 cardiac: mitral valve prolapse, increased risk of ischaemic heart disease 
 Due to loss of elastic tissue, patients have an increased incidence of mitral regurgitation, 
aortic regurgitation and aortic dissection. 
 gastrointestinal haemorrhage 
1607

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 8 
 Phenylketonuria (PKU) 
 Phenylalanine is an essential amino acid.  
 Phenylketonuria (PKU) is an autosomal recessive condition  
 Caused by a disorder of phenylalanine metabolism.  
 usually due to defect in phenylalanine hydroxylase , an enzyme which converts 
phenylalanine to tyrosine .

phenylalanine to tyrosine .  
 In a small number of cases the underlying defect is a deficiency of the tetrahyd robiopterin-
deficient cofactor, e.g. secondary to defective dihydrobiopterin reductase.  
 The gene for phenylalanine hydroxylase is located on chromosome 12.  
 The incidence of PKU is around 1 in 10,000 live births. 
 High levels of phenylalanine lead to problems such as learning difficulties and seizures.  
 
Features

Features 
 usually presents by 6 months e.g. with developmental delay, infantile spasms 
 child classically has fair hair and blue eyes 
 Even with dietary treatment some degree of cognitive impairment is seen  
 Microcephaly, prominent maxilla, growth retardation and wide-spaced teeth are found  in 
untreated children. 
 seizures, typically infantile spasms 
 About 25% of infants have seizures, but over 50% have an abnormal EEG.

 Cerebral white matter changes are seen in older patients and may reflect a combination of lat e 
diagnosis and dietary indiscretion. 
 eczema 
 'musty' odour  to urine and sweat* (*secondary to phenylacetate, a phenylketone)  
Diagnosis 
 Diagnosis of classic PKU requires raised Phe levels, increased urinary Phe metabolites  and 
normal cofactor (tetrahydrobiopterin) concentrations.  
 plasma levels of tyrosine are difficult to measure, and have diurnal variation. Whilst the

levels are often low in patients with PKU, the levels can be normal depending on what 
time of the day the sample is taken and whether or not the patients are being  treated. 
 Guthrie test: the 'heel-prick' test done at 5-9 days of life - also looks for oth er biochemical 
disorders such as hypothyroidism 
 hyperphenylalaninaemia 
 phenylpyruvic acid in urine 
 poor evidence base to suggest strict diet prevents learning disabilities

 dietary restrictions are however important during pregnancy as genetically normal fetuse s may 
be affected by high maternal phenylalanine levels 
Alkaptonuria 
The black  discoloration of sclera and urine becoming black  on standing should alert you to the 
likelihood of Alkaptonuria . 
 
 autosomal recessive disorder of phenylalanine and tyrosine metabolism  
1608

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 9 
  caused by  a deficiency of homogentisic acid oxidase  responsible for the degradation of 
homogentisic acid produced from phenylalanine and tyrosine. 
 Accumulation of homogentisic acid causes pigmentation of the urine, sclera and conne ctive 
tissues.

tissues.  
 Alkaptonuria is generally a benign and often asymptomatic condition.  
Features  
 pigmented sclera 
 urine turns black if left exposed to the air 
 Deposition in the joints causes cartilage pigmentation (ochronosis) and degeneration.  
 Patients develop arthritis at 40 years of age.  
 intervertebral disc calcification may result in back pain 
 The knees and spine are commonly affected.  
 The sacroiliac joint may be spared.  
 renal stones

 Homogentisic acid is a reducing agent, therefore it gives a false positive Glucostix test  but 
normal Clinitest. 
Treatment 
 high-dose vitamin C 
 dietary restriction of phenylalanine and tyrosine 
X-linked recessive 
 
 The abnormal gene is carried on the X chromosome, and in the carrier female, the norm al allele

on her other X chromosome protects her from the disease. Since the male does not h ave this 
protection, he manifests the disease.  
 only males are affected. An exception to this seen in examinations are patients with Turner's 
syndrome, who are affected due to only having one X chromosome.  
 Females only occasionally show mild sign of disease 
  X-linked recessive disorders are transmitted by heterozygote females (carriers) and  male- to-
male transmission is not seen.

male transmission is not seen.  
 Affected males can only have unaffected sons and carrier daughters.  
 heterozygous female carrier  
 50% of male children are affected  
 50% of female children are carrier  
 The possibility of an affected father having children with a heterozygous female carrier is 
generally speaking extremely rare. However, in certain Afro-Caribbean communities G6PD 
deficiency is relatively common and homozygous females with clinical manifestations of the

enzyme defect are seen.   
 Many of the inherited eye disorders such as retinitis pigmentosa and ocular albinism are 
inherited in an x-linked recessive pattern. 
 The following conditions are inherited in a X-linked recessive fashion:  
 Androgen insensitivity syndrome  
 Becker muscular dystrophy 
 Colour blindness 
 Duchenne muscular dystrophy 
 Fabry's disease 
 G6PD deficiency 
 Haemophilia A,B  Hunter's disease 
 Lesch-Nyhan syndrome 
 Nephrogenic diabetes insipidus

 Nephrogenic diabetes insipidus 
 Ocular albinism 
 Retinitis pigmentosa 
 Fragile X syndrome 
 
 The following diseases have varying patterns of inheritance, with the majority being in an 
X-linked recessive fashion:  
      - Chronic granulomatous disease (in > 70%)  
 
1609

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 10 
Fabry's disease 
 X-linked recessive,  lysosomal storage disorder characterised by myelin deposits in tubular 
epithelium and vascular endothelium, resulting in ischaemic nephropathy 
Aetiopathogenesis

Aetiopathogenesis 
 The molecular defect is a deficiency of α-galactosidase A  
 The affected lysosomal enzyme, α -galactosidase A, converts trihexosyl ceramide to 
lactosyl ceramide.  
 Accumulation of trihexosyl ceramide  in the endothelial smooth muscle cells of blood 
vessels causes ischemia and infarction, particularly in the kidneys, which explains the 
elevated BUN and proteinuria. 
Features and Complications 
The disorder has three distinct clinical entities:

1. Classical presentation in the male homozygote with early presentation in childhood - 
angiokeratomas, heart failure, cataracts and renal disease 
2. Male homozygotes with atypical presentation in adulthood with proteinuria, 
acroparaesthesia, angiokeratomas and cardiomegaly 
3. Female heterozygotes can present again in adulthood with similar mild symptoms. 
 An X linked recessively inherited condition can exist in female carriers who may exhibit

mild to moderate symptoms. This is due to variable expression according to random X 
inactivation of the affected gene in embryogenesis  
 
 often start in childhood or adolescence  
 Opacity of the lens and cornea ,  
 skin lesions  with telangiectasia and a warty, hyperkeratinized covering ( angiokeratoma ),  
 Angiokeratomas are present in 66% of male and 36% of female 
  They are non-blanching, red to blue-black lesions 1-5 mm in diameter.

 The earliest lesions are observed on the hands, knees, elbows and flanks. 
 Peripheral neuropathy  
 paresthesias in the extremities,  
 usually burning in nature,  
 painful stocking-glove neuropathy 
 Patients may complain of pain and burning in the hands and feet that worsens with  
exercise or hot weather  
 hypohidrosis  (decreased sweating) 
 vascular diseases of the brain, heart, and kidneys.

 accumulation of the sphingolipids can lead to systemic vasculopathy 
 Often, renal disease is progressive and can lead to death. 
 cardiac conduction defects  
most common symptoms  peripheral neuropathy, angiokeratomas, and hypohidrosis.  
 
Diagnosis 
 The diagnosis is confirmed by demonstration of  absent or deficient levels of alpha-
galactosidase A  in leucocytes, plasma or cultured fibroblasts.

 The most efficient means of diagnosis is by slit-lamp examination  of the cornea, which reveals 
microscopic lipid deposits 
 Microscopy of the spun urine sediment may demonstrate 'Maltese cross' lipid globules 
 Further clues to the diagnosis include skin angiokeratomas , decreased sweating  and leg 
lymphedema 
 
In Fabry disease, tissue accumulation of which is most likely to occur? 
 Trihexosyl ceramide  
 
X-linked dominant disorders  
 
 No carrier (the carrier of a defective gene associated with a disorder, will have the 1610

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 11 
 disorder)  
 affected woman  Half of the daughters and sons are affected 
 affected father  all his daughters are affected but none of his sons. 
 
 The gene responsible for a genetic disorder is located on the X chromosome, and only o ne copy

of the allele is sufficient to cause the disorder when inherited from a parent who h as the disorder. 
 X linked dominant disorders are rare (for example, vitamin D-resistant rickets ). 
 They affect both sexes but females more than males.  
 Males can only get an X chromosome from their mother whilst females get an X  
chromosome from both parents. As a result, females tend to show higher prevalence of X -
linked dominant disorders because they have more of a chance to inherit a faulty X

chromosome. 
 Homozygous mother  All children are affected. 
 An affected mother with the trait  half the sons and half the daughters inherit the disorder 
  when the mother alone is the carrier ; she herself will have the disorder.  
 50% Of her daughters and sons will have the disorder,  
 50% will be unaffected.  
 Affected females will transmit the condition to 50% of their children , whether male or 
female.

female.  
 When the father alone is the carrier of a defective gene associated with a disorder, he t oo will 
have the disorder.  
 100% Of his daughters will have the disorder, since all of his daughters will receive  one 
copy of his single X chromosome.  
 none of his sons will have the disorder; sons do not receive an X chromosome from t heir 
father.  
 affected father  all his daughters are affected but none of his sons.

Vitamin D-resistant rickets 
 Vitamin D-resistant rickets is a X-linked dominant  condition  
 affected female will transmit the disease to 50% of her sons and 50% of her da ughters. 
 affected male will transmit the condition to all of his daughters but none of his so ns. 
 usually presents in infancy with failure to thrive.  
  It is caused by impaired phosphate reabsorption in the renal tubules  
Features

Features  
 normal serum calcium, low phosphate, elevated alkaline phosphotase 
 x-ray changes: cupped metaphyses with widening of the epiphyses 
Diagnosis is made by demonstrating increased urinary phosphate 
 
 high-dose vitamin D supplements 
 oral phosphate supplements 
____________________________________________________________________ 
Mitochondrial diseases
 
1611

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 12 
   
myoclonic epilepsy with ragged red fibres 
(MERRF): 
a young patient  presenting with cognitive 
impairment developing after a period of normal 
development, seizures, myoclonic jerks, Wolff-
Parkinson White syndrome and worsening 
vision (consistent with optic atrophy). 
diagnosis  (MERRF), which is a

diagnosis  (MERRF), which is a 
mitochondrial DNA disorder diagnosed by   
ragged red fibres on muscle biopsy.  
 
 Whilst most DNA is found in the cell nucleus, a small amount of double-stranded DNA is p resent 
in the mitochondria. It encodes protein components of the respiratory chain and so me special 
types of RNA  
Mitochondrial inheritance has the following characteristics : 
 inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote

 all children of affected males will not inherit the disease 
 all children of affected females will inherit it 
 generally encode rare neurological diseases 
 poor genotype: phenotype correlation  - within a tissue or cell there can be different 
mitochondrial populations - this is known as heteroplasmy) 
Histology  
 muscle biopsy classically shows 'red, ragged fibres'  due to increased number of mitochondria 
 Leber's optic atrophy

 Leber's optic atrophy 
 Cyanocobalamin (a form of B12) should be avoided as it may lead to blindness in Le ber's 
disease patients. 
 MELAS syndrome: mitochondrial encephalomyopathy lactic acidosis and stroke-like ep isodes 
 MERRF syndrome: myoclonus epilepsy with ragged-red fibres 
Kearns-Sayre syndrome:  
Kearns-Sayre syndrome produces the classic triad of:

 Progressive external ophthalmoplegia 
 Pigmentary degeneration of the retina and 
 Heart block. 
 
 mitochondrial DNA mutation. 
 It is a slowly progressive neuromuscular disorder associated with progressive external 
ophthalmoplegia and heart conduction defect.  
 onset in patients < 20 years old 
 external ophthalmoplegia 
 retinitis pigmentosa 
 Ptosis may be seen 
 sensorineural hearing loss is almost universal in those who survive into the fourth decade o f life;

this may not be fully corrected with hearing aids.  
 Other associated features: cerebellar ataxia, cardiac conduction block, raised cerebrospinal fluid 
(CSF) proteins, and proximal myopathy. 
1612

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 13 
  short stature and multiple endocrinopathies  including diabetes mellitus, hypoparathyroidism, 
and Addison disease. 
 Muscle biopsy may reveal ragged red fibers. 
 Muscle histochemistry   reveals deficiency of cytochrome c oxidase (mitochondrial respiratory 
chain enzyme).

chain enzyme). 
 
 Kallman's syndrome  
 
 Kallman's syndrome is a recognised cause of delayed puberty secondary to hypogonado trophic 
hypogonadism.  
 It is usually inherited as an X-linked recessive  trait.  
 Whilst the majority of cases are sporadic, perhaps up to 50% of cases are due to g enetic 
inheritance. 
 caused by failure of GnRH-secreting neurons to migrate to the hypothalamus  gonadotrophin

releasing hormone (GnRH) deficiency 
 may arise due to abnormalities of the KAL-1 or KAL-2 gene (encoding an osmin-1 and FGF-1). 
 There is isolated gonadotrophic deficiency (may be evidenced by a normal prolactin).  
 The clue given in many questions is lack of smell (anosmia) in a boy with delayed puberty 
Incidence  
 1 in 10,000 males,  
 More common in men : male to female ratio of 4:1.  
Features  
 delayed puberty 
  hypogonadotrophic hypogonadism  
 sex hormone levels are low

 sex hormone levels are low 
 LH, FSH levels are inappropriately low/normal 
 Lack of development of secondary sexual characteristics  
 Primary amenorrhoea. 
 cryptorchidism (Cryptorchidism is more suggestive of Kallman's than Klinefelter's 
syndrome)  
 Cryptorchidism is the absence of one or both testes from the scrotum (undescended 
testis). 
 anosmia  (Lack sense of smell) due to failure of the olfactory bulb to develop, leading to 
loss of gonadotropin releasing hormones.

loss of gonadotropin releasing hormones.  
 Anosmia is present in 75%  
 Cleft lip/palate 
 visual defects : colour blindness,  
 deafness. 
 patients are typically of normal or above average height 
 no mental retardation 
Diagnosis 
 Diagnostic test  Fluorescent in situ hybridisation (FISH)   is currently the best means of a 
genetic diagnosis  
 Absent olfactory bulbs are present on 75% of MRI scans in these patients. 
1613

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 14 
  The appearance on cerebral MRI  Absent olfactory bulbs 
Treatment  
 For a male who begin a relationship with a woman  
 Pulsed (NOT Continuous)  GnRH treatment  is needed to restore LH and FSH release.  
 It needs to be continued for as long as fertility is required.

 As natural GnRH release is pulsatile, continuous therapy fails to lead to LH and 
FSH release. 
 Once his family is complete, switching to testosterone therapy may be more 
convenient for him. 
 Although Testosterone supplementation will restores secondary sexual 
characteristics, it doesn ’t restore fertility and is therefore not appropriate here. 
 FSH can be used to induce fertility, but it is less effective than pulsed GnRH 
therapy.

therapy.  
 LH can be used in conjunction with FSH to induce fertility in women with Kallmann 
syndrome . 
 For a woman who wants to start a family: 
 HCG  to drive production of gonadal steroid hormones, FSH to drive ovulation, harvesting 
of eggs, and IVF. This process is most effective in achieving successful pregnancy.  
Klinefelter's syndrome

Klinefelter's syndrome 
 
 Klinefelter's syndrome is associated with  male phenotype and 47, XXY karyotype  
 the commonest form of which is XXY, is the result of chromosomal non-dysjunction; as su ch, it 
does not follow a mendelian pattern of inheritance.  
 Population studies suggest that the rate of occurrence in live male births is between 1 in 500  and 
1 in 1000.   
 The rate of chromosomal non-dysjunction increases with increasing maternal age and inc reasing

paternal age, each parent contributing 50% of the risk. Around 60% of Klinefelter ca ses do not 
survive the fetal period.  
 has no specific genetic pattern of inheritance  
  chances of inheriting  the disorder   < 1%  
 
Features  
 often taller than average 
 lack of secondary sexual characteristics 
 small, firm testes 
 infertile,  azoospermia 
 gynaecomastia   
 increased incidence of breast cancer  (20 times higher than a normal male).

 elevated gonadotrophin levels ( ĹĹLH/FSH) due to testicular failure 
 Low testosterone levels  
 Low HDL cholesterol , elevated triglyceride ,normal or increased (LDL) 
 increased cardiovascular risk due to lipid abnormality. 
 decrease libido  
 decrease bone mineral density  increased risk of osteoporotic fractures. 
 
 Diagnosis is by chromosomal analysis  
 the most appropriate investigation in suspected cases  FSH, LH

 Both FSH and LH are raised in Klinefelter syndrome, and elevation would be a strong 
pointer to confirming the underlying diagnosis. 
1614

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 15 
   more useful than Testosterone (wouldn ’t indicate whether the defect was at the level of 
the pituitary or the testes) 
Treatment  with testosterone 
 Testosterone is known to improve bone mineralization and is the treatment of 
choice 

Turner's syndrome 
 
 Turner's syndrome is a chromosomal disorder affecting around 1 in 2,500 females.  
 It is caused by either the presence of only one sex chromosome (X) or a deletion of the short arm  
of one of the X chromosomes.  
  Turner's syndrome is denoted as 45,XO or 45,X  
Features  
 shield chest, widely spaced nipples 
 webbed neck 
 cardiac defects: bicuspid aortic valve (15%), coarctation of the aorta (5-10%) 
 primary amenorrhoea

 primary amenorrhoea 
 associated absent uterus and streak ovaries  
 cystic hygroma (often diagnosed prenatally) 
 short fourth metacarpal 
 multiple pigmented naevi 
 keloid scars  
 lymphoedema in neonates (especially feet) 
 Horseshoe kidney  is strongly associated with Turner ’s syndrome 
 often initially presents with stone disease, pelviureteric junction (PUJ) obstruction, trauma, 
infections and tumors.

infections and tumors.  
 In a pediatric patient with multiple urinary tract infections or renal stones, imaging must  be 
performed to rule out this congenital anomaly. 
1615

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 16 
  Which anatomical structures is responsible for horseshoe kidney anomaly during 
normal embryological development? 
 Inferior mesenteric artery 
 occurs when the isthmus of the kidney becomes trapped behind the inferior 
mesenteric artery as the kidneys ascend during embryonic life.  
Associated conditions

Associated conditions   
 autoimmune diseases: 
 autoimmune thyroiditis (hypothyroidism (much more common in Turner ’s) ) 
 and Crohn's disease 
 Hypertension is quite common in Turner syndrome (10%) and is typically idiopathic - 
essential.  In a small proportion causes can include:  
 coarctation of the aorta  
 and renal dysfunction due to horsehoe kidney. 
 metabolic abnormalities (dyslipidaemia and glucose intolerance) 
 recurrent otitis media. 
Diagnosis

Diagnosis 
    made by  karyotype  identification of 45X0 . 
 
Marfan's syndrome 
 autosomal dominant  connective tissue disorder.  
 caused by a defect in the fibrillin-1 gene on chromosome 15  
 affects around 1 in 3,000 people.  
 may occur as a spontaneous mutation, (1/3rd of cases), and this occurs more commonly to  
offspring of older males.  
Features

Features  
 tall stature with arm span to height ratio > 1.05 
 arachnodactyly 
 pectus excavatum 
 pes planus 
 scoliosis of > 20 degrees 
 crowded teeth. 
 Heart :  
 dilation of the aortic sinuses (seen in 90%)  which may lead to aortic aneurysm, aortic 
dissection, aortic regurgitation, mitral valve prolapse (75%), 
 lungs: repeated pneumothoraces 
 eyes:  
 upwards lens dislocation (superotemporal ectopia lentis)

 seen in 50% of patients ,  
 blue sclera,  
 myopia 
 early glaucoma, and early cataracts. 
 increased axial globe length 
 dural ectasia (ballooning of the dural sac at the lumbosacral level) 
 Dural ectasia affects around 60% of patients with Marfan's syndrome.  
 It may cause lower back pain associated with neurological problems such as 
bladder and bowel dysfunction. 
 
Diagnosis

Diagnosis 
 Unfortunately DNA testing for fibrillin gene mutations, whilst helpful, cannot exclude a 
diagnosis of Marfan  because a number of mutations exist (at least 130 ).  
 Hence diagnosis is made on the major and minor features associated with the syndrome.  
Prognosis & treatment : 
 The life expectancy of patients used to be around 40-50 years.  
 With the advent of regular echocardiography monitoring and beta-blocker/ACE-inhibito r therapy

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 17 
  Treatment with β -blockers reduces the rate of aortic dilatation and the risk of rupture 
 Aortic dissection and other cardiovascular problems remain the leading cause of death ho wever. 
 Pregnancy is associated with increased risk of aortic rupture

Homocystinuria 
 autosomal recessive disease  
 caused by deficiency of cystathionine beta synthase  which is responsible for converting 
homocysteine to cystathionine. Cystathionine is later converted to cysteine, so patients who have  
this enzyme deficiency need to supplement their diets with exogenous  cysteine .  
 Results in an accumulation of homocysteine which is then oxidized to homocystine.  
Types

Types 
 homocystinuria  type 1   a defect in cystathionine synthetase is responsible. 
 homocystinuria  type 2   defects in methylene tetrahydrofolate reductase  
 However, individuals with this condition rarely survive the neonatal period or, if they 
survive longer than this, they often have more severe mental retardation. 
Features  
 fine, fair hair 
 musculoskeletal: may be similar to Marfan's - arachnodactyly etc

 neurological: learning difficulties, mild to moderate mental handicap , seizures 
 ocular: downwards (inferonasal) dislocation of lens 
 The sudden visual deterioration could either be due to a thrombotic episode or to the lens 
dislocation associated with this condition.  
 increased risk of arterial and venous thromboembolism  (atherosclerosis, thrombosis, MI)  
 the most common cause of death.   
 malar flush,  
 livedo reticularis  
Diagnosis

Diagnosis  
 made by the cyanide-nitroprusside test , which is also positive in cystinuria 
Treatment    
 dietary modification aim to: 
  reduce intake of methionine  
  increase intake of cysteine.   
 vitamin B6 (pyridoxine) supplements 
 Folate and vitamin B12 are facilitate the conversion of homocysteine to methionine.  
 
Homocystinuria  VS Marfan's  
 
 homocystinuria  Marfan's syndrome 
inheritance autosomal recessive autosomal dominant 
lens

lens 
dislocation downward lens dislocation upward lens dislocation 
aortic 
incompetence heart rarely affected aortic incompetence may 
occur 
intellectual 
development mental retardation  (nearly 50%)  normal  
 livedo 
reticularis  seen due to the venous thrombosis in the small 
vessels of the skin NO 
other 
principle 
features osteoporosis , recurrent thromboembolism; 
characteristic laboratory features : 
 plasma methionine and homocystine levels are

plasma methionine and homocystine levels are 
elevated, homocystine is excreted in the urine, 
plasma cystine levels are reduced, positive urine 
cyanide-nitroprusside test; response to treatment 
with pyridoxine flat feet, herniae, scoliosis; 
there is a 50% reduction in 
life expectancy 
Fragile X syndrome  
Characteristics of individuals with Fragile X syndrome may include:

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 18 
  macroorchidism 
 prognathism 
 speech delays 
 prominent forehead 
 double-jointedness 
 autistic symptoms, and 
 occasional self-mutilation. 
 The face is typically long and narrow, with a high arched palate and large ears. 
 Otitis media, strabismus, and dental problems may be present

 hyperextensible joints 
 hypotonia, and 
 heart problems, including mitral valve prolapse. 
 In post pubertal males, abnormally large testes  are a distinctive feature. 
The following can occur In young children: 
 delayed motor development 
 hyperactivity 
 behavioural problems 
 toe walking, and 
 occasional seizures. 
Porphyrias 
 
Overview

Overview 
 
 Porphyria is a group of diseases characterised by excess production and excretion of porphy rins 
and their precursors. 
 They are caused by enzyme defects within the haem metabolic pathway. 
 Stress, infection, pregnancy, menstruation, starvation, and certain drugs may precipitate 
acute attacks. 
 Definite precipitants include sulphonamides, barbiturates, and phenytoin. 
 may be acute or non-acute

 may be acute or non-acute 
 The most common presenting sign of PCT is fragility of sun exposed skin after mechanical trauma , 
leading to erosions and bullae, worst on dorsal hands, forearms, and face. 
 
1618

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 19 
  
Acute intermittent porphyria  (AIP)  
 defect in porphobilinogen deaminase 
 caused by a defect in porphobilinogen deaminase, an enzyme involved in th e biosynthesis of 
haem.  
 20-40 year olds more likely to be affected ( only rarely presents before puberty)

 AIP is more common in females (5:1)  
 90% of affected individuals remain asymptomatic throughout their lives.  
 typically present with abdominal symptoms, neuropsychiatric symptoms 
 Seizures occur in 10-20% of patients with acute intermittent porphyria (AIP). 
 A range of psychiatric symptoms, including hypomania and delirium may be seen . 
 hypertension and tachycardia common 
 urine turns deep red on standing

 urine turns deep red on standing 
 Patients excrete urinary porphobilinogen (PBG) between and during acute attacks.  
 Faecal porphyrin excretion is usually normal or slightly increased. 
 Photosensitivity is  unusual  in AIP  
 All attacks of porphyria increase the activity of hepatic 5-aminolevulinate (ALA) syntha se. 
 Lab features 
 hyponatraemia,  
 mild leukocytosis. 
Factors precipitate an acute attack : 
 treatment of seizures in AIP  Gabapentin 
 
 Stress, 
 Infection

 Stress, 
 Infection 
 Menstruation 
 starvation  
 Drugs 
 sulphonamides, 
 barbiturates 
 phenytoin. 
 Most anti-epileptics should not be given, but gabapentin is safe and the most 
appropriate choice for  seizures occur in (AIP). 
 ACE inhibitors and calcium channel blockers  
 Ibuprofen is safe for use in acute intermittent porphyria, but diclofenac should be 
avoided. 
 
1619

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 20 
  
Acute intermittent porphyria: drugs 
 
Drugs which may precipitate attack  Safe Drugs  
 Alcohol 
 Barbiturates 
 Benzodiazepines 
 Tricyclic antidepressants 
 Halothane 
 Oral contraceptive pill 
 Cephalosporins 
 Erythromycin 
 flucloxacillin  
 Anabolic steroids

 Anabolic steroids 
  Sulphonylureas 
 Theophylline 
 Antihistamines 
 MAOIs 
 Amiodarone  
 Simvastatin. 
 calcium channel 
blockers 
  Paracetamol 
 Aspirin 
 Ibuprofen  
 Codeine 
 Morphine 
 Chlorpromazine 
 Gabapentin 
 Penicillin 
 amoxicillin  
 
Diagnosis 
 Urinary porphobilinogen assay is the optimal way to establish the diagnosis. 

 glucose and heme , which inhibit delta-aminolevulinic acid synthase, thereby decreasing heme 
precursor synthesis. 
 Two procedures have been shown to decrease the activity of ALA synthase in an imals: 
1. carbohydrate loading and  
2. parenteral infusion of haem arginate.   
Consequently, these two procedures are the mainstay of the treatment along with opiat e 
analgesia.  
 The treatment of choice in acute porphyria is intravenous haem arginate

 high-glucose diets or infusions have been used for mild attacks of pain without neurolog ical 
symptoms  
 
Distinguishing between lead poisoning and acute intermittent porphyri a 
Which one of the following features in an adult patient presenting with porphyrinuria would 
most suggest lead poisoning rather than acute intermittent porphyria as a cause? 
 Anaemia 
 Anaemia occurs only in lead poisoning and is due to:

 inhibition of ferrochelatase (the activity of this enzyme is normal in acute intermittent 
porphyria) 
 a decrease in red cell lifespan 
 enzyme inhibition (pyrimidine 5'-nucleotidase) leading to the accumulation of pyrim idine 
nucleotides in red cells, which in turn reduces the stability of the cell membrane (and is 
seen on a blood film as basophilic stippling) 
 
Porphyria cutanea tarda (PCT)  
 most common hepatic porphyria 
 defect in uro-porphyrinogen decarboxylase

 defect in uro-porphyrinogen decarboxylase 
 can be both acquired and inherited 
 may be caused by hepatocyte damage e.g. alcohol, oestrogens (oral contraceptive pil l)  
 classically photosensitive  rash with bullae ,  
 Bullae develop on sun-exposed areas 
 When exposed to light, uroporphyrinogen generates free radicals that cause bli stering of 
the skin. 
 lesions heal slowly, leaving scars. 1620

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 21 
  skin fragility on face and dorsal aspect of hands 
 Factors contributing to PCT are:  
  alcohol (the commonest cause),  
 excess iron and  
 excess oestrogens.  
 Urine: elevated uroporphyrinogen (Urinary porphyrins)and pink fluorescence of urin e under 
Wood's lamp

Wood's lamp   
 Porphyrins are increased in liver, plasma, urine and stool.  
 Porphobilinigen (PBG) is normal.  
 Assay of red blood cells for uroporphyrinogen decarboxylase (UROD) activity is now available  
 Antinuclear antibodies are frequently seen 
 manage with Chloroquine 
 PCT can be treated with phlebotomy to deplete the excess iron stores that exacerba te the 
porphyria. 
Variegate porphyria  
 defect in protoporphyrinogen oxidase

 defect in protoporphyrinogen oxidase 
 photosensitive blistering rash 
 abdominal and neurological symptoms 
 more common in South Africans 
Trinucleotide repeat disorders 
 
 Trinucleotide repeat disorders are genetic conditions caused by an abnormal number of  repeats 
(expansions) of a repetitive sequence of three nucleotides.

 These expansions are unstable and may enlarge which may lead to  an earlier age of onset in 
successive generations - a phenomenon known as anticipation . In most cases, an increase 
in the severity of symptoms is also noted  
Examples  - note dominance of neurological disorders  
 Fragile X (CGG) 
 Huntington's (CAG) 
 myotonic dystrophy (CTG) 
 Friedreich's ataxia* (GAA) (*Friedreich's ataxia is unusual in not demonstrating anticipation) 
 spinocerebellar ataxia

 spinocerebellar ataxia 
 spinobulbar muscular atrophy  
 Kennedy disease , also known as 'X-linked bulbospinal neuronopathy' 
 dentatorubral pallidoluysian atrophy 
Human genome  
Human genome - 25,000 protein-coding genes 
 The human genome is stored on 23 chromosome pairs.  
 The haploid human genome has a total of 3 billion DNA base pairs, making up an esti mated 
20,000-25,000 protein-coding genes

20,000-25,000 protein-coding genes 
Polygenic diseases 
 genetic disorder that is caused by the combined action of more than one gene.  
 Examples of polygenic conditions include: 
  hypertension,  
 coronary heart disease ,  
1621

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 22 
  diabetes 
  Amyotrophic lateral sclerosis (ALS)  
 Because such disorders depend on the presence of several genes, they are not inheri ted as 
simply as are single-gene diseases. 
 
Pseudoxanthoma elasticum

 Pseudoxanthoma elasticum is an inherited condition (usually autosomal recessive*) 
characterised by an abnormality in elastic fibres. 
 *there are reports of autosomal dominant inheritance in a minority of cases   
 
Features  
 'plucked chicken skin' appearance - small yellow papules on the neck, antecubital fossa and 
axillae 
 gastrointestinal haemorrhage

Causes of early developmental delay and learning difficulties 
Chromosomal abnormalities and fragile X syndrome are among the commonest cause s of early 
developmental delay and learning difficulties. 
Other potential causes of intellectual impairment include: 
 birth asphyxia 
 intraventricular haemorrhage 
 rhesus disease 
 congenital infections (toxoplasmosis, 
CMV, rubella, herpes)

CMV, rubella, herpes) 
 congenital hypothyroidism 
 tuberous sclerosis  trisomy 21 
 Tay-Sachs 
 Cornelia De Lange 
 homocystinuria 
 phenylketonuria 
 tryptophanuria, and 
 galactosaemia. 
 Maple syrup urine disease 
 
__________________________________________________________________ __ 
Autosomal recessive conditions 
_________________________________________________________________ __ 
Hurler's syndrome (MPS-1) & Hunter's syndrome (MPS- 2)

Which feature suggests a diagnosis of Hurler's syndrome rather than 
Hunter's syndrome?  Cloudy cornea . 
 Hunter's syndrome (MPS- 2) is of X linked inheritance. The corneas are clear. The skeletal 
involvement tends to be mild with no gibbous present, though scoliosis is often fo und.Mental 
retardation and heart involvement are less severe than in Hurler's syndrome. 
 Hurler's syndrome (MPS- 1) is autosomal recessive in inheritance and is associated with cloudy

cornea. There is severe mental retardation, and gibbous deformation of the spine is 
characteristic. There is the characteristic coarse facies with hepatosplenomegaly. 
Gaucher's disease  
 autosomal recessive mutation in a gene located on chromosome 1  
 Both parents must be carriers for a child to be affected.  
 If both parents are carriers, the chance of the disease is one in four, or 25%, with each

pregnancy for an affected child  
 Caused by deficiency of the enzyme glucocerebrosidase  (also known as 
glucosylceramidase),(also known as beta-glucosidase) which acts on glucocerebroside.  
 When the enzyme is defective, glucocerebroside accumulates in white blood cells splee n, liver, 
kidneys, lungs, brain, and bone marrow.  
 Gaucher's disease is the most common of the lysosomal storage diseases.It is a form  of

sphingolipidosis (a subgroup of lysosomal storage diseases), as it involves dysfunctional 
metabolism of sphingolipids.   1622

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 23 
  About one in 100 people in the United States are carriers of the most common type  of Gaucher 
disease. The carrier rate among Ashkenazi Jews is 8.9% while the birth incidence is one in 
450.  
 Parkinson's disease is more common in Gaucher's disease patients ( the most common

known genetic risk factor for Parkinson's ) 
 Cancer risk may be increased, particularly myeloma . 
 Patients with all types of disease have hepatosplenomegaly and large glucocerebrosid e-rich 
cells (Gaucher cells) infiltrating the bone marrow.  
Types 
 GD type I  (Chronic non-neuropathic; adult Gaucher disease)  
 most common form  of the disease, occurring in about one in 40,000 live births.  
 It occurs most often among persons of Ashkenazi Jewish  heritage.

 patients may live well into adulthood.  
 Symptoms:  
 massive hepatosplenomegaly; the spleen may rupture  
 bone weakness (Osteoporosis , aseptic necrosis of the femur joint).  
 pancytopaenia .Spleen enlargement and bone marrow replacement cause anemia, 
thrombocytopenia, and leukopenia. bruise easily (due to low levels of platelets).   
 Yellowish-brown skin pigmentation 
 Characteristic yellow or yellow-brown papules (pingueculae) develop at the 
sclerocorneal junctions.

sclerocorneal junctions.  
 The brain is not affected pathologically.  
 GD type II (Acute neuropathic; infantile Gaucher disease) 
 typically begins within 6 months of birth  
 incidence : 1 in 100,000 live births. 
  Symptoms include, hepatosplenomegaly, progressive brain damage, eye movemen t 
disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. 
 carries the worst prognosis , Affected children usually die by age two .

 GD type III (Subacute neuropathic; juvenile Gaucher disease )  
 can begin at any time  in childhood or even in adulthood, 
 occurs in about one in 100,000 live births. 
  characterized by slowly progressive, but milder neurologic symptoms compared to the 
acute or type II version. 
  Patients often live into their early teen years and adulthood 
 Diagnosis  enzyme analysis (Enzyme studies of blood leucocytes)  
 Some lysosomal enzymes are elevated, including:

 tartrate-resistant acid phosphatase ,  
 hexosaminidase,  
 chitinase 
 chitotriosidase  very useful for monitoring Gaucher's disease activity in 
response to treatment, and may reflect the severity of the disease 
 biochemical abnormalities : high  alkaline phosphatase, angiotensin-converting enzyme, and 
immunoglobulin levels  
 cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages.   
Treatment  
 recombinant glucocerebrosidase. 
 1623

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 24 
  
The slide shows yellow papules (pingueculae) in the cornea; these are characteristic of Gauche r 
disease. 
Glycogen storage disorders (GSD)  
Glycogen  
 Glycogen is the storage form of carbohydrate, found predominantly in muscle and liver.

 Chains of glucose residues are linked by alpha-1,4 glycosidic bonds , i.e. between the first 
carbon of one glucose and the fourth carbon of the next. Branches occur about every ten 
residues, and are formed by alpha-1,6 glycosidic linkages.  
 Glycogen synthesis and degradation occur at the tips of branches, with the branching structu re 
increasing the number of sites at which glucose residues can be added or removed.

Pompe's disease or acid maltase deficiency  (glycogen storage disorder type 2): is a 
deficiency in alpha-glucosidase . It produces a myopathy , restrictive cardiomyopathy and 
hepatomegaly. 
 
 Muscle involvement (muscle glycogenoses): Types II, III, IV, V 
 Liver involvement (liver glycogenoses): Types I, III, IV 
 Types III and IV (late-onset type) may present with both muscle and liver involvement 
 NO liver involvement  V

 NO liver involvement  V 
 
 All types of glycogen storage diseases result in abnormal metabolism and produ ct accumulation 
within cells. 
 Type IV(Andersen's disease) is the only one GSD involved in Glycogen Synthesis. The rest are 
involve in Glycogen degradation. 
Diagnosis 
 Periodic acid-Schiff stain  is helpful in diagnosing glycogen storage disorders. 
 
Type I (Von Gierke's disease) 
 Relative frequency 
 ∼25% 
 Deficient enzyme 
 Type 1a

 ∼25% 
 Type 1a  
 Glucose-6-phosphatase 
 Role of the enzyme  Hydrolysis of glucose-6-phosphate to glucose and 
inorganic phosphate 
 Type 1b  
 Glucose-6-phosphate translocase  
 Role of the enzyme  Transport of glucose-6-phosphate into the endoplasmic 
reticulum where it is hydrolyzed by glucose-6-phosphatase 
1624

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 25 
  Characteristic features 
 Hepatomegaly 
 Severe fasting hypoglycemia, mild ketosis 
 Severe hyperlipidemia → doll -like facies 
 Hyperuricemia 
 Lactic acidosis 
 Anemia 
 Failure to thrive 
Type II  (Pompe's disease)  
 ∼15% 
 Lysosomal acid maltase deficiency

 Lysosomal acid maltase deficiency 
 Role of the enzyme 
 Glycogenolysis within the lysosome 
 Characteristic features 
 Hypertrophic cardiomyopathy and/or conduction blocks 
 Proximal myopathy 
 Macroglossia 
Type III  (Cori's disease ) 
 ∼25% 
 deficiency of debranching enzyme (alpha-1,6-glucosidase). 
 Glycogenolysis 
 Generalized muscle weakness and/or cramps

 Generalized muscle weakness and/or cramps 
 Possibly cirrhosis (ascitis, splenomegaly) 
 Mild, fasting hypoglycemia and ketosis 
 Hyperlipidemia 
Type IV (Andersen's disease)  
 ∼3% 
 Glycogen branching enzyme 
 Glycogenesis 
 Possibly cirrhosis (ascites, splenomegaly) 
 
Type V  (McArdle's disease)  
 ∼2%

 ∼2% 
 Muscle phosphorylase (myophosphorylase) 
 Generalized muscle weakness, exercise intolerance (with a second wind phenomenon) , 
 Rhabdomyolysis and myoglobinuria 
 
McArdle's disease 
Overview 
 autosomal recessive  type V glycogen storage disease  
 caused by  myophosphorylase deficiency 1625

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 26 
   which is responsible for glycogen storage in skeletal muscles. 
 Myophosphorylase is involved in the breakdown of glycogen to glucose.  
 Ļ myophosphorylase  unable to release glucose from glycogen in muscle.   
  The gene for myophosphorylase (PYGM) is on chromosome 11.

 this causes decreased muscle glycogenolysis  
 It is now known as one of the most common disorders of muscle metabolism 
 prevalence :1 per 100,000 people. 
Features 
 muscle pain and stiffness following exercise (reversible)  
 in the first few minutes of activity. 
 Characterised by  'second wind' phenomenon  
 after about 8 minutes most patients achieve a 'second wind' and can then continu e 
exercise with less difficulty.

exercise with less difficulty. 
 Second wind  is a phenomenon in distance running, such as marathons  ( an 
athlete who is too tired to continue suddenly finds the strength to press on at to p 
performance with less exertion).  
 Mechanism  metabolic switch  
 When non-aerobic glycogen metabolism is insufficient to meet energy 
demands, physiologic mechanisms utilize alternative sources of energy 
such as fatty acids and proteins via aerobic respiration.

 muscle fibers use fat as a source of energy.   
 muscle cramps 
 myoglobinuria 
 low lactate levels during exercise 
 A history of painful muscle cramps that occur within a few minutes of initiating actvity and which 
subside rapidly with rest, in conjunction with a raised serum CK, is highly suggestive of McArdle's 
disease 
 Creatine kinase levels are elevated in more than 90%  
 NO increase in venous lactic acid levels following exercise testing.

 Urine study  myoglobinuria following exercise 
 muscle biopsy, which shows an excess of glycogen and absence of the muscle enzyme 
phosphorylase 
 In the UK, "hot spot" DNA testing for the two most common mutations.  
 Up to 85% of patients can be confirmed without muscle biopsy. 
 The gold standard  for the diagnosis of McArdle disease is gene sequencing. 
 No specific treatment exists. 
 Tourniquets should not be used during operative procedures

 advised to ingest snacks containing  sucrose  before exercise. 
 
The exertional thigh cramps, the presence of myoglobin and change in colour of 
urine after exercise suggests glycogen storage disease type V - McArdle's 
syndrome. the next most appropriate investigation Muscle biopsy  which reveals 
subsarcolemmal deposits of glycogen appearing at the periphery of fibres . 
 
linkage disequilibrium   
 linkage disequilibrium  is the non-random association of alleles at different loci in a given 
population.   
1626

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 27 
  Loci are said to be in linkage disequilibrium when the frequency of association of their di fferent 
alleles is higher or lower than what would be expected if the loci were independent and  
associated randomly. 
 Consider the scenario of two separate genetic loci A and B, where each locus carries two

possible alleles. If these two loci A and B are in linkage disequilibrium  An individual with 
locus A is likely to have locus B  
 Linkage disequilibrium almost always, but not invariably, occurs between alleles at gene tic loci 
that are closely linked in the genome. 
Imprinting  
 imprinting  is a phenomenon by which certain genes are expressed in a parent- of-origin-specific 
manner.

manner.  
 Genomic imprinting is a principle in which certain genes on a chromosome are only 
expressed depending on the maternal or paternal origins of the chromos ome. 
 the term 'imprinting' refers to  Differential expression of alleles contingent on 
their parental origin 
 If the allele inherited from the father is imprinted, it is thereby silenced, and only the 
allele from the mother is expressed.

allele from the mother is expressed.  
 If the allele from the mother is imprinted, then only the allele from the f ather is 
expressed. 
Mechanism 
  poorly understood, but does involve DNA methylation .  
 Disease may occur as a result of a defect in one allele if the other allele is imprinted an d hence 
not expressed. 
 
Examples 
 diseases involving genomic imprinting include:  
  Prader –Willi syndrome (paternally imprinted)  
 Angelman syndrome (maternally imprinted)

 Angelman syndrome (maternally imprinted) 
Prader-Willi syndrome 
 
 Prader-Willi syndrome is an example of genetic imprinting  where the phenotype depends on 
whether the deletion occurs on a gene inherited from the mother or father: 
 Prader-Willi syndrome if gene deleted from father 
 Angelman syndrome if gene deleted from mother

 Angelman syndrome if gene deleted from mother 
 Prader-Willi syndrome is associated with the absence of the active Prader-Willi gene on the  
long arm of chromosome 15. This may be due to: 
 microdeletion of paternal 15q11-13 (70% of cases) 
 maternal uniparental disomy of chromosome 15 
  the mode of inheritance is   Non-Mendelian  
Features 
 hypotonia during infancy 
 dysmorphic features 
 short stature (Growth hormone deficiency ) 
 hypogonadism and infertility

 hypogonadism and infertility 
 (risk factor for osteoporosis) 
 cryptorchidism  (undescended testis)  
 childhood obesity  
 due to Hyperphagia (abnormally desire for food  overeating  obesity)  
 behavioural problems in adolescence 
 
Treatment 
1627

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 28 
  administration of growth hormone and sex hormones (testosterone) is the treatment of 
choice 
 
September 2007 exam:  Which one of the following is the most common genetic cause of 
Prader-Willi syndrome? Microdeletion of the paternal 15q11- 13

Chromosome 15 is implicated in Prader-Willi , Angelman , and Marfan  syndromes. 
 
Angelman syndrome   
 Angelman syndrome is a genetic condition characterized by a mutation on the maternal copy  
of chromosome 15 .  
 occurs as a result of a phenomena known as genomic imprinting . 
 The imprinted copy of the gene is silenced through methylation or histone modification.

 Normally, certain paternal alleles on chromosome 15 are silenced and only the 
maternal alleles are expressed. However, in Angelman syndrome, the maternal a lleles are 
mutated. Hence, the patient will have disease since only the mutated maternal alleles are active.  
Features 
 developmental delay,  
 seizures,  
 hypo-pigmentation with blond hair,  
 ataxia ,  
 unprovoked laughter,  
 large mouth with tongue protrusion. 
 
Diagnosis

Diagnosis 
  genetic studies showing loss of function of the UBE3A gene. 
Mutations  
 Missense mutation 
 substitution in one amino acid in a protein 
 e.g: glutamic acid is substituted by valine in sickle-cell disease 
 nonsense mutation 
 the altered DNA sequence prematurely signals the cell to stop building a protein. This 
type of mutation results in a shortened protein that may function improperly or not a t all.

 insertion mutation 
 changes the number of DNA bases in a gene by adding a piece of DNA . As a result, the 
protein made by the gene may not function properly. 
McCune –Albright syndrome 
 
 due to a mutation in a G-protein. 
Features 
 Precocious puberty (typically gonadotropin-independent). This includes: 
  breast development,  
 genital maturation (with or without pubic hair growth), 
  increased height velocity

  increased height velocity  
 macro-orchidism in males. 
 Café- au-lait pigmentation.  
 This consists of spots ranging from light brown to dark brown in colour.  
 often display a segmental distribution and frequently are predominant on one side of th e 
body without crossing the midline;  
 these spots must be differentiated from those characteristic of neurofibromatosis. 
 Polyostotic fibrous dysplasia.

 Polyostotic fibrous dysplasia.  
 Multiple pathological fractures may be prominent early in the history; in many cases, bon y 
involvement is found to predominate clinically on one side; clinical manifestation s include gait 
anomalies, visible bony deformities (including abnormal bone growths of the skull), bone  pain 
and joint stiffness with pain. 
 Hyperthyroidism, which in infants can result in failure to thrive. 1628

Notes & Notes for MRCP                                                                                                     By Dr. Yousif Abdallah Hamad 29 
  increased risk of osteosarcoma and other connective tissue tumours,  
 In relation to precocious puberty, the patient is at increased risk of developing breast carcinoma.  
 
 1629

Basic – Biostatistics & EBM 
 
Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   1 
   
By
 
Basic science
 
Biostatistics & EBM
 
Updated 
 
2017
 
Contains: 
 
 1630

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   2 
  Significance tests 
Null hypothesis (H 0) 
 A null hypothesis (H 0) states that two treatments are equally effective (and is hence negatively phrased).  
 A significance test uses the sample data to assess how likely the null hypothesis i s to be correct.

 The null hypothesis is always that there is no difference between the variables we would like to tes t for a 
difference. 
 For example: 
 'there is no difference in the prevalence of colorectal cancer in patients taking low-dose aspirin com pared to 
those who are not' 
The alternative hypothesis (H 1)  
 is the opposite of the null hypothesis, i.e. There is a difference between the two treatments  
P value

P value    
 The p value  is the probability of obtaining a result by chance at least as extreme as the one that was ac tually 
observed, assuming that the null hypothesis is true. 
  It is therefore equal to the chance of making a type I error (see below). 
 the p-value is the probability of obtaining the observed results or results which are more extreme if the 
null hypothesis is true 
 
 Example : if p=0.03. What does ‘p=0.03 ’ mean?

 It means the probability that a difference between the two sample groups occurred by chance is 3%  
Statistical errors 
 Two types of errors may occur when testing the null hypothesis 
1. type I:  
 the null hypothesis is rejected when it is true,   
 ‘the null hypothesis is falsely rejected ’. – 
 i.e. Showing a difference between two groups when it doesn't exist,  
 a false positive.  
 This is determined against a preset significance level (termed alpha).

 As the significance level is determined in advance the chance of making a type I err or is not 
affected by sample size.  
 It is however increased if the number of end-points are increased. For example if a study has 20  
end-points it is likely one of these will be reached, just by chance.  i.e. the result is just a statistical 
fluke (صدفة .)
2. type II:  
 the null hypothesis is accepted when it is false ,   
 ‘the null hypothesis is falsely accepted ’.-

 ‘the null hypothesis is falsely accepted ’.-  
 i.e. Failing to spot a difference when one really exists ,  
 a false negative.  
 The probability of making a type II error is termed beta.  
 It is determined by both sample size  and alpha.  This can happen if the sample size is too small.   
 Increasing the sample size  reduces the standard error, meaning the estimate is more 
precise and the probability of a type-2 error is reduced.  1631

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   3 
   This type of error can be avoided by making explicit power calculations before embarking on  any 
study. This will answer the question ‘if I am studying an outcome that occurs in (say) 20% of a 
conventionally treated group and want to show a (say) halving in the rate of this outc ome, then

how many patients do I need to study? ’ 
  
Study accepts H 0 Study rejects H 0 
Reality H 0  Type 1 error (alpha) 
Reality H 1 Type 2 error (beta) Power (1 - beta) 
 
Error: type I (alpha) vs. type II (beta)  
 Type I (Alpha) Error: "There Is An Effect" where in reality there is none. 
 
The power  
 The power of a study is the probability of (correctly) rejecting the null hypothesis when  it is false, i.e. the 
probability of detecting a statistically significant difference

power = 1 - the probability of a type II error 
 power can be increased by increasing the sample size 
 As the power decreases, type II error (= 1-power) will increase. Therefore, the chance of ty pe II error will 
increase if the same sample size is used.  
 The statistical power will decrease if the standard deviation increases. 
 
 Power of the study' refer  The probability of a statistically significant treatment effect if the true 
treatment difference is at a prespecified level

treatment difference is at a prespecified level 
 Power is determined by sample size, effect size, and its standard error. 
1632

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   4 
   The statistical significance  of a result is the probability ('p value') that the observed relationship (eg between 
variables) or a difference (eg between means) in a sample occurred by pure chance and that in the populat ion 
from which the sample was drawn, no such relationship or differences exist

 The sample size can be reduced if the level of significance is increased. 
 The power increases with the set level of significance, if other variables remain th e same. 
Significance tests: types 
Correlation 
 parametric (normally distributed): Pearson's coefficient 
 non-parametric: Spearman's coefficient 
 The type of significance test used depends on whether the data is parametric (something whi ch can be

measured, usually normally distributed) or non-parametric 
 Parametric tests  
 Student's t-test - paired or unpaired* 
 Pearson's product-moment coefficient – correlation 
 Non-parametric tests  
 Mann -Whitney U test - unpaired data 
 Wilcoxon signed-rank test - compares two sets of observations on a single sample 
 chi-squared test - used to compare proportions or percentages 
 Spearman, Kendall rank - correlation

 Spearman, Kendall rank - correlation 
 *paired data refers to data obtained from a single group of patients, e.g. Measurement before and after an 
intervention. Unpaired data comes from two different groups of patients, e.g. Comparing response to different 
interventions in two groups 
Parametric & non- parametric methods 
 Theoretical distributions are described by quantities called parameters, notably the mea n and standard deviation.

  Methods that use distributional assumptions are called parametric  methods, because we estimate the 
parameters of the distribution assumed for the data.  
 Methods which do not require us to make distributional assumptions about the data, are call ed non-
parametric  methods.  
 A parametric test is a statistical test which assumes the data are normally distributed .

 Data which are not normally distributed can still be subject to a parametric test, but it need to be trans formed first. 
 The parametric assumption of normality is particularly worrisome for small sampl e sizes(n < 30). Nonparametric tests are 
often a good option for these data with a very small sample size. 
 Non-parametric methods are most often used to analyse data which do not meet the distributional req uirements of

parametric methods. In particular, skewed data are frequently analysed by non-parametric method s, although 
data transformation can often make the data suitable for parametric analyses  
 Nonparametric tests have two main drawbacks: 
1-  ͞Less powerful ͟ than parametric (a nonparametric test will require a slightly larger sample size 
to have the same power as the corresponding parametric test).  
2- their results are often less easy to interpret than the results of parametric tests

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   5 
  Parametric tests and analogous nonparametric procedures 
Analysis Type  Example  Parametric 
Procedure  Nonparametric 
Procedure  
Compare means 
between two 
distinct/independent 
groups  Is the mean systolic blood pressure (at 
baseline) for patients assigned to 
placebo different from the mean for

placebo different from the mean for 
patients assigned to the treatment 
group?  Two -sample t-
test Wilcoxon 
ranksum test  
Compare two 
quantitative 
measurements taken 
from the same individual  Was there a significant change in 
systolic blood pressure between 
baseline and the six-month followup 
measurement in the treatment group?  Paired t-test  Wilcoxon 
signedrank test  
between three or more 
groups  If our experiment had three groups

groups  If our experiment had three groups 
(e.g., placebo, new drug #1, new drug 
#2), we might want to know whether 
the mean systolic blood pressure at 
baseline differed among the three 
groups?.  Analysis of 
variance 
(ANOVA)  Kruskal-Wallis 
test 
Estimate the degree of 
association between two 
quantitative variables  Is systolic blood pressure associated 
with the patient ’s age?  Pearson 
coefficient of 
correlation  Spearman ’s rank 
correlation

correlation  
 
 Categorical variables are not continuous, e.g. drug / placebo, dead / alive. They should be described as  
percentages or proportions and compared with a Chi-squared test. 
 Normally distributed continuous data should be described as mean and standard deviati on and compared with a 
Student ’s t-test. 
 Skewed continuous data should be described as median and range and compared using a test suc h as the

Wilcoxon rank-sum test or the Mann-Whitney U-test. 
_____________________________________________________ ________________ 
Choosing the appropriate test 
 Choosing of a test to examine a statistical problem depends upon the scale of measurement (nominal, o rdinal, 
interval, ratio) and the type of question being asked 
 a non-parametric test would give less power 
Student's t- test   
 t -test can only be used for parametric (normally distributed) data .

 t-test can be used, for example, to determine if two sets of data are significantly different fro m each other.  
 The t-tests are applicable to quantitative variables  
 Paired t test 
 Compares a single measure  (variable) recorded on a single group  of individuals on two different 
occasions.  
  Is used to compare means in a single sample , for example, before and after treatment . 
  comparing means ( not proportions ) in the same subjects

 paired t-test is used to compare post-treatment and pre-treatment result of a single group. 1634

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   6 
   eg: the same subject measured before and after a process change, or the same subject measured at 
different times. 
 As both sets of measurements were made on the same patients, the measurements are not independent  
 unpaired t-test (independent sample t-test)

 unpaired t-test (independent sample t-test)  
  is the most appropriate statistical test to compare means of two independent samples. 
 compare the means of two  different populations  
 An independent sample t-test may be used in a study of two independent  treatment groups, and the 
sample sizes are relatively large  (>30 in each group) and the variable is Normally distributed .

 eg: Blood pressure is a continuous variable which is normally distributed; as such S tudent's t test is the 
most appropriate way to test for differences in the mean BPs between the two groups .  
 For example, suppose we are evaluating the effect of a medical treatment, and we enroll 100 subj ects 
into our study, then randomly assign 50 subjects to the treatment group and 50 subjects to the c ontrol

group. In this case, we have two independent samples and would use the unpaired form of the t-test.   
 eg: 2 groups (treatment group & placebo group) In a randomised controlled trial of drug A for treatment of 
hypercholesterolemia 
Pearson test  
 is used to assess the correlation (strength of association) between two variables 
 Pearson correlation coefficient is inappropriate if the data do not approximately follow normal 
distribution  
 (often called 'R')

 (often called 'R')  
 R is a measure of association between two continuous scale measurements  
Chi square test 
 is used for nominal data to find out if there is a significant difference between the proportion of ob servations falling 
in each group - for example, comparing the proportion of children developing measles between a grou p receiving 
a new measles vaccine and a group not given the vaccine  
 (used to test for independence between two categorical variables)

 It is a 2 × 2 contingency table for which there is a special chi squared formula that gives a va lue that can be 
looked up in a table giving the p value.   
 Is used to test categorical variables for association . 
 Should be used for 2 independent  samples. 
 In order to compare the  prevalence in two groups, the chi square test is most appropriate.  
Log-rank test  
 Is the most appropriate test to compare two survival curves  with censored data.

 Logrank test should be used to compare survival data between two groups, but not compare medi an survival. 
Mean survival is not known unless all patients have died. 
 If a question presented survival data and some observations are censored(ex: not came for follow up) an d the 
outcomes are not known. We need to use survival analysis for such data and the log-rank test is the appropria te 
test to use  to compare survivals in two independent groups .

 can be used to test the difference in relapse rate between the two groups  
Mann-Whitney U-test   
 is a non-parametric comparison of two distributions  
 used to compare medians or rank orders of two groups with non-normal distribution . 
Spearman's rank correlation coefficient   
 measures the correlation between the ranks of two variables  
 as it only compares ranks and not values, it is appropriate for use on an ordered categorical (ordinal) v ariable

such as the perception of pain (ranked on a scale of 
 1-10)  1635

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   7 
   Spearmann's correlation is the best method to determine two variables which do not follow a normal distr ibution.  
ANOVA (analysis of variance)  
 is used for more than two means  
 tests for a difference in mean values between a number of groups  
 Is the most appropriate to compare the means of more than two groups.

 One-way analysis of variance  is identical mathematically to the unpaired Student t-test when just two groups 
are being compared. 
 The one-way (analysis of variance) (ANOVA)  compares the means of the groups  
 The means should be presented with confidence intervals to give the reader an idea of wheth er the differences 
between the groups were significant 
McNemar's test  
 is applied to binary data, but is only applicable to paired data, used to compare proportions

 McNemar's test is used to compare paired samples - either case control studies where each case is matc hed to a 
control, or to studies where two treatments are given to matched subjects.  
 It cannot be used where the sample size differs.  
 is used to test for agreement of repeated observations.  
The Cox (proportional odds) regression (Cox proportional hazards regression):

 this method was devised specifically for the type of study in which many patients fail to r each the end-point (ie in 
statistical terms, are 'censored') and in which follow-up time varies.  
 Cox regression is designed specifically for the analysis of time to an event occurring.  
Multiple regression 
 is used to analyse the relationship between one dependent variable and one or more independe nt variables.  
Logistic regression

Logistic regression   
 This would allow us to determine whether one variable is dependent on another, ex: in cas e whether drug 
concentration was dependent on body surface area.  
 ANOVA is an example of logistic regression analysis.  
ANCOVA 
 is a statistical test which tests for co-variance between populations and is useful when v ariables such as age, sex 
or race may be expected to affect the treatment's effectiveness.  
Regression techniques

Regression techniques   
 are used to predict the value of one variable based on the other  1636

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   8 
   
May 2012 exam: A study is designed to assess severity of snoring before and after using a new mandibular 
device. What is the most appropriate statistical test to apply to this data?  Wilcoxon signed-rank test  
Normal distribution

Normal distribution 
 The normal distribution is also known as the Gaussian distribution or 'bell-shaped' dis tribution. It describes the 
spread of many biological and clinical measurements 
 Properties of the Normal distribution 
 symmetrical i.e. Mean = mode = median 
 68.3% of values lie within 1 SD of the mean 
 95.4% of values lie within 2 SD of the mean 
 99.7% of values lie within 3 SD of the mean

99.7% of values lie within 3 SD of the mean 
 this is often reversed, so that within 1.96 SD of the mean lie 95% of the sample values 
 the range of the mean - (1.96 *SD) to the mean + (1.96 * SD) is called the 95% confidence interv al, i.e. If 
a repeat sample of 100 observations are taken from the same group 95 of them would be expected to lie 
in that range 
 
1637

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   9 
  January 2009 exam : A study is designed to assess the efficacy of a new antihypertensive drug. Two groups of 
patients are randomly assigned, one to take the established drug for 3 months whilst the other takes the new 
drug for 3 months. blood pressure is measured before and 3 months .After period off medic ation the drug

swapped around and again, blood pressure is measured before and 3 months later. Which one of the following 
significance tests is it most appropriate to apply?  Student's paired t-test (comparing parametric data from the 
same patients (they swapped medication halfway through the study))  
 
Standard deviation 
SD = square root (variance)  
 
Remember that around two-thirds of values lie within 1 SD of the mean, one-third will therefore lie

outside 1 SD, and half of these (one-sixth) will be less than 1 SD below the mean 
 the standard deviation (SD) is a measure of how much dispersion exists from the mean 
 It is a measure of the spread of the sample distribution 
 SD = square root (variance) 
 The standard deviation  is a sort of average of the deviations of each observation from the mean, whereas the 
range  is simply the difference between the largest and smallest observations.

 The standard deviation is affected by outliers and would be larger than expected if outl iers are present 
 If the data are skewed, the standard deviation will tend to overestimate the spread in the data 
 If the standard deviation is reduced, the sample size required is smaller. 
 If SD increased the power of study is reduced . 
 The standard deviation would give the best estimate of a spread of a measurement about the mean

 Variance is the square of standard deviation. Standard deviation is the square root of v ariance. 
Skewed distributions 
Skewed distributions  
 alphabetical order: mean - median - mode 
 '>' for positive, '<' for negative  
 Normal (Gaussian) distributions: mean = median = mode ( bell-shaped ) 
 Positively skewed distribution: mean > median > mode

 Negatively skewed distribution mean < median < mode 
 To remember the above note how they are in alphabetical order, think positive going forward with '>', whil st 
negative going backwards '<' 
 1638

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   10 
  
 Mean, median and mode are measures of central tendency 
 Descriptive statistics provide mean, median and mode values for a distribution 
 
Example: The annual numbers of reported cases of leptospirosis in the USA over the 5-year period from 19 85 to 1990

were: 2, 1, 3, 4, 1, . What was the mean, median and modal number of cases per year? 
Answer: 
 The mean  is found by  summing all the values and dividing by 5; this gives a mean = 11/5=2.2 
 The mean is the average value of observations, and therefore very sensitive to extreme values 
in a distribution 
 If the mean is greater than the median, this indicates a positive skew. 
 For the median and mode  rewrite the values in ascending order: ie 1,1, 2,3,4,

 The median  is the middle value when the values are placed in order = 2 
 For an even number of values it is halfway between the two middle values, 
 If you forgot to sort the values before looking for the middle value, you will have got the incorrect 
answer = 3 
 The median is the observation that divides the frequency distribution by half  and is equal to the 50th 
centile (lies exactly between each end of a range of values)

 It responds to the number of extreme observations but not their value, and therefore is useful as  a 
measure of central tendency in extremely skewed distributions 
 In a normal distribution the median equals the mean 
 The mode  is the most common value; this is  1 , which occurs twice, whereas all other values occur only 
once 
 mode is the most commonly observed value 
 The distribution sample means will be normally distributed even if the population values are not normally

distributed.  
 The random sampling distribution of means would always tend to be normal, irrespective of  the population 
distribution for which the samples were drawn. Hence, even if the population distribution is skewed or in any non-
normal distribution, the sample means would be normally distributed.' 
 the mean of the random sampling distribution of means is equal to the mean of the original po pulation.

 In a distribution skewed by the presence of a number of positive outliers  Mean increases, median may 
increase, mode remains the same  
 
 1639

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   11 
  _________________________________________________________________________________________ 
Confidence interval and standard error of the mean 
 
 Definition of confidence interval   
 a range of values for a variable of interest constructed so that this range has a specified probabi lity of

including the true value of the variable.  
 The specified probability is called the confidence level, and the end points o f the confidence interval are 
called the confidence limits * 
 in simpler terms: a range of values within which the true effect of intervention is likel y to lie 
 A confidence interval is needed for almost all statistical estimates, including sensitivity or specificity of a 
diagnostic test.

diagnostic test.  
 Confidence intervals relate to values of the population mean and tell you how precisely y ou have determined the 
mean.  
 If the confidence interval includes the number 1,  the trial did not find a statistically significant  difference 
between the variables (this does not mean there was no difference) 
 A narrow confidence interval emphasises the significance  of the result, but it is the p-value that describes 
significance , not the confidence interval around it.

 If confidence interval of any study includes 1, This means the association is not statistic ally significant and 
therefore the p value should be above 0.05. 
 If confidence interval does not include 1. This means the association is statistically  significant and therefore the p 
value should be below 0.05. 
 
Key point 
 A 95% confidence interval: 
 Most commonly, the 95% confidence level is used 
 What is the best interpretation of the 95% confidence interval?  
1640

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   12 
   We are 95% confident that the mean in the value is between confidence limits 
 confidence interval at the 95% confidence level means that the confidence interval should contain th e true 
effect of intervention 95% of the time.

effect of intervention 95% of the time.  
 A 95% confidence interval means that there is only a 5% chance that the true mean value for the 
variable lies outside the ranges quoted 
 The 95% confidence limits will be the mean plus or minus 1.96 standard errors  
 lower limit = mean - (1.96 * SEM) 
 upper limit = mean + (1.96 * SEM) 
 For example, in a study the mean height in a sample taken from a population is 183cm. You kno w that

the standard error (SE) (the standard deviation of the mean) is 2cm. This gives a 95% confidence i nterval 
of 179-187cm (+/- 2 SE).  
 meaning that there is a 5% chance that the true population mean is not included in this range, in 
other words a 95% chance that the true population mean is included within this range  
 If the 95% confidence interval does not include 0 (zero), the difference is statistically significant

 If the p value is less than 0.05,  statistically significant  the 95% confidence interval should not 
include 0.  
 Standard error of the mean (SEM)  
 The standard error of the mean (SEM) is a measure of the spread expected for the mean of the 
observations - i.e. how 'accurate' the calculated sample mean is from the true population mean  
 SEM = SD / square root (n) 
 where SD = standard deviation and n = sample size 
 therefore the SEM gets smaller as the sample size (n) increases

 standard error of the mean  Gets smaller as the sample size increases  
 Increasing the sample size will reduce the standard error of the mean and the width of the 
confidence interval. 
 The standard error is  Smaller than the standard deviation  
Confounding variable  
 Is an extraneous variable  in a statistical model that correlates (directly or inversely) with both the depend ent

variable  and the independent variable .  
 To give a hypothetical  example  of a confounding variable: 
 A study shows that wearing sunglasses and putting on sun cream are linked - increases  in sun cream sales are 
higher when sales of sunglasses increase. It could be that sun cream makes individual s wear sunglasses or that 
wearing sunglasses reminds people that they need to put on sun cream. However, there is a third "conf ounding"

variable that affects BOTH sales of sunglasses and sun cream - the weather. It could be that ho t, sunny weather 
makes people both put on sunglasses and apply sun cream. 
 Another example : In a case-control study on the association between cola drinking and type 2 diabetes => BMI 
is likely to be a confounding variable  
 In general, a randomised controlled trial eliminates confounding  by known and unknown factors.

 Stratified analysis eliminates the confounding of the stratified data. 1641

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   13 
   Multivariable logistic regression can control and minimise confounding by sim ultaneous adjustment for multiple 
factors. 
Correlation and linear regression 
 The terms correlation and regression are related but are not synonymous .

 Correlation is used to test for association between variables (e.g. whether salary and IQ are related).  
 Once correlation between two variables has been shown regression can be used to predict values of other 
dependent variables from independent variables.  
 Regression is not used unless two variables have firstly been shown to correlate.  
Correlation  
 The degree of correlation is summarised by the correlation coefficient (r). This indicates how c losely the points lie

to a line drawn through the plotted data. In parametric data this is called Pearson's correlation coeff icient and can 
take any value between -1 to +1.  
 The value of 'r' (coefficient of variation) ranges from -1 to +1 
 For example 
 r = 1 - strong positive correlation (e.g. systolic blood pressure always increases with age) 
 r = 0 - no correlation (e.g. there is no correlation between systolic blood pressure and age)

 r = - 1 - strong negative correlation (e.g. systolic blood pressure always decreases with age) 
 Whilst correlation coefficients give information about how one variable may increase or de crease as another 
variable increases they do not give information about how much the variable will change. T hey also do not 
provide information on cause and effect.  
 Correlation is summarised when using parametric variables by Pearson's correlation coefficien t (represented by a 
small r).

small r).  
 In the situation of non parametric variables, Spearman's correlation coefficient is used. Spearman's corr elation 
coefficient is usually represented by the Greek letter p (rho), or by rs.  
 In the case of dichotomous variables logistic regression is used.  
 Linear (or simple linear) regression is used when looking for association between two cont inuous variables, and 
multiple regression is used when looking for association between more than two continuous variables.

Linear regression  
 In contrast to the correlation coefficient, linear regression may be used to predict how  much one variable changes 
when a second variable is changed.  
 A regression equation may be formed, y = a + bx, where:  
 y = the variable being calculated 
 a = the intercept value, when x = 0 
 b = the slope of the line or regression coefficient. Simply put, how much y changes for a gi ven change in x 
 x = the second variable 
Correlation coefficient

Correlation coefficient  
 The correlation coefficient measures the strength (and direction, if linear) of the relationshi p between two 
variables. 
 Correlation coefficient does not follow normal distribution. 
 Calculation of correlation coefficient does not need to assume normal distribution. 
  If there is perfect linear relationship with positive slope between the two variables, the  correlation coefficient is 1. 1642

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   14 
    If there is a perfect linear relationship with negative slope between the two variables,  the correlation coefficient is 
-1. 
  A correlation coefficient of 0 means that there is no linear relationship between the variab les. 
 The correlation is not necessarily linear

 The correlation is not necessarily linear 
 Correlation coefficient describes the linear relationship between two variables. If th e relationship between them is 
not linear, it can be misleading and should not be used. 
 The correlation coefficient does not depend on sample size.  Increasing the sample size will not change the 
correlation coefficient as its value does not depends on sample size. 
 The correlation coefficient can be a negative number .

 The correlation coefficient can range from -1 to +1. 
 Correlation and regression are different. 
  Correlation  describes how closely two variables are associated. 
  Regression  allows you describe one variable with respect to the other in terms of an equation. 
Screening test statistics 
 
Sensitivity = true positives / (true positives + false negatives)  
 
Specificity = true negatives / (true negatives + false positives)

The rule of thumb is that a high sensitivity helps to rule out  disease (SnOut) and a high specificity helps to rule in  
(SpIn) disease (Mnemonic "spin and snout") 
Contingency tables  
  also known as 2 * 2 tables, are used to illustrate and calculate test statistics such as sensi tivity.  
 TP = true positive; FP = false positive; TN = true negative; FN = false negative 
Disease present Disease absent 
Test positive  TP FP 
Test negative  FN TN 
 
 1643

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   15 
   
The table below lists the main statistical terms used in relation to screening tests : 
Measure Formula Plain English 
Sensitivity  TP / (TP + FN ) Proportion of patients with the condition who have a positive test result 
Specificity  TN / (TN + FP) Proportion of patients without the condition who have a negative test

result 
Positive predictive value  TP / (TP + FP)  The chance that the patient has the condition if the diagnostic test is 
positive 
Negative predictive value  TN / (TN + FN) The chance that the patient does not have the condition if the diagnostic 
test is negative 
Likelihood ratio for a 
positive test result  sensitivity / (1 - 
specificity) How much the odds of the disease increase when a test is positive 
negative test result  (1 - sensitivity) /

negative test result  (1 - sensitivity) / 
specificity How much the odds of the disease decrease when a test is negative 
Incidence and prevalence  
 The incidence equals the number of newly affected individuals divided by the number of people at risk for 
the disease for a given duration.  
 Prevalence equals the total number of cases divided by the total number of at risk. 
 Prevalence may be lower than incidence if the condition has high fatality or cure rate.

Sensitivity and specificity  
 Essentially a knowledge of the sensitivity/specificity is based on the disease state  itself, whereas 
predictive values are based on the test result . 
 Sensitivity and specificity  will not change with sample size. They will change only with:  
 composition of the sample (especially if subjects in the sample have different risks of disease) 
 performance of the test 
 diagnostic threshold, and 
 The "gold standard" to be compared with.

 The "gold standard" to be compared with. 
 The reliability  of estimates of sensitivity, specificity, positive and negative predictive value  will all increase with 
increasing sample size , which will reduce their confidence intervals . 
 Increasing the cut-off of a positive test result will decrease the number of false positives  and hence increase the 
specificity. 
Positive and negative predictive values  
 Positive and negative predictive values are prevalence dependent.

 The positive predictive value will increase and negative predictive value will decrease if the 
prevalence of the disease increases. 
Likelihood ratios  
 Likelihood ratios are not prevalence dependent. 1644

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   16 
   If the sensitivity increases, the likelihood ratio of a positive test will increase. If the specificity decreases, 
the likelihood ratio of a positive test will decrease. 
 The likelihood ratio of negative test will increase if the specificity of the test is decreased.

 The lower the likelihood ratio of a negative test, the less likely is the presence of disease  
 The likelihood ratio of a positive test helps to rule in disease and the likelihood ratio of a negative test helps to rule 
out disease. 
Posterior probability  
 Posterior probability = posterior odds / (1 + posterior odds) 
 Posterior odds of having disease = prior odds × likelihood ratio. 
 Prior odds of having disease =  Prevalence(P) / (1 − P)  
Precision

Precision  
 quantifies a tests ability to produce the same measurements with repeated tests. 
September 2009 exam : What is the correct formula to calculate the negative predictive value of a screening 
test?  TN / (TN + FP)  
Incidence and prevalence 
Incidence  is the number of new cases per 
population in a given time period.  Prevalence  is the total number of cases per 
population at a particular point in time.

population at a particular point in time.  
 These two terms are used to describe the frequency of a condition in a population. 
 The incidence  is the number of new cases per population in a given time period. 
 For example, if condition X has caused 40 new cases over the past 12 months per 1,000 of the popul ation the 
annual incidence is 0.04 or 4%. 
 The prevalence  is the total number of cases per population at a particular point in time.

 For example, imagine a questionnaire is sent to 2,500 adults asking them how much they weig h. If from this 
sample population of 500 of the adults were obese then the prevalence of obesity would be 0.2 or  20%. 
Relationship  
 prevalence = incidence * duration of condition 
 in chronic diseases the prevalence is much greater than the incidence 
 in acute diseases the prevalence and incidence are similar. For conditions such as the comm on cold the

incidence may be greater than the prevalence 
Relative risk 
Relative risk ratio  (RRR) = EER / CER 
 Relative risk (RR)  is the ratio of risk in the experimental group (experimental event rate, EER) to risk in the 
control group (control event rate, CER).  
 EER = rate at which events occur in the experimental group 
 CER = rate at which events occur in the control group

 For example, if we look at a trial comparing the use of paracetamol for dysmenorrhoea compared to plac ebo w e 
may get the following results 
 
 1645

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   17 
   
Total number of patients Experienced significant pain relief 
Paracetamol  100 60 
Placebo  80 20 
 Experimental even t rate, EER = 60 / 100 = 0.6 
Control event rate, CER = 20 / 80 = 0.25 
Therefore the relative risk ratio = EER / CER = 0.6 / 0.25 = 2.4

 If the risk ratio is > 1 then the rate of an event (in this case experiencing significa nt pain relief) is increased 
compared to controls. It is therefore appropriate to calculate the relative risk increase if necessary  (see below). 
 If the risk ratio is < 1 then the rate of an event is decreased compared to controls. The relativ e risk reduction 
should therefore be calculated (see below). 
 The relative risk is always positive

 The relative risk is always positive  
 Relative risk reduction (RRR) or relative risk increase (RRI) is calculated by dividing the absolute risk 
change by the control event rate  
Using the above data, RRI = (EER - CER) / CER = (0.6 - 0.25) / 0.25 = 1.4 = 140% 
 Relative risk reduction = 1 − relative risk  
Remember that risk and odds are different. If 20 patients die out of every 100 who have a myocardial inf arction

then the risk of dying is 20 / 100 = 0.2 whereas the odds are 20 / 80 = 0.25. 
Numbers needed to treat and absolute risk reduction 
Absolute risk reduction = (Control event rate) - (Experimental event rate)  
 
NNT = 1 / Absolute Risk Reduction  
 Numbers needed to treat (NNT)  is a measure that indicates how many patients would require an intervention to 
reduce the expected number of outcomes by one.

reduce the expected number of outcomes by one. 
 Example: if a study for stroke reveals that 20 patients need to be treated to prevent one event. 
 That means, if you treat a 1000 patients then you will expect to have 50 fewer strokes 
 It is calculated by 1/(Absolute risk reduction)  
Experimental event rate (EER)  = (Number who had particular outcome with the intervention) / (Total number 
who had the intervention)

who had the intervention) 
 Control event rate (CER)  = (Number who had particular outcome with the control/ (Total number who had the 
control) 
 Absolute risk reduction = CER-EER or EER-CER  
 ARR = risk in control group - risk in treated group. 
 For example : If a drug reduces the incidence of heart attacks from 12% to 8% then: 
 The control event rate (CER) is 12% 
 The experimental event rate (EER) is 8% 
 The relative risk reduction (RRR) is 33% ([EER-CER/CER] x 100)

 The absolute risk reduction (ARR) is 4% (CER-EER) 
 The number needed to treat (NNT) is 25 ([1/ARR] x 100) 
 
 1646

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   18 
  Number needed to harm 
 For many studies now, papers quote the number needed to harm. This uses the same principle to establi sh the 
difference in absolute risk of an adverse event occurring between two treatment strategies, calculating a number 
needed to harm by dividing 100 by the absolute risk. 
 
Hazard ratio

Hazard ratio 
 The hazard ratio (HR) is similar to relative risk but is used when risk is not constant to time. It is typically used 
when analysing survival over time 
 Example: A study is performed comparing two chemotherapy regimes for patients with small c ell lung cancer. The 
end point of the study is survival time. Which one of the following types statistical m easures is it most appropriate 
to compare survival time with?  Hazard ratio

to compare survival time with?  Hazard ratio 
___________________________________________________ _______________ 
Odds and odds ratio 
Odds - remember a ratio of the number of people who incur a particular outcome to the number of pe ople who do not 
incur the outcome 
NOT a ratio of the number of people who incur a particular outcom e to the total number of people  
 Odds are a ratio of the number of people who incur a particular outcome to the number of people who do

not incur the outcome.  The odds ratio may be defined as the ratio of the odds of a particular outcome with 
experimental treatment and that of control.  
Odds vs. probability  
In contrast, probability is the fraction of times you'd expect to see an event in many trials. W hen expressed as a single 
number probability is always between 0 and 1. So, if we take the example of rolling a d ice: 
 the probability of rolling a six is 1/6 or 0.166666 
 the odds of rolling a six is 1/5 or 0.2

 the odds of rolling a six is 1/5 or 0.2 
 Odds ratios are the usual reported measure in case-control studies. It approximates to relative risk if  the outcome 
of interest is rare. 
For example, if we look at a trial comparing the use of paracetamol for dysmenorrhoea compared to place bo we may get 
the following results 
Total number of patients Achieved = 50% pain relief 
Paracetamol  60 40 
Placebo  90 30 
The odds of achieving significant pain relief with paracetamol = 40 / 20 = 2

The odds of achieving significant pain relief with placebo = 30 / 60 = 0.5 
Therefore the odds ratio = 2 / 0.5 = 4 
Pre- and post- test odds and probability 
Pre-test probability  
 the proportion of people with the target disorder in the population at risk at a specific  time (point prevalence) or 
time interval (period prevalence). 
 For example, the prevalence of rheumatoid arthritis in the UK is 1%. 
Post-test probability

Post-test probability  
 The proportion of patients with that particular test result who have the target disorder. 
Post-test probability = post test odds / (1 + post-test odds). 1647

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   19 
  Pre-test odds  
 The odds that the patient has the target disorder before the test is carried out.  
 Pre-test odds = pre-test probability / (1 - pre-test probability). 
Post-test odds  
 The odds that the patient has the target disorder after the test is carried out. 
 Post-test odds = pre-test odds x likelihood ratio.

 where the likelihood ratio for a positive test result = sensitivity / (1 - specificit y). 
Screening: Wilson and Junger criteria 
1. The condition should be an important public health problem  
2. There should be an acceptable treatment for patients with recognised disease 
3. Facilities for diagnosis and treatment should be available 
4. There should be a recognised latent or early symptomatic stage

5. The natural history of the condition, including its development from latent to declared diseas e should be adequately 
understood 
6. There should be a suitable test or examination 
7. The test or examination should be acceptable to the population 
8. There should be agreed policy on whom to treat 
9. The cost of case-finding (including diagnosis and subsequent treatment of patients) s hould be economically balanced in 
relation to the possible expenditure as a whole

relation to the possible expenditure as a whole 
10. Case-finding should be a continuous process and not a 'once and for all' project 
________________________________________________________________________________________ 
R-values 
 A positive R-value means that as one variable increases, so does the other 
 A negative R-value means that as one variable decreases, the other increases ie the correlation  is inversed ( A 
negative R-value indicates an inverse association )

 An association or lack of association is indicated by how close the value of R is to zero and its statistical 
 significance is denoted by its p-value 
 P-values < 0.05 are considered to be significant  
Scales of measurement 
Data always come in one of the four scales of measurement:  
Nominal  Data are divided into qualitative groups, such as hot/cold, with no implication of order.

Ordinal  Data are placed in an order (hot/hotter/hottest), although the absolute levels are unknown and no 
conclusion can be made about the size of the interval. 
Interval  dividing a continuous measurement into groups (eg age 
groups). Data are placed in an order; and the exact value of the measurement is given, usually in 
measured quantities representing the difference between two measurements (81-90/91-100/101-110 °C) .

That is, differences between arbitrary pairs of measurements can be meaningfully compared. Ra tios 
between numbers of the scale are not meaningful, so operations such as multiplication and divis ion 
cannot be carried out directly. But ratios of differences can be expressed; for example, one difference 
can be twice Another lf the measurement scale does not have an absolute zero (ie no nu mbers exist 
below the zero) this is called interval data.

below the zero) this is called interval data. 
Ratio  Here, there is a value of 0 kelvin, and it isn't possible to get below this (ie absolute zero), therefore, the 
ratio between the values is meaningful, eg 271-280/281-290/291-300 kelvin. 
 1648

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   20 
  Select Study Design to Match the Research Goals 
Objective  Study design  
Describe of disease or spectrum  Case series or report 
Cross sectional study 
Determine operating characteristics of a new diagnostic 
test Cross sectional study 
Describe prognosis  Cohort study 
Determine cause-effect Cohort study

Determine cause-effect Cohort study 
Case control study 
Compare new interventions  Randomised clinical trial 
summarize literature  Meta-analysis 
 
 1649

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   21 
   
Select Study Design  
 
1650

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   22 
   
The following table highlights the main features of the main types of study : 
Study type Key features 
Randomised 
controlled trial  Participants randomly allocated to intervention or control group (e.g. standard treatment or 
placebo) 
Practical or ethical problems may limit use

Practical or ethical problems may limit use 
Cohort study  Observational and prospective. Two (or more)are selected according to their exposure to a 
particular agent (e.g. medicine, toxin) and followed up to see how many develop a disease 
or other outcome. 
The usual outcome measure is the relative risk.  
Examples include Framingham Heart Study 
Case-control study  Observational and retrospective. Patients with a particular condition (cases) are identified

and matched with controls. Data is then collected on past exposure to a possible causal 
agent for the condition. 
The usual outcome measure is the odds ratio.  
Inexpensive, produce quick results 
Useful for studying rare conditions 
Prone to confounding 
Cross-sectional 
survey  Provide a 'snapshot', sometimes called prevalence studies 
Provide weak evidence of cause and effect 
Grade of evidence  
 
1651

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   23 
  Randomised controlled trial (RCT) 
 is the 'gold standard' for evaluating a new intervention 
 The purpose of randomisation is to prevent systematic differences between treatment groups. 
 Classic errors in randomisation  are: 
 Consecutive sampling, which may well not be representative if the study time is shor t.

 Convenience sampling: strong potential for bias, with volunteers generally healthier than others . 
 Judgmental sample: including those that you want only. The potential for systematic error is enormous. 
 In RCT, the results best summarised as  Mean and confidence interval for the difference  between the 
active intervention group and the control that is of importance 
 In RCT, data analysed by analysis of covariance provides an efficient analysis without introducing bias

 An imbalance in a baseline variable will inevitably sometimes occur in well-conducted, randomised 
controlled trials, so  analysis should be undertaken to see if the imbalance alters the conclusions of the 
trial  
 A 'double-blind, randomised, placebo controlled study' would be time consuming, expens ive and unlikely to be 
powered enough to detect what may be a rare toxic effect.

With rare diseases and exposures, case control studies  are the best option. Although cohort studies are good for rare 
exposures , they are not good for rare diseases . 
To test relative potency: 
 Biological assays  are designed to measure the relative potency of different preparations.  
To test efficacy: 
 Blood pressure is highly variable and is subject to variability because of the p atient's level of anxiety and the 
method used by the observer to measure it.

method used by the observer to measure it. 
 In a test of efficacy  of an antihypertensive drug, a double blind, randomised design would be favourable.  
A sequential trial 
 a trial in which the data are analysed after each participant's results become available and the trial continues until 
a clear benefit is seen in one of the comparison groups, could also be used to assess eff icacy, but there would 
have to be a large expected difference from placebo.

 'Sequential' trial would be comparing one therapy to another sequentially (usually with wash out perio ds in 
between).  
Advantages of case-control studies are that: 
 They are particularly suitable for rare diseases 
 A wide range of risk factors can be investigated 
 There is no loss to follow up, and 
 They are relatively cheap and quick to perform. 
Disadvantages of case-control studies:  
Have the greatest problems with recall bias  
Cohort advantages and disadvantages

Cohort advantages and disadvantages 
 Disadvantages include:  
 Relatively time consuming  
 expensive to perform.  
 When the outcome of interest is rare a very large sample size is needed (Insufficient for rare disease)  1652

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   24 
  Advantages include   
  able to study exposure factors that are rare  
 Less susceptible to recall bias than case-control studies. 
  Able to measure the incidence/risk of a disease. 
Disadvantages of observational studies  
 From association in an observational study, we cannot infer cause and effect

Crossover trial 
 The principle of a crossover design is that a patient has one drug or treatment, then a washout p eriod, and then 
another drug, and the effect is compared between the two in a single individual.  
 For this reason it is a good study design for treatment of chronic conditions (eg: comparing analgesics in 
arthritis ) but not appropriate for acute conditions.

 In a crossover trial, the patient (who usually has a chronic stable disease) receives one drug (or placebo) 
and then the other drug after a washout period 
 Each patient will usually receive all drugs within the study 
 In this way, confounding can be greatly reduced 
 If a drug had long-lasting effects it may not be easy to see which of the trial drugs was  having an effect 
 A self-limiting illness is difficult to study in this way

 Because each person is acting as their own control, it is usually possible to use sm aller numbers to get the same 
power. 
 If any treatment in a cross-over trial is a disease-modifier (in the most extreme case, kills or cures th e 
patient), then the interpretation of results in any subsequent period becomes impossible . This is because 
disease modification implies that one course of the drug will permanently change the f uture timecourse of that

patient's disease in some way, making a cross- over study un-interpretable. In this case a parallel trial is the only 
appropriate option. 
Intention to treat analysis (ITT) 
 Intention to treat analysis is a method of analysis for randomized controlled trials in w hich all patients randomly 
assigned to one of the treatments are analysed together, regardless of whether or not they completed or rec eived

that treatment.  Include the patients who drop out in the final data set  
 Intention to treat analysis is done to avoid the effects of crossover and drop-out, which may affec t the 
randomization to the treatment groups. 
 Intention to treat helps to reduce bias by sticking to the original allocation of treatment and anal ysing the patient in 
that treatment group even if they do not recieve the treatment

 ITT is considered to be the analysis which is least subject to bias. Considered the most robust  
Per protocol analysis 
 A per protocol analysis  may exclude patients who suffered an event but then did not follow the protocol 
accurately, for example, a patient treated with the diabetes agent who was admitted to hospital, but mis sed one to 
two doses of medication. 
Sampling

Sampling 
 Sampling error arises when only a portion of the population is studied 
 Random sampling  implies that the sample has been selected from a sampling frame in such a way that every  
individual has the same chance of being selected 1653

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   25 
   In random sampling, defined criteria for sample selection are laid down 
 The standard error of the mean  is the standard deviation divided by the square root of the sample size, hence it 
must always be smaller than the standard deviation

 Inference  is the process of drawing conclusions about the population using the sample information 
  a sample statistic is a point estimate of a population parameter  
Bias  
Bias occurs when there is a systematic difference between the results from a randomised c ontrolled trial and the true 
state of affairs. 
 a selection bias  occurs when the study population is different from the population to whom the results wil l be

applied and there is therefore said to be  
 Allocation bias  occurs when patients are not randomly assigned to a particular treatment. 
 Assessment bias  occurs when the observer knows which treatment the subject is taking. 
 Observer bias  is when one observer consistently under or over reports a particular variable.  
 Recall bias  applies to case-control studies when a patient is more likely to remember a particular detail  of 
exposure if they go on to develop the disease.

exposure if they go on to develop the disease. 
Study design: evidence and recommendations 
Levels of evidence 
 Ia - evidence from meta-analysis of randomised controlled trials 
 Ib - evidence from at least one randomised controlled trial 
 IIa - evidence from at least one well designed controlled trial which is not randomis ed 
 IIb - evidence from at least one well designed experimental trial

 III - evidence from case, correlation and comparative studies 
 IV - evidence from a panel of experts 
Grading of recommendation 
 Grade A - based on evidence from at least one randomised controlled trial (i.e. Ia or Ib)  
 Grade B - based on evidence from non-randomised controlled trials (i.e. IIa, IIb or III) 
 Grade C - based on evidence from a panel of experts (i.e. IV) 
Study design: new drugs

Study design: new drugs 
Superiority trial  a large sample size is required to demonstrate a significant difference 
When a new drug is launched there are a number of options available in terms of study design. One o ption is a placebo 
controlled trial. Whilst this may provide robust evidence it may be considered unethical i f established treatments are 
available and it also does not provide a comparison with standard treatments.

If a drug is therefore to be compared to an existing treatment a statistician will need to decide w hether the trial is intended 
to show superiority, equivalence or non-inferiority: 
 Superiority : whilst this may seem the natural aim of a trial one problem is the large sample size needed to sho w 
a significant benefit over an existing treatment 1654

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   26 
   Equivalence : an equivalence margin is defined (-delta to +delta) on a specified outcome. If the confidence 
interval of the difference between the two drugs lies within the equivalence margin then the drugs ma y be 
assumed to have a similar effect

assumed to have a similar effect 
 Non-inferiority : similar to equivalence trials, but only the lower confidence interval needs to lie within the  
equivalence margin (i.e. -delta). Small sample sizes are needed for these trials. Once a drug has been show n to 
be non-inferior large studies may be performed to show superiority 
It should be remembered that drug companies may not necessarily want to show superiority over an exis ting product. If it

can be demonstrated that their product is equivalent or even non-inferior then they may compete on price or convenience. 
Post-marketing surveillance (PMS)/observational studies (phase IV studies): 
 designed to assess the potential side effects of new drugs  
 In contrast to the randomised controlled trials, PMS typically includes patients from  more extreme age groups and 
patients with comorbidity or other risk factors.

patients with comorbidity or other risk factors. 
 In order to cover a wide spectrum of patients and to observe rare events with sufficiently high probabi lity, PMS 
enrolls a large number of patients, typically several thousands. 
Phases of new drug development  
phase  goal notes  
Animal trial Safety for testing the drug in humans  
Phase I  Initial safety  
 most frequent side 
effects 
 How the drug is 
metabolized and

effects 
metabolized and 
excreted.  conducted in healthy 
volunteers.  
 The number of subjects 
ranges from 20 to 80. 
Phase II Effectiveness  
 ( RCTs) The number of subjects ranges from a 
few dozen to about 300. 
Phase III Comparative efficacy (Effectiveness 
compared to commonly used 
treatment)  The number of subjects 
ranges from several hundred 
to about 3,000  
 The best study for phase 3 is 
a randomised control study.

a randomised control study. 
Phase IV (post marketing) Side effects Enrolls a large number of patients, 
typically several thousands. 
Systematic review   (meta-analysis) 
 a study of studies. 
 statistical (quantitative) combination of results from two or more studies addressing the same resea rch question. 
 Metanalysis=  systematic reviews + Quantitative measures. 
 Usually used to treatment studies.

 Usually used to treatment studies.   
 A 'meta-analysis' would look at combining all previous data,. This is likely to be the quickest option to 
complete, and also produces the highest level of evidence.  
 rapid and efficient  1655

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   27 
   Publication bias might be present (positive results are published more often than the negative ones). 
 Publication bias can be examined by funnel plots if a sufficient number of studies is  found. 
 Non-randomised or other studies may or may not be included.

 However, randomised controlled trials usually have lower risk of bias and hence give us more c onfidence about 
validity of results and are preferred primary sources for systematic review.  
 Critical appraisal is an important part of systematic review and it has to be objectivel y performed using well-
defined criteria or appraisal tools. 
 Meta -analysis, that is, combining results numerically in a statistically appropriate way , though desirable, is not

always feasible, depending on the availability of usable data and heterogeneity.  (Meta-analysis is not always 
performed )  
 The search strategy in systematic review should be comprehensive involving electron ic databases and other 
sources and using well-defined search terms. 
 Case-control studies are not usually included in the search of literature in systematic review 
 The research question is always focused

 The research question is always focused  
 there are at least two authors to independently appraise the search results and primary studi es. 
 It is not mandatory to exclude studies with missing data. 
 The effect size should not affect the weight of each study, although it will affect the final  result. 
 Trial quality is usually not incorporated into meta-analysis nowadays since t he weightings can be subjective and 
arbitrary.

arbitrary. 
 The weight of each study should depend on the sample size  
 Funnel plots  
 show publication bias in meta-analyses 
 Forest plot  
 The most appropriate way of graphically depicting the results of meta-analysis. 
 
Fixed vs random effect model for meta-analysis 
The fixed effect model  The random effects model  
the most commonly used model for meta-analysis.  
Provides the best estimate of the treatment effect   
attempts to provide one single best estimate of

attempts to provide one single best estimate of 
treatment effect.  attempts to find an average treatment effect.  
assumes there is no heterogeneity between the 
trials.  assumes heterogeneity  
assumes a single treatment effect  allows multiple treatment effects.  
 
 1656

Notes & Notes for MRCP                                                                                  By Dr. Yousif Abdallah Hamad   28 
  ___________________________________________________________________ 
Graphical representation of data 
Charts and diagrams  
Quantitative data Qualitative data 
Histogram  
Scatter diagram  Bar diagram 
Pie diagram  
 
The interpretation of novel findings in a published clinical resear ch study

 The trustworthiness of a study should depend solely on its scientific validity, that i s, whether it is free of bias. 
 The conclusion should be treated with skepticism even if it is extensive ly peer-reviewed  
 
 1657

Pharmacology  
 
Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  1 
 
By
 
Pharmacology
 
Updated 
 
2017
 
Contains: 
 
 1658

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  2 
 
Basic pharmacology  
Pharmacokinetics: metabolism 
 
Drug metabolism usually involves two types of biochemical reactions - phase I and pha se II reactions. 
The majority of phase I and phase II reactions take place in the liver 
 phase I reactions:  oxidation, reduction, hydrolysis.

 Mainly performed by the P450 enzymes but some drugs are metabolised by specifi c enzymes, 
for example alcohol dehydrogenase and xanthine oxidase.  
 Products of phase I reactions are typically more active and potentially toxic 
 phase II reactions:  conjugation.  
 Products are typically inactive and excreted in urine or bile.  
 Glucuronyl, acetyl, methyl, sulphate and other groups are typically involve d 

Drug absorption 
 Diffusion.  
 Most drug absorption  in the gastrointestinal tract occurs by diffusion .  
 For diffusion to occur: 
 the drug must be dissolved so that individual drug molecules come into contact with the 
gut epithelium,  
 the drug must be lipid soluble so that it can cross the cell membrane . 
 Because the cell membrane is lipoid, lipid-soluble drugs diffuse most rapidly.  
 Drugs that are not ionized are lipid soluble and most likely to be well

absorbed from the gastrointestinal tract. 
 The ionized form has low lipid solubility (but high water solubility —ie, 
hydrophilic) and high electrical resistance and thus cannot penetrate cell 
membranes easily. 
 Theoretically, weakly acidic drugs (eg, aspirin ) are more readily absorbed from an acid medium 
(stomach)  than are weakly basic drugs (eg, quinidine). However, whether a drug is acidic or basic,

most absorption occurs in the small intestine because the surface area is larger and memb ranes are 
more permeable 
lipid soluble drug vs lipid insoluble drug  
lipid soluble drug lipid insoluble drug  
have good gastrointestinal absorption have poor gastrointestinal absorption  
can be given orally may need to be given parenterally  
will be widely distributed in the body

will be widely distributed in the body 
(large volume of distribution) has limited distribution (may not cross blood-brain 
barrier or placenta and less likely to be stored in fat 
tissue) 
 usually requires metabolism before elimination (to 
decrease lipid solubility) may be eliminated without metabolism  
 often have a long plasma half-life  (prolonged by 
‘reservoir ’ of drug in tissues and by requirement for 
metabolism). often have a short plasma half-life as elimination does

not require metabolism. 
Sep 2017 part 1 : What is the mechanism that make salmeterol acts as a LABA? 
 Its long duration results from its high lipid solubility  
 
1659

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  3 
  
 Chemical nature Clinical significance Example 
Lipophilic  Predominantly 
nonpolar 
compounds  can easily diffuse across the 
lipid bilayer of the cell 
membrane. 
 can be administered 
topically 
 can across the blood-
brain barrier 
 Metabolised in the liver and 
then excreted through the bile

then excreted through the bile 
duct   Scopolamine (hydroscine) 
 Tertiary amine  
 Used to treat motion sickness 
Hydrophilic  Predominantly 
polar 
compounds  can only cross the lipid bilayer 
via facilitated transport  
 Smaller hydrophilic molecules 
can diffuse along a 
concentration gradient through 
pores in the membrane 
 eliminated by the kidneys  Butylscopolamine (hyoscine 
butylbromide) 
 Quarternary amine  
 Used as an 
antispasmodic to treat 
GI colic

 Used as an 
GI colic 
Amphiphilic  Both lipophilic and hydrophilic Local anesthetics, e.g., lidocaine 
 
Drug metabolism in patients with advanced liver disease  
 Plasma proteins fall in liver disease and may negatively affect drug  distribution  
 Both intrahepatic and extrahepatic cholestasis may affect the metabolism  of drugs that are actively 
secreted into bile, eg ciprofloxacin

secreted into bile, eg ciprofloxacin 
 Conjugation reactions are affected to a lesser extent by advanced liver disease and on ly occur 
in very late stage disease 
Pharmacokinetics in chronic re prnal failure 
 Renal failure disturbs virtually every kinetic parameter including: 
 gastric absorption 
 hepatic metabolism of some drugs 
 protein binding 
 volume of distribution

 volume of distribution 
 The bioavailability of an intravenously administered drug is 100% and does not change in renal 
failure  
 
What is the reason for phenytoin toxicity in patient with chronic renal failure ?  
 Decreased protein binding of phenytoin   
 In CRF, drugs lose some of their affinity for protein binding  ↑↑ availability of free drug at any 
given dose  toxicity

given dose  toxicity  
 Because laboratory assays for phenytoin  usually measure total drug concentration, this give a 
false re-assurance ( drug level may be within therapeutic range )  
 In CRF dose reduction of phenytoin is therefore required  
 Other drugs may cause same problem  sodium valporate  and warfarin  
Effects of age on drug metabolism

Effects of age on drug metabolism 
 All of the following may account for differences in drug metabolism in the elderly:  
 diminished renal function 
 altered proportions of body fat and water 
 reduced cardiac output  
 some degree of altered hepatic metabolism 
 diseases 
 general debility 
 concomitant medication use 
 For these reasons, 'box-ticking' healthy elderly studies are rarely able to de tect problems associated 
with the use of new drugs in the elderly age group

 Many problems associated with the use of new drugs in the elderly may only be di scovered through 
adverse event reporting during the post-launch period 
 Which medications would require greatest caution when prescribed for older adults? 1660

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  4 
  diuretics, 
 Older adults are more susceptible to the volume depletion and hyponatraemic effects o f 
diuretics. 
 digoxin,  
 antihypertensives,  
 anti-inflammatory agents 
 drugs acting on the central nervous system (CNS). 
First-pass metabolism

First-pass metabolism  
 This is a phenomenon where the concentration of a drug is greatly reduced before it rea ches the 
systemic circulation due to hepatic  metabolism.  
 As a consequence much larger doses are need orally than if given by other routes.  
 This effect is seen in many drugs, including:  
 Aspirin 
 isosorbide dinitrate 
 glyceryl trinitrate 
 lignocaine 
 propranolol  verapamil 
 isoprenaline 
 testosterone 
 hydrocortisone 
 morphine

 morphine 
 Drugs with high first-pass metabolism should be used with caution in liver diseas e, since poor 
hepatic function may lead to their accumulation because of increased bioavailability   
 
What is the reason for a different dose of sublingual glyceryl trinitrate (GTN) and oral isosorbide 
mononitrate? 
 First-pass metabolism  

Saturation kinetics ( first order  + zero order kinetics ) 
 In drugs which have saturation kinetics  initially Small doses of the drug lead to a linear increase in 
serum drug concentration(follow a linear line)  (first order kinetics)  
 Then their metabolism slows down leading to a plateau of the line, for example due to e nzyme 
depletion. Small doses in the drug then lead to large increases in plasma concentration  (zero order

kinetics). This response is typical of drugs such as phenytoin (saturates liver metabolism). 
 Types of drug kinetics 
1. Zero order kinetics : The rate of metabolism and/or elimination remains constant and is 
independent of the concentration of the drug (e.g., metabolism of alcohol)  
2. First order kinetics : The rate of metabolism and/or elimination is directly proportional to the 
plasma concentration of the drug (applies to most drugs)

Zero-order kinetics  
 
 Zero-order kinetics describes: 
 metabolic pathways becoming saturated resulting in  constant amount of drug being 
eliminated per unit time (metabolism which is independent of the concentration o f the reactant) .  
 This explains why people may fail a breathalyser test in the morning if they hav e been drinking the night 
before

before 
 Drugs following zero order kinetics continue to be metabolised at a steady rate , independent of the 
concentration of the substrate.  
 The plot of metabolism against time is linear . 
Drugs exhibiting zero-order kinetics  
 salicylates (e.g. high-dose aspirin)  heparin 
 ethanol  
1661

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  5 
  
Acetylator status  
 50% of the UK population are deficient in hepatic N-acetyltransferase 
 Greater than 60% of Japanese are recognised to be fast acetylators

 Approximately 50% of black and Caucasian people are 'slow acetylators' and the rest are 'r apid 
acetylators'.  
 The majority of Eskimos and Orientals are 'rapid acetylators'. 
 Slow acetylation   ↑↑drug concentrations   ↑↑toxicity from drugs adverse effects.  
 fast acetylation   
 ↓↓response to the drug effect 
 ↑↑ blood levels of the toxic metabolite   
Drugs affected by acetylator status  (slow acetylators   increased unwanted effects) 
1. isoniazid

1. isoniazid   
 Slow acetylation  ↑↑drug concentrations   (peripheral neuropathy and toxic hepatitis  
2. hydralazine  (drug-induced lupus) 
3. dapsone  (haemolysis and neuropathy but not fibrosis) 
4. sulfasalazine  (haemolysis) 
5.  procainamide 
1662

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  6 
Drug transporter  : P-glycoprotein (P -gp) 
P-glycoprotein (P- gp)  
 (P-gp) is an efflux transporter that takes drug molecules from the cell cyto plasm and transports them 
back into the intestinal lumen for excretion. thus ↓↓ their bioavailability.

 P-gp transports many drugs that are substrates of CYP3A4.    
 P-gp and CYP3A4 act as barriers to the systemic exposure of exogenous substances including d rugs.   
 P-gp prevent saturation of CYP3A4.  This results in an increase in the efficiency of first-pass drug 
metabolism.العلاقة بينهما عكسية  
 CYP3A4 concentrations decrease from the proximal to distal portions of the intestine. P-gp content

increases from the proximal to distal intestine. Thus, where an excess of CYP3A4 is availabl e for 
metabolism, less P-gp is present. Conversely, where CYP3A4 concentrations are lower, more P- gp is 
found to prevent saturation of the enzyme. 
 An inhibitor of P-gp will increase the bioavailability of a P-gp substrate, whereas induction of P-gp will 
reduce the bioavailability of a substrate drug.   
 P-gp inhibits digoxin bioavailability .

 P-gp inhibits digoxin bioavailability .   
 Co-administration of the P-gp inhibitors (eg: erythromycin or clarithromycin)  to patients receiving 
chronic digoxin ↑ serum digoxin   ↑central nervous system side effects 
 Conversely, P-gp inducers  ↓ serum digoxin.  
Substrates, Inhibitors, and Inducers of P-glycoprotein 
Substrates Inhibitors Inducers 
Colchicine 
Digoxin 
Fexofenadine 
Indinavir 
Morphine 
Sirolimus Amiodarone 
Clarithromycin 
Ketoconazole 
Quinidine

Quinidine 
Saquinavir 
Verapamil Carbamazepine 
Rifampin 
St. John's wort 
Tipranavir 
Half-life 
ĹĹ lipid solubility  ĹĹtissue binding of the drug  ĻĻ renal and hepatic clearance rate  ĹĹ half life  
 
 The half-life is the time taken for the concentration of a drug to reduce by 50%  
 Plasma half-life is the most important pharmacokinetic factor in determining the appropriate

timing between doses  
 The half-lives are related to : 
1. lipid solubility (amiodarone, fluoxetine and diazepam are very lipid-soluble) 
2. the rate of drug clearance 
 Amiodarone the longest half-life = 25 days  , fluoxetine 53 h; diazepam 43 h; gentamicin 2-3 h; and 
bumetanide 0.8 h 
 
After 4 half-lives, more than 90% of the drug is eliminated  
Trough level 
  The lowest concentration

  The lowest concentration  
reached by a drug before the 
next dose is administered, often 
used in therapeutic drug 
monitoring. 
 Half-life is the major determinant 
of trough concentration 
 
1663

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  7 
  
Affinity & efficacy  
 Affinity  is the measure of the attraction between a drug and its receptor . 
 (the affinity of a drug for its receptor   Potency ) 
 Affinity and intrinsic activity are determinants of potency. 
 Potency

 Potency  
 'Potency' is a term often used incorrectly to describe dose-response 
 Potency is merely the effect of a drug , weight for weight, compared against another  
 Efficacy   
 contributes both to potency and to the maximum effect of the agonist.  
 Efficacy is a measure of the efficiency of the drug-receptor complex in init iating the signal 
transduction process. 
 Therapeutic efficacy (eg in a change in mmHg) is a much better measure of dose -response

 dose-response curves can be plotted for efficacy and toxic effects 
 Therapeutic index   (the maximum tolerated dose divided by the minimum effective 
dose)  
Dose-response 
 The dose-response curve  for loop diuretics such as furosemide is steeply rising and prolonged, 
indicating a large improvement in drug effect across a range of increasing doses

 In contrast, the dose-response curve for thiazide diuretics rapidly reaches a plateau afte r the use of 
relatively low doses, indicating that there is no point in increasing doses above 2.5 mg in the case of 
bendrofluazide for instance 
 The dose-response curve reaches a plateau for pioglitazone at above 45 mg (licensed doses  30 mg 
and 45 mg) 
 With respect to losartan, two doses are available, but the dose increment between 50 and 100 m g only

results in a relatively modest further drop in blood pressure 
loading dose  
Why is a loading dose used in amiodarone? Because Amiodarone is widely bound in body tissues  
 Tissue-binding sites must be ‘filled up' by a loading dose before a therapeutic plasma concentration can 
be achieved.  
 Metabolism/elimination/clearance rates and plasma half-life determine the time t aken to achieve a

steady-state plasma concentration and the level of that steady-state concentrat ion when a steady 
dosing regimen is established. 
 The loading dose is calculated (using various models) by taking into account age, crea tinine clearance, 
body surface area, etc. 
 The loading dose is mainly dependent on the  volume of distribution  of a drug but  in patient with 
moderate renal failure it depends on renal clearance.

 Volume of distribution becomes important particularly when body weight is 40  kg or less.  
 What is the main factor that determines the choice of loading dose of digoxin  in patient with 
high creatinine? 
 Renal clearance 
 Digoxin is cleared by the kidneys so the maintenance dose would require adjustment in 
renal failure. 
 In digoxin both the initial loading dose and the maintenance dose must be 
reduced in patients with underlying renal disease.

 most useful for drugs which have a long   half-life such as: 
 Amiodarone  
 digoxin, 
 teicoplanin, 
 antibiotic  inhibit bacterial cell wall synthesis. 
 spectrum of activity similar to vancomycin  against Gram-positive bacteria 
including Staphylococci  and Clostridium  spp.  
 Oral teicoplanin is effective in the treatment of pseudomembranous colitis   
 voriconazole,  
 procainamide and  
 fulvestrant. 
 selective estrogen receptor degrader (SERD)

 selective estrogen receptor degrader (SERD)  
 used to treat hormone receptor (HR)-positive metastatic breast cancer 1664

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  8 
 Loading dose vs maintenance dose:  
 Loading doses  usually do not need to be adjusted in patients with chronic kidney disease, but 
maintenance doses  should be adjusted by: dose reduction, lengthening the dosing interval, or both.

  in renal or liver disease, dosage of the same drug when given as maintenance dose  is decreased and 
when it is given as loading dose  is usually unchanged.  
Bioavailability   
 Bioavailability is a measure of the proportion of an oral administered dose that reaches the 
systemic circulation  
 Where a drug is administered intravenously, it has 100% bioavailability 
 Bioavailability is affected by two mechanisms:

 Bioavailability is affected by two mechanisms: 
1. First pass effect :  
 Orally administered drugs are absorbed from the GI tract and reach the liver via t he 
portal circulation, where they undergo some degree of metabolism before they enter 
systemic circulation. This decreases the bioavailability of the drug.  
2. Ability to pass through lipid membranes 
Extraction ratio

Extraction ratio 
 The extraction ratio is a measure of how much drug is extracted from the plasma by  the kidney 
 It determines the clearance  (= renal plasma flow x extraction ratio) 
 The extraction ratio is determined by assessing drug concentration on the arterial and venous 
sides of the renal circulation   
Drug level and elimination

Drug level and elimination  
Example:  if the half-life of a drug is 4 h , what  percentage  of the drug will be eliminated after 20 h?  
 The concentration of the drug reduces by 50% over each 4-h period 
 After 4 h   50% remaining  
After 20 h  X % remaining 
X% = (0.5 x 20) /4 = 2.5 (remaining after 20 h) 
 This means that approximately 97% of the drug concentration has been eliminated after 20 h

Example : 630 mg of a drug with half-life of 30 min, how much time will it take before the drug level falls 
below 20 mg? 
 
 20/630 = approximately 1/32 = 1/2x1/2x1/2x1/2x1/2 =  5 half-lives (for less than 20 mg to 
remain) 
 5 half-lives equals 5 x 30 min = 150 min  
 
Example : The half-life of a drug is 4 h, calculate the plasma concentration  12 h after administration of drug 
that gives a peak initial plasma concentration of 2 mg/dl ? 
 
 the half-life here, which is 4 h,

 the half-life here, which is 4 h, 
 12 h is equal to three half-lives 
 Therefore, the plasma concentration at 12 h will be 2/(2 x 2 x 2) = 0.25   
 
Example:  On admission the lithium level was 2.4 mmol/l;  After what period of time post admission is the 
lithium level likely to be approaching 0?  
 The half-life of lithium is around 20 h 
 The level would be 1.2 mmol/l after 20 h, 0.6 mmol/l after 40 h, 0.3 mmol/l after 60 h and 0.15 mmol/l 
after 80 h

after 80 h  
Clinical trial: phases  
Clinical trials are commonly classified into 4 phases;  
Phase Goal Notes 
I Determines pharmacokinetics and 
pharmacodynamics and side-effects 
prior to larger studies Conducted on healthy volunteers 
II Assess efficacy + dosage Involves small number of patients affected by 
particular disease 
May be subdivided into: 1665

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  9 
 Phase Goal Notes 
 IIa - assesses optimal dosing 
 IIb - assesses efficacy  
III Assess effectiveness Typically involves 100-1000's of people, often 
as part of a randomised controlled trial, 
comparing new treatment with established 
IV Postmarketing surveillance Monitors for long-term effectiveness and side-

effects 
 
How many patients would need to be recruited to detect one adverse event? 
 Roughly speaking, to detect one adverse event in a clinical trial you would need to en rol three times as 
many patients as the expected event frequency 
 So If the frequency expected was 1 in 10 000, then you would need to recruit 30  000 patients  
Testing of a new drug pharmacokinetic

Testing of a new drug pharmacokinetic 
In designing a new drug, which of the following compounds, according to its mode of clearance, is most likely 
to show stable pharmacokinetic properties when tested between patients? 
 
 CYP2D6 shows the greatest genetic variability  ĹĹ pharmacokinetic differences between patients in 
drugs metabolised down this route 
 CYP3A4 is the P450 isoform pathway  significant drug interaction

 Therefore, the preferred pathway for drug clearance is one-third via the kidneys and two-t hirds 
via P450 isoforms, but not CYP2D6 
 the ideal profile of our candidate drug should be neither an inhibitor nor an inducer  of the P450 system 
 To maximise drug absorption, the ideal compound should be: 
 small molecular weight (of less than 300 kDa)  
 have intermediate lipophilicity and hydrophilicity  
Bioequivalence

Bioequivalence  
 Bioequivalence means that  the two drugs compared have the same pharmacokinetic and 
pharmacodynamic effects 
 A pharmaceutical company wants to bring generic drug to the market.  What kind of study is needed 
to obtain approval to market the drug?  
 Phase-I bioequivalence study.  Generic medicines have to be therapeutically 
equivalent to their branded product.  
Some definitions

Some definitions 
 Competitive antagonists  bind to the site of action for the endogenous receptor ligand and can be  
displaced, (eg prazosin) 
 Non-competitive antagonists  (eg phenoxybenzamine) cannot be displaced or have their effects 
diminished by an endogenous receptor ligand 
 A partial agonist  (eg acebutolol) may exhibit strong receptor-binding activity, but have a lim ited 
physiological response 

Adverse drug reactions 
 Type A  (augmented) reactions occur owing to a pharmacological effect of the drug  
 they are dose-related and can occur in anyone 
 Type B  (bizarre) reactions are unpredictable  and not related to a pharmacological effect of the drug 
 Type C  (continuous) reactions occur because of prolonged drug use  (eg analgesic nephropathy or 
visual-field defects with vigabatrin ,) 
 Type D  (delayed) reactions are teratogenic or carcinogenic  reactions (eg thalidomide)

 Type E  (end of use) reactions are withdrawal phenomena  identified after a drug is discontinued  
 
Side-effects Classification 
 Very common side-effects are said to occur with a frequency of greater than 1 in 10 patients 
 Common side-effects: in 1 in 100 to 1 in 10 
 Uncommon side-effects: in 1 in 1000 to 1 in 100 
 Rare side-effects: in 1 in 10 000 to 1 in 1000 
 Very rare side-effects: in less than 1 in 10 000 patients 1666

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  10 
  
The Yellow Card recording system of drug adverse effects: 
Only 10% of serious adverse drug reactions are identified by Yellow Cards  
Prodrugs   
Prodrug  Active form  Note 
Levodopa Dopamine converted by dopa decarboxylase to dopamine in

the brain (in the striatum). 
Enalapril Enalaprilat  
S-methyldopa Alpha 
methylnorepinephrine It is converted to α-
methylnorepinephrine  by dopamine beta-
hydroxylase  activation of 
α2 adrenergic receptors in the brainstem 
Ļsympathetic output  Ļ BP.  
Loratadine desloratadine non-sedating antihistamine 
Terfenadine  fexofenadine  non-sedating antihistamine 
 Terfenadine, withdrawn from the market 
because of serious side effect.  
 fexofenadine, is safe, does not carry the

 fexofenadine, is safe, does not carry the 
same risks as the parent compound.  
salicin  salicylic acid salicin is a β-D-glucopyranoside that is cleaved by 
esterases to release salicylic acid. 
 codeine and morphine  (morphine-
glucuronides) codeine and morphine 
is enzymatically activated to form sugar 
derivatives (morphine-glucuronides) that are more 
active than the parent compound 
Mercaptopurine Methymercaptopurine 
ribonucleotide  
Fluouracil Fluororidine 
monophosphate

monophosphate  
Cyclophosphamide Aldophosphamide, 
Phosphormide 
mustard  
Sulfasalazine 5-Aminosalicyclic 
acid  
Becampicillin Ampicillin  
Prednisone Prednisolone  
Proguanil Proguanil triazine Antimalarial  
is an inhibitor of dihydrofolate reductase 
Hydrazide MAO inhibitors Hydrazine derivatives  
Dipivefrine Epinephrine used to treat open-angle glaucoma 
 
 Prodrugs can be classified into two major types: 
 Type I prodrugs  are bioactivated intracellularly .

 Examples of these are: 
 anti-viral nucleoside analogs that must be phosphorylated 
 lipid-lowering statins. 
 Type II prodrugs  are bioactivated extracellularly, in GIT or blood.  
 Examples: 
 salicin  
1667

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  11 
  antibody-, gene- or virus-directed enzyme prodrugs used in chemotherapy or 
immunotherapy.  
P450 enzyme system 
 3  "O" antibi otics inhibit Ors  isOniazid , cipr Ofloxacine  , erythr Omycin 
 1 "C " antibiotic indu Cer   rifampi Cine

1 "C " antibiotic indu Cer   rifampi Cine 
Induction usually requires prolonged exposure to the inducing drug, as opposed to P45 0 inhibitors, where 
effects are often seen rapidly 
Inhibitors of the P450 system include 
 
 antibiotics: ciprofloxacin, erythromycin 
 isoniazid   
 cimetidine, omeprazole 
 imidazoles: ketoconazole, fluconazole  SSRIs: fluoxetine, sertraline  
 Disulfiram  
 ritonavir 
 sodium valproate

 acute alcohol intake 
 quinupristin 
 
Inducers of the P450 system include : 
 antiepileptics: phenytoin, carbamazepine 
 barbiturates: phenobarbitone 
 St John's Wort  chronic alcohol intake 
 smoking (affects CYP1A2, reason why 
smokers require more aminophylline) 
 
Carbamazepine is an inducer of the P450 system. This    in    turn    increa ses    the metabolism of carbamazepine 
itself - auto- induction

itself - auto- induction  
P450 drug interactions: more detail 
the most important and common reason for drug interactions is the P450 CYP3A4 system . 
The table below shows the main enzyme systems that are affected by common drugs.  
 
P450 system Substrates Inhibitors Inducers 
CYP3A4  Macrolides 
Antiretrovirals 
Calcium channel 
blockers 
simvastatin Macrolides 
Protease inhibitors (including 
ritonavir) 
Imidazoles 
grapefruit juice  Carbamazepine 
Phenytoin 
Phenobarbitone 
Rifampicin

Phenytoin 
Rifampicin 
St John's Wort 
CYP2D6  Tricyclic 
Antipsychotics SSRIs 
Ritonavir  
CYP2C9  Warfarin  
Sulfonylureas Imidazoles 
Amiodarone  
Sodium valproate Rifampicin 
CYP1A2  Theophylline Ciprofloxacin Smoking 
Omeprazole 
CYP2E1  Alcohol  Chronic alcohol 
Isoniazid 
 
Interestingly, codeine and dihydrocodeine  are metabolised by cytochrome P450 2D6  to morphine, which

provides the analgesic effect; therefore, those patients who are CYP-2D6 poor m etabolisers will have a 
reduced analgesic effect with codeine or Dihydrocodeine 
 
1668

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  12 
 CYP-2C8 CYP-2C18/19 CYP-2D6 
Omeprazole Diazepam Tricyclic antidepressants 
Diazepam Tricyclic antidepressants β-blockers  
Barbiturates Omeprazole Dihydrocodeine 
 Proguanil Ecstasy (MDMA) 
  Selective serotonin reuptake 
 
Drug interactions with cytochrome P450

Drug interactions with cytochrome P450 
 Drug interactions with the cytochrome P450 system are only clinically significant for  drugs that have a 
narrow therapeutic index (ie small changes in plasma concentrations lead to the dr ug concentration 
being either sub-therapeutic or toxic) 
 Examples of these drugs include: 
 Ciclosporin   
 warfarin  
 theophylline and 
  phenytoin 
 Lithium has a narrow therapeutic index owing to changes in absorption and excretion and does not

interact with cytochrome P450 
Drugs required therapeutic monitoring 
Antiepileptics 
 Carbamazepine 
 Phenobarbital 
 Phenytoin 
 Valproic Acid 
 Antiarrhythmics 
 Digitoxin 
 Digoxin 
 Lidocaine 
 NAPA  
 Procainamide 
 Antibiotics 
 Gentamicin 
 Tobramycin 
 Vancomycin  
 
Immunosuppressants 
 Cyclosporine 
 Mycophenolic Acid 
 Sirolimus 
 Tacrolimus  Antimanics 
 Lithium 
 Bronchodilators 
 Theophylline

 Lithium 
 
Drug induced manifestations  
__________________________________________________________ ___________ 
Drug causes gingival hyperplasia 
 
Drug causes of gingival hyperplasia 
 calcium channel blockers  (especially nifedipine) 
Other causes of gingival hyperplasia include 
 acute myeloid leukaemia (myelomonocytic and monocytic types)

Drug affects folic acid metabolism 
Drugs which inhibit dihydrofolate reductase are: 
 Methotrexate 
 Pyrimethamine , and 
 Trimethoprim. 
Drugs which interfere with absorption/storage of folate are : 
1669

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  13 
  Phenytoin 
 Primidone, and 
 Oral contraceptives. 
Drug causes SIADH 
most commonly causes SIADH Other causes 
 Thiazide diuretics 
 Vinblastine 
 Cyclophosphamide  Chlorpropamide 
 Phenothiazines

 Phenothiazines 
 Clofibrate 
 Oxytocin 
 Vasopressin 
 Morphine 
 Nicotine 
Drug causes of urticaria 
The following drugs commonly cau se urticaria: 
 aspirin 
 NSAIDs 
 opiates 
Drugs induced galactorrhoea 
Drug causes of raised prolactin

Drug causes of raised prolactin 
 metoclopramide , Domperidone 
 Domperidone is a dopamine antagonist producing large rises in pr olactin concentrations. 
 phenothiazines 
 haloperidol 
 Cimetidine produces hyperprolactinaemia only  when given intravenously (IV). 
 very rare: SSRIs, opioids 
Drugs associated with gynaecomastia. 
 Spironolactone (the  most common ), causes gynaecomastia  by several mechanisms.

 block androgen production  by inhibiting enzymes in the testosterone synthetic pathway,  
 block recceptor binding of testosterone  and dihydrotestosterone.  
 increases free oestrogen levels  by displace oestradiol from sex hormone binding globulin 
(SHBG)  
 inhibitors of testosterone synthesis: 
 ketoconazole 
 metronidazole 
 cimetidine, Omeprazole 
 etomidate, and 
 cisplatin. 
 Oestrogens:    
 Digoxin   direct action at oestrogen 
 LHRH analogues

 LHRH analogues 
 Finasteride.  marijuana 
 heroin 
 calcium-channel blockers 
 busulphan 
 diazepam 
Drug-induced impaired glucose tolerance 
 Drugs which are known to cause impaired glucose tolerance include: 
 thiazides, furosemide (less common) 
 steroids 1670

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  14 
  tacrolimus, ciclosporin 
 interferon-alpha 
 nicotinic acid 
 atypical antipsychotics e.g. olanzapine 
 Beta-blockers an glycemic status: 
 beta -2-adrenergic antagonism   inhibition of hepatic gluconeogenesis  
 unselective beta-blockade associated with hypoglycemia  (e.g. propranolol  rather

than the use of beta-1 selective blockers e.g. atenolol, metoprolol). 
 selective beta-1 blockers  would not lead to hypoglycaemia - however "...in patients 
with abnormal energy requirements or metabolism, administration of beta 1- selective-
adrenergic antagonists may be associated with hypoglycaemia  
 Beta-blockers cause a slight impairment of glucose tolerance.  
 They should also be used with caution in diabetics as they can interfere with the metabolic and

autonomic responses to hypoglycaemia 
_________ _________________________________________________________ ___ 
Hepatocellular Picture  Cholestasis (+/- Hepatitis)  Liver Cirrhosis  
 Alcohol 
 Anti-tuberculosis: isoniazid, 
rifampicin, pyrazinamide 
 MAOIs 
 Methyldopa 
 Paracetamol 
 Sodium valproate, phenytoin 
 Statins  
 nitrofurantoin  
  Anabolic steroids, 
testosterones 
 Antibiotics: flucloxacillin, co-

amoxiclav* , erythromycin**, 
nitrofurantoin 
 Fibrates  
 Phenothiazines: 
 chlorpromazine, 
 prochlorperazine 
 Rarely: nifedipine 
 Sulphonylureas  Amiodarone 
 
* A four-week delay in symptoms and signs is not unusual . 
**risk may be reduced with erythromycin stearate 

Prescribing in patients with renal failure See nephrology  
Drug-induced  lupus erythematosus  
 statins 
Drug-induced pancytopaenia 
 
Drug causes of pancytopaenia 
 cytotoxics

 cytotoxics 
 antibiotics: trimethoprim , chloramphenicol 
 anti-rheumatoid: gold, penicillamine 
 carbimazole (causes both agranulocytosis and pancytopaenia) 
 anti-epileptics: carbamazepine 
1671

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  15 
  sulphonylureas: tolbutamide 
 Although both azathioprine  and mesalazine  cause pancytopenia, it is  more commonly seen in 
patients undergoing azathioprine therapy . 
Drug-induced thrombocytopenia 
Drug-induced thrombocytopenia (probable immune mediated)

 quinine 
 abciximab 
 NSAIDS 
 diuretics: furosemide 
 antibiotics: penicillins, sulphonamides, rifampicin 
 anticonvulsants: carbamazepine, valproate 
 heparin 
 Sulfa drugs  
 Hypersensitivity reactions to sulfa medications are common and are usually limited to pruritic rashes.  
 An acronym for remembering sulfa drugs is Popular FACTSSS:  
 Probenecid,  
 Furosemide,  
 Acetazolamide, 
 Celecoxib,

 Celecoxib,  
 Thiazides,  
 Sulfonamide antibiotics,  
 Sulfasalazine,  
 Sulfonylureas. 
 Furosemide,  
 Most loop diuretic, such as furosemide are sulfa-containing drugs,  
 sulfa-containing drugs can cause interstitial nephritis.  
 Interstitium is the site of furosemide toxicity.  
 For these patients, ethacrynic acid  can be used instead, because it does not contain 
a sulfa group.

a sulfa group. 
 alcohol antagonist drug used to treat chronic alcoholism   
Action 
 Ethanol is metabolized by two enzymes: 
1. Alcohol dehydrogenase, which is located in the cytosol, converts ethanol to acetaldehyde.  
2. Aldehyde dehydrogenase, which is located in the mitochondria , converts acetaldehyde to 
acetyl CoA. Both enzymes require NAD+ for function.

 Disulfiram is an inhibitor of aldehyde dehydrogenase  and causes accumulation of acetaldehyde, 
leading to severe nausea and vomiting if alcohol is consumed. 
Disulfiram reaction   
 The elevations in serum acetaldehyde levels cause the symptoms of disulfiram reaction  which 
include: 
 flushing,  
 headache,  
 nausea, vomiting  
 sweating  
 blurred vision,  
 dyspnea,  
 palpitations, hypotension, chest pain and syncope.

 avoid all alcohol-containing products (e.g., cough and cold syrups, mouthwash, or foods contai ning 
alcohol) while taking this medication. 
 Disulfiram typically causes an acute hepatitis like syndrome 2 to 12 weeks after s tarting the 
medication  that can be severe and lead to acute liver failure or need for liver transplantation. 
 1672

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  16 
 Disulfiram  inhibitor of Aldehyde dehydrogenase, which is located in the mitochondria  
Fomepizole  inhibitor of Alcohol dehydrogenase, which is located in the cytosol  
 
The target of disulfiram is located in which cellular compartments?  
 Mitochondria  
 
Drug-induced ethanol intolerance (disulfiram-like reaction)

 As in the case with disulfiram, the underlying mechanism is believed to be the accum ulation of 
acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases.   
 drugs which can produce DISULFIRAM like reaction when taken with Alcohol: 
 chloramphenicol,  
 furazolidone, 
 nitroimidazole antibiotics, including metronidazole , and  
 quinacrine, 
 First-generation sulfonylureas, e.g. tolbutamide and chlorpropamide

 cephalosporins, including cefoperazone, cefamandole and cefotetan 
 antifungal eg:  Griseofulvin 
 Procarbazine  
______________ _______________________________________________________  
Drug -induced long QT 
Commonly medications that cause QT prolongation 
class Examples 
Antiarrhythmic   Amiodarone  
 Disopyramide  
 Ibutilide  Procainamide 
 Quinidine  
 Sotalol  
antipsychotics  Chlorpromazine  
 Clozapine 
 Haloperidol  Quetiapine 
 Risperidone  
 Thioridazine

 Thioridazine   
antibiotics  Azithromycin 
 Clarithromycin  
 Erythromycin   
 Levofloxacin  Ofloxacin  
 Trimethoprim – sulpha 
 Ketoconazole 
 Fluconazole 
 itraconazole 
Antidepressants  Amitriptyline 
 Citalopram 
 Desipramine 
 Doxepin 
 fluoxetine  Imipramine 
 Nortriptyline  
 Paroxetine 
 Sertraline 
 venlavaxine 
Antiemetics  Ondansetron   prochlorperazine 

Drugs causing ocular problems 
Visual 
disturbance cataract Corneal 
opacities 
 Optic neuritis 
 Retinopathy 
 Blue tinge 
in vision Yellow-
green 
tinge 
Drug steroids Amiodarone 
Indomethacin 
 Ethambutol 
Metronidazole 
 Chloroquine, 
quinine 
 Sildenafil 
 Digoxin 
Sildenafil can cause both blue discolouration and non-arteritic anterior ischaemic neurop athy 
1673

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  17 
 Drug induced photosensitivity  
Rash on the forearms and face is typical of a photosensitivity rash  
 
 Tetracyclines, sulphonamides, ciprofloxacin 
 Amiodarone  NSAIDs e.g. Piroxicam 
 Psoralens 
 Sulphonylureas 
Mnemonic: FAST-N  (Fluoroquinolones eg: cipro. Amiodarone. Sulfo.Tetracyclines. NSAIDs)

Drug induced ototoxicity 
 Causes 
 Aminoglycosides 
 Streptomycin  irreversible cochlear and vestibular dysfunction 
 platinum-based antineoplastic agents,  
 salicylates,  
 quinine,  
 loop diuretics. 
 Ototoxicity is typically associated with bilateral high-frequency sensorineural hearing loss and tinnitus.  
 The time of onset is unpredictable: 
 marked hearing loss can occur even after a single dose.

 may occur several weeks or months after completion of antibiotic or antineoplastic therapy.  
 usually irreversible with most agents.  
Drug induced seizures 
Drugs that cause seizures as a drug reaction include isoniazid (vitami 
B6 deficiency), bupropion, imipenem/cilastatin, tramadol, and enflurane. 
 
Isoniazid, Bupropion, Imipenem/cilastatin, Tramadol, Enflurane. 
 
With seizures, I BITE my tongue.

With seizures, I BITE my tongue. 
Drug causes erythema multiforme, and the Stevens-Johnson syndrome subtype. 
 Allopurinol   (the Most commonly associated) 
 Recent drugs - nevirapine, lamotrigine, sertraline, pantoprazole, tramadol 
 Antibiotics - sulphonamides, co-trimoxazole, penicillin, cephalosporins, fluoroquinolones, vancomycin

 NSAIDs - piroxicam, fenbufen, ibuprofen, ketoprofen, naproxen, tenoxicam, diclofen ac, sulindac 
 Anti-TB - rifampicin, ethambutol, isoniazid, pyrazinamide 
 Anticonvulsants - barbiturates, carbamazepine, phenytoin, valproate, lamotrigine 
 Antifungals - fluconazole, nystatin, griseofulvin 
 Antidepressants - lamotrigine, sertraline. 
 Sulfasalazine 
Drugs causes  weight loss 
 Thyroxine,

 Thyroxine, 
 Abuse of thyroxine by doctors used to be more common as a method of keeping awak e and 
active, before the European Working Time Directive was introduced.  
 Excessive use results in proximal muscle weakness  , tachycardic cardiomyopathy, 
arrhythmias, palpitations, muscle cramps, diarrhoea, tremors, restlessness, sweat ing, 
headaches and insomnia .  
 Causes features of hyperthyroidism 
 Laxatives

 Laxatives  
 cause weight loss by volume depletion, not reduced fat. 
 Metformin  
 can cause diarrhoea and headaches but does not cause muscle weakness. 
Drugs which act on serotonin receptors 
 Below is a summary of drugs which are known to act via modulation of the serotonin (5 -HT) system.  
 It should be noted that 5-HT receptor agonists are used in the acute treatmen t of migraine whilst 5-HT 1674

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  18 
 receptor antagonists are used in prophylaxis .  
Agonists  
 sumatriptan is a 5-HT1D receptor agonist which is used in the acute treatment of migraine  
 ergotamine is a partial agonist of 5-HT1 receptors 
Antagonists 
 pizotifen is a 5-HT2 receptor antagonist used in the prophylaxis of migraine attac ks.

 Methysergide is another antagonist of the 5-HT2 receptor but is rarely used due to t he risk of 
retroperitoneal fibrosis 
 cyproheptadine is a 5-HT2 receptor antagonist which is used to control diarrhoea in patients 
with carcinoid syndrome 
 ondansetron is a 5-HT3 receptor antagonist and is used as an antiemetic 
5HT-2 receptor inhibition   
 5HT-2 receptor inhibition also reduces platelet aggregation

  one example is sarpogrelate developed in North East Asia primarily as an alternative to aspirin 
because of its association with a lower risk of haemorrhage.  
Drugs that can be cleared with Hemodialysis - mnemonic: BLAST  
 Barbiturate 
 Lithium 
 Alcohol (inc methanol, ethylene glycol) 
 Salicylates 
 Theophyllines  (charcoal  hemoperfusion  is 
preferable) Drugs which cannot be cleared with HD include

 Tricyclics 
  Benzodiazepines 
(diazepam,midazolam,alprazolam)  
 Dextropropoxyphene (co-proxamol) 
 DigoxiŶ, β -blockers 
Drug fever 
 'Drug fever' as an isolated phenomenon can occur with 
 Penicillins, 
 pheny toin, 
 hydralazine  
 and quinidine 
 Such fevers are usually of low grade and the patient is generally not very ill 
 The fever subsides within a few days of stopping the drug

Cardiovascular drugs 
 
Prescribing in patients with heart failure 
The following medications may exac erbate heart failure:  
 thiazolidinediones : pioglitazone is contraindicated as it causes fluid retention 
  pioglitazone is now the only thiazolidinedione on the market   
 verapamil:  negative inotropic effect

 verapamil:  negative inotropic effect 
 NSAIDs & glucocorticoids : should be used with caution as they cause fluid retention 
 low-dose aspirin is an exception - many patients will have coexistent cardiov ascular disease and the 
benefits of taking aspirin easily outweigh the risks 
 class I antiarrhythmics; flecainide  (negative inotropic and proarrhythmic effect) 
 Celecoxib  (rofecoxib has been withdrawn) acts by inhibiting prostaglandin synthesis via inhibition  of

cyclo-oxygenase-2 (COX-2).It causes fluid retention and can worsen an already pre-exi sting heart 
failure. The CSM reminds prescribers that celecoxib is contraindicated  in: 
 patients with severe congestive heart failure, 
  active peptic ulceration  
 or gastrointestinal bleeding. 
 
 1675

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  19 
Antiarrhythmics: Vaughan Williams classification 
The Vaughan Williams classification of antiarrhythmics is still widely used although it shou ld be noted that a number of

common drugs are not included in the classification e.g. adenosine, atropine, digoxin and magnesium 
AP = action potential 
Class Examples Mechanism of action 
Ia Quinidine 
Disopyramide 1. Block sodium channels 
2. Increases AP duration 
Notes: 
 Quinidine toxicity causes cinchonism (headache, tinnitus, thrombocytopaenia) 
 Procainamide may cause drug-induced lupus 
 Disopyramide toxicity  Urinary retention   
Ib Lidocaine 
Mexiletine 
Tocainide 1. Block sodium channels

Tocainide 1. Block sodium channels 
2. Decreases AP duration 
Ic Flecainide 
Encainide 
Propafenone 1. Block sodium channels 
2. No effect on AP duration 
II Propranolol 
Atenolol 
Bisoprolol 
Metoprolol Beta-adrenoceptor antagonists 
III Amiodarone 
Sotalol 
Ibutilide 
Bretylium Block potassium channels 
IV Verapamil  
Diltiazem Calcium channel blockers 
Antiarrhythmic agents

Antiarrhythmic agents 
 Calcium-channel blockers  act mainly on (SA) (AV) nodes (direct membrane effect),  as these 
structures are almost exclusively depolarised by the slow calcium channels  
 Flecainide  binds to the sodium channel and decreases the speed of depolarisation (in other words, 
decreases conduction velocity)  (Slows the upstroke of the action potential)  
 Atenolol  decreases sympathetic tone

 Atenolol  decreases sympathetic tone 
 Amiodarone  and sotalol  increase the action-potential duration and therefore the refractory periods  
 they have little effect on conduction velocity   
 Sotalol have a high risk of producing torsades de pointe 
 Class V agents (digitalis agents) affect SA and AV nodes by increasing vagal tone  
Atropine 
Action

Atropine 
Action 
 Atropine is an antagonist of the muscarinic acetylcholine receptor 
Uses*  
 treatment of organophosphate poisoning 
 *atropine is no longer used in resuscitation  
Physiological effects 
 mydriasis 
 
January 2008 exam: Which physiological effect would be expected following administration of atropine? 
Tachycardia + mydriasis  
 
 1676

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  20 
 ____________________________________________________________________  
Adenosine 
 
 causes transient heart block in the AV node 
 agonist of the A1 receptor which inhibits adenylyl cyclase thus reducing cAMP an d causing 
hyperpolarization by increasing outward potassium flux

 Acts on specific adenosine cell surface receptors (A1 and A2)  
 Stress testing: A2A adenosine receptor agonist;  
 activation of the A2A adenosine receptor produces coronary vasodilation and increases 
coronary blood flow 
 Ĺ coronary vasodilatation ( Adenosine is an important mediator of metabolic vasodilatation)   
 Increasing O 2 demands are met by  adenosine production  vasodilatation  increased blood 
supply.  
 Adenosine effect on renal

supply.  
 Adenosine effect on renal 
 In the renal vasculature, in contrast, adenosine can produce vasoconstriction 
 However, the vasoconstriction elicited by an intravenous infusion of adenosi ne is only short 
lasting, being replaced within 1-2 min by vasodilatation.  
 It appears that the steady-state response to the increase of plasma adenosine levels i s global 
renal vasorelaxation that is the result of A2A receptor activation

 Adenosine lowers glomerular filtration rate (GFR) by constricting afferent art erioles, especially in 
superficial nephrons. In contrast, it leads to vasodilation in deep cortex an d medulla. 
 ĻĻ sinus node automaticity and AVN conduction.  
 adenosine has a very short half-life of about 8-10 seconds 
 Inactivated by adenosine deaminase.  
 transient facial flushing  (18%) (most common) 
 Dyspnea (12%)  
 It should be avoided in asthmatics

 It should be avoided in asthmatics  
 choking sensation, where patients often clutch their chest 
 can enhance conduction down accessory pathways, resulting in increased ventricular rate (e.g.  WPW 
syndrome) 
 The effects of adenosine are enhanced by dipyridamole (anti-platelet agent)  
 Adenosine transported out of the cell to the extracellular space by specific bi-dir ectional

nucleoside transporters. Inhibitors of these transporters , such as dipyridamole, increase the 
extracellular concentrations of adenosine and are useful clinically to treat certain cardiovascu lar 
 Adenosine effects blocked by theophyllines. 
 Unlike verapamil it may be used following β -blockade  
 
Adenosine is a coronary vasodilator (which is why we use it in cardiac stress testing) and a 
bronchoconstrictor (action opposed by theophylline).  
 
Adenosine receptors (ARs)

Adenosine receptors (ARs) 
 ARs are classified based on their differential coupling to adenylyl cyclase to re gulate cyclic AMP levels. 
 The A 1 and A 3ARs  
 are coupled to G i/o proteins 
 In contrast, activation of the A 1 and A 3AR inhibits cyclic AMP production and decreases 
PKA activity  
 A2AAR and A 2BAR  
 are coupled to G s/olf proteins 
 activation of the A 2A and A 2BARs increase cyclic AMP production, resulting in activation 
1677

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  21 
 of protein kinase A (PKA)  
Flecainide 
Action 
 Flecainide is a Vaughan Williams class 1c antiarrhythmic.  
 It slows conduction of the action potential by acting as a potent sodium channel blocker .  
 Slows the upstroke of the action potential

 Slows the upstroke of the action potential 
 does not alter the overall length of the action-potential duration. 
 This may be reflected by widening of the QRS complex and prolongation of t he PR interval 
 SVT associated with accessory pathway e.g. Wolf-Parkinson-White syndrome 
 post myocardial infarction  increase mortality 
 negatively inotropic 
 proarrhythmic  oral paraesthesia

 proarrhythmic  oral paraesthesia 
 visual disturbances 
 
 Amiodarone is a class III antiarrhythmic agent   
 used in the treatment of atrial, nodal and ventricular tachycardias. 
 metabolized in the liver via cytochrome P450 3A4 .  
Action 
 The main mechanism of action is by blocking potassium channels which inhibits repolarisation an d 
hence prolongs the action potential.

hence prolongs the action potential.  
 Amiodarone prolongs the refractory period  of the cardiac conducting system. 
 Its antiarrhythmic effects are due mostly to the  inhibition of the rapid component of the 
delayed potassium rectifier IKr channel  (as with sotalol) but also have an effect on the slow 
component.  
 Amiodarone also has other actions such as blocking sodium channels (a class I effect) 
Several factors limit the use of amiodarone:  
 long half-life (20-100 days)

 long half-life (20-100 days) 
 Because of its long half-life there is a potential for drug interactions to occur for several weeks 
after amiodarone has been stopped. 
 should ideally be given into central veins (causes thrombophlebitis) 
 has proarrhythmic effects due to lengthening of the QT interval 
 interacts with drugs commonly used concurrently e.g. Decreases metabolism of warfarin 
 numerous long-term adverse effects. 
Monitoring of patients taking amiodarone

Monitoring of patients taking amiodarone 
 TFT, LFT, U&E, CXR prior to treatment 
 TFT, LFT every 6 months 
 and for up to 12months after discontinuation of amiodarone 
 An increase of up to 40% above the baseline T4 is a normal effect of amiodarone . This 
occurs approximately 2 months after initiation of therapy & does not require discontinuation . 
Administration  
 300 mg of amiodarone made up to 20 ml with 5% dextrose given as an intravenous bolus is the drug of

choice in treating refractory ventricular fibrillation or pulseless ventricular tachycardia (100 mg of 
lidocaine may be given intravenously when amiodarone is unavailable). 
Adverse effects   
 thyroid dysfunction: both hypothyroidism and hyperthyroidism  
 Amiodarone blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3 ) hypo  
 hypothyroidism occurs in up to 20% of patients taking amiodarone. 
 ↑T4 , reverse T3 and TSH  
 ↓T3.

 ↓T3. 
 It is also a potential source of large amounts of inorganic iodine  hyper  
 Hyperthyroidism occurs in 3% of patients in iodine-deficient areas, but in 20% in areas in 
1678

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  22 
 areas where iodine is sufficient. 
 Corneal deposits :  
 present in most patients ,  
 almost universal in patients taking amiodarone therapy (at least 90%).  
 rarely interfere with vision,  becomes manifest by the presence of night-time visual glare, noticed 
while driving.  
 usually reversible on withdrawal of drug

 usually reversible on withdrawal of drug 
 Skin deposits result in photodermatitis and a greyish-blue discoloration on sun-exposed 
areas  ('slate-grey' appearance ( Skin sensitivity)  
 can be prevented by using a sun block  
 pulmonary fibrosis/pneumonitis 
  5-7%. 
 liver cirrhosis/hepatitis 
 peripheral neuropathy, myopathy 
 thrombophlebitis and injection site reactions 
 bradycardia

 Persistent slate-grey skin discoloration (ceruloderma)  
 
 more common in males than females. 
 the pigmentation consists of brownish-yellow deposits of amiodarone, iron and others (not 
including melanin or hemosiderin)  
 On biopsy of these lesions, which cell type is laden with pigment? 
  histiocytes  of the dermis  
 appears in sun-exposed areas  and is thought to be activated by an UVA-
related hypersensitivity response.

related hypersensitivity response.  
 Sun exposure is not recommended for patients on amiodarone.  
 discontinuation of the drug  
 if not disappeared after discontinuation   laser-based therapy. 
 Neutropenia 
 Nightmares , sleep disturbance 
Important drug interactions of amiodarone include: 
 decreased metabolism of warfarin, therefore increased INR 
  Decrease warfarin dose by 33- 50% and monitor the INR weekly 
 increased digoxin levels

 increased digoxin levels 
  the dose of digoxin should be halved when patients are started on amiodarone. 
  There is an increased risk of ventricular arrhythmias when amiodarone is given with tricyclics , 
hence concomitant use should be avoided. 
Amiodarone and the thyroid gland 
 Around 1 in 6 patients taking amiodarone develop thyroid dysfunction 
 Amiodarone contains 75 mg of iodine per 200 mg tablet.

 In addition, the half-life is very long (100 days) and can result in prolonged effects ev en after stopping 
therapy for several months. 
Amiodarone-induced hypothyroidism (AIH) 
pathophysiology  
 high iodine content of amiodarone causing a Wolff-Chaikoff effect (an autoregulatory phenomenon where 
thyroxine formation is inhibited due to high levels of circulating iodide)  
 amiodarone inhibits the peripheral conversion of T4 to T3  (Normal T4 , Ļ T3 ,  Ĺ TSH) These 
1679

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  23 
 results are typical of amiodarone-induced hypothyroidism) 
  
Amiodarone-induced thyrotoxicosis (AIT)  
Amiodarone-induced thyrotoxicosis (AIT) may be divided into two types:  
Differentiating between the two forms of Amiodarone-Induced Thyrotoxicosis (A IT) 
 AIT type 1  AIT type 2

AIT type 1  AIT type 2  
Epidemiology  Most often seen in iodine-deficient 
areas. most common in Europe and North 
America 
Pathophysiology  AŵiodaroŶe coŶtaiŶs↑ iodiŶe  ↑ 
thyroid hormone synthesis  (Jod-
Basedow effect )  Amiodarone-related destructive thyroiditis  
history Occurs in patients with underlying 
thyroid pathology, such as a nodular 
goitre or Graves disease.  Occurs in patients without underlying 
thyroid disease.  
Goitre  Present  Absent

Goitre  Present  Absent  
Color Doppler  ↑ Blood flow  ↓ Blood flow  
iodine-131 
uptake scan  normal or high  minimal or none 
IL-6 levels  Low or normal  markedly elevated 
Management  Carbimazole ± potassium perchlorate 
or lithium carbonate Corticosteroids ± Antithyroid  
 Differentiation between type 1 and type 2   
 Colour flow Doppler is most likely test to differentiate between Amiodarone induced 
thyrotoxicosis (AIT) type 1 and type 2.

thyrotoxicosis (AIT) type 1 and type 2.  
 It appears to be superior to IL- 6. 
 Interleukin 6 levels may be markedly elevated in AIT type 2, although this is not  
invariable and IL-6 may also be raised by concurrent non-thyroidal illness. 
 Unlike in AIH, amiodarone should be stopped if possible in patients who develop AIT 
  Jod-Basedow effect but in cases such as VT, this decision should be considered

carefully in conjunction with a cardiologist, so the next management step will be S tart 
carbimazole 40 mg od. 
 Mild amiodarone-induced hyperthyroidism can resolve spontaneously on stopping amiodarone. 
However, the majority of cases require treatment.  
 In both types, if amiodarone cannot be withdrawn then total thyroidectomy should be consi dered. 
  AIT type 1  should be treated when stable with either radioiodine therapy or thyroidectomy,

 Type 2 amiodarone-induced thyrotoxicosis:  
 the most appropriate treatment is withdrawal of the amiodarone and steroid therapy. 
 eventually  may progress to hypothyroidism, and patients should be monitored for this possibility.  
 
The presence of markedly elevated serum IL-6 concentrations and low thyroidal radioiod ine uptake (RAIU) 
values in patients with AIT without underlying thyroid disease suggests the presence of amiodarone-

induced thyroiditis as the etiology of thyrotoxicosis.  
Dobutamine 
Action  
 Direct Sympathomimetics  
 β1> β 2, agonist  
 positive inotropic effect  
 Cardiogenic shock 
 Acute heart failure 
 Cardiac stress testing 
 
 1680

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  24 
  
Antiplatelets: summary of latest guidance 
The table below summarises the most recent guidelines regarding antiplatelets: 
 
Diagnosis 1st line 2nd line 
NSTEMI Aspirin (lifelong) & clopidogrel (12

NSTEMI Aspirin (lifelong) & clopidogrel (12 
months) If aspirin contraindicated, clopidogrel (lifelong) 
STEMI Aspirin (lifelong) & clopidogrel (1m if 
no/bare stent, 12 m if drug-eluting 
stent) If aspirin contraindicated, clopidogrel (lifelong) 
TIA* Clopidogrel (lifelong) Aspirin (lifelong) & dipyridamole (lifelong) 
Ischaemic 
stroke Clopidogrel (lifelong) Aspirin (lifelong) & dipyridamole (lifelong) 
arterial disease Clopidogrel (lifelong) Asprin (lifelong)

*the guidelines for TIA are based on the 2012 Royal College of Physicians National cli nical guideline for stroke. These 
guidelines corrected the anomaly where patients who've had a stroke were given clopidogrel, but thos e who'd suffered a 
TIA were given aspirin + dipyridamole.  
 
Peri-Operative Management of Anticoagulation and Antiplatelet Therapy 
(British society for Haematology guidelines 2016)  
 Warfarin and other vitamin K antagonists 
 Emergency surgery in patients on warfarin

 Emergency surgery in patients on warfarin 
 If surgery can wait for 6 –8 h then 5 mg of intravenous phytomenadione  can restore 
coagulation factors;  
 if this is not possible, anticoagulation can be reversed with 25 –50 u/kg of four-factor 
prothrombin complex concentrate  
 Consider  bridging with treatment dose heparin in:  
1) Patients with a VTE within previous 3 months . 
2) Very high risk patients such as patients with a previous VTE whilst on ther apeutic

anticoagulation who now have a target INR of 3·5. 
3) Patients with a previous stroke/TIA in last 3 months . 
4) Patients with a previous stroke/TIA and three or more of the following risk f actors: 
 Congestive cardiac failure 
 Hypertension (>140/90 mmHg or on medication) 
 Age >75 years 
 Diabetes mellitus 
5) mechanical heart valve (MHV)  patients other than those with a bileaflet aortic valve and 
no other risk factors

no other risk factors 
  the post-operative bridging (i.e. full dose anticoagulation) should not started until  at least 48 h 
after high bleeding risk surgery  although thromboprophylaxis should be given if indicated. 
 Warfarin should be stopped for 5 days before an elective procedure  if anticoagulation needs 
to be discontinued 
 Antiplatelet therapy 
 aspirin monotherapy (for secondary prevention of cardiovascular disease) can be continued f or 
most invasive non-cardiac procedures

most invasive non-cardiac procedures 
 Aspirin can be continued both before and after coronary artery bypass surgery 
 
1681

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  25 
 Ref: http://www.b-s-h.org.uk/guidelines/guidelines/peri-operative-management- of-anticoagulation- and-
antiplatelet-therapy/  
____________________________ ________________________________________ 
Aspirin 
 
 Aspirin works by blocking the action of both cyclooxygenase-1 and 2.

 Cyclooxygenase is responsible for prostaglandin, prostacyclin and thromboxane synthesis. 
 Cyclo-oxygenase is an enzyme that converts arachidonic acid to thromboxane A2 (TXA2) , a strong 
platelet agonist 
 Because the platelet has no protein synthetic apparatus the effects of aspirin are irr eversible and last 
for the life of the platelet (8-10 days) 
 Ĺ bleeding time (PT and PTT unchanged)

 Ĺ bleeding time (PT and PTT unchanged)  
 The blocking of thromboxane A2 formation in platelets reduces the ability of platelet s to aggregate 
which has lead to the widespread use of low-dose aspirin in cardiovascular disease. 
 Until recent guidelines changed all patients with established cardiovascular disease took asp irin if there 
was no contraindication. Following the 2010 technology appraisal of clopidogrel this i s no longer the 
case.

case. 
 Two recent trials (the Aspirin for Asymptomatic Atherosclerosis and the Antithro mbotic Trialists 
Collaboration) have cast doubt on the use of aspirin in primary prevention of cardiovascu lar disease. 
Guidelines have not yet changed to reflect this.  
 However the Medicines and Healthcare products Regulatory Agency (MHRA) issued a drug sa fety 
update in January 2010 reminding prescribers that aspirin is not licensed for primary  prevention.

What do the current  guidelines recommend? 
 first-line for patients with ischaemic heart disease 
 Current NICE guidelines advise that  people with acute upper gastrointestinal bleeding who take 
aspirin for secondary prevention of vascular events and in whom haemostasis has been 
achieved continue on low dose aspirin. 
 the U.S. Preventive Services Task Force (USPSTF), recommended that, for som e people, aspirin can

be used to help reduce their risk of cardiovascular disease and colorectal cancer.  
Potentiates  
 oral hypoglycaemics 
 warfarin 
 steroids 
In hypersensitive patients aspirin can cause : 
 Angioedema 
 Bronchospasm, and 
 Urticaria (skin rashes). 
 
ASA can be continued normally if patient is going for dental procedure 
 
Aspirin is not considered to be safe in breast-feeding due to the risk of causing Reye's syndrome in 
the baby.

the baby.  
Salicylate overdose 
The mixed respiratory alkalosis and metabolic acidosis in a sweaty, confused patient  point towards salicylate 
overdose.  
The development of pulmonary edema suggests severe poisoning and is an ind ication for hemodialysis 
 
 A key concept for the exam is to understand that salicylate overdose leads to a mixed  respiratory 
alkalosis and metabolic acidosis.  
1682

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  26 
  Early stimulation of the respiratory centre leads to a respiratory alkalosis whilst later the direct acid 
effects of salicylates (combined with acute renal failure) may lead to an acidosis.  
 In children metabolic acidosis tends to predominate.

 The metabolic acidosis can increase the transfer of salicylates across the blood-brain barr ier, thereby 
increasing CNS toxicity 
Features  
early features:  
 hyperventilation (centrally stimulates respiration)  respiratory alkalosis 
 the most prominent feature of the early period after aspirin overdose 
 tinnitus: typically occurs at plasma salicylate concentrations above 400-500 mg/l 
 vertigo 
 lethargy 
 sweating, pyrexia

 vertigo 
 lethargy 
 sweating, pyrexia  
 salicylates cause the uncoupling of oxidative phosphorylation leading to decreased adenosine 
triphosphate production, increased oxygen consumption and increased carbon dioxide and heat 
 peripheral vasodilatation and bounding pulse  
 nausea/vomiting  dehydration 
later features:  
 by uncoupling oxidative phosphorylation , leading to a build- up of organic acids in the blood.

 hyperglycaemia and hypoglycaemia  
 Hypoglycaemia is commonly seen in children but not in adults 
 seizures 
 coma 
 Although decreased consciousness is seen in aspirin overdose, it is seen late, and is associated 
with severe metabolic acidosis and hypokalaemia. 
 Early presentation with coma will suggest that another drug has been taken in addition to 
aspirin.  
 
Treatment 
 no specific antidote

aspirin.  
 
Treatment 
 no specific antidote  
 The management is supportive, with measures to prevent further absorption fr om the gastrointestinal 
tract and enhance excretion.  
 general (ABC, charcoal)  Multi-dose activated charcoal may be indicated   
 activated charcoal should be repeated as bezoars may form, resulting in delayed absorption of 
salicylate. This should continue until salicylate levels have peaked.  
 urinary alkalinization

 urinary alkalinization 
 alkalinisation of the urine should be considered in patients with a plasma level > 300 mg/L.  
 urine and serum alkalinization through intravenous sodium bicarbonate  ( 1.25% or 8.4% )  
 By alkalinizing the urine, charged salicylic acid will become protein bound and secreted through 
the proximal tubule, which minimizes the diffusion of uncharged salicylate back into the renal 
epithelium.

epithelium.  
 The ionisation of a weak acid, such as salicylic acid, is increased in an alkaline 
environment.  
 The administration of an intravenous infusion of sodium bicarbonate aiming for a urinary 
pH of 7.5-8 will increase the excretion of the acid 10-fold. 
 Alkalinization of the serum further promotes diffusion of salicylate out of the br ain. 
 Haemodialysis 
 Indications for haemodialysis in salicylate overdose  
 serum concentration > 700mg/L

 serum concentration > 700mg/L 
 metabolic acidosis resistant to treatment 
 acute renal failure 
 pulmonary oedema 
 neurological impairment (coma, hallucinations or seizures) 
 
 1683

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  27 
Clopidogrel 
most (PPIs) ↓ Clopidogrel effect but lansoprazole is OK 
 
 Clopidogrel is an antiplatelet agent used in the management of cardiovascular di sease.

 Clopidogrel belongs to a class of drugs known as thienopyridines which have a similar mechan ism of 
action. Other examples include: 
 prasugrel 
 ticagrelor 
 ticlopidine 
Mechanism (Inhibition of the platelet ADP receptor ) 
 antagonist of the P2Y 12 adenosine diphosphate (ADP) receptor, inhibiting the activation of platelets 
Indications: 
 clopidogrel is used in addition to aspirin in patients with an acute coronary syndrome. The dose is 300 
mg.

mg.  
 NICE now recommend clopidogrel first-line following an ischaemic stro ke and for peripheral arterial 
disease.  
 Recent Royal College of Physician (RCP) guidelines support the use of clopidog rel in TIAs. However 
the older NICE guidelines still recommend aspirin + dipyridamole 
Interactions 
 concurrent use of proton pump inhibitors (PPIs) may make clopidogrel less effective (MHR A July 2009)

 this advice was updated by the MHRA in April 2010, evidence seems inconsistent but omeprazol e and 
esomeprazole still cause for concern. Other PPIs such as lansoprazole should be OK   
 
 action  antagonist of the P2Y12  adenosine diphosphate (ADP) receptor , inhibiting the activation of 
platelets 
 other members of the same class (thienopyridines): 
 ticlopidine

 Indications    1st line for : ACS , an ischaemic stroke , TIA and peripheral arterial disease.  
 Interaction  most (PPIs) Ļ Clopidogrel effect but lansoprazole is OK  
 
Prasugrel  
 a third-generation thienopyridine antiplatelet agent 
 ADP receptor inhibitors 
 advantages compared with clopidogrel 
 faster onset of action, 
 greater potency in the inhibition of adenosine-induced platelet aggregation,

 more consistent antiplatelet response 
 Prasugrel is contra-indicated in patients with prior transient ischaemic attac k or stroke.  
 In the TRITON-TIMI 38 trial, patients in this group had a higher rate of st roke when taking 
Prasugrel compared with those taking Clopidogrel. 
IIb/IIIa inhibitors (eg: Abciximab) 
 Other members of this drug group  
 abciximab 
 eptifibatide 
 tirofiban 
 action

 action 
 monoclonal antibody antagonizes IIb/IIIa glycoprotein receptor  on activated 
platelets 
 prevents platelet aggregation 
  Abciximab is a humanised monoclonal antibody 
 
 1684

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  28 
 ___________________________________________________ __________________ 
Phospho diesterase  III (PDE ) inhibitors (dipyridamole  & cilostazol ) 
 
 inhibits phosphodiesterase   increase platelet cAMP (due to decreased breakdown of cAMP) 

reduce intracellular calcium levels  inhibition of platelet aggregation. 
 direct arterial vasodilation 
 inhibits cellular uptake of adenosine  more available to act on coronary vessels  
vasodilation 
 inhibition of thromboxane synthase 
 
 Dipyridamole is an antiplatelet mainly used in combination with aspirin after an ischaemic strok e or 
 Cilostazol  is currently licensed for the management of patients with intermittent claudication

without rest pain and with no signs of tissue necrosis.   
 It is a first-line medication for the treatment of claudication caused by periph eral artery disease 
(PAD).  
 Trials show an improvement in time to initial pain on walking and maxim al walking distance 
when compared to placebo.  
 metabolised by cytochrome P450 3A4.  
 known bleeding tendencies (e.g. active peptic ulcer disease, previous haemorrhagic stroke i n the last 6 
months).

months).  
 Asthmatics   (may provoke bronchospasm) 
Adrenaline 
Adrenaline is a sympathomimetic amine with both alpha and beta  adrenergic stimulating properties. 
The β - effect will cause significant tachycardia  
 
 cardiac arrest 
Recommend Adult Life Support (ALS) adrenaline doses  
 anaphylaxis: 0.5ml 1:1,000 IM 
 cardiac arrest: 10ml 1:10,000 IV or 1ml of 1:1000 IV

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  29 
  local infiltration of phentolamine 
 An alternative possibility is locally applied GTN paste  
Anaphylaxis  
 Where there is a history of a typical allergic reaction, current United  Kingdom resuscitation guidelines 
suggest adrenaline if there is : 
 Stridor 
 Wheeze 
 Respiratory distress, or

 Stridor 
 Wheeze 
 Respiratory distress, or 
 Clinical evidence of shock. 
 Adrenalin is used for its alpha-agonist effects  that include increased peripheral vascular resistance 
and reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. 
 Beta-agonist effects  include bronchodilatation, chronotropic cardiac activity, and positive inotropic 
effects. 
 IM administration is preferred because of a superior safety profile with respect to cardi ac adverse

events compared with the IV route, although 1:10000 adrenalin IV may be used in a life-th reatening 
 The intramuscular (IM) route for adrenaline is the route of choice  for most healthcare providers. 
 Adult EpiPen  which allergy sufferers can carry with them contains 0.3 mg or 0.15 mg adrenaline i n a 
1:1000 dilution for intramuscular (IM) injection.  
Angiotensin-converting enzyme (ACE) inhibitors

Angiotensin-converting enzyme (ACE) inhibitors  
Mechanism of action: 
 Inhibit the conversion angiotensin I to angiotensin II 
 first-line treatment in younger patients with hypertension and are also extensiv ely used to treat  
 less effective in treating hypertensive Afro-Caribbean patients.  
 diabetic nephropathy  
 heart failure. 
 secondary prevention of IHD. 
Side-effects: 
 Cough:  
 occurs in around 15% of patients

 Cough:  
 occurs in around 15% of patients   
 may occur up to a year after starting treatment. 
 Thought to be due to increased bradykinin levels  
 The enzyme ACE is also responsible for the metabolism of bradykinin in mast cells and A CEi 
leads to its bradykinin accumulatio n  
 This phenomenon is not seen in subjects taking angiotensin receptor blockers such as losar tan. 
 Angioedema:  
 may occur up to a year after starting treatment

 ACE inhibitors are the most common cause of drug-induced angioedema  (swelling of his 
lips and tongue )  
 Hyperkalaemia 
 ACEi  dilate the efferent arteriole  of the glomerulus,  ↓GFR  Ĺ creatinine and BUN.  
 1st-dose hypotension: more common in patients taking diuretics 
Cautions and contraindications 
 Pregnancy and breastfeeding – avoid ( ACEi & ARB  renal dysgenesis in the fetus)

Exposure to ACE inhibitors in the first trimester  showed a significant increase in major (in particular, 
cardiovascular) congenital malformation. 
 Renovascular disease - significant renal impairment may occur in patients who hav e undiagnosed 
bilateral renal artery stenosis 
 Aortic stenosis - may result in hypotension 
 Patients receiving high-dose diuretic therapy (more than 80 mg of furosemide a day ) - signficantly 
increases the risk of hypotension

increases the risk of hypotension 
 Hereditary of idiopathic angioedema 1686

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  30 
  The co-administration of a potassium-sparing diuretic  and an ACE inhibitor, may result in profound 
hyperkalaemia . Thus patients on both these drugs should have their potassium monitored closely. 
 Urea and electrolytes should be checked before treatment is initiated and after i ncreasing dose

 Monitoring of renal function and potassium is important after commencement of an ACE 
inhibitor. 
 The optimum period to check this is one to two weeks after commencing the 
medication.  
 A rise in the creatinine and potassium may be expected after starting AC E inhibitors.  
 Acceptable increases are an increase in serum creatinine, up to 50% from baseline or up 
to 265μmol/l  (whichever is smaller) and an increase in potassium up to 5.5 mmol/l.

 NICE guidelines state that when initiating ACE inhibitor therapy a 25% reduction in the eGFR  
or 30% increase in the serum creatinine  is tolerable  and should not lead to changes in 
dosing.  
 ACE inhibitors should also be stopped or dose adjusted if is there is a rise in the serum 
potassium level to greater than 6 mmol/l. 
 Other causes of a deterioration in renal function should be excluded first before stoppi ng the 
ACE inhibitor.  
 e.g: patient taking trimethoprim

 e.g: patient taking trimethoprim  
 This drug competes with creatinine for excretion in the nephron   ↑ serum 
creatinine .  
 the appropriate option would be to re-check the blood tests in one to two 
weeks once trimethoprim has been discontinued to see whether the level of 
renal dysfunction is sustained or improves. 
Usage of ACEi & ARB as combination (NICE January 2015 )  
 Do not combine an ACE inhibitor with an ARB to treat hypertension .

 no significant benefits of ACEi & ARB combination were seen in people who did not  have heart failure 
and there was an increased risk of hyperkalaemia, hypotension, and impaired renal func tion. 
 The NICE guideline on chronic heart failure  recommends that, after seeking specialist advice, the 
addition of an ARB licensed for heart failure is an option that could be consi dered for people who 
remain symptomatic despite optimal therapy with an ACE inhibitor and a beta-blocker

 Candesartan and valsartan are the only ARBs licensed as add-on therapy to ACE inhi bitors in 
this situation.  
 Other options are adding an aldosterone antagonist licensed for heart failure or hydralazine in 
combination with nitrate. 
 
direct renin inhibitors  
 Aliskiren (branded as Rasilez)  Direct renin inhibitor   
 Action:  by inhibiting renin blocks the conversion of angiotensinogen to angiotensin I

 indication:  only current role would seem to be in patients who are intolerant of more established 
antihypertensive drugs 
 no trials have looked at mortality data yet. Trials have only investigated fall in blood pr essure. Initial 
trials suggest aliskiren reduces blood pressure to a similar extent as angiotensin converting  enzyme 
(ACE) inhibitors or angiotensin-II receptor antagonists 
 adverse effects  were uncommon in trials although diarrhoea was occasionally seen 

 Enalapril is a prodrug for enalaprat, the active agent  
 irbesartan : the dose response is linear, as such dose can be titrated more ea sily from a base of 
75 mg to a maximum of 300 mg.  
Adrenoceptor antagonists 
Doxazosin is an α -1 adrenoceptor antagonist used in the treatment of hypertension and b enign 
prostatic hypertrophy 
 
Alpha antagonists 
 alpha-1: doxazosin

 alpha-1: doxazosin 
 cause  orthostatic hypotension 
 alpha-1a: tamsulosin - acts mainly on urogenital tract 1687

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  31 
  alpha-2: yohimbine 
Phenoxybenzamine   presurgical management of hypertension in phaeochromocytoma. 
 beta-1: atenolol 
Carvedilol and labetalol are mixed alpha and beta antagonists

Beta-blockers  
 
 angina 
 post-myocardial infarction 
 Heart failure: there is now strong evidence that certain beta-blockers improve both sy mptoms and 
mortality. Especially Bisoprolol 
 arrhythmias: beta-blockers have now replaced digoxin as the rate-control drug of choi ce in atrial 
fibrillation

fibrillation 
 hypertension: the role of beta-blockers has diminished in recent years due t o a lack of evidence in 
terms of reducing stroke and myocardial infarction. 
 migraine prophylaxis 
 anxiety 
Beta- blocker in heart failure  
 NICE recommends β blockers in all HF patients.  
 In chronic obstructive pulmonary disease (COPD) patients with HF, cardioselective β blockers  appear 
safer at lower doses  than higher doses or non- selective β blockers.

 Bisoprolol 5 mgs is too high an initial starting dose, a low dose can always be titrated up later, if 
tolerated. ( starting dose  Bisoprolol 1.25 mg od   ) 
 Carvedilol though effective treatment for heart failure is not selective and theref ore carries a greater risk 
of causing bronchospasm. 
 Atenolol though cardioselective has no clinical evidence for prognostic benefit in hea rt failure.

 The patient should be closely monitored for deterioration in lung function post-ad ministration. 
 
Examples 
Atenolol:   
 Atenolol is a water soluble beta-blocker,  
 taken once daily  
 not associated with drowsiness/sleep disturbance like the lipid-soluble beta-blockers. 
Propranolol :  
 one of the first beta-blockers to be developed.  
 Lipid soluble therefore crosses the blood-brain barrier 
Nebivolol:   
 has a vasodilatory action in addition to β -blocking effects

 associated with a lower incidence of erectile dysfunction compared with other β -blocking agents 
Bisoprolol:  
1688

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  32 
  the most cardio-selective beta-blocker  
Metoprolol: 
 the most lipid-soluble and therefore has the largest volume of distribution  
 ↑lipid solubility  greater penetration across the blood-brain barrier (and also into other tissues), a nd 
therefore a greater incidence of night terrors

therefore a greater incidence of night terrors  
 Maximal gastrointestinal absorption of drugs occurs when there is intermediate lipid and water 
solubility, so that drugs with greater lipid solubility, although allowing greater tissue penetration, 
may be more poorly absorbed  
 Metoprolol though selective is shorter acting . 
Oxprenolol  
 has an intrinsic sympathomimetic properties.  
 
Carvedilol  Bisoprolol 
Not β1 - selective  Highly β1 - selective

Not β1 - selective  Highly β1 - selective  
Vasodilatation due to α -1- blockade No α -1- blocking activity 
Lipids effects 
Positive lipid effect  ↑↑HDL  &  ↓↓LDL  
Negative lipid effect  ↑↑ cholesterol , TG, VLDL  Lipid profile almost not affected 
Oral bioavailability of digoxin increased  No interaction with other CV drugs known 
Sensitive to liver enzyme induction  Not sensitive to liver enzyme induction 
Extensive metabolism in the liver (CYP2D6)(dose

Extensive metabolism in the liver (CYP2D6)(dose 
adjustment in liver impairment) No dose adjustment required  
 
 cold peripheries 
 β-Blockers cause a rise in peripheral vascular resistance due to the unopposed α-adrenoceptor effects 
(vasoconstriction) 
 Fatigue   
 fatigue is a frequent side effect  
 typically is felt two hours and beyond after taking the drug. 
 sleep disturbances, including nightmares

 sleep disturbances, including nightmares 
 β-blockers associated with increased dreams/possible night terrors  
 uncontrolled heart failure 
 asthma 
 sick sinus syndrome 
 concurrent verapamil use: may precipitate severe bradycardia 
 There is a theoretical risk of intrauterine growth retardation  with the use of atenolol in pregnancy 
although the studies which showed this effect were done with very large doses  of atenolol . 
 
Beta-blocker overdose 
 
Features

Features 
 hypotension  heart failure 
 syncope 
 if bradycardic then atropine 
 in resistant cases glucagon may be used 
 Glucagon acts by bypassing the blocked β -receptor, thus activating adenyl cyclase  formation of 
cyclic AMP from ATP. Cyclic AMP in turn exerts a direct stimulant action on the heart.  
 The action of glucagon, essential for reversing the effect of beta-blocker overdo se  Promotes

the formation of cyclic AMP.  
 Doses of glucagon used are much higher than those conventionally used for reversing 
hypoglycaemia in diabetes, with a bolus of 3-10 mg being required, then 2-5 mg/hr by infusion. 
 Haemodialysis is not effective in beta-blocker overdose 
1689

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  33 
Calcium channel blockers 
 
 Voltage-gated calcium channels are present in myocardial cells, cells of the conduction sy stem and 
those of the vascular smooth muscle.

those of the vascular smooth muscle.  
 The various types of calcium channel blockers have varying effects on these three areas and it is 
therefore important to differentiate their uses and actions. 
 
Examples Indications & notes Side-effects and cautions 
Verapamil  Angina, hypertension, arrhythmias  
 
Highly negatively inotropic 
 
Should not be given with beta-blockers as may cause 
heart block Heart failure, constipation, 
hypotension, bradycardia, 
flushing

flushing 
 
Diltiazem  Angina, hypertension  
 
Less negatively inotropic than verapamil but caution 
should still be exercised when patients have heart 
failure or are taking beta-blockers Hypotension, bradycardia, 
heart failure, ankle swelling 
Nifedipine, amlodipine, 
felodipine  
(dihydropyridines)  Hypertension, angina, Raynaud's 
 
Affects the peripheral vascular smooth muscle more 
than the myocardium and therefore do not result in

worsening of heart failure Flushing, headache, ankle 
swelling 
 
Centrally acting antihypertensives 
Methyldopa  not utilised in a patient with abnormal LFTs 
Examples of centrally acting antihypertensives include: 
 methyldopa: used in the management of hypertension during pregnancy 
 moxonidine: used in the management of essential hypertension when conventional 
antihypertensives have failed to control blood pressure

 clonidine: the antihypertensive effect is mediated through stimulating alpha-2 adrenoceptors i n 
the vasomotor centre 
 
1690

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  34 
  
Bosentan 
 Bosentan is a competitive antagonist of both endothelin-A (ETa) and endothelin-B (ETb) receptors , 
leading to falls in both pulmonary and systemic vascular resistances without an i ncrease in heart rate

 effective in patients with pulmonary arterial hypertension 
 It is excreted in bile following metabolism by the cytochrome P450 enzymes and this is a potential 
source of interaction with drugs metabolised by the same isoenzyme  
 Common unwanted effects  include 
 flushing 
 hypotension 
 dyspepsia  
 fatigue 
 Haemoglobin concentrations can fall by up to 1 g/dl during bosentan treatment 
 Hepatotoxicity:

 Hepatotoxicity: 
 The most serious unwanted effect is dose-dependent hepatotoxicity, and it is there fore 
contraindicated in patients with moderate to severe liver disease 
 Generally, hepatotoxicity occurs within the first 3-4 months of treatment  
 teratogenic and therefore contraindicated in pregnancy  
____________________________ _______________________________________ 
Nitroglycerin

Nitroglycerin 
 Nitroglycerin products are both venous capacitance dilators and coronary and systemic artery dilators  
 Administration of nitroglycerin results in: 
 dilation of systemic veins 
 decreased myocardial wall tension 
 decreased oxygen demand 
 vasodilation of large and medium-sized coronary arteries 
 increased coronary blood flow to the subendocardium 
 reduced afterload 
 reduced preload 
 increased ventricular compliance 
 Nitrates may cause  haemolytic anaemia

 Nitrates may cause  haemolytic anaemia 
Nicorandil 
Action 
 acts through the opening of potassium channels .  
 Nicorandil is an activator of ATP- dependent potassium channels 
 Effect  relaxation of smooth muscle in veins   venodilatation  ↓ ventricular filling pressures + 
dilatation of the coronary arterioles 
 It relaxes vascular smooth muscle through membrane hyperpolarisation via increased transme mbrane

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  35 
 potassium conductance and, like nitrates, through an increase in intracellular cyclic guanosine 
monophosphate (GMP). 
 now second-line treatment for angina 
 Use nicorandil for treatment of stable angina only in patients whose angina is ina dequately controlled

by first line anti-anginal therapies, or who have a contraindication or intolerance to first line anti-anginal 
therapies such as beta-blockers or calcium antagonists  
 Headache  
 The most common  unwanted effect  (- 35% of patients),  
 appears to be dose-dependent  
 resolves with continued treatment 
 Ulceration s   
 oral ulceration, flushing and gastrointestinal disturbances 
 (ulceration  of the upper and lower gastrointestinal tract and may present with life

threatening bleeding)  
 Nicorandil can cause serious skin, mucosal, and eye ulceration, including gastrointestinal ul cers 
which may progress to perforation, haemorrhage, fistula, or abscess 
Contraindication 
 Use with phosphodiesterase inhibitors such as sildenafil is contraindicated since they can 
potentiate the hypotensive effects of nicorandil 
Digoxin and digoxin toxicity

Digoxin and digoxin toxicity 
The half-life of digoxin is around 36-48 hours. This results  in a delay before steady plasma levels are seen, 
it may take a week to start its action 
 
 Digoxin is a cardiac glycoside now mainly used for rate control in the management of atrial fibrillation.  
 As it has positive inotropic properties it is sometimes used for improving symptoms  (but not mortality) in 
patients with heart failure.   
 digoxin is highly water-soluble

 digoxin is highly water-soluble  
 Digoxin has a high volume of distribution and long half-life (36-48 h), which mea ns that loading doses 
are required to allow the drug to reach a steady-state concentration more quickly. 
 If initiated on a maintenance dose (without loading), it will take several days to r each a steady 
state. 
 Digoxin is almost exclusively renally cleared; as a result, renal impairment  will significantly alter the 
half-life of this medication.

half-life of this medication.  
 decreases conduction through the atrioventricular node which slows the ventricular r ate in atrial 
fibrillation and flutter 
 Increases the force of cardiac muscle contraction due to inhibition of the Na+/K+ATPase pump  which is 
located in the sarcolemmal membrane.  
 Also stimulates vagus ner ve 
What is the pharmacokinetic reason that drives the practice of loading with digoxi n? 
 Volume of distribution.

 Volume of distribution.  
 The volume of distribution for Digoxin is very large (510 litres). This means that administered doses are 
rapidly distributed to body tissues.  
 The initial distribution lasts for some 6-8hrs, which drives the typical loading  regimen for Digoxin of two 
larger doses (500mcg) some 6-12hrs apart.  
 Without loading Digoxin typically takes a few days to reach therapeutic e ffect. 
Digoxin can worsen hyperkalaemia

Digoxin can worsen hyperkalaemia  
 Translocation of potassium from the cells into the extracellular space can occur from  digoxin overdose 
due to its dose-dependent Na-K-ATPase pump inhibition. 
1692

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  36 
  
Digoxin toxicity  
 Plasma concentration alone does not determine whether a patient has developed digoxin toxi city.  
 The BNF advises that the likelihood of toxicity increases progressively from 1.5 t o 3 mcg/l.  
 Samples taken after 6 h will be more accurate in estimating the bo dy’s digoxin

 the mechanism of action leading to tachy-arrhythmias in digoxin toxicity  Inhibition of the 
sodium pump  
Features 
 generally unwell, lethargy, anorexia,  
 The earliest features  of digitalis toxicity include: Nausea, vomiting, anorexia. 
 cholinergic  effects : nausea, vomiting, diarrhea 
 yellow -green  vision 
 arrhythmias (e.g. AV block, bradycardia)  
 (Digoxin toxicity can result in any abnormal cardiac rhythm except  type-ll second-degree

atrioventricular (AV) block) 
 classically: hypokalaemia 
 (hyperkalaemia may also worsen digoxin toxicity, although this is very small pri nt) 
 myocardial ischaemia 
 hypomagnesaemia,  
 hyper calcaemia,  
 hyper natraemia,  
 acidosis 
 drugs: amiodarone, quinidine, verapamil , diltiazem, spironolactone (competes for secretion in distal

convoluted tubule therefore reduce excretion), ciclosporin. Also drugs which cause hypokalaemi a e.g. 
thiazides and loop diuretics  
 Bumetanide is a loop diuretic and may cause hypokalaemia as a side effect. The 
potassium loss caused by bumetanide increases the toxicity of digoxin. 
 
1693

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  37 
  
Antidote "KLAM"  
 slowly normalize  K+  
 digoxin Antibodies (anti-dig Fab fragments) 
 Mg2+ 
 
Phenytoin may be used as an alternative to lidocaine (both are class IB agents)  if immune therapy is 
unsuccessful or unavailable in the treatment of tachyarrhythmias secondary to digoxin tox icity.

 Treatment of digoxin toxicity should be guided by the patient ’s signs and symptoms and the specific 
toxic effects and not necessarily by digoxin levels alone.  
 Activated charcoal if presented within 1 h of an overdose  
 The first-line treatment for acute ingestion is repeated dosing of activated cha rcoal to reduce 
absorption and interrupt enterohepatic circulation.  
 Binding resins (eg, cholestyramine)  
 may bind enterohepatically-recycled digoxin.

 may bind enterohepatically-recycled digoxin.  
 may be more appropriately used for treatment of chronic toxicity in patients with r enal 
 correct arrhythmias 
 severe sinus bradycardia (hemodynamically unstable bradyarrhythmic patients )  Atropine 
 ventricular tachycardia   responds best to digoxin immune therapy, but phenytoin and lidocaine are 
useful if immune therapy is ineffective or unavailable.

 These drugs depress the enhanced ventricular automaticity without significantly slo wing AV 
conduction 
 Magnesium sulfate, 2 g IV over 5 minutes, has been shown to terminate dysrhythmias i n digoxin-toxic 
patients with and without overt cardiac disease. 
 Magnesium is contraindicated in the setting of bradycardia or AV block and should be used 
cautiously in patients with renal failure.

cautiously in patients with renal failure. 
 Premature ventricular contractions (PVCs), bigeminy, or trigeminy may requir e only observation unless 
the patient is hemodynamically unstable, in which case lidocaine may be effective.  
 Digibind 
 Its brand name of Digoxin immune fab  or Digoxin-specific antibody  is an antidote for 
overdose of digoxin 
  Action: bind to the digoxin  unable to bind to its action sites 
 is an immunoglobulin fragment that binds with digoxin.

 first-line treatment for significant dysrhythmias from digitalis toxi city  
 Indications for digoxin-specific antibodies include: 
 Hemodynamically unstable arrhythmia 
 Tachyarrhythmias  with hypotension  
 bradycardia with hypotension that do not respond to atropine treatment. 
 End organ damage 
 digoxin level > 4ng/ml if chronic ingestion 
 digoxin level > 10 ng/ml if acute ingestion (taken 6 h after the last dose)

 Hyperkalaemia  (if not respond to insulin-dextrose infusions): potassium > 5 mEq/L and 
symptomatic  
 SE  Serum sickness  
 If digoxin-specific antibodies not available  lidocaine or phenytoin 
 Digoxin toxicity related ventricular tachycardia : 
 Phenytoin and lidocaine are useful for ventricular tachycardia if immune therapy is 
ineffective or unavailable  
 Phenytoin is thought to suppress the pro-arrhythmic properties of digoxin without 
diminishing its inotropic effects.

diminishing its inotropic effects. 
 lidocaine is useful for chemical cardioversion of digoxin toxicity related 
ventricular tachycardia.  This is because it can reduce ventricular automaticity without 
significantly slowing AV conduction. 
 Calcium channel blockers are contraindicated because they may increase digoxin levels. 
 Amiodarone is shown to increase digoxin levels and as such can worsen the risk of rhythm 1694

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  38 
 disturbance further. 
 VT in digoxin toxicity is resistant to electrical cardioversion, which may actually precipitate  VF 
and asystole. 
 Bretylium is contraindicated in the treatment of digoxin induced arrhythmias as it can actual ly 
precipitate ventricular tachycardia.

precipitate ventricular tachycardia. 
 Quinidine worsens AV and SA conductivity and reduces digoxin tissue binding and is t herefore 
also contraindicated. 
 conventional dialysis is ineffective 
 monitor potassium 
 Electrolytes 
 In acute toxicity , hyperkalemia  is common 
 Although calcium is often used to ameliorate cardiac toxicity from hyperkalemia, 
it is not recommended in patients with digoxin toxicity because it can delay after -

depolarization and may precipitate ventricular tachycardia or fibrillation. This is 
based on the fact that intracellular calcium levels are already high in this setting.  
 potassium level  > 5 mEq/L  digoxin Fab fragments 
 Chronic toxicity  is often accompanied by  hypokalemia  and hypomagnesemia 
 Concomitant hypomagnesemia may result in refractory hypokalemia 
 Correction of electrolyte imbalances may reverse dysrhythmias.

Which measurement would be most useful when monitoring patient for  digoxin efficacy ? 
 Pulse rate 
 Measuring drug plasma concentration will tell you whether digoxin is at therapeutic 
concentrations in the blood, but not whether it is having a therapeutic eff ect.  
____________________________ _________________________________________  
Diuretics  
Class  Compound  Action  Side effects  
Loop Diuretics  Furosemide  
Bumetanide 
ethacrynic acid  inhibit  NKCC2  in 
the thick ascending

the thick ascending 
loop of Henle 
 Deafness  
Thiazides  hydrochlorothiazide, 
indapamide inhibit NaCl  co-
transporter in early 
distal tubule hyponatraemia,  
hypokalaemia,  
hypercalcaemia 
 
K+ sparing agents  spironolactone Aldosterone 
receptor antagonist  Hyperkalemia 
 
amiloride, 
triamterene  inhibit Na channel in   
late distal tubule Hyperkalemia 
 
Osmotic Diuretics  mannitol Inhibit water 
throughout the 
tubules, but mostly 
in the proximal

in the proximal 
tubule Pulmonary edema  
 
Action 
 Furosemide and bumetanide are loop diuretics that act by inhibiting the Na-K-Cl cotr ansporter (NKCC) 
in the thick ascending limb of the loop of Henle, reducing the absorption of N aCl.  
 There are two variants of NKCC; loop diuretics act on NKCC2 , which is more prevalent in the 
kidneys. 
 heart failure: both acute (usually intravenously) and chronic (usually orally)

 resistant hypertension, particularly in patients with renal impairment 
 hypotension  hypocalcaemia 1695

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  39 
 hypochloraemic alkalosis 
 ototoxicity  renal impairment (from dehydration + direct toxic effect) 
 hyperglycaemia (less common than with thiazides) 
 gout 
 
 Loop diuretics induces ototoxicity by affecting Na+/K+/2Cl- cotransporters present in t he inner 
ear.

ear.  
 Explanation of respond to i.v furosemide but not oral in heart failure  Increased bioavailability  
 In right heart failure  The patient has a lot of gut oedema which would  reduce the 
absorption of oral furosemide. Intravenous furosemide would have a much better bioavailab ility 
and thus therapeutic effect. 
 Protein binding of drugs may be reduced in elderly patients, this may be due to malnutrition.

 Explanation of not responding to furosemide in chronic kidney disease (CKD)  Tubular 
secretion of furosemide is reduced in CKD  
 Organic acids accumulate in renal failure and compete for tubular secretion with furose mide. 
This competition can be overcome by using a larger dose of the drug. 
 
A 76-year-old lady taking perindopril 2 mg, bisoprolol 1.25 mg and had recently had her dose of furosemide

increased from 40 mg to 80 mg. C/O dizziness, particularly when standing upright after being seated. There 
were no clinical signs of cardiac failure. Serum urea : 13.3 mmol/L . Serum creatinine: 221  µmol/L.  What is the 
next step in her management?  
 Stop the furosemide temporarily and restart at a lower dose within a few  days  
 This lady is developing postural hypotension after the recent increase in furosem ide 
dose. 
 She has moderate renal impairment.

dose. 
 She has moderate renal impairment. 
 Stopping either her beta-blocker or ACE inhibitor  is not the best option for treatment at 
this stage.  
Bendroflumethiazide 
 
the target of action of thiazide diuretics  NaCl  co-transporter 
the target of action of loop diuretics   NKCC2  
 Bendroflumethiazide (bendrofluazide) is a thiazide diuretic which works by inhibiti ng sodium absorption

at the beginning of the distal convoluted tubule (DCT). 
 The NaCl co-transporter : 
 the target of thiazide diuretics   
 it contributes to the reabsorption of about 10% of the filtered load  of sodium.  
 Mutations causing loss of function of the NaCl co-transporter cause Gitelman's sy ndrome, the 
commonest monogenic cause of hypokalaemia in adults. 
 Potassium is lost as a result of more sodium reaching the collecting ducts.

 Bendroflumethiazide has a role in the treatment of mild heart failure although l oop diuretics are better 
for reducing overload. 
 The main use of bendroflumethiazide was in the management of hypertension but recen t NICE 
guidelines now recommend other thiazide-like diuretics such as indapamide and chlortalidone. 
 
Bendroflumethiazide - mechanism of Hypokalemi a: 
 ↑ sodiuŵ reachiŶg the collectiŶg ducts  
 Activation of the renin-angiotensin-aldosterone 
 
1696

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  40 
  
Common adverse effects   
 postural hypotension 
 hyponatraemia, hypokalaemia,  
Hypomagnesaemia,  hypercalcaemia  
 gout 
 impotence Rare adverse effects 
 agranulocytosis 
 photosensitivity rash 
 hypochloraemic alkalosis

 hypochloraemic alkalosis  
 
Amiloride   
 The potassium-sparing diuretic amiloride  inhibits sodium channels in the distal segment of the distal 
convoluted tubule 
 Amiloride inhibits the action of aldosterone on the distal convoluted tubule producing potassium 
reabsorption.  
 In treating a patient with congestive heart failure who develops hypokalaemia, the best  choice is 
to add a small dose of amiloride to his furosemide therapy 
 
Triamterene

Triamterene   
 Triamterene, a potassium sparing diuretic similar to amiloride. 
 occasionally prescribed with thiazide or loop diuretics, to prevent hypokalaemia.  
 It inhibits the movement of sodium through channels towards the end of the dist al tubule and collecting 
ducts, preventing the passage of sodium from the urinary space into the tubular cel ls. This action 
causes hyperpolarisation of the apical plasma membrane, preventing the secretion of po tassium into

the collecting ducts.  
 Hyperkalaemia is common  (>5%), and is unaffected by concurrent potassium depleting diuretics. 
 In mild hyperkalaemia , (eg: K = 5.9 mmol/l) with no evidence of cardiac toxicity. The 
management involves stopping the triamterene, and repeating the U&E in one week.  
Spironolactone 
 Spironolactone is an aldosterone antagonist

 Spironolactone is an aldosterone antagonist  
 acts in the cortical distal convoluted tubule  and collecting duct. 
 ascites: patients with cirrhosis develop a secondary hyperaldosteronism. Relatively large doses such as 
100 or 200mg are often used 
 hypertension: used in some patients as a NICE 'step 4' treatment 
 heart failure (see RALES study below) 
 Conn's syndrome

 Conn's syndrome 
 Spironolactone  is a diuretic with anti-androgen effects . This makes it a useful agent in the treatment 
of hormonal acne and hirsutism. 
 It blocks the androgen receptor and 5α -reductase enzyme that is responsible for the synthesis 
of dihydrotestosterone (DHT) and can be used to treat hirsutism.  
 gynaecomastia 
 Spironolactone and eplerenone  are both aldosterone receptor antagonists that have shown

survival benefit in patients with NYHA III/IV systolic heart failure.  
 Eplerenone has a lower antiandrogenic effect compared to spironolactone and may, 
therefore, be preferable if patient develops erectile dysfunction and bilateral 
gynecomastia. 
RALES 
 NYHA III + IV, patients already taking ACE inhibitor 
 low dose spironolactone reduces all-cause mortality 
___________________________ _________________________________________ 
Eplerenone 
Indications

 Eplerenone is a spironolactone-like agent  indicated as an add-on to standard therapy after a 
myocardial infarction, and heart failure 
 Common side-effects : hyperkalaemia , dizziness, hypotension, diarrhoea, nausea and prerenal renal 
 Uncommon side-effects  : eosinophilia, dehydration, hypercholesterolemia and hypertriglyceridaemia 1697

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  41 
 Cautions 
 The drug is metabolised via the CYP3A4 system, so that inducers or inhibitors of the 3A4  enzyme 
subtype may precipitate drug interactions 
___________ __________________________________________________________ 
Diuretic abuse 
 Diuretic abuse is not uncommon amongst athletes and jockeys as a means of weight loss.

 The patient has a hypokalaemic alkalosis, and urine potassium excretion is high despite 
the hypokalaemia. 
Proto-oncogene stimulation 
 β-Agonists and angiotensin II   augment proto-oncogene expression,  stimulate protein synthesis 
and induce the synthesis of fetal forms of actin and myosin,  leading to hypertrophy of smooth 
muscle

muscle  
 Thyroxine acts directly via nuclear receptors to regulate myosin heavy-chain gene transcri ption  
____________________________ ________________________________ 
Respiratory drugs 
Theophylline 
 Theophylline, like caffeine, is one of the naturally occurring methylxant hines.  
 The main use of theophyllines in clinical medicine is as a bronchodilator in the man agement of asthma 
and COPD 
Action

and COPD 
Action  
 The exact mechanism of action has yet to be discovered.  
 One theory suggests theophyllines may be a non-specific inhibitor of phosphodiesterase  resulting in 
an increase in cAMP.  
 antagonism of adenosine  and prostaglandin inhibition  
 It blocks the adenosine receptor 
 Blockade of the receptors by theophylline results in: 
 relaxation of smooth muscles, especially bronchial muscles 
 constriction of cerebral blood vessels

 constriction of cerebral blood vessels 
 stimulation of the cardiac pacemaker 
 stimulation of gastric secretions 
 Theophylline also releases calcium ions from the sarcoplasmic reticulum in skeletal and cardiac 
muscle, thus enhancing their contractility, including diaphragmatic contracti lity 
 plasma theophylline concentration of between 10 and 20 mg/l is required for satisfactory 
bronchodilatation. 
Side effect

Side effect  
 At therapeutic doses , the side-effect of Aminophylline  Jitteriness  
 adverse effects can occur within the range 10-20 mg/l and both the frequency  
 severity increase at concentrations above 20 mg/l  
Factors increasing the plasma theophylline concentration: 
 cirrhosis 
 viral infections 
 increased age (the elderly) 
 Diet: 
 Obesity 
 High carbohydrate intake 
 High methylxanthine intake (for example, tea, coffee)

 drugs that inhibit  its metabolism  
 Commonly prescribed drugs that can increase serum theophylline levels include: 
 clarithromycin,  erythromycin   
 ciprofloxacin ,  
 cimetidine,  
 oral contraceptives 
 allopurinol.  
 Fluvoxamine 
 Consideration should be given to reducing theophylline dose when these drugs are prescribed.  
 cessation of enzyme-inducing drugs. 
Factors decreasing the plasma theophylline concentration: ( increasing theophylline clearance):  1698

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  42 
  Diet: 
 Low carbohydrate 
 High protein intake 
 Social: 
 chronic alcoholism without cirrhosis 
 smoking 
 Smoking cessation  sudden increase in theophylline level 
 Regular tobacco use up-regulates hepatic enzyme activity; cessation will be

associated with a decrease of hepatic enzyme activity, such that theophylline 
concentrations may increase. 
 Drugs: drugs that induce  liver metabolism: eg:  
 Rifampicin 
 Carbamazepine.  
 
Theophylline poisoning  
 Theophylline has a narrow therapeutic window and needs close monitoring of it s serum level to 
avoid toxicity  
 Symptoms of toxicity may be delayed following the ingestion of sustained -release preparations for up to 
48 h

48 h 
 Theophylline toxicity occurs with concomitant use of clarithromycin due to inhibition of cytochrome 
P450 (CYP1A2 and CYP3A4) by clarithromycin.  
 Features of mild to moderate theophylline toxicity include nausea, vomiting, epigastric, tremor, 
tachycardia, restlessness and hallucinations. Severe toxicity can cause convulsions, arrhythmias and 
metabolic acidosis. 
 Studies have shown an approximate 20% increase in both peak and trough theophylline levels with

concomitant use of clarithromycin and it is recommended that theophylline levels should be moni tored 
prior, during and on cessation of clarithromycin and dosage adjustment of theophylline mad e 
accordingly. 
 Features  
 mild to moderate theophylline toxicity 
 nausea, vomiting, epigastric,  
 tremor,  
 tachycardia,  
 restlessness and  
 hallucinations. 
 Severe toxicity: 
 convulsions,  
 arrhythmias  
 metabolic acidosis,  hypokalaemia  and hyperglycaemia 

 activated charcoal 
 charcoal haemoperfusion is preferable to haemodialysis 
 
In cases of severe theophylline toxicity, charcoal haemoperfusion can be used 
 
Antimuscarinic agent  
 Muscarinic antagonists (antimuscarinic agents) are a group of anticholiner gic drugs that competitively 
inhibit postganglionic muscarinic receptors.

inhibit postganglionic muscarinic receptors. 
  Which organ systems are most affected by an antimuscarinic agent depends on  the specific 
characteristics of the agent, particularly its lipophilicity .  
 Lipophilic agents (i.e., atropine or benztropine) are able to cross the blood-brain barrier and 
therefore affect the central nervous system (CNS) in addition to other orga n systems.  
 Less lipophilic agents (i.e., ipratropium or butylscopolamine) are administered if the CNS does

not need to be targeted, specifically for respiratory (e.g., asthma), gastrointestinal (e.g., irritable 
bowel syndrome), or genitourinary applications (e.g., urinary incontinence).  
 
 1699

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  43 
 Action 
 Muscarinic antagonists (the majority of anticholinergic drugs) inhibit the  effect of acetylcholine on 
muscarinic receptors,  
Effects of muscarinic antagonists   
Muscarinic 
receptors  Organ/Tissue Effects 
M1, M4, M5 Central nervous 
system  Influences neurologic function (e.g., cognitive impairment)

M2 Heart   Ĺ Heart  rate 
 Increases AV-node  conduction ĺ arrhythmias  
M3 Smooth muscle  Gastrointestinal tract  
 Ļ Intestinal  peristalsis , 
 Ļ Salivary  and gastric secretions 
 Urinary tract  
 Ļ Bladder  contraction (decreases detrusor muscle tone, 
increases the internal urethral sphincter tone) 
 Airway  
 Bronchodilation  
 Ļ Bronchial  secretions 
 Eye 
 Mydriasis ĺ narrowing of the iridocorneal angle  
 Impaired accommodation

 Impaired accommodation 
 Blood vessels : minimal effect on vascular tone and blood 
pressure  
Exocrine glands  Ļ Secretions  (sweat) 
  
Antimuscarinic side effects 
"Blind as a bat (mydriasis), mad as a hatter (delirium), red as a beet (flushing ), hot as a hare 
(hyperthermia), dry as a bone (decreased secretions and dry skin), the bowel and bladde r lose their 
tone (urinary retention and paralytic ileus), and the heart runs alone (tachycardia). ” 
 
 Side effect Contraindications

Side effect Contraindications  
Impaired 
secretion by 
exocrine glands  Dry mouth and sore throat  
 Ļ Respiratory  tract secretions  
 Hyperthermia und warm, dry skin   Acute asthma 
 Respiratory distress 
system  Tachycardia   Tachyarrhythmias 
 Heart failure  
Decreased 
tone  Gastroesophageal reflux  
 Obstipation or ileus  
 Impaired micturition/urinary retention

 Impaired micturition/urinary retention  
 Vasodilatation and flush   Hiatal hernia associated 
with reflux esophagitis 
 Ulcerative colitis  
 Paralytic ileus 
 Obstructive disease of the 
gastrointestinal tract 
(e.g., achalasia, pyloric 
stenosis or duodenal 
stenosis) 
 Obstructive 
uropathy (e.g., benign 
prostatic 
hyperplasia, urinary 
retention) 
Eye  Mydriasis and photophobia 
 Blurred vision   Narrow-angle glaucoma

 Blurred vision   Narrow-angle glaucoma  
CNS   Excitement, agitation, and hallucinations with the  Myasthenia gravis 1700

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  44 
  Side effect Contraindications  
use 
of lipophilic parasympatholytics   (e.g., atropine), 
especially in elderly patients 
 Confusion, disorientation 
 Coma, seizure, and rarely death 
 
Lipophilic antimuscarinic (good oral bioavailability and CNS penetration) (Tertiary ami nes) 
Drug  Effect  Indication

Drug  Effect  Indication  
 Atropine  Ĺ Heart rate   
 Ļ Secretions  of exocrine 
glands 
 Ļ Tone  and motility of 
smooth muscles 
 ĻCholinergic overactivity in 
CNS  
 Mydriasis and cycloplegia  First drug of choice in unstable 
(symptomatic) 
sinus bradycardia (IV) 
 Premedication: prior 
to intubation to decrease 
salivary, respiratory, and 
gastric secretions 
 Ophthalmology: uveitis  
 Antidote for 
anticholinesterase poisoning    
 Scorpion stings

 Scorpion stings  
 Scopolamine(hyoscine)  Ļ Vestibular disturbances 
(antiemetic )  Motion sickness 
 Homatropine 
 Tropicamide  Mydriasis 
 Impair accommodation  Ophthalmology 
 Therapeutic use: in 
patients with uveitis  
 Diagnostic use: 
pupillary dilation to 
allow ocular fundus 
examination and 
cycloplegia to allow 
refractory testing 
 
 Benztropine 
 Biperiden 
 Trihexyphenidyl  ↓ Cholinergic  overactivity 
in CNS   Antiparkisonian effect 
(Parkinson disease)

(Parkinson disease) 
 Ļ Extrapyramidal  symptoms 
(EPS) caused 
by antipsychotics 
 Oxybutynin 
 Tolterodine 
 Solifenacin 
 Dicyclomine  ↓ Tone and motility of 
smooth muscle cells   Oxybutynin, tolterodine, and 
solifenacin: overactive bladder 
incontinence  
 Dicyclomine: irritable bowel 
syndrome 
 Darifenacin  Ĺ Sphincter  tone  Urinary urgency, urge 
incontinence, urinary 
frequency, 
and/or nocturia(symptoms 
resulting from, e.g., overactive 
bladder) 
 
 1701

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  45 
 Hydrophilic (poor oral bioavailability and CNS penetration) (Quarternary amines)  
 Glycopyrrolate  Decreases 
secretions of 
exocrine glands  Peptic ulcer disease treatment 
 Ipratropium 
bromide 
 Tiotropium 
bromide  Bronchodilation    COPD and bronchial asthma 
 Ipratropium bromide:

 Ipratropium bromide: 
 COPD grade I and higher 
 Acute management of 
refractory asthma 
 Tiotropium bromide: 
 Longer duration of action 
 Long -term treatment 
of COPD (grade II and above) 
 
Anticholinergic syndrome (overdose) 
 Etiology 
 Belladonna poisoning  
 Jimson weed/Angel's trumpet ( Datura stramonium ) poisoning  
 Medications 
 Anticholinergic agents (e.g., atropine, benztropine, trihexyphenidyl ) 
 Drugs with anticholinergic properties

 Drugs with anticholinergic properties 
 Tricyclic antidepressives (predominantly doxepin, amitriptyline, imipramine , 
and trimipramine) 
 Antipsychotics (e.g., clozapine, quetiapine) 
 First-generation antihistamines (e.g., promethazine, dimenhydrinate) 
 Dry mouth, warm, flushed skin, thirst, tachycardia, arrhythmias, mydriasis, con fusion, and 
agitation 
 Possibly anticholinergic delirium: Excessive use of tricyclic antidepressants (or other

medications with significant anticholinergic effects) can cause life-
threatening delirium, hallucinations, and psychomotor symptoms. 
 Treatment : antidote for purely anticholinergic poisoning  (e.g. atropine ): physostigmine   
 
One mnemonic used to remember the symptoms of anticholinergic toxicity is: 
 
Hot as a hare: increased body temperature 
Blind as a bat: mydriasis (dilated pupils) 
Dry as a bone: dry mouth, dry eyes, decreased sweat 
Red as a beet: flushed face

Red as a beet: flushed face 
Mad as a hatter: delirium 
 
Tiotropium 
 Tiotropium is a specific long-acting antimuscarinic agent indicated as maintenance therapy for 
patients with (COPD) 
Cautions 
 Caution is advised in patients with narrow-angle glaucoma, prostatic hyperplasia or blad der-neck 
 Dry mouth  
 Paradoxical bronchospasm  
 Rarer side-effects include tachycardia, blurred vision, urinary retention and constipation

Doxapram 
 Doxapram is a centrally acting respiratory stimulant, used in patients with severe respi ratory disease 
who are deemed unsuitable for admission to the Intensive Therapy Unit 
 Intravenous doxapram only used if the patient is not suitable for either int ubation or non-invasive 
ventilation. 
 The main purpose in using doxapram is to allow time for recovery from an acu te respiratory event

 The usual dosing regimen is 1-4 mg/min given as an intravenous infusion 1702

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  46 
 Contraindications 
 heart disease, 
  epilepsy, cerebral oedema, strok e, 
  status asthmaticus, 
 hypertension, hyperthyroidism  and phaeochromocytoma 
 hypertension, 
 exacerbation of apparent dyspnoea,  
 agitation,  
 sweating,  cough,  
 dizziness,  
 nausea, vomiting

 nausea, vomiting  
 urinary retention  
Sodium cromoglicate 
 Sodium cromoglicate principally acts by reducing the degranulation of mast cells t riggered by the 
interaction of antigen and IgE 
 The inhibitory effect on mast cells  appears to be cell-type specific, since cromoglicate has little 
inhibitory effect on mediator release from human basophils

 More recent research has also shown that cromoglicate may act on eosinophils to reduce their  
inflammatory response to inhaled allergens, but this is not the most probable mechanism  of action of 
sodium cromoglicate in the prophylaxis of asthma  
Magnesium treatment in asthma 
 Intravenous magnesium (1.2 - 2 g given over 20 minutes) is now indicated in the  management of 
severe life threatening acute asthma attacks

severe life threatening acute asthma attacks 
Its principal actions are to: 
 inhibit acetylcholine release at the neuromuscular junction 
 relax bronchial smooth muscle 
 stabilise mast cells 
Unwanted effects  are uncommon following single-dose therapy, although a slight decrease in blood pr essure 
can be noticed and flushing can occur 
Symptoms of hypermagnesaemia include : 
 nausea 
 diarrhoea 
 flushing 
 hypertension  confusion 
 coma 
 loss of tendon reflexes

 coma 
 loss of tendon reflexes 
 
CNS & Psychiatric drugs 
Anti-convulsants  
Remarkable side effects of anti-epileptic drugs are: 
 SIADH and rash (carbamazepine) 
 Liver toxicity (sodium valproate) 
 Severe rash (lamotrigine) 
 Retinal damage (vigabatrin) 
 Aplastic anaemia (felbamate). 
 Topiramate

 Topiramate 
 anticonvulsant ,most frequently prescribed for the prevention of migraines 
 Renal stones 
 topiramate causes systemic metabolic acidosis, lowers urinary citrate excretion, 
and increases urinary pH. These changes increase the propensity to form 
calcium phosphate stones.  
 weight loss (weight gain with sodium valproate),  
 impaired taste sensation,  
 cognitive dysfunction 
 depression. 
 Tingling in extremities. 1703

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  47 
  Felbamate   
 Because of its potentially fatal toxic effects  (especially aplastic anemia  and hepatic failure), 
the use of felbamate should be restricted to patients with severe partial epilepsy or Lennox -
Gastaut syndrome who do not respond to other medications. 
 Lamotrigine

 Lamotrigine has a black box warning because of its association with Stevens-Johnson 
syndrome.  
 the risk of tevens- Johnson syndrome increases if it is  co-administered with 
valproate .  
 When co-administered with valproate, the dosage of lamotrigine should be half t hat 
required in the absence of valproate and should be very slowly escalated.  
Epilepsy medication in pregnancy

Epilepsy medication in pregnancy 
 There is an increased risk of neural tube defects associated with anti-convulsants during preg nancy. 
 However, the risks associated with treatment are outweighed by the benefits in p reventing seizures, so 
the drug should be continued. 
 The risks may be minimised through use of folate supplements. 
 If a patient is planning on pregnancy, then registry studies suggest that  lamotrigine would be 
the best choice

the best choice 
 lamotrigine  is the most appropriate choice  in women of child-bearing age because:  
 low risk of congenital malformations.  
 it does not affect the effectiveness of the oral contraceptive pill 
 Percentage of Congenital malformations associated with Anti-epileptics 
 Valproate  6% (neural tube defects in the fetus) 
 Valproate should be avoided in pregnancy if possible 
 NICE guidance suggests that phenytoin should be avoided in women of child-bearing

age because of the risk of congenital malformations. 
 Topiramate   4.3%  
 Phenytoin   3.5% (fetal hydantoin syndrome with facial dysmorphism)  
 Carbamazepine   2.5%  
 General population 1.5%   
 Primidone and phenobarbital  withdrawal symptoms in the newborn  
 
Contraception in epilepsy 
 Phenytoin induces liver enzymes, thereby increasing oestrogen breakdown and reducing the 
effectiveness of oestrogen-containing contraceptives

 Where the combined contraceptive pill is used in conjunction with phenytoin, the con traceptive should 
contain high dose oestrogen: 50 mg ethinylestradiol or more 
 Lamotrigine is a suitable first-line treatment for partial epilepsy, and  does not alter oestrogen 
metabolism  
 Whilst Carbamazepine  is a potent enzyme inducer and therefore  can't be used in combination with 
the pill  
 
Antiepileptic and weight  (medical-masterclass.com  2017 part 2)

 Two antiepileptic medications have been found to induce weight loss ; topiramate and 
zonisamide .  
 Valproate, vigabatrin, gabapentin, carbamazepine, and pregabalin induce weight gain .  
 Levetiracetam, lamotrigine, and phenytoin are weight neutral.  
 
Sodium valproate 
 Sodium valproate is used in the management of epilepsy and is first line therapy for generalised 
seizures.

seizures.  
 It works by increasing GABA activity. 
 gastrointestinal: nausea  hepatitis 
1704

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  48 
  increased appetite and weight gain 
 alopecia: regrowth may be curly  
(note that phenytoin ĺ hirsutism  
 while valporate ĺ alopecia ) 
 ataxia 
 tremor   pancreatitis  
 thromobcytopaenia 
 teratogenic 
 polycystic ovarian (PCOS) syndrome

 polycystic ovarian (PCOS) syndrome 
 
Sodium valproate can lead to severe hepatic toxicity.  more commonly if the patient has a metabolic or 
degenerative disorder, organic brain disease or severe seizures associated with mental retardation.  Usually 
this reaction occurs within the first three months of therapy. 
_________________________________________________________ ____________ 
Phenytoin 
Phenytoin is used in the management of seizures. 

 refractory period of voltage-gated Na+ channels  decreasing the sodium influx into neurons which in 
turn decreases excitability 
Phenytoin is associated with a large number of adverse effects. These may be divided into acute,  chronic, 
idiosyncratic and teratogenic 
Acute  
 initially: dizziness, diplopia, nystagmus, slurred speech, ataxia 
 later: confusion, seizures 
Chronic

Chronic 
 common: gingival hyperplasia  (secondary to increased expression of platelet derived growth factor, 
PDGF),  hirsutism , coarsening of facial features, drowsiness 
 megaloblastic anaemia (secondary to altered folate metabolism) 
 peripheral neuropathy 
 enhanced vitamin D metabolism causing osteomalacia 
 dyskinesia 
Idiosyncratic 
 fever 
 rashes, including severe reactions such as toxic epidermal necrolysis 

 hepatitis 
 Dupuytren's contracture (although not listed in the BNF ) 
 aplastic anaemia 
 drug-induced lupus 
 Hypocalcaemia 
 Pseudolymphoma or, rarely, malignant lymphoma and mycosis-fungoides-like lesions . 
Teratogenic 
 associated with cleft palate and congenital heart disease 
 Phenytoin would speed up metabolism of ethinyloestradiol making the pill l ess effective. 
 Cimetidine increases the efficacy of phenytoin by reducing its hepatic metabolism

 Sucralfate may decrease the pharmacological effects of phenytoin when administered concurr ently  
 Effect on other anti-epileptic: 
 Phenytoin usually lowers the serum concentration of carbamazepine, clonazepam, topiramate 
and sodium valproate,  
 elevates the serum level of phenobarbitone .  
 Phenytoin does not appear to influence the serum concentration of levetiracetam. 
In renal failure

In renal failure  
Renal failure  ↓ drug affinity for protein binding  ↑ free drug  toxicity  (drug level may be within 
the therapeutic range )  
 In patients with renal failure, dose reduction of phenytoin is therefore required . 
 Other drugs where this may be a problem include sodium valproate and warfarin. 
 1705

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  49 
 There is no oral preparation of fosphenytoin; it is used in status epilepticus only.  
 
Phenytoin toxicity typically gives rise to a cerebellar-like syndrome. Nystagmus is present even in mild 
toxicity. 
 
Carbamazepine

Carbamazepine 
Carbamazepine is chemically similar to the tricyclic antidepressant drugs.  
 most commonly used in the treatment of epilepsy, particularly partial seizures, where carbamazepine 
remains a first-line medication.  
 Other uses include 
 neuropathic pain (e.g. trigeminal neuralgia, diabetic neuropathy) 
 bipolar disorder 
 binds to sodium channels increases their refractory period 
 P450 enzyme inducer

 P450 enzyme inducer 
 Auto-induction of carbamazepine metabolism  need to increase the dose to achieve a 
therapeutic plasma concentration. 
 In patients on carbamazepine who develop Hashimoto's thyroiditis the dose of t hyroxine should 
be increased to maintain therapeutic levels 
 dizziness and ataxia 
 drowsiness 
 headache 
 visual disturbances (especially diplopia)

 visual disturbances (especially diplopia) 
 The most common dose-related adverse effects of carbamazepine are diplopia and ataxia 
 Steven- Johnson syndrome  
 HLA-B*1502 in individuals of Han Chinese and Thai origin  has been shown to be strongly 
associated with the risk of developing Stevens-Johnson syndrome (SJS) when treated w ith 
carbamazepine.  
 The prevalence of the HLA-B*1502 carrier is about 10% in Han Chinese and Thai populations.

 Whenever possible, these individuals should be screened for this allele before starting  treatment 
with carbamazepine 
 leucopenia and agranulocytosis 
 syndrome of inappropriate ADH secretion 
 Carbamazepine is nephrotoxic and may cause proteinuria.  
Carbamazine overdose presents with: 
 Drowsiness 
 Slurred speech 
 Ataxia 
 Nausea 
 Vomiting  Tremor 
 Blurred vision 
 Seizures 
 Oliguria, and 
 Bullous skin lesions. 
 
Contraindications:

Contraindications: 
 atrioventricular (AV) conduction abnormalities 
 history of bone marrow depression  
___________________________________________________________ __________ 
Vigabatrin 
Vigabatrin  Visual field defects 1706

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  50 
 Indication: 
 Vigabatrin should be used only in combination with other anti-epileptic drugs for pati ents with resistant 
partial epilepsy when all other appropriate drug combinations have proved inadequate or hav e not been 
tolerated.

 Vigabatrin is the drug of choice for infantile spasms, is not generally used outside the sit uation of 
Adverse effects: 
 reduced peripheral vision  
 40% of patients develop visual field defects, which may be irreversible 
 The pattern of the field defect is typically a bilateral, absolute concentric constr iction of the 
visual field, the severity of which varies from mild to severe.

 visual fields should be checked  before the start of treatment and every 6 months  
 aggression 
 alopecia 
 retinal atrophy 
Topiramate   
The patient with epilepsy and hepatic impairment  Topiramate  
 Topiramate is one of the few antiepileptic drugs (also including gabapenti n) with almost exclusively 
renal metabolism 
 It would be less likely to cause worsening of hepatic function

 adverse effects  of topiramate include 
 renal stones 
 weight loss  
 and neuropsychiatric side-effects 
Gabapentin  
 used for add-on therapy in partial or generalised seizures. 
 does not induce cytochrome P450 unlike other anticonvulsants such as phenytoin and phenobarbitone. 
 Requires dose adjustment in renal disease  

Levetiracetam (Keppra)   
 Is an adjunctive treatment for partial seizures with or without secondary generalisatio n. 
  mechanism of action is unknown. 
 rapidly absorbed orally, it does not affect hepatic enzymes but dose reduction is r equired in renal 
failure. 
 The drug appears to be well tolerated with few side effects. 
 has least interactions and is safe with warfarin .  
 
Procyclidine 
 action

 action 
 antimuscarinic 
 indication 
 used to treat the Parkinsonian side effects of neuroleptics; 
 Signs of procyclidine overdose  include: 
 Confusion 
 Sleeplessness lasting up to 24 hours or more 
 Pupils are dilated and unreactive to light. 
 Visual and auditory hallucinations and tachycardia have also been reported. 
1707

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  51 
 Barbiturates 
 Examples 
 phenobarbital, pentobarbital, thiopental, and secobarbital  
 increases GABA A action by ↑ duration of Cl- channel opening resulting in ↓ neuron firing  
 barbitDURATE 
 CNS depressant for anxiety and seizures 
 induction of anesthesia (thiopental) 
 kinetics

 kinetics 
 induction of P450 
 tolerance/dependence 
 Phenobarbitone suppress the central nervous system causing: 
 Hypoventilation (and therefore a respiratory acidosis) 
 Hypotension, and 
 Hypothermia. 
Anticholinergic syndrome 
common causes  Signs and symptoms Management 
 atropine 
 H-1-antihistamines  hot, dry skin 
 urinary retention

 dilated pupils ( mydriasis ) 
 Agitated delirium can also occur supportive 
 Although physostigmine, a reversible inhibitor of acteylcholinesterase, is effective in tr eating symptoms, 
there is a significant risk of cardiac toxicity (bradycardia, AV conduction def ects and asystole).  
 Treatment therefore consists of withdrawal of the precipitating drug and supporti ve care. 
____________________________ _________________________________________

Serotonin syndrome 
Causes 
 monoamine oxidase inhibitors 
 SSRIs 
 ecstasy 
 amphetamines 
 The serotonin syndrome occurs primarily because of interactions between monoamine-oxidase 
inhibitors (MAOI) and drugs that enhance serotonin function (eg selective serotonin-reup take inhibitors 
(SSRIs)) 
Features 
 neuromuscular excitation (e.g. hyperreflexia, myoclonus, Tremor, rigidity)  
 autonomic nervous system excitation (e.g. hyperthermia) 
 altered mental state 
 sweating

 sweating 
Management (Cyproheptadine may be useful in treatment) 
 stopping the precipitating drugs 
 instituting generalised cooling measures and diazepam to reduce agitation 
 Studies have suggested that drugs possessing serotonin-antagonist activity (eg cyproheptadine , 
methysergide) may provide some benefit in the management of patients with the serotonin syndrome 
____________________________ ____________________________________ _____

Oculogyric crisis 
An oculogyric crisis is a dystonic reaction to certain drugs or medical condition s 
Features  
 restlessness, agitation 
 involuntary upward deviation of the eyes 
Causes 
 Usually a consequence of typical neuroleptic drugs  such as haloperidol or chlorpromazine, but 1708

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  52 
 is unusual with newer agents  such as olanzapine or clozapine. 
 postencephalitic Parkinson's disease 
The condition is often precipitated by re-introduction of the agen t. 
 procyclidine   (usually IV or IM)   

Overview 
 shown to be as effective as tricyclic antidepressants in the treatment of mild-modera te depression 
 mechanism: thought to be similar to SSRIs (although noradrenaline uptake inhibition has al so been 
demonstrated) 
 NICE advise 'may be of benefit in mild or moderate depression, but its use shoul d not be prescribed or 
advised because of uncertainty about appropriate doses, variation in the nature of preparations, and

potential serious interactions with other drugs' 
 profile in trials similar to placebo 
 can cause serotonin syndrome 
 inducer of P450 system , therefore decreased levels of drugs such as warfarin, ciclosporin. The 
effectiveness of the combined oral contraceptive pill may also be reduced. 
Dopamine receptor agonists 
Overview  
 e.g. bromocriptine , cabergoline , ropinirole,  apomorphine

 ergot-derived dopamine receptor agonists (bromocriptine , cabergoline, pergolide*) have been 
associated with pulmonary, retroperitoneal and cardiac fibrosis .  
 The Committee on Safety of Medicines advice that an ESR, creatinine and chest x- ray should 
be obtained prior to treatment and patients should be closely monitored 
 *pergolide was withdrawn from the US market in March 2007 due to concern regarding increased 
incidence of valvular dysfunction 
Action:

Action: 
 L-DOPA is a precursor of dopamine. Dopamine iteself does not cross the  blood-brain barrier and so is 
no effective as a drug. 
 Levodopa exerts its therapeutic action after being converted by dopa decarboxylase to dopami ne in the 
brain (in the striatum).  
 It is also converted to dopamine in the periphery, causing nausea and vomiting through action at the 
area postrema, which lies outside the blood-brain barrier in the brain stem.

 Currently treatment is delayed until the onset of disabling symptoms  
 If the patient is elderly, L-dopa is sometimes used as an initial treatmen t 
 prolactinoma/ galactorrhoea 
 cyclical breast disease 
 hallucinations 
 daytime somnolence   
Dopa-decarboxylase inhibitors

Dopa-decarboxylase inhibitors   
 Reduce the extracerebral complications of L-dopa therapy.  These include nausea, vomiting, 
postural hypotension and cardiac arrhythmias. 
 When given in combination with dopamine agonists dyskinetic movements are more li kely. 1709

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  53 
  Carbidopa is an inhibitor of dopa decarboxylase that does not cross the blood-brain bar rier, so it 
reduces peripheral, but not central, metabolism of levodopa to dopamine, thereby reducin g the 
unwanted side effect but not the therapeutic action.

 Benserazide is another peripheral dopa decarboxylase inhibitor that is commonly used in combina tion 
with levodopa (as co-beneldopa (Madopar)). 
 
Amitriptyline  (tricyclic antidepressants) 
Antimuscarinic effects : relatively common and occur before an antidepressant effect is obtained. 
 Dry mouth 
 Constipation  paralytic ileus 
 Urinary retention   Blurred vision and disturbances in

accommodation 
 Increased intraocular pressure, and 
 Hyperthermia. 
 Tolerance is often achieved if treatment is continued 
 adverse effects may be less troublesome if treatment is begun with small doses and  then increased 
gradually, although this may delay the clinical response. 
Neurological adverse effects : 
 Drowsiness  
 Headache 
 Tremor 
 Ataxia 
 Epileptiform seizures 
 Tinnitus  extrapyramidal symptoms including speech

difficulties (dysarthria).Confusion, 
hallucinations, or delirium may occur, 
particularly in the elderly, and mania or 
hypomania, and behavioural disturbances 
(particularly in children) have been reported. 
Gastrointestinal complaints include : 
 Sour or metallic taste 
 Stomatitis, and 
 Gastric irritation with nausea and vomiting. 
 rarely, cholestatic jaundice 
cardiovascular  
 Orthostatic hypotension and tachycardia can occur in patients without a history of cardiovascul ar

disease, and may be particularly troublesome in the elderly. 
blood disorders:  
 Bone marrow depression 
 Thrombocytopenia 
 Leucopenia, and 
 Agranulocytosis. 
Endocrine effects   
 testicular enlargement  
 gynaecomastia and breast enlargement, and galactorrhoea.  
 Sexual dysfunction. 
 Changes in blood sugar concentrations 
 hyponatraemia associated with inappropriate secretion of antidiuretic hormone.

 increased appetite with weight gain (or occasionally anorexia with weight loss).  
 Sweating may be a problem. 
Others 1710

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  54 
  Hypersensitivity reactions, such as urticaria and angioedema, and photosensiti sation have been 
reported  
Tricyclic overdose 
 
 Overdose of tricyclic antidepressants is a common presentation to emergency departments.

Amitriptyline and dosulepin (dothiepin) are particularly dangerous in overdose. 
 Other tricyclic antidepressants includes  imipramine  
 Early features relate to anticholinergic properties: dry mouth, dilated pupils, agi tation, sinus tachycardia, 
blurred vision. 
 
Features of severe poisoning include:  
 Hypertension  
 results from the blockade of norepinephrine reuptake 
 is an early and transient finding.

 is an early and transient finding.  
 Catecholamines are eventually depleted and in most patients hypertension is mild and self-
limiting and is best left untreated. 
 Orthostasis and hypotensio n  
 are the result of direct myocardial depression, catecholamine depletion, alpha-adrenergic 
blockade, and arrhythmias.  
 The combination of decreased contractility and vasodilation produce decreased preload and can 
result in severe and refractory hypotension.  
 Arrhythmias

 Arrhythmias 
 secondary to blockage or slowing of fast sodium channels (causing a quinidine-like e ffect)  
 the most serious consequence of TCA overdose. 
 Mild overdoses  produce sinus tachycardia , mostly as a result of anticholinergic effects . 
 More severe overdoses  result in prolonged QRS and QTc intervals , followed by a  
prolonged PR interval , and, finally, ventricular arrhythmias , including ventricular 
tachycardia  and ventricular fibrillation . 
 seizures

 seizures 
 coma 
ECG changes include: ( ECG is the most appropriate initial action ) 
 sinus tachycardia 
 widening of QRS 
 prolongation of QT interval 
 
Widening of QRS > 100ms is associated with an increased risk of seizures whilst QRS  > 160ms is associate d 
with ventricular arrhythmias 
 Check U&Es, looking specifically for hypokalaemia, and ABG looking for acidosis. Hypokalaemia

should be corrected. ECG should be done to assess the QRS interval. 
 Gastric lavage should only be considered if it is within one hour a potentially fatal overdose. 50 g o f 
charcoal can be given if it is within one hour of ingestion. 
 50 ml of 8.4% sodium bicarbonate should be given if the pH is less than 7.1, QR S interval is more than 
0.16 s, or there are cardiac arrhythmias or hypotension. 
 
 Indication for sodium bicarbonate in tricyclic poisoning includes wide QRS complex .

 Intravenous sodium bicarbonate is the standard initial therapy for patients who develop 
cardiotoxicity (usually a QRS > 100ms or a ventricular arrhythmia) as a result of tricy clic 
antidepressant (TCA) overdose. 
 Mechanism of Sodium bicarbonate action: 
 alkalinisation of blood to a pH of 7.45-7.55 uncouples TCA from myocardial 
sodium channels;   
1711

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  55 
  also, additional sodium increases extracellular sodium concentration, thereby 
improving the gradient across the channel. 
 Intravenous magnesium sulphate can be used as a second-line agent in refractory arr hythmias. 
 IV bicarbonate may reduce the risk of seizures and arrhythmias in severe toxicity

 arrhythmias: class 1a (e.g. Quinidine) and class Ic antiarrhythmics (e.g. Flecainide) are  contraindicated 
as they prolong depolarisation. Class III drugs such as amiodarone should also be avoided as they 
prolong the QT interval. Response to lignocaine is variable and it should be emphasized that correcti on 
of acidosis is the first line in management of tricyclic induced arrhythmias  
 intravenous lipid emulsion is increasingly used to bind free drug and reduce toxicity

 dialysis is ineffective in removing tricyclics 
 Patients who display signs of toxicity should be monitored for a minimum of 12 hours. 
Tricyclic Withdrawal symptoms rare and include:  
 cholinergic  effects such as: abdominal cramps, diarrhoea, vomiting and dehydration 
 extrapyramidal  symptoms such as: anxiety, psychosis, delirium and mania 
_____________ _____________________ ___________________________________  
Monoamine oxidase (MAO) inhibitors  
Overview

Overview 
 serotonin and noradrenaline are metabolised by monoamine oxidase in the presynaptic cell 
Non-selective monoamine oxidase inhibitors 
 e.g. tranylcypromine, phenelzine 
 used in the treatment of atypical depression (e.g. hyperphagia) and other psychiatric disorder 
 not used frequently due to side-effects 
 Abrupt withdrawal of phenelzine leads to panic, shaking, sweats and nausea

Adverse effects of non-selective monoamine oxidase inhibitors 
 hypertensive reactions with tyramine containing foods e.g. cheese, pickled herri ng, Bovril, Oxo, 
Marmite, broad beans 
 anticholinergic effects 
___________________________________________________ ________________ 
Selective serotonin reuptake inhibitors (SSRIs) 
Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatment f or the majority of patients 
with depression.

with depression.  
 citalopram and fluoxetine are currently the preferred SSRIs 
 sertraline is useful post myocardial infarction  as there is more evidence for its safe use in this 
situation than other antidepressants 
 SSRIs should be used with caution in children and adolescents. Fluoxetine is the drug of cho ice when 
an antidepressant is indicated 
 gastrointestinal symptoms are the most common side-effect

 there is an increased risk of gastrointestinal bleeding in patients taking S SRIs. A proton pump inhibitor 
should be prescribed if a patient is also taking a NSAID 
 patients should be counselled to be vigilant (ح)for increased anxiety and agitation after starting a 
SSRI  
 fluoxetine and paroxetine have a higher propensity for drug interactions 
  The Committee on Safety of Medicines (CSM) have reported that hyponatraemia is associated with

all types of antidepressants;  however it has been reported  more frequently with selective 
serotonin reuptake inhibitors (SSRIs) than with other antidepressants. 
 Hyponatraemia should be considered in all patients who develop drowsiness, confusion or convulsi ons 
whilst taking an antidepressant.   
Citalopram and the QT interval 
 citalopram and escitalopram are associated with dose- dependent QT interval prolongation and should 
not be used in those with:

not be used in those with:  
 congenital long QT syndrome; 
 known pre-existing QT interval prolongation;  
 or in combination with other medicines that prolong the QT interval 
 the maximum daily dose is now 40 mg for adults; 20 mg for patients olde r than 65 years; and 20 mg for 
those with hepatic impairment 
Interactions 1712

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  56 
  NSAIDs: NICE guidelines advise 'do not normally offer SSRIs', but if  given co-prescribe a proton pump 
inhibitor 
 warfarin / heparin: NICE guidelines recommend avoiding SSRIs and considering  mirtazapine  
 aspirin: see above 
 triptans: avoid SSRIs 
 monoamine oxidase inhibitor (MAOI)  serotonin syndrome  
follow up

follow up 
 Following the initiation of antidepressant therapy patients should normally be reviewed by a doctor after 
2 weeks.  
 For patients under the age of 30 years or at increased risk of suicide they  should be reviewed after 1 
week.  
 If a patient makes a good response to antidepressant therapy they should continue on t reatment for at 
least 6 months after remission as this reduces the risk of relapse.  
Discontinuation symptoms

Discontinuation symptoms  
 When stopping a SSRI the dose should be gradually reduced over a 4 week period ( this is not 
necessary with fluoxetine).  
 Paroxetine has a higher incidence of discontinuation symptoms 
 Withdrawal of paroxetine can lead to deterioration in mood and cognition and orofaci al 
dystonias  
 increased mood change 
 restlessness 
 difficulty sleeping 
 unsteadiness  sweating 
 gastrointestinal symptoms: pain, 
cramping, diarrhoea, vomiting

cramping, diarrhoea, vomiting 
Lithium 
 
 Lithium is mood stabilising drug used most commonly prophylactically in bipolar disorder but al so as an 
adjunct in refractory depression.  
 It has a very narrow therapeutic range (0.4-1.0 mmol/L) and a long plasm a half-life being excreted 
primarily by the kidneys. 
Mechanism of action  - not fully understood, two theories:

 interferes with inositol triphosphate formation 
 interferes with cAMP formation 
 
 nausea/vomiting, diarrhoea 
 fine tremor 
 polyuria (secondary to nephrogenic diabetes insipidus) 
 thyroid enlargement, may lead to hypothyroidism 
 ECG: T wave flattening/inversion 
 Hypercalcaemia and primary hyperparathyroidism.  
 It has been suggested that lithium  alters the sensitivity of the parathyroid cells to calcium  
hyperplasia.

hyperplasia.  
 Other studies have however failed to confirm an excess of parathyroid hyperplasia in this 
population, suggesting instead that lithium selectively stimulates growth of parathyr oid 
adenomas in susceptible patients, who are best treated therefore with adenoma excision ra ther 
than total parathyroidectomy. 
1713

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  57 
 Pregnancy  
 Exposure to lithium in utero is associated with Ebstein's anomaly. 
 Lithium is contraindicated during the first trimester and when breast-feeding. 
 In the first trimester lithium can cause atrialisation of the right ventricl e.

 During the second and third trimesters lithium can be used, but dose requirements are incr eased. 
 Immediately after delivery lithium dose requirements return to normal abruptly. Lithium levels can rise 
dangerously if a high dose is continued.  
 Lithium is excreted in breast milk and if the infant becomes dehydrated, then toxic lithium levels 
develop rapidly. 
Monitoring of patients on lithium therapy 
 NICE and the National Patient Safety Agency (NPSA) recommends:

1. lithium blood level should 'normally' be checked every 3 months. Levels should be taken 12  
hours post-dose 
2. thyroid and renal function should be checked before starting treatment and then every 6 months  
3. patients should be issued with an information booklet, alert card and record book 
4. monitor serum lithium levels 1 week after treatment starts and every dose change , and then 
every 3 months. 
 
Lithium monitori ng (NICE 2017):

Lithium monitori ng (NICE 2017):  
thyroid and renal function serum lithium levels ECG  
before treatment 1 week after treatment starts For people at high risk of 
cardiovascular disease every 6 months every dose change 
 every 3 months  
 
Sodium valproate is the second line therapy for bipolar disorder in patients who don ’t tolerate lithium 
or where it ’s contraindicated.  
Interaction: 
 Acetazolamide leads to decreased lithium concentration

 Osmotic diuretics and carbonic anhydrase inhibitors such as acetazolamide lead to decreased 
lithium concentration because of increased excretion 
 Calcium channel blockers combined with lithium may cause a syndrome of ataxia, confusion and 
sleepiness, which is reversible on stopping the drug. 
 ACE inhibitors lead to increased lithium concentration because of decreased excretion. 
 thiazide diuretics increased lithium reabsorption and may cause lithium intoxication.

 Methyldopa also leads to increased risk of neurotoxicity. 
Lithium toxicity 
Toxicity may be precipitated by dehydration, renal failure, diuretics (Especially 
bendroflumethiazide) or ACE inhibitors and ARBs  
 Lithium has a very narrow therapeutic range (0.4-1.0 mmol/L)  
 long plasma half-life (20 h)  
 excreted primarily by the kidneys.  
 Lithium toxicity generally occurs following concentrations > 1.5 mmol/L.

 Toxicity may be precipitated by dehydration,  electrolyte imbalance, renal failure, , and drugs  
Drugs that may precipitate lithium toxicity include: 
 diuretics (especially bendroflumethiazide),  
 ACE inhibitors   & ARB  
 NSAIDs 
 Metronidazole 
 Tetracycline 
 Methyldopa  
Features of toxicity  1714

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  58 
  coarse tremor (a fine tremor is seen in therapeutic levels) 
 acute confusion 
 dysarthria 
 ataxia 
 seizure 
 coma 
Mild to moderate toxicity  
(levels less than 2 mmol/L)  severe toxicity 
 (levels more than 2 mmol/L)  
 anorexia 
 vomiting 
 ataxia 
 blurring of vision

 ataxia 
 blurring of vision 
 coarse tremor 
 drowsiness, and 
 muscle weakness.  circulatory failure 
 coma 
 convulsions 
 hyper-reflexia 
 oliguria 
 psychosis, and 
 death (in severe cases). 
 
 mild-moderate toxicity may respond to volume resuscitation with normal saline.   
 In case of  significant hypernatraemia , 5% dextrose is an initial option f or fluid replacement 
 haemodialysis may be needed in severe toxicity

 haemodialysis may be needed in severe toxicity 
 indication of Haemodialysis: 
 if serum lithium levels > 4 mmol/l or 
 serum lithium levels  > 2.5 mmol/l with signs of significant lithium toxicity (e.g. seizures, 
depressed mental status) or inability to excrete lithium (e.g. renal disease, 
decompensated heart failure). 
 sodium bicarbonate is sometimes used but there is limited evidence to support this. By  increasing the 
alkalinity of the urine it promotes lithium excretion

 Activated charcoal does not bind lithium effectively and is therefore ineffectiv e except where co-
ingestion of other poisons is suspected.  
Prognosis 
 10% of patients who survive severe lithium toxicity will be left with a ne urological deficit. 
Therapeutic drug monitoring 
Lithium 
 range = 0.4 - 1.0 mmol/l 
 take 12 hrs post-dose 
Digoxin 
 at least 6 hrs post-dose 
Ciclosporin

Digoxin 
Ciclosporin 
 trough levels immediately before dose 
Phenytoin 
Baclofen 
 The primary site of action is the spinal cord by depressing monosynaptic  and polysynaptic 
transmission.  
 It can hyperpolarise cells by increasing K+ conductance and inhibit Ca2+ channels in others.

 Avoid abrupt withdrawal as it can cause serious side-effects including: 
 Autonomic dysreflexia.   
  hallucinations   
Baclofen toxicity  
 Onset of toxicity is rapid and its effect can last up to 35- 40 hours post ingestion. 1715

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  59 
  Features include: 
 Coma 
 CO2 retention is likely to be due to central nervous system depression and reduct ion in 
diaphragmatic contraction secondary to baclofen toxicity.  
 Hyporeflexia 
 Hypotonia 
 Hypothermia, and 
 Hypotension.

 Bradycardia with first degree heart block and prolongation of Q-T interval can occur. 
 Treatment is usually supportive and often requires intensive care. 
 Intubation and mechanical ventilation  
 Patients with a high risk of aspiration pneumonia (Ļ glasgow coma scale (GCS)  ) are a contraindication 
to non-invasive ventilation. 
Endocrinology drugs

Endocrinology drugs 
For all diabetic drugs   See endocrinology  
lipid -lowering agents 
See endocrinology (Hyperlipidaemia: management) 
Octreotide 
Octreotide   Stimulation of the somatostatin (SMS) receptor   
 
Overview 
 long-acting analogue of somatostatin

Overview 
 long-acting analogue of somatostatin 
 somatostatin is released from D cells of pancreas and inhibits the release of growth hormone,  glucagon 
and insulin 
Uses 
 acute treatment of variceal haemorrhage 
  gastrinomas 
 prevent complications following pancreatic surgery 
 VIPomas 
 refractory diarrhoea 
 gallstones (secondary to biliary stasis) 

Orlistat   Reduces fat absorption from the intestine  
 Orlistat promotes weight loss and improves co-morbidities in obese patients 
 Orlistat operates by preventing the absorption of fat molecules in the intestinal tr act 
 Approximately 30% of fat that would otherwise have been absorbed passes straight thr ough the bowel 
and is excreted in the faeces 
 As a result it can cause 'fatty stools', urgency and increased frequency of def aecation often with anal 
leakage or oily spotting

leakage or oily spotting 
 these effects encourage people taking the drug to limit fat intake 
 Orlistat itself is not absorbed, except in very small quantities and thus its side- effects are restricted to 
the gastrointestinal tract 
 Patients taking orlistat may require concomitant vitamin supplements because of m alabsorption of fat-
soluble vitamins such as vitamins A, D, K and E 
 Orlistat is shown to be clinically efficacious in reducing a person's weight over a period of a year

 Study results also showed significant improvement in reducing fasting glucose, total cholester ol, LDL-1716

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  60 
 cholesterol and blood pressure 
Obs & Gyna drugs 
Prescribing in pregnant patients 
Very few drugs are known to be completely safe in pregnancy. The list below largely compri ses of those known

to be harmful.  
 
Drugs  Antibiotics  
 ACE inhibitors, ARBs 
 Statins 
 Warfarin 
 Sulfonylureas 
 Retinoids (including topical) 
 Cytotoxic agents  Tetracyclines 
 Aminoglycosides 
 Trimethoprim 
 Quinolones: the BNF advises to avoid 
due to arthropathy in some animal 
studies 
 The majority of antiepileptics including valproate, carbamazepine and phenytoin are known to  be

potentially harmful. The decision to stop such treatments however is difficult  as uncontrolled epilepsy is 
also a risk. 
  Verapamil is relatively safe in pregnancy  and has been widely used to treat maternal and fetal 
supraventricular tachycardias.  
 Amiodarone is associated with fetal hypothyroidism,  
 lisinopril with oligohydramnios,  
 lithium with Ebstein ’s anomaly,  
 and warfarin with facial / CNS abnormalities.

 and warfarin with facial / CNS abnormalities. 
Combined oral contraceptive pill: contraindications 
The decision of whether to start a women on the combined oral contraceptive pill i s now guided by the UK 
Medical Eligibility Criteria (UKMEC). This scale categorises the potent ial cautions and contraindications 
according to a four point scale, as detailed below:

 UKMEC 1: a condition for which there is no restriction for the use of the contraceptive method 
 UKMEC 2: advantages generally outweigh the disadvantages 
 UKMEC 3: disadvantages generally outweigh the advantages 
 UKMEC 4: represents an unacceptable health risk 
Examples of UKMEC 3 conditions incl ude 
 more than 35 years old and smoking less than 15 cigarettes/day 
 BMI > 35 kg/m^2* 
 migraine without aura and more than 35 years old

 family history of thromboembolic disease in first degree relatives < 45 years 
 controlled hypertension 
 immobility e.g. wheel chair use 
 breast feeding 6 weeks - 6 months postpartum 
Examples of UKMEC 4 conditions include  
 more than 35 years old and smoking more than 15 cigarettes/day 
 migraine with aura 
 history of thromboembolic disease or thrombogenic mutation 
 history of stroke or ischaemic heart disease 
 breast feeding < 6 weeks post-partum 
 uncontrolled hypertension

 uncontrolled hypertension 
 breast cancer 
 major surgery with prolonged immobilisation 
Diabetes mellitus diagnosed > 20 years ago is classified as UKMEC 3 or 4 depending on  severity 
1717

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  61 
  
Progestogen only pill: advantages/disadvantages 
 highly effective (failure rate = 1 per 100 woman years) 
 doesn't interfere with sex 
 contraceptive effects reversible upon stopping 
 can be used whilst breast-feeding

 can be used whilst breast-feeding 
 can be used in situations where the combined oral contraceptive pill is contraindicated e .g. in smokers 
> 35 years of age and women with a history of venous thromboembolic disease 
Disadvantages 
 irregular periods: some users may not have periods whilst others may have irregular or l ight periods. 
This is the most common adverse effect 
 doesn't protect against sexually transmitted infections 
 increased incidence of functional ovarian cysts

 common side-effects include breast tenderness,  weight gain, acne and headaches. These symptoms 
generally subside after the first few months 
Breast feeding: contraindications 
Breast feeding is acceptable with nearly all anti-epileptic drugs  
The major breastfeeding contraindications tested in exams relate to drugs (see below). Other contraindications 
of note include: 
 galactosaemia

 galactosaemia 
 viral infections - this is controversial with respect to HIV in the developing world. T his is because there 
is such an increased infant mortality and morbidity associated with bottle feeding that so me doctors 
think the benefits outweigh the risk of HIV transmission 
SAFE  DANGEROUS  
 Antibiotics: penicillins, cephalosporins, 
trimethoprim 
 Endocrine: glucocorticoids (avoid high doses), 
levothyroxine* 
 Epilepsy: sodium valproate, carbamazepine

 Epilepsy: sodium valproate, carbamazepine 
 Asthma: salbutamol, theophyllines 
 Psychiatric drugs: tricyclic
 antidepressants, antipsychotics** 
 Hypertension: β-blockers, hydralazine, 
methyldopa 
 Anticoagulants: warfarin, heparin 
 Digoxin  Antibiotics: ciprofloxacin, tetracycline,  
chloramphenicol, sulphonamides 
 Psychiatric drugs: lithium, benzodiazepines, 
clozapine 
 Aspirin 
 Carbimazole 
 Cytotoxic drugs 
 vitamin A derivatives.

 vitamin A derivatives. 
*the BNF advises that the amount is too small to affect neonatal hypothyroidism screen ing 
**clozapine should be avoided 
Drug causes teratogenesis 
Some common drugs and their potential teratogenic effect are given below: 
drug teratogenic effect 
Androgens cardiac deformities 
Alcohol fetal alcohol syndrome 
Carbamazepine microcephaly 
Diethylstilbestrol vaginal carcinoma

Diethylstilbestrol vaginal carcinoma 
Lithium cretinism 
Phenobarbital cleft palate 
Sodium valproate neural tube defects 
Thalidomide phocomelia 
Warfarin chondrodysplasia punctata 
 1718

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  62 
 Unwanted drug effects in pregnancy 
 
drug effects in pregnancy 
ACE inhibitors oligohydramnios, impaired renal function 
Aspirin kernicterus 
β-Blockers hypoglycaemia, intrauterine growth retardation, fetal bradycardia 
Carbimazole neonatal goitre 
 NSAIDs close ductus arteriosus 
Sulphonamides kernicterus

Sulphonamides kernicterus 
Thiazide diuretics: neonatal thrombocytopenia 
 
Antimicrobial 
Antibiotics: bactericidal vs. bacteriostatic 
Bactericidal antibiotics Bacteriostatic antibiotics 
 aminoglycosides 
 nitrofurantoin 
 metronidazole 
 quinolones 
 isoniazid  chloramphenicol 
 macrolides

 1719

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  63 
  
Antibiotics: mechanisms of action 
  
1720

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  64 
 The lists below summarise the site of action of the commonly used antibiotics   
Inhibit cell wall formation  Inhibit protein synthesis 
(by acting on ribosome)  Inhibit DNA synthesis  Inhibit 
RNA 
synthesis 
peptidoglycan cross-linking 
 β-lactams  
 Penicillins 
 Cephalosporins 
 carbopenems 
 
Ļpeptidoglycan synthesis

Ļpeptidoglycan synthesis  
 glycopeptides 
 Vancomycin 
 teicoplanin 
 
(Those organisms lacking a cell wall 
are resistant to these drugs eg. 
Chlamydia's) 50S subunit 
1. chloramphenicol 
2. macrolides (e.g. 
erythromycin) 
3. fusidic acid 
4. (Quin/Dalfo)pristin 
5. Linezolid 
30S subunit 
1. aminoglycosides 
(cause misreading 
of mRNA) 
2. tetracyclines 
 • quinolones (e.g.  
ciprofloxacin) 
Damages DNA   
1. metronidazole 
Inhibits folic acid 
formation

formation 
1. sulphonamides 
2. trimethoprim •Rifampicin  
 
Antibiotics: anaerobic activity 
antibiotics have anti-anaerobic activity  antibiotics do not have anti-anaerobic activity  
 cephalosporins (except ceftazidime) 
 erythromycin 
 tetracycline  gentamicin 
 ciprofloxacin 
 ceftazidime 
 
Skin rash with antibiotics

Skin rash with antibiotics 
 Ampicillin and amoxicillin can cause skin rashes that are not allergic  in nature 
 Erythromycin, benzylpenicillin, cefuroxime and cefadroxil all produce a diffuse, papu lar, non-purpuric 
rash that may be intensely pruritic  
 A maculopapular rash is also seen when tonsillitis/pharyngitis is related to EBV infecti on 
Cephalosporins 
 Cephalosporins are safe in penicillin allergy if it is only a rash. 
 Only ceftazidime and cefepime will cover Pseudomonas

Co-trimoxazole 
 now only indicated for oral prophylaxis against Pneumocystis pneumonia, toxoplasmosis and 
nocardiosis 
 It should only be considered in the treatment of chronic bronchitis or urinar y tract infection where there 
is no other alternative 
 
 nausea, vomiting,  
 allergy : rash (including Stephens-Johnson syndrome), toxic epidermal necrolysis and photosensitivity

 Blood disorders: neutropenia , thrombocytopenia and, rarely, agranulocytosis 
Cautions/contraindications 
 used with caution (or avoided) in renal or hepatic impairment 
Aminoglycosides   
Action 
  bactericidal antibiotics that bind to the 30S ribosome and inhibit bacterial protein synthesis. 
 active only against aerobic gram-negative  bacilli and cocci. 
1721

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  65 
   ineffective against anaerobic bacteria  as they require O 2 to enter bacterial cells. 
 endocarditis  in combination with penicillin (gentamycin) 
 added to a beta-lactam antibiotic when serious Pseudomonas aeruginosa  (cystic fibrosis) 
 tuberculosis (streptomycin) 
 nephrotoxicity

 nephrotoxicity  
 The reversible acute tubular necrosis after aminoglycoside reflects a concurrent i mpairment in 
the concentrating ability, and most patients are non-oliguric. 
 Irreversible tubulointerstitial damage, however, is uncommon after discontinuing 
aminoglycoside. 
 We expect a diagnosis of acute renal failure beginning more than five days after the 
initiation of gentamicin;

initiation of gentamicin;   
 Aminoglycoside nephrotoxicity correlates with  Frequency of aminoglycoside dosing  
 ototoxicity: 
 Streptomycin, tobramycin, and gentamycin are primarily vestibulotoxic  
 Kanamycin, amikacin, neomycin, and dihydrostreptomycin are preferentially cochleotoxic . 
 Cochlear toxicity that results in hearing loss usually begins in the high frequencies  and is secondary

to irreversible destruction of outer hair cells in the organ of Corti, predominantly at t he basal turn of 
the cochlea  
 What is the explanation of progression of hearing loss or onset of hearing l oss after cessation of 
aminoglycoside treatment? 
 Aminoglycosides are cleared more slowly from inner ear fluids than from serum 
  monitor the patient for cochleotoxic and vestibulotoxic effects up to 6 months after 
cessation of aminoglycoside treatment is important.

 What is the initial manifestation of early hearing loss ?  
  increase in the threshold of highest frequencies (>4000 Hz).  
 what is the main teratogenic effect of aminoglycosides. 
 CN VIII toxicity  
 What is the mechanism of resistance of Aminoglycosides? 
 Bacterial transferase enzymes;  
 they inactivate the drug by acetylation, phosphorylation or adenylation  
 Why is the gentamycin trough level likely to be too high in patients with chronic renal failure?

 Prolongation of the half-life  
 The usual half-life of gentamicin is between 2 and 3 h, although this can be considerab ly 
prolonged in patients with renal failure.  
 There are two commonly used regimens  for dosing gentamicin. Both require the patient's body 
weight to ensure accurate dosing. For patients who are over their ideal body weight, this value rather 
than the patient's actual weight should be used. Ideal body weight can be calculated usi ng age, sex

and height on a number of online applications. 
1. The most commonly used dosing regimen in the UK is the once daily regime , which is thought 
to be associated with reduced toxicity whilst being effective against gram-negative inf ections. 
 It is not recommended for patients with a creatinine clearance of less tha n 60 ml/min. 
  The dose used is 7 mg/kg IV every 24 hours. 
  Levels should be monitored for patients on this regimen for 3 days or  more, with a level

taken 6-14 hours following the third dose. A nomogram is then used to de termine 
whether the interval between doses should be altered. 1722

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  66 
 2. Patients with creatinine clearance of less than 60 ml/min are usually given a reduce d dose of 
gentamicin with a multiple-daily dosing regimen. This may also be recommended by 
microbiologists for the treatment of serious gram-negative infections such as Pseudom onas. 
Dosing is dependent on creatinine clearance:

Dosing is dependent on creatinine clearance: 
 >60 ml/min: 1.5-1.7 mg/kg IV every 8 hours 
 40-60 ml/min: 1.2-1.5 mg/kg IV every 12 hours 
 20-40 ml/min: 1.2-1.5 mg/kg IV every 12-24 hours 
 <20 ml/min: 2 mg/kg loading dose then discuss with microbiology and pharmacy 
 On this regimen monitoring is typically initiated after the 3rd or 4th dose, which allows a steady-state to 
be reached. Peak levels should be taken 30 minutes following the end of the inf usion, and a trough

level taken before the next dose. The desired trough level is less than 2 microgr ams/ml, with a peak 
level of 5-8 micrograms/ml. 
 
Administering gentamicin in conjunction with loop diuretics ↑↑ risk of exacerbating renal 
and ototoxicity 
 Aminoglycosides Ototoxicity: 
 mechanism: 
 cochlear dysfunction  (e.g., tinnitus, hearing impairment) by damaging cochlear cells , 
and/or  
 vestibulopathy (e.g., nausea, vomiting, dizziness, vertigo, oscillopsia , ataxia) by

damaging hair cells of the inner ear . 
  nystagmus  may be present as an early sign. 
 The vestibular dysfunction of gentamicin toxicity is typically bilateral; accordi ngly, 
there is no imbalance between right-sided and left-sided input to the central 
nervous system, so patients do not typically experience vertigo.  
 However, patients can experience oscillopsia and an abnormal head thrust test in 
both horizontal directions.

both horizontal directions. 
 Oscillopsia is a visual disturbance in which stationary objects appear to 
oscillate. 
 occur only when the head is moving.  
 Quick movements of the head are associated with transient visual 
blurring.  
 This can cause difficulties with seeing signs while driving or 
recognizing people's faces while walking.  
 Head thrust test (Head impulse test) 
 a physical examination maneuver to test for vestibular neuritis.

While the patient fixates on a target, the examiner administers 
brisk, horizontal head rotations to the side.  
 Considered positive if the patient is unable to maintain visual 
fixation, in which case the patient requires corrective saccades 
(quick eye movements) to re-fixate back to the target). 
Macrolides 
 Erythromycin was the first macrolide used clinically. Newer examples include clarithromycin and 
azithromycin.

azithromycin. 
 They are used against intracellular pathogens, including Mycoplasma and Legionella, and can also be 
used as alternatives in case of penicillin allergy .  
Action  
 Macrolides act by inhibiting bacterial protein synthesis by blocking translocation.  
 Macrolides are bacteriostatic  agents that inhibit protein synthesis by binding to the 50S subunit 
of the bacterial ribosome . If used in high doses, they may be bactericidal.

 If pushed to give an answer they are bacteriostatic in nature, but in reality this de pends on the dose and 
type of organism being treated.  
  bacteriostatic at low doses and bactericidal at high doses  1723

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  67 
  
Macrolides  (erythromycin, azithromycin and clarithromycin),  aminoglycosides and 
chloramphenicol  bind to bacterial ribosomes and disrupt protein synthesis 
 
 Clarithromycin is a macrolide antibiotic with good gram positive cover and that of atypical organisms.

It's mechanism of action is via reversible inhibition of 50s ribosome subunit . 
 
 post-transcriptional methylation of the 23S bacterial ribosomal RNA 
 gastrointestinal side-effects are common. Nausea is less common with clarithromycin t han 
erythromycin 
 cholestatic jaundice: risk may be reduced if erythromycin stearate is used 
 P450 inhibitor (see below) 
Common interactions

Common interactions 
 statins should be stopped whilst taking a course of macrolides. Macrolides inhibit the cyt ochrome P450 
isoenzyme CYP3A4 that metabolises statins. Taking macrolides concurrently with statins sig nificantly 
increases the risk of myopathy and rhabdomyolysis. 
 Clarithromycin enhances anticoagulant effect of coumarins  This is because warfarin is met abolised by 
the same CYP3A isozyme as clarithromycin. Clarithromycin, known to inhibit CYP3A, and a d rug

primarily metabolised by CYP3A may be associated with elevations in drug concentrations that could 
increase or prolong both therapeutic and adverse effects of the concomitant drug. 
 Clarithromycin is a potent inhibitor of CYP3A4, and as such may interfere significantly wi th metabolism 
of a number of medications, including theophylline , simvastatin , and cyclosporine  as the most 
important drug interactions.

important drug interactions. 
 The effect of  warfarin  and digoxin  may also be potentiated by clarithromycin. 
Erythromycin  
 Was the 1st macrolide used clinically. Newer examples include clarithromycin and azit hromycin.  
 Erythromycin may potentially interact with amiodarone, warfarin and simvastatin  
 Erythromycin would inhibit the metabolism of theophylline.

 Macrolides act by inhibiting bacterial protein synthesis.  
type of organism being treated. 
Erythromycin is used in gastroparesis as it has prokinetic properties, Promotes g astric emptying 
 Used in diabetic gastropathy,  
Adverse effects of erythromycin 
 GI side-effects are common 
 Cholestatic jaundice: risk may be ↓ if erythromycin stearate is used  
 P450 inhibitor

 P450 inhibitor   
 associated with prolonged QT interval and torsades de pointes,  
Quinolones 
Quinolones are a group of antibiotics which work by inhibiting DNA synthesis and are bactericidal in natu re. 
 levofloxacin 
 inhibit topoisomeras II (DNA gyrase) and topoisomerase IV 
Mechanism of resistance

Mechanism of resistance 
 mutations to DNA gyrase, efflux pumps which reduce intracellular quinolone concentration 
 lower seizure threshold in patients with epilepsy 
1724

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  68 
  tendon damage (including rupture) - the risk is increased in patients also ta king steroids 
 Rupture has been reported in the achilles, shoulder and hand. 
 This may occur due to disruption of the extracellular matrix and depletion of collagen which is 
observed in animal models.

observed in animal models. 
 cartilage damage has been demonstrated in animal models and for this reason quino lones are 
generally avoided (but not necessarily contraindicated) in children 
Interaction & contraindication  
 It should not be used with drugs that prolong the QT interval (eg erythrom ycin, tricyclic antidepressants) 
since there is an increased risk of cardiac arrhythmias 
 Contraindicated in left heart failure with reduced ejection fraction

 It should not be given at the same time as bivalent or trivalent cations (e g aluminium, iron) as these 
reduce absorption. Antacids  reduce quinolones absorption leading to therapeutic failure. 
 Quinolone absorption is markedly reduced with antacids  containing aluminium, magnesium and/or 
calcium and therapeutic failure may result. Other metallic ion-containing drugs , such as sucralfate, 
iron salts , and zinc salts, can also reduce absorption.

 The affinity of quinolones for the gamma-aminobutyric acid (GABA)  receptor may induce CNS adverse 
effects; these effects are enhanced by some nonsteroidal anti-inflammatory drugs (NS AIDs). 
Co-amoxiclav  
 Because of cholestatic jaundice, prescription of co-amoxiclav is not recommended for 
longer than 14 days. 
 If patient developed cholestatic jaundice  the co-amoxiclav should be withdrawn, and

the combination avoided in future.  
Probenecid 
 Drugs can be excreted into the proximal convoluted tubule of the nephron by cation or anion 
transporters: 
 cation transporters: basic drugs, eg quinine, pethidine, morphine 
 anion transporters: acidic drugs, eg penicillins, bendroflumethiazide, furosemide, 
cephalosporins

cephalosporins 
 The anion transporters are inhibited by probenecid, which can lead to increased plasma concentrat ions 
of acidic drugs 
 probenecid used clinically to increase the plasma half-life and therefore the therap eutic duration of the 
drug 
 For example, in the management of gonorrhoea infection, probenecid may be combined wi th oral 
penicillin  to increase the half-life of the penicillin  
Sulfonamides

Sulfonamides  
Antibacterial sulfonamides act as competitive inhibitors of the enzyme dihydropteroate sy nthetase 
(DHPS), an enzyme involved in folate synthesis. 
Other uses  
 The sulfonamide chemical moiety is also present in other medications that are not antimicrobials, 
including thiazide diuretics (including hydrochlorothiazide, metolazone, and indapamide, among 
others), loop diuretics (including furosemide, bumetanide and torsemide) sulfonylureas (including

glipizide, glyburide, among others), some COX-2 inhibitors (e. g. celecoxib) and acetazolamide. 
 Sulfasalazine, in addition to its use as an antibiotic, is also utilized in the treat ment of inflammatory 
bowel disease. 
 Co-trimoxazole: sulfonamide antibiotic combination of trimethoprim and sulfamethoxazole, in the ratio 
of 1 to 5, used in the treatment of a variety of bacterial infections.  The name co-trimoxazole is the

British Approved Name, and has been marketed worldwide under many trade names including  Septra, 
Bactrim, and various generic preparations. Sources differ as to whether co-trimoxazol e usually is 
bactericidal or bacteriostatic 
 
 1725

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  69 
Vancomycin  
 
Spectrum of the drug – MEC 
 M – MRSA 
 E – Enterococcus 
 C - Cl. difficle   
 
 Side effects – RON 
 R - Red man syndrome  
 O – Ototoxicity  
 N - Nephrotoxicity  
Action 
 Bactericidal

Action 
 Bactericidal 
 inhibits formation of peptidoglycan in bacterial cell walls, but a step earlier in the process compared 
to β-lactams 
 binds D-ala-D-ala moities of the peptides  
Resistance  
 D-ala-D-ala mutates to D-ala-D-lac, conferring resistance 
 IV administration for serious, multidrug resistant Gram-positive infections  
 including methicillin-resistant Staphylococcus aureus  infections (MRSA) 
 including Enterococcus

 including Enterococcus 
 including multidrug resistant Staph epidermidis 
 Given orally for C. difficile  not systemically absorbed when given orally 
 Red man syndrome 
 infuse drug too fast ĺ release of histamine ĺ red rash  
 Ototoxicity   
 more likely in patients with high plasma concentrations, renal impairment or pre-existing hearing 
loss. 
 may progress after drug withdrawal, 
 may be irreversible.

 may be irreversible. 
 Hearing loss may be preceded by tinnitus, which must be regarded as a sign to stop  treatment. 
 Thrombophlebitis 
 
Monitoring  
 Vancomycin  requires plasma level monitoring (after three or four doses if the renal function is 
normal, or earlier if renal impairment is present) 
 The important level to measure here is the trough level  as opposed to the peak level with gentamicin. 
 The trough level toxic threshold (30 mg/l).

 The trough level toxic threshold (30 mg/l). 
 If trough level > 30 mg/l  Omit dose and restart when level <15 mg/l 
 dose omission is required to reduce the risk of significant complications (includi ng 
ototoxicity and nephrotoxicity).  
 The BNF recommends trough levels of 15-20 mg/l for endocarditis.  
Which molecular change is responsible for vancomycin resistance? 
 D-ala D-ala to D-ala D-lac  
 Vancomycin resistance is involves its Binding sites the D- Ala-D-Ala.

 terminal D-Ala is replaced by D-Lactate( D-Lac).   
Linezolid  
 is a type of oxazolidinones antibiotic class 
Action 
 inhibits bacterial protein synthesis  by binding at the 50S subunit of the bacterial ribosome  
 linezolid occupies the A site of the 50S ribosomal subunit, inducing a conformational 
change that prevents tRNA from entering the site  and ultimately forcing tRNA to separate 
from the ribosome  1726

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  70 
  work on the first step of protein synthesis, initiation , unlike most other protein synthesis 
inhibitors, which inhibit elongation   
 bacteriostatic 
Spectrum , highly active against Gram positive organisms including: 
 MRSA (Methicillin-resistant Staphylococcus aureus ) 
 VRE (Vancomycin-resistant enterococcus)

 VRE (Vancomycin-resistant enterococcus) 
 GISA (Glycopeptide Intermediate Staphylococcus aureus ) 
 high bioavailability  (close to 100%) when given by mouth:  
 the entire dose reaches the bloodstream, as if it had been given intravenously.   
 Bone marrow suppression (especially thrombocytopenia ) 
 (reversible on stopping) 
 GI upset 
 Serotonin syndrome  

 Concurrent use with monoamine oxidase inhibitors ( MAOI)  and selective serotonin reuptake inhibitors 
(SSRIs )  
 tyramine diet 
Carba penem s  
 Carbapenems  are antibiotics used for multidrug-resistant (MDR) bacteria.  
 members 
 imipenem (+ cilastatin) 
 normal kidneys break down imipenem with a dihydropeptidase

 cilastatin, a selective dihydropeptidase inhibitor, is always given with imipenem 
 inhibits renal dihydropeptidase I, thereby decreasing inactivation of drug in renal tubules  
 cilastatin not needed for meropenem 
 meropenem 
 Their use is primarily in people who are hospitalized.  
 Like the penicillins and cephalosporins, they are members of the beta lactam class of antibiotics, which 
kill bacteria by binding to penicillin-binding proteins and inhibiting cell wall synthesis .

 Side effect 
 Gastrointestinal distress, skin rash and seizures  are three common complications 
of carbapenem administration when there are high plasma levels. 
 5-10% of patients with penicillin allergy are also allergic to carbapenems 
Meropenem   
 Which Carbapanem antibiotic has less CNS toxicity?  Meropenem  
 Meropenem is a carbapanem antibiotic that does not need to be coadministered with Cilastat in. 
 
Trimethoprim 
 Trimethoprim is an antibiotic, mainly used in the management of urinary tract infec tions. 
 It is combined with sulfamethoxazole for synergistic reasons  
 interferes with DNA synthesis by inhibiting dihydrofolate reductase 
 transient rise in creatinine : trimethoprim competitively inhibits the tubular secretion of creatini ne 
resulting in a temporary increase which reverses upon stopping the drug

 Trimethoprim interferes with tubular handling of creatinine and thereby leads to  an increase in 
serum creatinine, without impairment of GFR. 
 Megaloblastic anaemia may occur owing to folate deficiency 
 
 1727

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  71 
Quinupristin & dalfopristin antibiotics 
Overview 
 injectable streptogrammin antibiotic  Only administered via a central line. 
 combination of group A and group B streptogrammin  respectively.

 inhibits bacterial protein synthesis by blocking tRNA complexes binding to the ribosome 
Spectrum 
 most Gram positive bacteria 
 Particularly useful against multi- resistant Strep. pneumoniae  and Staph. aureus . 
 exception: Enterococcus faecalis * 
 thrombophlebitis (give via a central line) 
 P450 inhibitor 
*not to be confused with Enterococcus faecium, which is sensitive to Quinupristin & dalfopr istin

Drug Most common side effects 
Rifampicin Orange bodily fluids, rash, hepatotoxicity, drug interactions 
Isoniazid Peripheral neuropathy, psychosis, hepatotoxicity 
Pyrazinamide Arthralgia, gout, hepatotoxicity, nausea 
Ethambutol Optic neuritis, rash 
 
 mechanism of action: inhibits bacterial DNA dependent RNA polymerase prevent ing transcription of

DNA into mRNA 
 potent liver enzyme inducer 
 hepatitis,  
 orange secretions 
Patients on rifampicin should be warned that their urine, tears and other secretion s will develop 
a bright orange-red colour 
 acute interstitial nephritis (pt may present with acute renal failure after 1 month of sta rting 
rifampicin) 
 
 Interact with oral contraceptive induces  failure of the oral contraceptive treatment

 Rifampicin is a potent hepatic enzyme inducer that increases the metabolism of many drug s, including 
all the steroid hormones 
 Barrier contraceptives must be used during treatment with rifampicin and for 4-8 wee ks after a course 
of rifampicin is completed  
 
Isoniazid 
 
 mechanism of action: inhibits mycolic acid synthesis 
 peripheral neuropathy:  
 Occurs in less than 1% 
1728

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  72 
  Those with N-acetyltransferase type-2 gene defect  resulting in abnormal isoniazid 
metabolism  predisposed to neuropathy 
 Prevented  with 10 mg  pyridoxine (Vitamin B6) 
 hepatitis, raised transaminases in 10- 20% 
 Isoniazid-induced hepatitis occurs in ~1% of individuals and is much commoner in people

more than 35-years-old (risk of hepatitis is less than 0.3% in patients under  20 years; 2-3% risk 
in individuals over 50 years). 
 liver enzyme inhibitor 
 isoniazid inhibits the conversion of tryptophan to niacin  nicotinic acid (niacin) deficienc y  
Pellagra (the 3 D's - dermatitis, diarrhoea and dementia) 
  systemic lupus erythematosus (SLE)-like syndrome. 
 Isoniazid toxicity

 Isoniazid toxicity  
 Isoniazid toxicity should be suspected in any patient with intractable seizures and 
profound metabolic acidosis with an elevated anion gap. 
 Intravenous pyridoxine (vitamin B6) is the treatment of choice. 
 The acidosis may need to be corrected with bicarbonate. 
 
Pyrazinamide 
 mechanism of action: converted by pyrazinamidase into pyrazinoic acid which in turn inhibi ts fatty acid 
synthase (FAS) I 
 hyperuricaemia causing gout 
 arthralgia, myalgia

 arthralgia, myalgia 
Ethambutol 
 mechanism of action: inhibits the enzyme arabinosyl transferase which polymerizes ar abinose into 
arabinan 
 optic neuritis: check visual acuity before and during treatment 
 dose needs adjusting in patients with renal impairment 
The main adverse effects of ethambutol are: 
 loss of visual acuity 
 restriction of visual fields 
 colour blindness  
 retrobulbar neuritis  
 arthralgia.  
 
Uncommonly it may be associated with

Uncommonly it may be associated with 
 hyperuricaemia, and with interstitial nephritis. This is thought to occur less frequently than with 
rifampicin. 
Antiviral agents 
Drug Mechanism of action Indications Adverse 
effects/toxicity 
Aciclovir  Guanosine analog, phosphorylated by thymidine 
kinase which in turn inhibits the viral DNA 
polymerase  HSV, VZV Crystalline 
nephropathy

nephropathy 
Ganciclovir  Guanosine analog, phosphorylated by thymidine 
polymerase  CMV Myelosuppression/
agranulocytosis 
Ribavirin  Guanosine analog which inhibits inosine 
monophosphate (IMP) dehydrogenase, interferes 
with the capping of viral mRNA  Chronic 
hepatitis C, 
RSV Haemolytic 
anaemia 
Amantadine  Inhibits uncoating (M2 protein) of virus in cell. 
Also releases dopamine from nerve endings Influenza,

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  73 
 Drug Mechanism of action Indications Adverse 
disease 
Oseltamivir  Inhibits neuraminidase Influenza  
Foscarnet  Pyrophosphate analog which inhibits viiral DNA 
polymerase CMV, HSV if 
not responding 
to aciclovir Nephrotoxicity, 
hypocalcaemia, 
hypomagnasaemia, 
seizures

seizures 
Interferon- α Human glycoproteins which inhibit synthesis of 
mRNA  Chronic 
hepatitis B & 
C, hairy cell 
leukaemia Flu-like symptoms, 
anorexia, 
myelosuppression 
Cidofovir  Acyclic nucleoside phosphonate, and is therefore 
independent of phosphorylation by viral enzymes 
(compare and contrast with aciclovir/ganciclovir) CMV retinitis 
in HIV Nephrotoxicity 
 
HIV: anti-retrovirals

Highly active anti-retroviral therapy (HAART) involves a combination of at lea st three drugs, typically two 
nucleoside reverse transcriptase inhibitors (NRTI) and either a protease inhibitor (P I) or a non-nucleoside 
reverse transcriptase inhibitor (NNRTI). This combination both decreases viral replication but also reduces the 
risk of viral resistance emerging 
Anti-retroviral agent used in HIV  About 
Nucleoside  Analogue 
Reverse Transcriptase Inhibitors

Reverse Transcriptase Inhibitors 
(NRTI) Examples: zalcitabine, zidovudine (AZT), didanosine,
 lamivudine, stavudine, 
Protease inhibitors (PI)  Inhibits a protease needed to make virus able to 
survive outside the cell 
 Examples: indinavir, nelfinavir, ritonavir, saquinavir 
Non-Nucleoside  Reverse 
Transcriptase Inhibitors (NNRTI) examples: nevirapine, efavirenz 
 
Nucleoside analogue reverse transcriptase inhibitors (NRTI)

 examples: zidovudine (AZT), didanosine, lamivudine, stavudine, zalcitabine 
 zidovudine: anaemia, myopathy, black nails 
 didanosine: pancreatitis 
Non-nucleoside reverse transcriptase inhibitors (NNRTI) 
 examples: nevirapine, efavirenz 
 side-effects: P450 enzyme interaction (nevirapine induces), rash es 
Protease inhibitors (PI) 
 Protease inhibitors are multi-pathway inhibitors of rivaroxaban clearance and elimination.

 examples: indinavir, nelfinavir, ritonavir, saquinavir 
 side-effects: diabetes, hyperlipidaemia , buffalo hump, central obesity, P450 enzyme inhibition 
 indinavir: renal stones, asymptomatic hyperbilirubinaemia 
 ritonavir: a potent inhibitor of the P450 system 
 
1730

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  74 
  
HIV: anti-retrovirals - P450 interaction 
 nevirapine (NNRTI): induces P450 
 protease inhibit ors: inhibit s P450  
Abnormalities of serum lipid levels are likely to be multifactorial in patients wit h HIV disease, but appear much 
commoner in patients taking protease inhibitors.

commoner in patients taking protease inhibitors. 
Isolated hypertriglyceridaemia  can occur in HIV disease in the absence of protease inhibitors, but extremely 
high serum triglycerides have been documented in some patients treated with these drugs. 
Oseltamivir (Tamiflu) 
 Oseltamivir (Tamiflu) like its predecessor zanamivir (Relenza) functions as an antiviral through

inhibition of the enzyme neuraminidase, thus slowing viral replication down rather tha n directly killing 
the virus particle.  
 This slowing down of replication is important in permitting time for the body's own immun e system to 
deal with the virus. 
 Unlike inhaled zanamivir, oseltamivir is administered orally. 
 Oseltamivir  It is of value in prophylaxis against influenza  
 However, viral replication is rapid and to be effective the drug must be given as ear ly as possible after

the development of symptoms of flu and preferably within 48 hours. 
Anti-fungal 
 Nystatin  is poorly absorbed through mucous membranes and is thus useful in oral, vaginal an d enteric 
candidiasis 
 Terbinafine  is used to treat superficial mycoses such as dermatophyte infections 
 Fluconazole  is useful in candidiasis and central nervous system infections with Cryptococcus

neoformans and is usually commenced after initial treatment with amphoterici n and flucytosine 
 Itraconazole  is the agent of choice for non-life threatening blastomycosis and histoplasmosis it is also 
moderately effective against invasive aspergillosis 
 Amphotericin B   treatment of Aspergilloma 
 The drug may exert either fungicidal or fungistatic activity, depending on its concentration at the 
site of infection and sensitivity of the organism

 increases the permeability of the fungal cell wall by binding to ergosterol and forming 
micropores 
 side effect  nephrotoxicity associated with hypokalaemia  and hypomagnesaemia 
 To decrease toxicity, newer lipid-bound preparations are now available 
Griseofulvin   
 Is not active against Candida albicans . It is active against trichophytons (tinea) and other 
dermatophytes.

dermatophytes. 
 It is metabolised in the liver (note also it's an enzyme inducer). Only 0.1-0.2% excreted in urine. 
 Treatment with griseofulvin is often needed for a long period, sometimes yea rs, depending on the rate 
of nail growth. 
 It is associated with drug-induced Stevens- Johnson syndrome  
Diethylcarbamazine  
Indication: 
 Treatment of individual patients with certain filarial diseases.

 These diseases include: lymphatic filariasis caused by infection with Wuchereria bancrofti, Brugia 
malayi, or Brugia timori; (ELEPHANTiasis) tropical pulmonary eosinophilia, and lo iasis. 
Overdose of antimalarial medications 
Chloroquine 
Symptoms 1731

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  75 
  Nausea 
 Headaches 
 Visual disturbances  Cardiac arrhythmias 
 Convulsions 
 Coma 
 
Treatment 
 Activated charcoal should be given to patients who present within 1 h 
 The initial hypokalemia that occurs appears to be cardio-protective  and should not be corrected for 
at least 8 h after the ingestion

at least 8 h after the ingestion 
 In patients with severe toxicity, high-dose (2 mg/kg) diazepam and adrenaline (0.25 pg /kg per 
min) have been shown to reduce mortality 
Quinine toxicity (cinchonism) 
 Quinine is a remarkably toxic drug; something which is not so readily acknowledged. I t is used as an 
antimalarial drug and also as a prophylactic agent against leg cramps, although both uses are

increasingly falling from vogue due to the availability of better, safer ag ents. 
  Quinine toxicity, known as cinchonism, may be fatal, usually by cardiac arrhythmia or  flash pulmonary 
oedema in the short term, although incipient renal failure may be fatal more long-term.  
 Cardiac arrhythmia is a common finding in cinchonism due to blockade of sodium and po tassium 
channels prolonging QRS and QT intervals respectively and these rhythms may degen erate into

ventricular tachyarrhythmias or fibrillation causing death.  
 Hypoglycaemia is also a common finding in cinchonism since quinine stimulates pancreatic i nsulin 
secretion and this should be corrected rapidly if present.  
 Flash pulmonary oedema may develop causing hypoxia and necessitating positive pressure ventilation. 
  Classical hallmarks of cinchonism are tinnitus, visual blurring, flushed an d dry skin and abdominal 
pain.

pain.  
 Other visual complications, including blindness,  can occur and may be permanent  
 Clinically, quinine toxicity is difficult to distinguish from aspirin poisoning  and so measurement of serum 
salicylate levels is important when this clinical picture is seen.  
 In terms of management however, whereas aspirin can be cleared from overdose victim s by 
haemofiltration, quinine cannot be extracted easily by extracorporeal methods.

  Central nervous symptoms such as tinnitus, deafness and visual defects which m ay occur with aspirin 
are usually transient whereas quinine leaves permanent neural damage, if the pati ent survives.  
 Management of quinine poisoning is largely supportive with fluids, inotropes and bicarbonate as 
needed as well as positive pressure ventilation for pulmonary oedema. 
 Lidocaine (lignocaine) should not be used in the management of cardiac arrhythmias as this can

increase the risk of seizures 
 Urine acidification is not recommended as whilst it increases quinine elimination , it also increases the 
risk of cardiotoxicity 
 
Ciclosporin  (Cyclosporine)  
 
Mode of action  
1732

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  76 
  It acts by binding to cyclophilin  forming a complex which   inhibits calcineurin , (a phosphotase 
that activates various transcription factors in T cells )  reducing IL-2  release  decreases clonal 
proliferation of T cells  immunosuppression  
 
 following organ transplantation 
 rheumatoid arthritis

 psoriasis (has a direct effect on keratinocytes as well as modulating T cell function)  
 ulcerative colitis 
 pure red cell aplasia 
 atopic dermatitis (AD)  (T lymphocytes are involved in the pathophysiology of AD and increased 
production of cytokines particularly IL- 4) 
 
Adverse effects  (note how everything is increased - fluid, BP, K+, hair, gums, glucose ) 
 Chronic interstitial nephritis is a major side-effect of ciclosporin

 Fluconazole inhibits the metabolism of ciclosporin which increases the risk of 
ciclosporin nephrotoxicity. 
 hepatotoxicity 
 fluid retention 
 hypertrichosis 
 gingival hyperplasia 
 increased susceptibility to severe infection 
 Tremor 
 cause coarse tremor .  
 In the first instance the dose  should be reduced .  
 Usually the neurological side effects of cyclosporin are dose dependent .

 increased risk for Squamous cell carcinoma  
 Cutaneous squamous cell carcinoma (SCC) is the second most common human cancer 
 transplant-associated SCC (TSCC), which occurs in immune-suppressed solid organ transplant 
recipients (OTRs) may be considerably more aggressive than SCC in immune competent 
patients, with metastatic rates as high as 8% 
 IL-22 receptor is most highly expressed in TSCC and is induced by cyclosporine A.

 Treatment with anti –IL-22 antibody decreases SCC tumor number and tumor burden. 
Note: 
 Interestingly for an immunosuppressant, ciclosporin is noted by the BNF to be 'virtually non-
myelotoxic' . 
 
Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through 
IL-22 (September 2016)  
 
 These patients are seen monthly to have their blood pressure, urea, and electrolytes checked.  

Tacrolimus  
Mode of action 
 similar to the action of ciclosporin  
Tacrolimus vs Ciclosporin:   
 It has a very similar action to ciclosporin ( inhibits calcineurin , reducing IL-2 release  ) 
 The action of tacrolimus differs from ciclosporin  in that it binds to a protein called FKBP rather than 
cyclophilin  
 Tacrolimus is more potent than ciclosporin and hence the incidence of organ rejection is less.   
 However, nephrotoxicity and impaired glucose tolerance is more common 1733

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  77 
 Indications 
 immunosuppressant to prevent transplant rejection. 
 Other T-cell medicated diseases 
 Eczema (as ointment)  
 Sever refractory uveitis after bone marrow transplant 
 Vitiligo   
 Tacrolimus levels can be affected by concomitant use of other drugs and changes in gut absorption,

and so need to be monitored carefully.  
 
Many side effects of tacrolimus are similar to cyclosporine A, but tacrolimus does not  cause gingival 
hyperplasia or hirsutism 
Sirolimus  
Overview  
 A macrolide compound  
 Also known as rapamycin 
 binding with intracellular FKBP-12 protein   inhibition of mTORC1  ↓ cytokine-induced T-cell 
proliferation  immunosuppression

proliferation  immunosuppression  
 Sirolimus binds to the immunophilin FK binding protein 12 (FKBP12), and the drug-immunophilin 
complex acts on the Target of Rapamycin (rapamycin being the original name of  sirolimus) to interrupt 
stimulation of cell proliferation via the interleukin-2 receptor.  
 What is the target of action of sirolimus? 
 FK binding protein 12 (FKBP12) 
 treatment of acute rejection. 
Adverse Effects  
 Pancytopenia 
 Hyperlipidemia

 Hyperlipidemia  
 Peripheral edema 
 Insulin resistance 
 Inhibition of mTORC2  diabetes- like symptoms  
Azathioprine 
 
Azathioprine  check thiopurine methyltransferase deficiency (TPMT) before treatment 
 Azathioprine is metabolised to the active compound mercaptopurine, a purine analogue that inhibits 
purine synthesis  Impaired DNA synthesis

purine synthesis  Impaired DNA synthesis  
 A thiopurine methyltransferase (TPMT) test may be needed to look for individual s prone to azathioprine 
toxicity. 
 
 The enzyme activity of thiopurine methyltransferase (TPMT) is under the con trol of a genetic 
polymorphism. 
 90 % of the population have normal or high (TPMT) enzyme activity . 10 % have 
intermediate levels 
 One in 300 people have no functional enzyme activity.

 Several groups of patients have developed azathioprine induced myelosuppression linked t o 
TPMT deficiency. 
 
Adverse effects include  
 bone marrow depression  Pancytopenia  
 It suppresses lymphocyte numbers and function  
 Hepatotoxicity 
 100-fold increased risk of skin cancers and lymphomas.  1734

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  78 
  
 (BNF) suggest monitoring CBC, LFTs and U&E every 3 months once patients are est ablished and 
stable on azathioprine treatment. 
interaction 
 Azathioprine and 6-MP are metabolized by xanthine oxidase. Therefore, allopurinol –a xanthine oxidase 
inhibitor –increases the risk of azathioprine and 6-MP toxicity.

 A significant interaction may occur with allopurinol and hence lower doses of azathioprine sho uld be 
used.  
 Allopurinol acts by inhibition of xanthine oxidase and thus inhibits the metabol ism of 6-
mercaptopurine, an active metabolite of azathioprine. 
 The prodrug azathioprine is metabolised to its active compound 6-mercaptopurine (6-MP). 6-M P 
undergoes catabolic oxidation to 6-thiouric acid by xanthine oxidase.

 Allopurinol has a peak onset of action of one to two weeks and works by inh ibiting xanthine 
oxidase.   
 Co-administration of (Azathioprine + Allopurinol)  accumulation of 6-MP (6-MP toxicity)  ↑ 
risk of myelosuppression (aplastic anaemia) 
 if concomitant use is to occur, a dose reduction in azathioprine by 25%  is advised with 
regular blood count monitoring.  
Usage in pregnancy 
 Azathioprine can be used in pregnancy without significant risk to the fet us

Methotrexate 
Action 
 Methotrexate is an antimetabolite  which inhibits dihydrofolate reductase , an enzyme essential for 
the synthesis of purines and pyrimidines 
 Methotrexate inhibits dihydrofolate reductase , thereby inhibiting the production of 
tetrhydrofolate required for thymidine and purine synthesis.  
 inhibits purine and pyrimidine synthesis by competing for the active site  of dihydrofolate

reductase (by competitive inhibition ). 
 It is cytotoxic during the S-phase of the cell cycle , and has a greater toxic effect on rapidly 
dividing cells. 
 Take 6 -12 weeks to achieve full affect  
 psoriasis (Methotrexate would be the only correct treatment for someone with erythrodermic 
psoriasis ) 
 mucositis 
 myelosuppression

 Macrocytosis is seen as a consequence of long term methotrexate therapy. 
 pneumonitis 
 liver cirrhosis 
 What is the toxicity of Methotrexate (MTX) at the liver? 
 Macrovesicular fatty change 
Pregnancy 
 women should avoid pregnancy for at least 3 months after treatment has stopped 
 the BNF also advises that men using methotrexate need to use effective contraception f or at least 3 
months after treatment

months after treatment 
Prescribing methotrexate 
 methotrexate is taken weekly, rather than daily 
 FBC, U&E and LFTs need to be regularly monitored.  
 The Committee on Safety of Medicines recomme nd 'FBC and renal and LFTs before starting 
treatment and repeated weekly until therapy stabilised, thereafter patients should be 
monitored every 2-3 months'  1735

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  79 
  Folic acid 5mg once weekly should be co-prescribed , taken more than 24 hours after methotrexate 
dose 
 the starting dose of methotrexate is 7.5 mg once weekly, can be increased by 2.5 m g every 6 weeks, to 
a maximum of 20 mg weekly (Ref: oxford handbook of practical drug therapy)

 only one strength of methotrexate tablet should be prescribed (usually 2.5 mg) 
 do not prescribe with aspirin or NSAIDs  ↓ methotrexate excretion  ↑ toxicity  
 avoid prescribing anti-folate antibiotics trimethoprim or cotrimoxazole concurrently - i ncreases 
risk of marrow aplasia 
 In the circumstances of infection one should consider temporarily stopping methotrexate as it  
is an immunosuppressant.  
 OAT-1 inhibitors

 OAT-1 inhibitors  
 Methotrexate is a substrate for the OAT-1 renal transporter and levels of methotrex ate are 
therefore affected by decreased renal function.  
 OAT-1 inhibitors include drugs such as probenecid , and therefore should not be used in 
conjunction with methotrexate.  
 Omeprazole   
 Omeprazole is also known to affect clearance of methotrexate ; this interaction is not 
thought to be via OAT-1, but is thought to be related to inhibition of breast cancer

resistance protein , which is responsible for methotrexate transport. 
 Clinicians are recommended to check FBC fortnightly until 6 weeks  after the last dose increase. 
 Provided it is stable , it can be checked monthly  thereafter until the dose and disease is stable 
for one year. 
 Thereafter, monitoring is guided by clinical judgement. If white cell count is less t han 3.5, 
neutrophils less than 2 or platelets less than 150, methotrexate should be withheld pending

discussion with the specialist team. 
  An MCV greater than 105 fL warrants checking B12, folate and TSH and treating any 
abnormality. If these are normal, discuss with the specialist team. 
 Liver function tests  should be checked three monthly . If there is an unexplained decrease in 
albumin, or AST/ALT twice the upper limit of normal, the specialist team  should be informed. 
 Urea, creatinine and electrolytes  should be checked six monthly . If the estimated glomerular

filtration rate falls below 50 mL/minute, methotrexate should be withheld until the result has been 
discussed with the specialist team. 
Drug MOA 
Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase 
Azathioprine metabolised to the active compound mercaptopurine a purine analogue that 
inhibits DNA synthesis. purine synthesis inhibitor 
Methotrexate antimetabolite which inhibits dihydrofolate reductase 
 
Methotrexate overdose  
Methotrexate overdose  Folinic acid

Methotrexate overdose  Folinic acid  
 
 Methotrexate is a folic acid antagonist which can result in multi-organ failure in overdose.  
 medication errors with respect to rheumatoid arthritis are not uncommon.  
 Patients occasionally find it difficult to understand that they must take the ir medication weekly as 
opposed to daily.  
 Calcium folinate is a potent antagonist for the effects of methotrexate  on the haematopoeic

system, given by IV infusion at doses up to 75mg in the first 12hrs. This can then be followed by doses 
of 6-12mg every 4hrs.  
 Folinic acid  is the antidote  and should be given intravenously as soon as possible, regardless of the 
liver function tests.  
 Blood transfusion may also be required in exceptional circumstances.  
 Where massive overdose of methotrexate has occurred, hydration and urinary alkalinisation may  be an 
option.

option.  
 Standard dialysis is ineffective in removing methotrexate, although intermittent hig h flux dialysis may be 
of value. 1736

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  80 
Mycophenolate mofetil 
 inhibits inosine monophosphate dehydrogenase, which is needed for purine synthesis 
 as T and B cells are particularly dependent on this pathway it can reduce prolif eration of immune cells 
 adverse effects

 adverse effects  
 Pancytopenia 
 Hyperglycemia 
Hydroxychloroquine  
 Hydroxychloroquine ocular toxicity includes:  
 Keratopathy  
 Ciliary body involvement  
 Lens opacities (Lenticular deposits)  
 Retinopathy.  
 Retinopathy is the major concern; the others are more common but benign.  
 The incidence of true hydroxychloroquine retinopathy is exceedingly low.  
 Risk factors include:

 Risk factors include:  
 Daily dosage of hydroxychloroquine  
 Cumulative dosage  
 Duration of treatment 
 Coexisting renal or liver disease  
 Patient age, and 
 Concomitant retinal disease.  
 Patients usually complain of difficulty in reading, decreased vision, missing central 
vision, glare, blurred vision, light flashes, and metamorphopsia.  
 They can also be asymptomatic.  
 Most patients with advanced retinopathy have a bull's eye (also known as target, as in

darts) fundoscopic appearance. All patients have field defects including paracentral,  
peri-central, and central and peripheral field loss.  
 Regular screening may be necessary to detect reversible premaculopathy.  
 Cessation of the drug is the only effective management of the toxicity . 
Sulfasalazine  
 hypersensitivity,  
 myelosuppression ,  
 macrocytosis, and  
 azoospermia in males.

 azoospermia in males.  
sulfasalazine toxicity  
 There are numerous signs of sulfasalazine toxicity.  
 Rash and oral ulceration  should be asked about and, if severe, the drug should be withheld until 
specialist advice has been sought.  
 Nausea, dizziness and headache can be common and sometimes necessitate dose reduction.  
 If patients present with abnormal bruising or sore throat an urgent CBC should be done, and

sulfasalazine withheld until results are available.  
 CBC  
 CBC should be monitored monthly for the first 3 months.  
 Sulphasalazine should be withheld until discussion with the specialist team if:  
 The white cell count is less than 3.5  
 Neutrophils is less than 2, or  1737

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  81 
  Platelets are less than 150.  
 If (MCV) > 105 fl, vitamin B12, folate and TSH should be checked and treated if found t o be 
abnormal. If these are all normal it should be discussed with the specialist team.   
 If counts remain normal within the first 3 months, CBC can be checked 3 mon thly.

 Liver function tests (LFTs)  
 should also be checked monthly for the first 3 months. 
 If either AST or ALT are more than twice the upper limit of normal , sulfasalazine should be 
withheld until discussion with the specialist team.   
 If the LFTs remain normal for the first 3 months, monitoring can be decreased to 3 monthly.  
 If, following the first year, the dose has not been increased and blood results ha ve been stable,

the frequency of monitoring can be reduced to every six months for the second y ear of 
treatment. Thereafter monitoring is not required, although CBC and LFTs shoul d be checked 
one month after any dose increase.  
Leflunomide  
 an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active m oderate- to-
severe rheumatoid arthrit is and psoriatic arthritis.

 It is a pyrimidine synthesis inhibitor .  
  achieves its effects by inhibiting the mitochondrial enzyme dihydroorotate 
dehydrogenase (DHODH),  which plays a key role in the de novo  synthesis of uridine 
monophosphate (rUMP), which is required for the synthesis of DNA and RNA. Hence,  leflunomide 
inhibits the reproduction of rapidly dividing cells, especially lymphocytes.  
 Hepatotoxicity (occurring in 15-20% of cases)

 Hepatotoxicity (occurring in 15-20% of cases) 
 most hepatic events occur within the first 6 months of use. 
 signs of leflunomide toxicity should be monitored. If the patient develops a rash or itch  dose reduction 
should be considered, with or without the addition of antihistamines. If severe, l eflunomide should be 
stopped and washout considered.  
 Hair loss, headaches and gastrointestinal upset  may also warrant dose reduction or washout.

 A blood pressure of greater than 140/90  mmHg should be treated as per NICE guidelines. If it 
remains elevated, stop leflunomide and consider washout.  
 Weight should be monitored, and a weight loss  of greater than 10% should be identified. If no other 
cause can be found, consider dose reduction or washout.  
 If there is increasing shortness of breath, pneumonitis should be considered and leflunomide should 
be stopped.  
 Leflunomide reduces sperm count . 
 LFT

 LFT 
 (LFTs) should be checked monthly for 6 months and, if stable, 2 monthly thereaf ter.  
 If AST or ALT is between 2 and 3 times the upper limit of normal, an d the leflunomide dose is 
more than 10 mg daily, the dose should be reduced to 10 mg and LFTs rechecked wee kly until 
normalised. If the ALT and AST are returning to normal, the patient should be l eft on 10 mg per 
day. It the LFTs remain elevated, leflunomide should be stopped and discussed with the

specialist team.  
 If the AST or ALT is more than 3 times the upper limit of normal,  the LFTs should be rechecked 
within 72 hours. If they remain more than 3 times the reference range, lefl unomide should be 
stopped and washout considered (cholestyramine and activated charcoal).  
 It is important to note that the half-life of leflunomide is usually 2 weeks (mean 14) therefore if a 
rapid response is required, washout should be considered.  1738

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  82 
  CBC  
 (CBC) should be checked monthly for six months and, if stable, two monthly ther eafter.  
 White cell count less than 3.5, neutrophils less than 2 or platelets less than 150 should  be 
discussed with the specialist team, and leflunomide withheld until this has taken place .

Poisoning &Toxicology 
 
Overdose and poisoning: management 
The table below outlines the main management for common overdoses: 
 
Toxin Treatment 
Paracetamol  Management 
 activated charcoal if ingested < 1 hour ago 
 N-acetylcysteine (NAC) 
Salicylate  Management

Salicylate  Management 
 urinary alkalinization is now rarely used - it is contraindicated in 
cerebral and pulmonary oedema with most units now proceeding 
straight to haemodialysis in cases of severe poisoning 
Opioid/opiates  Naloxone 
Benzodiazepines  Flumazenil 
Tricyclic 
antidepressants  Management 
 
 IV bicarbonate may reduce the risk of seizures and arrhythmias in 
severe toxicity 
 arrhythmias: class 1a (e.g. Quinidine) and class Ic

antiarrhythmics (e.g. Flecainide) are contraindicated as they 
prolong depolarisation. Class III drugs such as amiodarone should 
also be avoided as they prolong the QT interval. Response to 
lignocaine is variable and it should be emphasized that correction 
of acidosis is the first line in management of tricyclic induced 
arrhythmias 
Lithium  Management 
 
 mild-moderate toxicity may respond to volume resuscitation with 
normal saline

normal saline 
 sodium bicarbonate is sometimes used but there is limited 
evidence to support this. By increasing the alkalinity of the urine 
it promotes lithium excretion 
Warfarin  Vitamin K, prothrombin complex 
Heparin  Protamine sulphate 
Beta-blockers  Management 
 if bradycardic then atropine 1739

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  83 
 Toxin Treatment 
Ethylene glycol  Management has changed in recent times 
 ethanol has been used for many years 
 works by competing with ethylene glycol for the enzyme alcohol 
dehydrogenase 
 this limits the formation of toxic metabolites (e.g. Glycoaldehyde

and glycolic acid) which are responsible for the 
haemodynamic/metabolic features of poisoning 
 fomepizole , an inhibitor of alcohol dehydrogenase, is now used 
first-line in preference to ethanol 
 haemodialysis also has a role in refractory cases 
Methanol poisoning  Management 
 fomepizole or ethanol 
Organophosphate 
insecticides  Management 
 atropine 
 the role of pralidoxime is still unclear - meta-analyses to date 
have failed to show any clear benefit

have failed to show any clear benefit 
Digoxin  Digoxin-specific antibody fragments 
Iron  Desferrioxamine, a chelating agent 
Lead  Dimercaprol, calcium edetate 
Carbon monoxide  Management 
 100% oxygen 
Cyanide  Hydroxocobalamin; also combination of amyl nitrite, sodium nitrite, and 
sodium thiosulfate 
Sarin 
(organophosphorus) Pralidoxime   reactivates acetyl cholinesterase enzyme. It should be 
used in the first few hours. 
Drug poisoning: Hypersalivation

Drug poisoning: Hypersalivation 
Hypersalivation is seen with: 
 Parasympathomimetic agents 
 Insecticides 
 Arsenic 
 Strychnine 
 Chlormethiazole, and 
 Clozapine. 
Other poisoning signs 
Acneiform rash around the buccal cavity  Solvent abuse 
Nasal septum perforation (and hypertension)  Cocaine abuse 
 
 1740

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  84 
Drug poisoning: Altered serum glucose in unknown overdose 
 
Alteration in serum glucose concentration, in addition to other clinical signs and symptoms, can be 
helpful in diagnosing the ingestion of an unknown drug:

Drugs induce hyper glycaemia  Drug induce hypo glycaemia  
 Corticosteroids, 
 thiazide diuretics,  
 theophylline,  
 iron (during the initial  period 
after overdose),  
 caffeine and  
 B2-agonists  insulin, sulphonylureas, 
 Salicylates   
 sodium valproate, 
 propranolol, 
 iron (later if hepatic failure ensues) 
 
Drugs cleared by alkalization of the urine

Drugs cleared by alkalization of the urine  
The clearance of which drug would be increased by alkalization of the urine? 
 Weak acids are ionized in an alkaline environment, and this lessens their tubul ar absorption.  
 Alkalization of urine, achieved by IV infusion of sodium bicarbonate, can thereby be used  to increase 
the urinary elimination of: 
1. barbiturates,  
2. salicylates and  
3. isoniazid. 
Ref  www.medical-masterclass.com  2017 part 2

Ref  www.medical-masterclass.com  2017 part 2 
 Measurement of drug concentrations  
 Measurement of drug concentrations is clinically important for relatively fe w compounds.  
 Drug concentrations are particularly important for those compounds where the concen tration is 
predictive of serious toxicity in an otherwise asymptomatic patient. 
Compounds where measurement of drug concentration is clinically indicated:

 Theophylline concentrations predict the risk of seizures and cardiac toxicity in both acut e and 
chronic toxicity 
 Patients who have ingested more than 10 mg kg−1 of theophylline should receive repeated 
doses of activated charcoal.  
 Digoxin 
 Iron 
 Lithium 
 Salicylate   
 Ethylene glycol 
 An ethylene glycol concentration of >50 mg dl−1 is a possible indication for haemodialysis and a

definite indication for 4-methylpyrazole (4MP) or ethanol infusion  
 Methanol 
 A methanol level of greater than 50 mg dl−1 is a possible indication for haemodialysis and a 
definite indication for 4MP or ethanol infusion. 
 haemodialysis usually considered at methanol concentrations above 20 mmol/l  
(approximately 90 mg/dl). 
 Ethanol 
 Anticonvulsants 
 Measurement of anticonvulsant concentrations will confirm ingestion but do not  substantially

influence treatment in overdose, which is supportive care. 
 Paraquat 
 non-selective contact herbicide  
 paraquat concentrations are useful for confirming ingestion and defining prognosis but do not 
influence treatment, which is predominantly supportive care  
__________________________________________________________________  1741

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  85 
 Drug toxicity in renal failure 
 A wide range of drug-handling processes occur in the kidney: 
 Filtration 
 tubular secretion 
 active and passive tubular reabsorption 
 The overall renal clearance of drugs declines in parallel with falls in the glom erular filtration rate and 
creatinine clearance 
Norpethidine

Norpethidine 
 In patients with renal impairment pethidine is metabolised to norpethidine, but at this stage metabolism 
stops and norpethidine accumulates  rather than being excreted through the kidneys 
 Norpethidine is toxic and is associated with a risk of seizures  
Morphine 
 A similar accumulation of morphine 6-glucuronide occurs after morphine admini stration in patients with 
renal impairment, which may lead to narcosis

renal impairment, which may lead to narcosis  
 fluid overloaded + pin point pupils in a patient taking morphine with renal impair ment  the 
most likely cause of his symptoms  Renal failure leading to accumulation of morphine  (not 
overdose) (masterclass 2017 part 2 )   
 Patients with relapsed ovarian cancer may develop an obstructive nephropathy due to pelvic 
recurrence. If they are on morphine they may get accumulation of this drug and signs of  opiate

toxicity superimposed on the signs of renal failure. 
Other drugs 
 Other drugs where physiologically active metabolites accumulate leading to toxicity in renal f ailure 
include: 
 nitroprusside (active metabolite thiocyanate) 
 allopurinol (accumulation of oxypurinol leads to rash and allergy) 
Characteristic smells of toxins/poisons

Characteristic smells of toxins/poisons 
 
Certain toxins/poisons have characteristic smells that can assist in the identification of substances taken. 
Below is a list of well-recognised smells/odours and the poisons/toxins for whi ch they are characteristic. 
 Garlic: Arsenic, selenium 
 Bitter almonds: Cyanide 
 Rotten eggs: Hydrogen sulphide, mercaptans  
 Wintergreen: Methyl salicylate 
 Mothballs: Naphthalene 

Arsenic toxicity  
The combination of mixed sensorimotor polyneuropathy in the presence of possible exposure to pe sticides in a 
farmer would suggest a diagnosis of chronic arsenic poisoning. 
.   
 Arsenic is a heavy metal which is a natural component of the earth's crust.  
 exists in organic or inorganic . It is highly toxic in its inorganic form . 
 organic arsenics found in fish and seafood are non-toxic 
 Arsenic exposure is usually occupational or environmental

 routes of exposure include: 
 Groundwater most often becomes contaminated naturally 
 Arsenic contamination of groundwater is widespread  
 most common in Bangladesh, West Bengal and india 
 Occupational exposures: toxic waste sites and traditional medicines.  
 Features 
 Acute 
 GI (nausea, vomiting, hemorragic gastroenteritis, garlic breath) 
 CNS (coma, seizures) 
 Chronic 
 Skin changes: dermatitis, hyperkeratosis & hyperpigmentation 
 The first symptoms of long-term exposure

 The first symptoms of long-term exposure 
 the most common effect of chronic exposure 
 Keratoses on the palms and soles are characteristic.  
 occur after a minimum exposure of approximately five years  
 may be a precursor to skin cancer. 
 Mees lines: leukonychia striata ( transverse white lines on the finger nails ) 
 Sensory-motor Peripheral neuropathy 
 Diabetes 1742

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  86 
  Cancers (lung, bladder, skin). 
 Arsenic can interfere with the mechanism of hemoglobin synthesis and the ribosomes may form dot-
like precipitates, called basophilic stippling , at the periphery of RBCs.  
 Basophilic stippling is also found in: 
 thrombotic thrombocytopenic purpura, in hemoglobin H disease (rarely)

 megaloblastic anemia.  
 It indicates a RBC cell line maturation defect in the bone marrow. 
 The hematological effects of arsenic toxicity include: 
 Anemia 
 Hemolysis in some cases 
 Acute exposure  Chelation: 
 Consider chelation therapy in patients who are symptomatic and/or have urine 
concentration >200 mcg/L. 
 DMPS is the chelation agent of choice.  
 DMSA is an alternative (oral preparation only, so unsuitable if the patient is 
vomiting).

vomiting). 
 Chronic exposure 
 arsenic-free drinking water, to reduce the risk of further disease  
 It is recommended that all patients with skin lesions be given multivitamins.  
Drugs altered pupil size 
 
Many drugs can cause changes in pupil size as detailed below: 
 Dilated pupils (mydriasis): 
 sympathomimetic drugs, eg cocaine, dopamine, amphetamines

  anticholinergic drugs, eg antihistamines, atropine, tricyclic antidepressants 
 Constricted pupils (miosis): 
 sympatholytic drugs, eg opiates, phenothiazines, clonidine, sodium valproate 
 cholinergic drugs, eg organophosphates, pilocarpine  
Charcoal  
 reduce drug absorption from the gastrointestinal tract, and interrupting  enterohepatic recirculation.

 Which factor  would be most strongly influence your decision to administer or avoid oral 
activated charcoal? 
 Absence of bowel sounds  
 It is generally safe, but should be administered only in patients who are able to p rotect 
their airway. The absence of bowel sounds may indicate a paralytic ileus, which is 
surprisingly common after overdose, and which is associated with an increased risk of 
charcoal aspiration and pneumonitis.

charcoal aspiration and pneumonitis.  
 Iron, lithium and other cations are not adsorbed by charcoal; alcohols including ethanol, methanol and 
ethylene glycol are not adsorbed either. 
 Activated charcoal is capable of adsorbing around 10% of its own weight, so adm inistration of charcoal 
50 g might be expected to adsorb around 5 g of drug. 
 should normally be administered within 1 hour of drug overdose, but may be effective when

administered after a longer interval, particularly after modified-release preparations.  
 
Multi-dose activated charcoal  
 
When Activated charcoal can be repeatedly given to increase elimination of the poison? 
 When the drug circulates through the enterohepatic circulation 
 
 Multi-dose activated charcoal means giving 50 g of activated charcoal every 3-4 h 
 It is useful in patients who have taken significant amounts of salicylates, and shoul d be continued until

plasma salicylate concentrations have peaked 
 It is also useful in the management of patients who have taken drugs wit h significant enterohepatic 
circulation (carbamazepine, phenobarbital, theophylline and quinine) and sustained-/m odified-release 
 It is contraindicated in patients with signs of bowel obstruction, 
 
 1743

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  87 
Methanol poisoning 
 Methanol, like ethanol, is metabolised by alcohol dehydrogenase to form formaldehyde . 
Formaldehyde  is then further metabolised by aldehyde dehydrogenase  to formic acid . 
 Formate formation leads to:

 Formate formation leads to: 
  severe metabolic acidosis , and  
 crystals forming within the eye can lead to so called  'snow field' cataract formation . 
Feature 
 Early signs  (are due to methanol) include: 
 Headache,  
 Confusion. 
 later signs  (are due to its metabolite, formic acid)  
 high gap metabolic acidosis 
 Anion gap = (Na + K) - (Cl + HCO 3); normal range 7-17 mmol/L.  
 Although elevated, the lactate level does not account for the anion gap.

 visual problems, retinal injury, including blindness (methanol-associated visual loss) 
 accumulation of formic acid  a form of optic neuropathy 
 The differential diagnosis of this form of  a high anion gap metabolic acidosis  is (SLUMPED) 
(salicylates, lactic acidosis, uremia, methanol/ethylene glycol, paraldehyde, ethanol, and diabetic 
ketoacidosis).  
Similarities between Methanol and ethylene glycol intoxication

 Both are causes a very similar biochemical and clinical picture. 
 Both require the enzyme alcohol dehydrogenase for metabolism. 
 Both are treated with fomepizole or ethanol, which inhibit alcohol dehydrogenase 
 Both can present with metabolic acidosis, hyperpnea and tachypnea, coma, seizures, and hypotension.  
 The fruity smell suggests ketosis.  
Differences between Methanol and ethylene glycol intoxication 
 From history

 From history 
 Methanol is pure distilled alcohol, more likely to be consumed by those with a history of alcohol 
abuse.  
 Ethylene glycol is antifreeze, usually consumed by those with suicidal intent or history  of 
deliberate self-harm.  
 From examination 
 eye signs ( macular oedema and poor pupillary responses)  methanol  
 In exams, cases involving methanol toxicity often involve patients not meeting y our gaze

or asking for the lights to be switched on, as well as the more traditi onal visual acuity 
results. 
 Methanol leads to the formation of formate , which causes retinal damage with optic disc 
hypemia and edema, blindness, and basal ganglia infarcts.  
 Ethylene glycol causes the formation of calcium oxalate crystals, leading to renal  failure and 
hypocalcemia  ( tetany) 
 Oxalate crystals  are a specific sign of ethylene glycol toxicity.  
 
 formate is the toxic metabolite of methanol

formate is the toxic metabolite of methanol  
 oxalic acid is the toxic metabolite of ethylene glycol 
 
 fomepizole or ethanol  Inhibition of methanol metabolism by alcohol dehydrogenase  is the treatment 
of choice. 
 1st line  fomepizole which is an inhibitor of alcohol dehydrogenase.  
 2nd line  If fomepizole is not available, then ethanol is recommended. 
 sodium bicarbonate if necessary to correct severe acidaemia (pH <7.20)  
 Haemodialysis 1744

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  88 
  
Treatment is aimed at: 
1. Eliminating formic acid (alkaline diuresis or haemodialysis ). 
2. Correcting acidosis with IV bicarbonate. 
3. Preventing metabolism of methanol to formic acid by administering IV ethanol. 
Ethylene glycol toxicity

Ethylene glycol toxicity 
 
 Ethylene glycol is a type of alcohol used as a coolant or antifreeze 
Features of toxicity  are divided into 3 stages: 
 Stage 1: symptoms similar to alcohol intoxication: confusion, slurred speech, dizziness 
 Stage 2: metabolic acidosis with high anion gap and high osmolar gap. Also tachycardia, hypertension 
 Stage 3: acute renal failure 
 renal, respiratory and cardiac failure.

 renal, respiratory and cardiac failure. 
 Multi-organ failure is thought to occur at least in part due to widespread deposition of 
calcium oxalate crystals around 12 h after the initial insult. 
 treatment is often given based on clinical suspicion due to a delay in obtaini ng ethylene glycol levels in 
most centres. 
 fomepizole , an inhibitor of alcohol dehydrogenase, is now used  first-line in preference to ethanol

  prevents metabolism of ethylene glycol to oxalic acid , responsible for the acidosis and renal 
failure  
 Because of the potential formation of calcium oxalate, calcium levels should also be 
assessed .  
 works by competing with ethylene glycol for the enzyme alcohol dehydrogenase 
 this limits the formation of toxic metabolites (e.g. glycoaldehyde and glycolic acid ) which are 
responsible for the haemodynamic/metabolic features  of poisoning

 IV fluids with bicarbonate  to correct the metabolic acidosis in severe lactic acidosis . 
 Calcium gluconate for hypocalcemia, 
 haemodialysis  also has a role in refractory cases  
 
Isopropyl alcohol (Isopropanol) intoxication  
 It is a clear colorless liquid with a BITTER TASTE and fruity odor . 
 commonly used as a rubbing alcohol and as a solvent in hair-care products, skin lotions and ho me 
aerosols.

aerosols.  
 Also found in products including cleaners, disinfectants, antifreezes, cosmetics, solvent s, inks, and 
pharmaceuticals. 
 Inexpensive and can be a substitute for ethanol. 
 the second most common alcohol intoxication next to ethanol. 
  It is twice as potent as ethanol as a central nervous system depressant but witho ut an early elation 
phase. 
Feature: 
 Severe isopropanol poisoning results in CNS and respiratory depression and circulator y collapse.

 GIT and CNS symptoms are predominates,  
 alcohol , benzodiazepines, isopropyl alcohol , lithium, and organophosphates may all lead to miosis  
(constriction of the pupil) 
 Large ingestions can result in coma.  
1745

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  89 
  The most common metabolic effects are an increased osmol (osmolal) gap, keton emia, and ketonuria  
 metabolic acidosis - unlike in other alcohols intoxication - is not pres ent, this is because isopropyl 
alcohol is metabolized by alcohol dehydrogenase to acetone, (a ketone is not an acid).

 therefore ketone appear in breath and in urine. 
 Isopropyl alcohol intoxication can be remembered as "ketosis without acidosis".   
 Another unique finding is "pseudo renal failure" or ISOLATED false elevation of creatinine with a 
normal BUN.  
 An osmol gap, ketonemia, and/or ketonuria without metabolic acidosis , along with a fruity or sweet 
odor on the breath and CNS depression support the diagnosis.

  Although ethylene glycol, methanol, and ethanol ingestions result in anion gap and osmolar gap, 
isopropyl alcohol results in only an osmolar gap.  
 Osmolar gap = Osmola lity  – Osmola rity 
 Osmola lity is measured  in laboratory by osmometers  
 Osmola rity is calculated  = (2 x [Na+]) + [glucose] + [urea] 
 normal = < 10 
 the units of osmola lity are mOsm/ kg of solute 
 the units of osmola rity are mOsm/ L 

 supportive care (is the mainstay of management)  Patients usually make a full recovery 
 hemodialysis  elimination of isopropanol and acetone  only in severe life-threatening poisonings. 
 
Acidosis + eye signs  methanol poisoning  
Acidosis without eye signs  ethylene glycol poisoning  
Ketosis without acidosis  isopropyl alcohol poisoning   
Ecstasy poisoning

Ecstasy poisoning 
 Ecstasy is an amphetamine derivative (MDMA, 3,4- Methylene- Dioxy- Meth-Amphetamine) use became 
popular in the 1990's during the emergence of dance music culture 
 is a semi-synthetic hallucinogen used as a recreational drug. 
 neurological: agitation, anxiety, confusion, ataxia 
 cardiovascular: tachycardia, hypertension 
 Hyperventilation 
 hyperthermia 
Management   supportive ( no specific antidote)

Management   supportive ( no specific antidote) 
 Cold intravenous fluids if the core temperature is over 39 °C  
 dantrolene may be used for hyperthermia if simple measures fail  
 and/or paralysis and ventilation  
 Treatment of associated hyperthermia  
Opioid misuse 
Acute confusion and visual hallucinations are common symptoms of opioid toxicity an d pin point pupils and 
myoclonas are common signs.

myoclonas are common signs.  
Opioids are substances which bind to opioid receptors. This includes both naturally occurrin g opiates such as 
morphine and synthetic opioids such as buprenorphine and methadone. 
Features of opioid misuse  
 rhinorrhoea 
 needle track marks 
 pinpoint pupils 
 watering eyes 
 yawning 
Complications of opioid misuse 1746

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  90 
  viral infection secondary to sharing needles: HIV, hepatitis B & C 
 bacterial infection secondary to injection: infective endocarditis, septic arthritis, septi caemia, necrotising 
fasciitis 
 overdose may lead to respiratory depression and death 
 psychological problems: craving

 psychological problems: craving 
 social problems: crime, prostitution, homelessness 
Emergency management of opioid overdose 
 IV or IM naloxone : has a rapid onset and relatively short duration of action 
 intravenous naloxone (0.4 mg), repeated up to a total dose of 2 mg depending on clini cal response. 
 The half-life of naloxone is shorter than that of opioids , hence if the patient wakes up it can be 
anticipated that he will 're-narcose'. A naloxone infusion may be necessar y.

Harm reduction interventions may include 
 needle exchange 
 offering testing for HIV, hepatitis B & C 
Management of opioid dependence 
 patients are usually managed by specialist drug dependence clinics although some GPs w ith a 
specialist interest offer similar services 
 patients may be offered maintenance therapy or detoxification 
 NICE recommend methadone or buprenorphine as the first-line treatment in opioi d detoxification 
 compliance is monitored using urinalysis

 compliance is monitored using urinalysis 
 detoxification should normally last up to 4 weeks in an inpatient/residential setting and up to 12 weeks 
in the community 
Dihydrocodeine  
 Dihydrocodeine is an opiate analgesic and when taken in overdose has a number of toxic effec ts. 
  It acts as a respiratory depressant leading to reduced respiratory rate. 
  It can cause bradycardia and hypotension in large doses.  
 Pupillary constriction is a diagnostic feature in opiate overdose.

 It is also a central nervous system depressant and therefore causes coma in overdose. 
Pain relief 
 Titrating the dose of morphine needed for analgesia should be done with rapidly acting f ormulations of 
morphine, and once adequate analgesia is obtained sustained-release morphine can then be 
substituted (at the same total daily dose) 
Analgesia in opiate users (eg: on methadon e) 
 Discontinuation of methadone may result in symptoms of acute opiate withdrawal and thi s is not

 Continuation of methadone and consideration of analgesics with a different mode of action ( ie 
non-steroidals such as parenteral diclofenac) is recommended 
 
Opioid withdrawal  
 The symptoms and signs of opioid withdrawal include dysphoric mood, yawning, insom nia, nausea, 
vomiting, diarrhoea, muscle aches, lacrimation / rhinorrhoea, pupillary dilatation, piloerectio n, sweating 
and fever.

and fever. 
 Initially give 10 mg of methadone syrup and wait about 60 min to de termine its effect. Continue 
administering in 10 mg doses until symptoms are under control. It is rare to exceed a total dose of 40 
mg over 24 hours. 
Morphine 
Side-effects including: 
 Nausea, vomiting 
 Nausea affects up to two-thirds of patients starting morphine but in t he majority of these it is 
self-limiting to within 1 week.

self-limiting to within 1 week. 
 Haloperidol is the first-line drug for opioid-induced nausea , kidney disease and 
hypercalcaemia  
 drowsiness, confusion 
 others, including: bronchospasm, angioedema, urinary retention, ureteric or bil iary spasm, dry mouth,  
sweating , rash, facial flushing, vertigo, tachycardia, bradycardia, palpitations, orthosta tic hypotension, 
hypothermia, restlessness, mood change, hallucinations, seizures (adults and children) and miosis, 1747

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  91 
 headache and allergic reactions (including anaphylaxis) and decreased libido or potency 
 raised intracranial pressure  
 Muscle rigidity may occur with high doses 
 biliary sphincter constriction  Elevated liver enzymes 
 Large doses can lead to respiratory depression, circulatory failure and coma  
Morphine vs pethidine

Morphine vs pethidine  
 Morphine acts for four to five hours while pethidine works for two to three hours.  
 This means that pethidine would have to be given at more frequent intervals to produce the 
same analgesic effects as morphine. 
Pethidine  
 Meperidine (Pethidine) is a full opioid agonist at mu receptors. 
  the only opioid that acts as an  antimuscarinic

 Pethidine is contraindicated in most cases of sickle cell pain . It is metabolized into a 
cerebral irritant that can lead to clonus, seizures, or altered mental status.  
 Pethidine is preferred to morphine in the preoperative management  of biliary colic and in the 
management of acute diverticulitis. 
 Pethidine is comparable to morphine in its sedative and tranquillizing effects, but the analgesia 
and respiratory depression it produces are of shorter duration , and it induces less

smooth muscle spasm.  
 It is largely metabolized in the liver and the end- products are excreted in the urine. 
 Bronchial asthma, emphysema or heart failure secondary to chronic lung disease. 
 Increased intracranial pressure, head injury or brain tumour. 
 Severe hepatic impairment, adrenocortical insufficiency, hypothyroidism. 
 Convulsive disorders, acute alcoholism, delirium tremens. 
 Use of monoamine oxidase inhibitors within the previous 14 days.

Buprenorphine  
Action 
 partial  opiate agonist at mu and kappa opioid receptors.  
 meaning that by occupying the receptor, it doesn ’t achieve the effects of full agonism , and 
thus has less addictive  potential versus other opiates . 
 Due to the fact that buprenorphine is a partial agonist, at higher doses i t displays “functional

antagonism ”, meaning that by occupying the receptor it blunts the effects of other full 
opiate agonists.  
 It also has a long half-life of up to 32hrs.  
 This means that it can be utilised in cases of addiction to short-acting op iates such as 
diamorphine because it reduces the highs, and thus addictive potential, associated with these 
agents. 
 Since buprenorphine  is a partial agonist at opioid receptors , it will antagonise the action of a full

agonist  such as morphine  
 therefore it is appropriate to substitute morphine for buprenorphine, but not  to add the two together 
 
MRCP UK- part-1- jan- 2017: What is the mode of action of buprenorphine?  
 Partial mu opioid receptor agonist  
Cocaine 
 Cocaine is an alkaloid derived from the coca plant. 
  cocaine toxicity becoming a much more frequent clinical problem.  

 cocaine blocks the uptake of dopamine, noradrenaline and serotonin 
 
The use of cocaine is associated with a wide variety of adverse effects: 
Cardiovascular effects  
 cocaine-induced MI is thought to be related to coronary artery spasm 
 It is probably caused by stimulation of the α -adrenergic receptors in smooth muscle cells. In 
addition, cocaine increases endothelin-1 (a vasoconstrictor) and decreases nitric  oxide 1748

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  92 
 (vasodilator). 
 both tachycardia and bradycardia may occur 
 (Blockage of noradrenaline (norepinephrine) re-uptake leads to tachycardia, & ĹĹBP)  
 QRS widening and QT prolongation 
 aortic dissection 
Neurological effects 
 seizures 
 hypertonia 
 haemorrhagic stroke

 haemorrhagic stroke  
 cocaine-induced spinal cord infarct : 
 The constellation of quadriparesis, spinothalamic sensory loss with sparing of posterior 
columns and sphincter dysfunction is most suggestive of an anterior spinal cord 
syndrome.  
 The areflexia may reflect spinal cord shock. 
 With a C3/4 spinal cord lesion, it is not surprising that the patient has resp iratory 
difficulties. 
  detection of cocaine in the urine suggesting he was using it

Psychiatric effects 
 agitation  ( inhibition of dopamine re-uptake  psychomotor agitation)  
 hallucinations ( serotonin re-uptake blockade leads to  hallucinations)  
Others 
 hyperthermia  which may lead to rhabdomyolysis and renal failure  
Management of cocaine toxicity 
 in general benzodiazipines are generally first-line for most cocaine related probl ems

 Agitation, seizures and hypertension are best treated with benzodiazepines (such as 
midazolam) initially.  
 Diazepam is useful for the treatment of anxiety and may precipitate a small reduc tion in blood 
pressure, but will not treat coronary artery vasospasm.  
 Calcium channel blockers (such as nifedipine) can be used as a second line treatment for 
hypertension  if benzodiazepines are ineffective. 
 chest pain:  
 benzodiazipines + glyceryl trinitrate .

 benzodiazipines + glyceryl trinitrate .  
 Other option include calcium antagonists,  
 If myocardial infarction develops then primary percutaneous coronary intervention 
 hypertension:  
 benzodiazipines + sodium nitroprusside 
 Beta blockers should be avoided in cocaine associated myocardial ischaemia or infarction as they  can 
potentiate coronary vasoconstriction.  
 Beta blockers are contraindicated as they can cause unopposed alpha activity and worsen 
hypertension.

 Intubation and ventilation  will lower  blood pressure and improve the ischaemia 
 the most appropriate next intervention if diazepam fail to control the acute symptoms 
(eg: seizure )  
 Whilst IV sodium valproate and IV phenytoin may be effective in terminating the 
recurrent seizures, these options would cost precious time with respect to controlling 
blood pressure and pyrexia

blood pressure and pyrexia 
 
January 2016 exam:  A 23-year-old man found 'collapsed' in the bathroom at a house party. Then C/O 
severe abdominal pain + blood in his stool. What is the single most likely ca use of his abdominal 
pain? Ischaemic colitis (Ischaemic colitis is a recognised phenomenon following cocaine ingestion and 
should be considered if patients develop abdominal pain or rectal bleeding)  
 
 1749

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  93 
Heroin withdrawal 
 The following are all signs of heroin withdrawal: 
 rhinorrhoea 
 diarrhoea 
 lacrimation 
 irritability and restlessness, which are cardinal features  
Heroin substitutes in medical management of withdrawal

 Both buprenorphine and methadone may be considered for use as heroin replacements 
 Buprenorphine may be associated with less risk in overdose, but NICE recommends that unless 
circumstances dictate otherwise, methadone should be the first-choice therapy  
 Co-abuse of alcohol and benzodiazepines may drive preferential use of buprenorphine, as these 
agents increase the risk of significant CNS depression 

Benzodiazepine overdose 
 Benzodiazepine overdose is very rarely life-threatening unless associated with t he co-ingestion of 
alcohol or other respiratory depressants 
 Clinical features : 
 CNS depression : lethargy, somnolence, hyporeflexia 
 Mild hypotension 
 Ataxia 
 Slurred speech 
 Supportive therapy  
 GCS ≤ 8: endotracheal intubation 
 Hypotension: fluid resuscitation 
 Antidote : flumazenil 
 Indications

 Severe respiratory depression 
 Overdose in benzodiazepine-naive patients (e.g., accidental ingestion in children, 
periprocedural oversedation with benzodiazepines) 
 Routine use of flumazenil for benzodiazepine overdose is not recommended 
 Most cases of benzodiazepine overdose occur in patients who are on chronic 
benzodiazepine therapy. Flumazenil can precipitate withdrawal 
symptoms and seizures in patients with benzodiazepine dependence.

Cathinone toxicity 
 NRG -1 is a synthetic cathinone drug which is increasingly used recreationally. 
  Pharmacologically it is a derivative of phenylpropanone which is a naturally occurring psychotrope in 
khat ( Catha edulis ).  
 Synthetic cathinones became increasingly popular in the last ten years as an alternative to ec stasy

since they were cheaper, easier to produce and initially were unrestricted. As legislation changes, 
chemical substitutions are made to molecular moieties to create similar drugs t o avoid restrictions. 
  All exert their effect by increasing synaptic concentrations of noradrenaline, dopamine and serotonin, 
giving users the sensation of euphoria, detachment and wellbeing as well as upregulation o f the 
sympathetic system.

sympathetic system.  
 Toxicity is often seen due to lack of regulation of constituents and act ive ingredients 
Features 
 Tachycardia and hypertension may be seen due to the sympathomimetic effects of t he drug and in 
some cases myocardial ischaemia can be seen.  
 In the majority of cases of toxicity, however, similar to ecstasy toxicit y, hyponatraemia and serotonin 
syndrome  are seen. Hyponatraemia occurs as a consequence of significant water intake to r educe

body temperature. Serum sodium levels may be markedly low and patients may present seizing. 
  Serotonin syndrome  is due to massive flooding of synapses with liberated serotonin and causes 
agitation, confusion, muscle hyperactivity with fasciculations, hypertonia and clonus.  
 Creatine kinase and white cell counts are often raised and body temperature may be  extremely high. 
Treatment

Treatment 
 If there is evidence of neurological compromise with an accompanying hyponatraemia, rapid correc tion 1750

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  94 
 of sodium is recommended with infusion of 3% saline solution at a maximum rate o f 1ml/kg/hour.  
 0.9% saline solution is not recommended in patients with hyponatraemia and agitation due to the r isk of 
worsening the hyponatraemia.  
Cannabinoids

Cannabinoids  
 Cannabinoids are derived from the resin of cannabis sativa,  
  9-tetrahydrocannabinol (9-THC) is its most important pharmacologicall y active constituent. 
 Oral bioavailability of THC, whether given in the pure form or as TH C in marijuana, is low and extremely 
variable, ranging between 5% and 20%, with effects occurring 0.5-3 hours later. 
 Bioavailability of THC in a marijuana cigarette or pipe also rarely ex ceeds 10-20%.

 Naloxone and other opioid receptor antagonists block the analgesic actions of cannabinoids. 
 Synthetic cannabinoids reduce arachidonic acid-induced inflammation by inhibiting eicosanoid 
 Cyanide poisoning 
cyanide mechanism of action  Inhibition of enzyme cytochrome oxidase c  
 Cyanide may be used in: 
  insecticides,  
 photograph development and   
 production of certain metals.

 production of certain metals.  
 Acute cyanide toxicity may occur secondary to burning plastics in the house fire.  
 Toxicity results from reversible inhibition of cellular oxidising enzymes 
 Cyanide ions inhibit mitochondrial cytochrome oxidase , preventing aerobic respiration,  which is 
an essential part of the mitochondrial electron transfer chain (ETC). It t herefore interferes with the basic

process of cellular respiration, preventing the formation of ATP and causing rapid cell dea th. 
Presentation  (classical features: brick-red skin, smell of bitter almonds) 
 manifests in normal oxygen saturations, a high pO2 and flushing (or 'brick r ed' skin) brought on by the 
excess oxygenation of venous blood. (it is important to note that the blood gas sampl e given is venous 
rather than arterial) 
 acute: hypoxia, hypotension, headache, confusion

 increased anion gap, consistent with high lactate (generated by anaerobic respiration  due to the 
inability to use available oxygen). 
 very high lactate and high venous pO2 fit better with cyanide toxicity. 
 chronic: ataxia, peripheral neuropathy, dermatitis 
 supportive measures: 100% oxygen 
 definitive: hydroxocobalamin (intravenously), also combination of amyl nitrite  (inhaled), sodium nitrite 
(intravenously), and sodium thiosulfate (intravenously)

 The recommended treatment for moderate cyanide toxicity in the UK is o ne of three options:  
1. Hydroxocobalamin,  
 has the best side-effect profile and speed of onset compared with other treatmen ts 
2. dicobalt edetate,  
 only  given when the patient is tending to lose or has lost consciousness.   
 When the patient is fully conscious, it is unlikely that the extent o f poisoning 
warrants the use of Dicobalt Edetate Injection.

warrants the use of Dicobalt Edetate Injection. 
 Dangerous if given without confirmed cyanide poisoning 
 Other antidotes such as hydroxocobalamin or sodium thiosulphate are preferred. 
3. sodium thiosulfate  
 
 1751

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  95 
  
Hydroxocobalamin 
 also known as vitamin B12a  and hydroxycobalamin,  
 is an injectable form of vitamin B 12  
 vitamin B 12 deficiency 
 cyanide poisoning,  
 Leber's optic atrophy,  
 toxic amblyopia (Nutritional optic neuropathy)

 toxic amblyopia (Nutritional optic neuropathy) 
 a condition where a toxic  reaction in the optic nerve results in visual loss.  
 Various poisonous substances may cause the condition as well as nutritional factors.  
 Tobacco amblyopia  is a form of toxic amblyopia  caused by tobacco containing 
cyanide. 
 
Sarin gas

Sarin gas   
 Sarin gas and related agents cause inhibition of the enzyme acetylcholinesterase, causing levels of  
acetylcholine to build up in the nervous system causing prolonged sustained contraction of the  
diaphragm. This hinders and eventually paralyses normal breathing. 
 Sarin has muscarinic and nicotinic effects. 
 Muscarinic effects: 
 Paralysis 
 Fasciculations 
 Hyperglycaemia, and 
 Ketosis. 
 Nicotinic effects: 
 Hypotension 
 Meiosis 
 Dyspnoea, and

 Meiosis 
 Dyspnoea, and 
 GI disturbance. 
Arsenic   
 Arsenic causes inhibition of the enzyme pyruvate dehydrogenase which is necessary for the 
conversion of pyruvate to acetyl CoA. This also interferes with the basic process of cellular r espiration, 
as pyruvate formed during glycolysis cannot be changed to acetyl CoA to enter t he Kreb's cycle.

 Arsenic and mustards  cause mutational damage to DNA  ↑ risks of skin and haematological 
malignancy in the longer term.  
 Arsenic can also accelerate atherosclerosis. 
Acid poisoning 
Pathology 
 Acids cause injury by coagulative necrosis 
 Acid effects are mainly topical, with corrosive burns to the mouth, oropharynx  and stomach

 They are less likely than alkalis to cause significant localised damage to th e oesophagus 
 Aspiration can lead to inflammation and a chemical pneumonitis 
 Neutralisation of acids is not appropriate, since this can generate increased heat and so ex acerbate 
any injury sustained 
 Gastric lavage is contraindicated due to the increased risk of oesophageal perforat ion 
 Management consists of supportive  care and early endoscopy

 Early surgical intervention is required to prevent mediastinitis, from which the re is a high mortality, in 
those patients with signs or symptoms of perforation 
 Hydrofluoric acid  causes significant hypocalcaemia as it binds calcium, 
 even small amounts (topically or ingested) can produce significant hypocalcaemia and be 
rapidly fatal 
 in cases of significant topical exposure, patients should be monitored for signs of syst emic 
hypocalcaemia

 patient treated with intravenous calcium supplementation if required . 
 Calcium gluconate applied both topically and injected around the burn may be req uired 
 Systemic fluorosis may occur as a complication 1752

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  96 
Alkali poisoning 
 Alkalis cause saponification (liquefactive necrosis) of tissue 
 Neutralisation of alkalis is not appropriate, as this can generate increased heat and so ex acerbate any 
injury sustained

injury sustained 
 Assuming survival, fluorosis may lead to further problems later on 
Radiosensitiser drugs 
Radiosensitiser drugs  radiation toxicity  
 dactinomycin, 
 5-fluorouracil 
 gemcitabine 
 cisplatin  hydroxyurea 
 paclitaxel 
 mitomycin C 
 topotecan 
 
Radioprotector  
 Amifostine is a radioprotector  

Management of body packers 
 The management of body packers and body stuffers is relatively straightf orward 
 Abdominal radiographs may show some  packages in the gastrointestinal tract - they appear as air 
halos trapped within the packages, but not all packages  may contain trapped air 
  In patients with no signs of drug-associated toxicity, whole-bowel irrig ation with polyethylene glycol will 
clear the gastrointestinal tract of all the swallowed packages

 Endoscopy may also be useful in removing packages that are still in the stomach, but pa ckages should 
be carefully removed to prevent damage and drug release 
 Gastric lavage may increase the risk of package rupture 
 Laxatives may also help the packages to pass naturally, but paraffin-based laxatives should not be 
used since they increase the risk of package rupture 
 Surgical intervention to remove all the remaining packages may be necessary in patient s who start to

develop signs of drug toxicity, since the strength and amount of drug in eac h package is unknown 
 
Heavy metal poisoning 
Causes 
 lead: most common 
 mercury 
 manganese 
 cadmium 
 thallium  
Lead poisoning 
 Along with acute intermittent porphyria, lead poisoning should be considered  in questions giving a

combination of abdominal pain and neurological signs 
 Lead can also be absorbed through the skin and by inhalation. 
Aetiology: ingestion of:  
 lead-containing compounds, deliberate (pica) or inadvertent 
 contaminated water from old lead water pipes 
 occupation, such as a painter have a lead exposure while stripping the walls in old houses.  
 certain traditional remedies such as ayurvedic medicines

Features 
 nausea 
 constipation  
 peripheral neuropathy (mainly motor) due to demyelination 1753

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  97 
  fatigue 
 blue lines on gum margin (only 20% of adult patients, very rare in children) 
 may be associated with anterior  uveitis or iritis 
Laboratory tests 
 Whole blood lead levels: 
 <10 μg/dL - normal. 
 >10 μg/dL - may cause impaired cognitive development in children.

 >45 μg/dL - GI symptoms in adults and children. 
 >70 μg/dL - high risk of acute CNS symptoms. 
 >100 μg/dL - may be life-threatenin g. 
 Abdominal radiographs are essential to see if there is any unabsorbed lead present, which can be 
removed by whole-bowel irrigation  
 The blood lead level is usually used for diagnosis. Levels greater than 10 mcg/dl are considered 
significant  
 full blood count:  
 microcytic anaemia.

 microcytic anaemia.  
 Blood film shows red cell abnormalities including: 
 basophilic stippling  and  
 This occurs due to accumulation of (RNA) in the RBCs  due to inhibition of 
pyrimidine 5 nucleotidase by lead.  
 clover-leaf morphology 
 raised serum and urine levels of delta aminolaevulinic acid may be seen making it som etimes difficult to 
differentiate from acute intermittent porphyria

differentiate from acute intermittent porphyria 
 urinary coproporphyrin is also increased (urinary porphobilinogen and uroporphyrin levels ar e normal to 
slightly increased) 
 
Management - various chelating agents are currently used: 
 dimercaptosuccinic acid (DMSA) 
 the most appropriate intervention 
 The recommended dose is 10 mg/kg three times per day for five days, followed by  10 mg/kg 
twice per day for two weeks.  
 EDTA

 EDTA 
 This is used IV or IM, which makes administration less convenient than DMSA.   
 It is considered for patients with symptoms of severe acute lead poisoning. 
 dimercaprol 
 
 containing foods 
1754

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  98 
 Mercury poisoning 
Features 
 visual field defects 
 ataxia 
 dysarthria  
 hearing loss 
 irritability 
 renal tubular acidosis 
 Chronic poisoning from the inhalation of mercury vapour results in a classic  triad  of tremor, 
neuropsychiatric disturbance and gingivostomatitis

Cadmium (Cd) poisoning 
 Workers in zinc factories are at risk of cadmium (Cd) poisoning. 
Feature 
 Bone pain, osteopenia 
 Renal failure.  
 The Cd-protein complex is mainly taken up by proximal tubular cells. This may g ive rise to a 
tubular proteinuria  
 may also cause a Fanconi syndrome-like presentation, with amino aciduria  and phosphaturia .  
 Prolonged renal tubular toxicity may cause glomerular damage.

 Another renal effect of prolonged Cd exposure is calcium phosphate stones . 
Thallium poisoning  
Features 
 painful polyneuropathy 
 alopecia 
Treatment  is chelation therapy with oral Prussian Blue.  
Iron overdose 
 Undissolved iron tablets are radio-opaque 

 Early features of iron overdose are due to the direct corrosive effects of iron and includ e vomiting, 
diarrhoea and gastrointestinal bleeding 
 Typically, there is then a latent phase of up to 24 h when the patient is asymptomatic  
 This is then followed by widespread organ failure 
 Initial hyperglycaemia can occur following significant ingestion of iron , but hypoglycaemia can 
be seen later in cases of severe poisoning with associated hepatic failure

 In patients who recover, there may be long-term GI strictures and possible g astrointestinal obstruction 
due to the initial corrosive effects of iron  
Treatment 
 Iron is a metal and therefore will not be adsorbed by activated charcoal 
 Patients with serum iron concentrations over 90 mmol/l, as well as those with signs of  severe toxicity, 
require chelation therapy with desferrioxamine 
 
LSD intoxication

LSD intoxication 
Lysergic acid diethylamide (LSD) 
 No medicinal use.  
 Recreationally used as a hallucinogen and for its ability to alter human perception  and mood. 
Pharmacodynamics:   
 LSD is primarily a non-selective 5-HT agonist.  
 LSD may exert its hallucinogenic effect by interacting with 5-HT2A receptors  as a partial agonist and 
modulating the NMDA receptor-mediated sensory, perceptual, affective and cogniti ve processes.

 LSD mimics 5-HT at 5-HT1A receptors, producing a marked slowing of th e firing rate of serotonergic 
neurons.  1755

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  99 
 Features 
 heightened sense of awareness 
 synaesthesia 
 palinopsia 
_________________________________________________________________  
New recreational drugs 
Drug types Street names 
Gamma-hydroxybutyric acid (GHB) and gamma-
butyrolactone (GBL) G, Geebs or Liquid Ecstasy

butyrolactone (GBL) G, Geebs or Liquid Ecstasy 
Synthetic agonists of the CB1 receptor Spice 
Methoxetamine (derivative of ketamine) Mexxy 
Benzylpiperazine Exodus, Legal X, Legal E 
Nitrous oxide Hippie crack 
Paracetamol overdose  
 it is the most common agent of intentional self-harm  
 it is  the most common cause of acute liver failure

 As little as 10 –15 g (20 –30 tablets) in an adult or 150 mg/kg of paracetamol taken within 24 h may 
cause severe hepatocellular necrosis and, less frequently, renal tubular necrosis.  
 
Paracetamol is conjugated to glucuronic acid and sulphate under normal conditions. 
In overdose these processes become saturated and the drug is then results in a toxic metab olite, N-
acetyl-p-benzoquinone imine (NAPQI) 
(NAPQI) inactivated by glutathione, rapidly preventing any harm.

If the glutathione supply is depleted then a toxic metabolite is formed. 
After ingestion of a therapeutic dose:  
 The liver normally conjugates paracetamol with glucuronic acid/sulphate .  
 and the resulting non-toxic metabolites are excreted in the urine.  
 About 4% of a therapeutic dose is metabolised by the cytochromes P450, mainly C YP2E1, to a 
potentially toxic intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQ I).

 NAPQI combines with intracellular glutathione to become a non-toxic mercapturate de rivative with 
urinary excretion. 
 
after ingestion of an overdose :  
 the conjugation system becomes saturated leading to oxidation by P450 mixed funct ion oxidases *.  
 the normally minor CYP2E1 pathway becomes important.  
 This produces a toxic metabolite (N-acetyl-B-benzoquinone imine)  
 *this explains why there is a lower threshold for treating patients who take P450 inducing

medications e.g. phenytoin or rifampicin 
 Normally glutathione acts as a defence mechanism by conjugating with the toxin forming the non-toxic 
mercapturic acid .  
 If glutathione stores run-out, the toxin leads to cell death of hepatocytes and renal tubules 
 
Paracetamol overdose: risk factors 
The following groups of patients are at an increased risk of developing hepatotoxicity  following a 
paracetamol overdose:

paracetamol overdose: 
 patients taking liver enzyme-inducing drugs (rifampicin, phenytoin, carba mazepine, chronic alcohol 
excess, St John's Wort) 
 malnourished patients (e.g. anorexia or bulimia, cystic fibrosis, hepatitis C, al coholism, HIV  1756

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  100 
  ↓ glutathioŶe stores  
 patients who have not eaten for a few days 
 Human immunodeficiency virus (HIV) positive patients. 
 
 Paracetamol level: take paracetamol level 
1.  four hours post-ingestion , or  
2. as soon as the patient arrives if: 
 Time of overdose is greater than four hours.

 Time of overdose is greater than four hours. 
 Staggered overdose (in staggered overdoses, the level is not interpretable 
except to confirm ingestion). 
The essentials of management are: 
1. Check paracetamol level four hours after ingestion, check levels against t he Rumack-Matthew 
nomogram. 
2. Gastric lavage if large dose ingested (more than 7.5 g) and/or presenting wit hin eight hours of 
ingestion; consider oral charcoal. 
3. Give N-acetylcysteine or methionine.

3. Give N-acetylcysteine or methionine. 
4. Hourly BMs monitored. 
5. Check INR 12 hourly.  
 
if patient present with ingestion of non-significant amount (<150mg/kg) and timing of ingestion is known (1- 4 
hrs)  No immediate action   
 A single dose of activated charcoal (50g for adults) can be given up to 1 hour after ingestion  
 Acetylcysteine should  be started immediately  or empirically when: 
  if a significant amount has been taken (>150mg/kg).

 Serum paracetamol level: 100 mg/L at 4 hours and 15 mg/L at 15 hours after ingestion  
 patients who present late (8-24 hours) 
 Serum paracetamol level is not available within an 8-hour time window 
 If there is any doubt about the timing of the ingestion (including a sta ggered overdose over one 
hour or more).  
 Patients are unconscious or have a suspected overdose. 
 Hepatotoxicity is unlikely if it is >24 hours since last ingestion of para cetamol and all the following 
apply:

apply: 
1. Patient is asymptomatic. 
2. Paracetamol concentration is <5 mg/L. 
3. INR is 1.3 or less. 
4. ALT is less than 2 times upper limit of normal. 
 If all of the above criteria are fulfilled then acetylcysteine may be st opped, and the patient 
discharged with the advice to return if he or she becomes symptomatic (vomiting, abdomi nal 
pain). 
 Repeated supratherapeutic ingestion 
 Patients who have ingested <75 mg/kg in a period of 24 hours are very unlikely to  develop

hepatotoxicity.  
 Those who have ingested 75 mg or less/kg/24 hours of paracetamol require no treatment. 
 Those who have ingested 75-150 mg/kg/24 hours should be considered for acetylcysteine 
(based on amount ingested, timing, and other relevant features) 
 Those who have ingested >150 mg/kg/24 hours are treated with acetylcysteine. 1757

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  101 
  
Prescribing N-acetyl cysteine (NAC) 
 Acetylcysteine is the treatment of choice and is given intravenously (in the US an d some other places it 
1758

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  102 
 is still occasionally given orally). 
 Although the oral route is simpler, it frequently causes nausea and vomiting and is unpleasant. 
Additionally, the standard oral regimen is 72 hours in duration compared w ith 21 hours intravenously,

 N-acetyl cysteine is used in the management of paracetamol overdose as it is a precursor  of 
glutathione and hence can increase hepatic glutathione production 
 Acetylcysteine should be administer ed by intravenous infusion  preferably using Glucose 5%  as the 
infusion fluid. Sodium Chloride 0.9% solution may be used if Glucose 5% is not suitab le.  
 The full course of treatment with acetylcysteine comprises of 3 consecutive intravenous infusions.

 The new guidelines have increased the recommended duration of the first infusion to 60 minutes 
from 15 minutes previously. 
 The patient should receive a total dose of 300 mg/kg body weight over a 21 hour period.  
 First infusion 
 Add the appropriate volume of acetylcysteine injection to 200 mL of infusion fluid  and 
infuse over 1 hour.  
 Second infusion 
 Add the appropriate volume of acetylcysteine injection to 500 mL of infusion  fluid and 
infuse over the next 4 hours .

infuse over the next 4 hours . 
 Third infusion 
 Add the appropriate volume of acetylcysteine injection to  1 litre of infusion fluid and 
infuse over the next 16 hours. 
 N-acety Icysteine is most effective when administered within 8 h of ingestion  
 If acetylcysteine is started within 8 hours of the ingestion, hepatotoxicity i s extremely unlikely.   
 N-Acetylcysteine is recommended in all cases where the paracetamol overdose exceeds 150 mg/ kg 
body weight

body weight  
 All patients with a plasma paracetamol level ≥ 100 mg/L at 4 hours or ≥  15 mg/L at 15 hours after 
ingestion should receive acetylcysteine regardless of risk factors for hepatotoxicity.  
 The paracetamol level is not used to guide treatment in the settin g of a staggered overdose,  and N-
acetylcysteine should be given without delay to reduce the risk of  liver failure. 
 In the case of staggered overdose or unclear timing of overdose, acetylc ysteine should be 
given.

given.  
 The urgency of treatment is underlined by the fact that the incidence of hepatotoxicity is worse if 
treatment is delaye d. 
 Trials of N-acetylcysteine suggest that the incidence of hepatotoxicity i s 1% in those treated 
within eight hours as opposed to 46% in those treated after 16 hours. 
Reactions to NAC  (eg: patient became flushed and hypotensive) : 
 Reactions to NAC are well recognized and are not related to hypersensitivity.

 The majority of dose-related adverse reactions occur within the first hour of  the initial infusion of 
acetylcysteine.  
 The MHRA now recommends extending the time of the initial infusion from 15 minutes to 60 
minutes  in order to reduce the incidence of adverse reactions.  
 Even if a patient has a history of a previous reaction to intravenous acetylcisteine, the benefits 
outweigh the risks and patient should receive treatment .

 Any 'hypersensitivity-like' reactions are more likely to be anaphylactoid in  nature (i.e. not 
immunologically mediated) and therefore may not occur on repeated exposure.  
 Management:  IV chlorpheniramine and restart NAC infusion once symptoms resolved  
 NAC can almost always be safely restarted and total dose safely administered aft er symptomatic 
 Oral methionine may be an alternative but is definitely second line.  
Paracetamol overdose during pregnan cy

Paracetamol overdose during pregnan cy 
 resulting toxic metabolites can cross the placenta and lead to hepatocellular necrosis of  maternal and 
fetal liver cells.  
 NAC can bind the toxic metabolites in the mother and fetal circulation as it crosses  the placenta.  
 NAC appears to be safe during pregnancy and therefore should be administered. 
 
 1759

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  103 
  
King's College Hospital criteria for liver transplantation in paracetamol-induced acute liver failure 
List for transplantation if : 
 Arterial pH <7.3 or arterial lactate >3.0 mmol/L after adequate fluid resusc itation; OR 
 If all three of the following occur in a 24-hour period: 
 Creatinine >300 μmol/L.

 Creatinine >300 μmol/L.  
 PT >100 seconds (INR >6.5). 
 Grade III/IV encephalopathy. 
Strongly consider transplantation if : 
 Arterial lactate >3.5 mmol/L after early fluid resuscitation. 
 
The criteria for transfer to a specialist liver unit are: (poor prognostic factors) 
 Encephalopathy 
 INR: >2.0 at < 48 hours, or > 3.5 at < 72 hours 
  synthetic function (as determined by INR or PT) is the best indicator. 
 Serum creatinine: >200 μmol/L  
 Blood pH: <7.3

 Blood pH: <7.3 
 Systolic BP: <80 mmHg. 
Monitoring and endpoints for treatment 
Hepatotoxicity 
 In patients being treated with acetylcysteine for liver toxicity the acetylcyst eine should be continued until 
the INR is 1.3 or less OR INR is falling towards normal on two consecutive blood tests, and less than 
3.0. 
 Blood tests (urea and electrolytes, creatinine, INR, and ALT) should be re-check ed every 8 to 16 hours

to assess the progress of the hepatic injury. There is no clinical benefit in conti nuing treatment with 
acetylcysteine for a rise in ALT if the INR has normalised. 
Time-sensitive treatment issues 
 8-hour window 
 the need for acetylcysteine treatment should be based on a serum paracetamol concentrat ion 
determined within this 8-hour window.  
 acetylcysteine within 8 hours of an acute ingestion  prevent hepatic injury in nearly all patients

 Empiric acetylcysteine therapy should be initiated for patients who:  
 present later than 8 hours after ingestion; 
 when serum paracetamol concentrations cannot be determined within 8 hours;  
 or if the exact timing of the ingestion is uncertain. 
adverse effects 
 oral acetylcysteine  nausea and vomiting.    
 intravenous acetylcysteine   anaphylactoid reaction (e.g., nausea, flushing, vomiting, rash, urticaria,

pruritus, angio-oedema, dyspnoea, wheezing, bronchospasm, tachycardia, and hypotension) ,  
 Previous anaphylactoid reaction to acetylcysteine is not a contraindication to receiving  acetylcysteine. 
 Patients with a previous anaphylactoid reaction should be given an H1 and an H2 antagonist.  
 Patients with previous bronchospasm reaction to acetylcysteine can be given nebulised 
salbutamol. 
 Patients considered at risk of anaphylactoid reactions (e.g., those with atopy, bronchospasm,

asthma, or a previous reaction) should be administered prophylactic medication such as 
antihistamines to reduce adverse reactions. 
 Methionine is used as an oral antidote for paracetamol poisoning in those who ca nnot tolerate 
N-acetylcysteine  1760

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  104 
  
Paracetamol and smoking 
 Enzyme induction with cigarette smoking does affect paracetamol metabolism. It s importance however, 
is in toxicity.  
 Smokers would be classified as in a high risk for paracetamol overdose and are assessed using a 
different time - paracetamol level curve. 
 
 Untreated paracetamol poisoning may cause varying degrees of liver injury over the 2 to 4 
days following ingestion, including fulminant hepatic failure.  
 Hepatotoxicity is extremely rare in patients treated with acetylcyst eine within 8 hours of an 
acute paracetamol overdose. 
 Lactic acidosis is recognised complication  
 Hypoglycaemia is seen when paracetamol toxicity leads to significant impairment of hepati c 
synthetic function

synthetic function  
 Severe hypoglycaemia affects 40% of patients with fulminant liver failure , which exacerbates 
encephalopathy.  
 Paracetamol nephrotoxicity  
  can develop later than liver toxicity  
 The mechanism of kidney injury is similar to that of the liver,  
 there is little evidence that N-acetyl cysteine confers any renal protection.  
 usually the renal function returns to baseline after a few weeks.

 Haemodialysis may be required to support the patient during the acute episode.  
 
Prognosis 
The prognosis is poor in those with 
 Blood PH less than 7.0 
 Prolonged prothrombin time (more than 100s) and 
 Serum creatinine more than 300 uM. 
 Mortality is greater if the patient is more than 40 years of age. 
 1761

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  105 
  
paracetamol overdose treatment nomogram  
 
Adult Dosage Table (Royal College of Emergency Medicine Guidance. http://www.rcem.ac.uk ) 
 
Although hepatotoxic in high doses  even in fairly advanced chronic liver disease paracetamol can be

used safely as long as doses do not exceed 2-3 g per day. The main exception to this is  alcoholic liver 
disease  where the patient continues to drink, in this setting induction of enzymes and depletion of glutathione 
increases the chances of hepatotoxicity . 
Paraquat poisoning 
Properties of Paraquat 
 Paraquat is a very toxic compound 
 As little as 2 g is potentially fatal (10 ml of a concentrated 20% solution)

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  106 
  Initial signs of toxicity are due to its corrosive effects on the gastrointest inal tract and oropharynx 
Pathology 
 Paraquat is rapidly absorbed and is sequestered in the lungs, where it reacts with oxygen  to form 
hydrogen peroxide and superoxide anions

hydrogen peroxide and superoxide anions 
 Hydrogen peroxide and superoxide anions are responsible for cell death, which leads to an acute 
alveolitis 
Prognosis 
 Death tends to occur within hours to days in patients who have ingested more than 6 g of Para quat 
 Death tends to occur within days in those who have ingested 3-6 g of Paraquat 
 Illness following ingestion of 1.5-3 g Paraquat follows a much more protracted course  and delayed 
pulmonary

pulmonary 
 fibrosis can lead to death up to 6 weeks after ingestion 
 activated charcoal to reduce absorption 
 oxygen supplementation can increase pulmonary toxicity , by increasing the rate of hydrogen 
peroxide and superoxide anion production 
 
Organophosphate insecticide poisoning 
Organophosphate is an anticholinesterase, thus prolonging the effects of acetyl choline.

One of the effects of organophosphate poisoning is inhibition of acetylcholinesterase 
Organophosphates are rapidly absorbed through the gastrointestinal and respiratory t racts and the skin 
Mechanism  
 The principal action of organophosphates is inhibition of acetylcholinesterases 
 This results in the accumulation of acetylcholine at muscarinic receptors, nicotinic recept ors and in the 
central nervous system

central nervous system 
Features  can be predicted by the accumulation of acetylcholine (mnemonic = SLUD)  
Hypersalivation and miosis are the specific clues to acetycholine overactivity . 
 Salivation 
 Lacrimation 
 Urination 
 Defecation/diarrhoea 
 cardiovascular: hypotension, bradycardia 
 also: small pupils, muscle fasciculation 
The presentation relates to the sites of accumulation of acetylcholine 
 Accumulation at muscarinic receptors leads to: 
 miosis

 miosis 
 hypersalivation 
 sweating 
 excessive bronchial secretions 
 Accumulation at nicotinic receptors leads to: 
 muscle fasciculations 
 tremor 
 Accumulation in the central nervous system leads to: 
 anxiety 
 loss of memory 
 headache 
 coma 
 Organophosphate-induced neuropathy starts to develop 2 weeks after exposure 
 Initial presentation of neuropathy is a flaccid paralysis 
1763

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  107 
  Later, hypertonia, hyperreflexia and a spastic paralysis occur  
 atropine 
 the role of pralidoxime(an activator of cholinesterase) is still unclear - me ta-analyses to date have failed 
to show any clear benefit  
Carbon Monoxide Poisoning

Carbon Monoxide Poisoning  
 
 A hypoxemic poisoning syndrome seen in patients who have been exposed to automobile exhaust, 
smoke inhalation, barbecues, or old appliances in poorly ventilated locations. 
 Presents with hypoxemia, cherry-red skin (rare), confusion, and headaches. Coma o r seizures occur in 
severe cases. 
 Chronic low- level exposure may cause ﬂ ulike symptoms with generalized myalgias, nausea, and 
headaches. Ask about symptoms in others living in the same house.

 Suspect smoke inhalation in the presence of singed nose hairs, facial burns, hoarseness, wheezin g, or 
carbonaceous sputum. 
Diagnosis  
 Check an ABG and serum carboxyhemoglobin level (normal is < 5% in nonsmokers an d < 10% in 
smokers).  
 Check an ECG in the elderly and in patients with a history of cardiac disease. 
Treatment 
 100% O2  
 Patients with airway burns or smoke inhalation may require early intubation, since upper  airway edema 
can rapidly lead to complete obstruction.

can rapidly lead to complete obstruction. 
_____ _____________________________________________________________  
Antiemetic  
Antiemetics 
 Aprepitant  is a neurokinin receptor blocker used in the prevention of chemotherapy induced 
nausea.  
 Ondansteron  is a selective 5-HT3 ( 5-hydroxytryptamine 3A receptor ) antagonist both centrally 
and peripherally and as such is a potent antiemetic.

 Ondansetron is the first line drug for chemotherapy related nausea and vomiting.  
 Its effects are thought to be on both peripheral  and central nerves .  
 One part is to reduce the activity of the vagus nerve, which is a nerve that activates the 
1764

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  108 
 vomiting center in the medulla oblongata,  
 the other is a blockage of serotonin receptors in the chemoreceptor trigger zone.  
 Common side effects of ondansetron are headache, drowsiness, and dizziness. 
 Hyoscine  antiemetics functions as a cholinergic muscarinic antagonist

 It acts as a competitive antagonist at muscarinic acetylcholine receptors; it is thu s classified as 
an anticholinergic or as an antimuscarinic drug.  
 Metoclopramide  is a dopamine receptor antagonist that can induce parkinsonism.  It can also 
worsen control in patients with idiopathic Parkinson's disease to its antagonistic effect on dopamine 
 Domperidone  is also a dopamine antagonist but acts peripherally.

 Best drug for nausea and vomiting associated with Parkinson treatment. 
 Drugs such as apomorphine and bromocriptine cause vomiting through peripheral stimulation of 
the chemoreceptor trigger zone. Worsening of Parkinson ’s disease may result from the use of 
dopamine antagonists; however, domperidone is much less likely to cross the blood –brain 
barrier and is therefore the preferred agent in this case.

 Haloperidol: the main site of action for haloperidol with regards anti-emetic effec ts --> 
Chemoreceptor trigger zone 
 Haloperidol is an anti-dopaminergic agent licensed for and used mainly as an anti -psychotic 
agent 
 It does result in more extrapyramidal side-effects than phenothiazine-type agents,  but is 
associated with less hypotension 
 Phenothiazines  (e.g. promethazine) and domperidone are also used as anti-emetic agents and act at 
the chemoreceptor trigger zone

the chemoreceptor trigger zone 
 Cyclizine  is an anticholinergic antihistamine acting through the vomiting centre. 
5-HT3 antagonists  
 5-HT3 antagonists are antiemetics used mainly in the management of chemothe rapy related nausea. 
They mainly act in the chemoreceptor trigger zone area of the medulla oblongata. 
Examples  
 ondansetron 
 granisetron 
 constipation is common

 constipation is common 
Metoclopramide 
Metoclopramide is a D2 receptor antagonist mainly used in the management of nausea. O ther uses include: 
 gastro-oesophageal reflux disease 
 prokinetic action is useful in gastroparesis secondary to diabetic neuropathy 
 often combined with analgesics for the treatment of migraine (migraine att acks result in gastroparesis,

slowing the absorption of analgesics) 
 extrapyramidal effects: oculogyric crisis. This is particularly a problem in chi ldren and young adults , 
especially  girls ,  usually subsides within 24 hours following cessation of treatment and can be treated 
with procyclidine 5-10 mg i.m. (antimuscarinic).  
 hyperprolactinaemia 
 tardive dyskinesia 
Acute dystonic-dyskinetic reactions   
 mostly occur in children and young adults and about 70% of cases are female.

 It occurs more commonly when excess of the recommended dose of metoclopramide is administ ered. 
 The effects usually occur within 72 hours but have been reported to occur within 30 minutes of  starting 
 Symptoms include: 
 oculogyric crisis 
 opisthotonus 
 torticollis 
 trismus, and 
 tetanus-like reactions. 1765

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  109 
  A blue discolouration of the tongue has also been described. 
 Although generally self-limiting, the reaction can be reversed by an antichol inergic such as 
benzatropine  or procyclidine or an antihistamine such as diphenhydramine. 
 
Other drugs

Antihistamines 
 Antihistamines (H 1 inhibitors) are of value in the treatment of allergic rhinitis and urticar ia.  
 Sedation and headaches are the most common adverse effects of antihistamines 
 First generation antihistamines (chlorpheriramine and diphenhydramine) are more sedating than the 
newer agents. 
 
Examples of sedating antihistamines  
 Cyproheptadine 
 Chlorpheniramine

 Chlorpheniramine 
 As well as being sedating these antihistamines have some antimuscarinic properties (e.g. 
urinary retention, dry mouth). 
Examples of non-sedating antihistamines  
 loratidine 
 cetirizine 
 Desloratadine 
 is a long-acting H-1-receptor antagonist 
 has poor penetration into the central nervous system 
 does not interact with antibiotics or other co-administered medications

 Of the non-sedating antihistamines there is some evidence that cetirizine may cau se more drowsiness 
than other drugs in the class. 
 Of the newer antihistamines, cetirizine and levocetirizine are more sedating t han loratadine and 
desloratadine, and possibly more sedating than fexofenadine. 
 
 Terfenadine (a pro-drug) has been associated with cardiac arrhythmias (torsades de poi ntes) 
especially in individuals with prolonged QT intervals.

 Fexofenadine is the active metabolite of terfenadine and does not appear to have the  same 
arrhythmogenic effects as terfenadine. 
 Cetirizine, desloratadine and fexofenadine are prescribed for allergic rhinitis (hay  fever) and all three 
are equally effective 
 cetirizine and fexofenadine interact with erythromycin and other macrolides 
 Chlorphenamine maleate and terfenadine cause drowsiness and also interact with erythromycin

Human and animal bite 
 Co-amoxiclav  is recommended as first-line treatment for all cat or human bites and ot her complicated 
animal bites. 
 In patients who are pencillin allergic, doxycycline plus metronidazole is a typical first  choice regimen.  
 Only 15 - 20% of dog bites become infected, and providing the wound is appropri ately cleaned and not

considered at risk (for example, crush or deep wounds) then antibiotic prophylaxis may not be required.  
Botox  Paralysis of frontalis    eyebrows are drooping (eyebrow ptosis).  
 Botox (onabotulinumtoxinA) is an injectable neuro-toxin used for the treatment of chroni c migraines, 
limb spasticity, axillary hyperhidrosis, cervical dystonia, strabismus, and blepharospasm .

 Botox is a neurotoxin derived from the bacteria, Clostridium botulinum . It blocks neuromuscular 
transmission inhibition of acetylcholine release at the presynaptic membrane. T he end result is that the 
muscle contraction is inhibited. 
 The action of Botox is not permanent because collateral axonal sprouting establishes new 
neuromuscular junctions, restoring muscle function.  1766

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  110 
  Frontalis is a quadrilateral muscle found on the forehead that elevates the eyebrows; hence paraly sis of 
this muscle can lead to eyebrow ptosis. 
D-Penicillamine   
 used to reduce the body copper in Wilson's disease & as a chelating agent in lead

poisoning 
 D-Penicillamine  is associated with  pancytopenia and tubulointerstitial nephritis 
Isotretinoin  
 
 Isotretinoin is an oral retinoid used in the treatment of severe acne. 
 Two-thirds of patients have a long term remission or cure following a course o f oral isotretinoin 
 Teratogenicity : ♀s MUST  be using two forms of contraception (e.g. COCP and condoms).

 Women must have a negative pregnancy test before treatment 
  and be on effective contraception for at least a month before the course begins , during the 
course and for a month after it finishes  
 Congenital deafness  , CNS  and heart defects may occur in children exposed to isotretinoin in 
utero 
 Dry skin, eyes and lips: the most common side-effect of isotretinoin 
 Low mood, depression 
 Raised triglycerides 
 Hair thinning 
 Nose bleeds (caused by dryness of the nasal mucosa)

 Benign intracranial hypertension: isotretinoin treatment should not be combined with t etracyclines for 
this reason 
Cinnarizine  
 Cinnarizine is thought to be particularly useful for the treatment of motion sickness  as it has a dual 
action: 
 it acts as a depressant of the vestibular system 
 it dampens down smooth muscle contraction in the gut 

Ergotamine 
 Ergotamine is an old drug and a member of the family of ergot alkaloids.  
 It is licensed as a treatment and prophylaxis for migraines but has been largel y superseded by newer 
agents despite its efficacy, cost and relatively benign side effect profile.  
 A derivative of the drug, ergometrine, is used in obstetrics to reduce the incidence of post partum 
haemorrhage.

haemorrhage. 
  Ergotamine, like all ergot alkaloids, is a potent vasoconstrictor which is partly  how it exerts its clinical 
effects, however in overdosage it can cause significant peripheral vasoconstriction causin g critical 
ischaemia and gangrene. Coronary vasoconstriction may occur, with or without flow lim iting lesions 
causing cardiac ischaemia which may be manifest as chest pain, arrhythmia or even sudden death.

 Contraindications to the use of ergotamine are flow limiting coronary lesions or peripheral vascular 
disease. 
  Additionally, ergotamine has a complex series of effects on central nervous ne urotransmitter systems 
including serotonergic, dopaminergic and noradrenergic systems which can cause excitement,  
confusion, paranoia, visual and auditory hallucinations and delusions in overdose. 
1767

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  111 
   It is also a metabolic precursor to the highly hallucinogenic chemical lysergic acid diethylamide (LSD) 
which inactivates 5-HT2A receptors in the brain.  
 At normal doses, side effects of ergotamine are relatively minor and unlikely t o cause significant clinical

signs in the absence of underlying pathology. However, metabolism of ergot  alkaloids is predominantly 
by the hepatic enzyme CYP3A4 which is almost totally inhibited by macrolide antibiotics. Co-
administration of ergotamine and clarithromycin may be expected to produce a rapi d picture of ergotism 
with confusion, psychosis, muscle cramps, seizures, peripheral and coronary vasospasm, severe 
headache and gastrointestinal symptoms of bowel ischaemia, cramps, diarrhoea and GI ha emorrhage.

Myocardial infarction, renal infarction, stroke and critical limb ischaemia may occur if not treated. 
  Interestingly, ergot alkaloid derivatives are naturally produced by the fungus Claviceps pu rpurea which 
may infect crops.  
 Historically, significant outbreaks of ergotism have been seen due to ingestion of crops contaminated 
with ergot and there is some historical evidence that claims of witchcraft are asc ribable to the psychosis 
of ergot poisoning.

of ergot poisoning. 
Finasteride 
 
 Finasteride is an inhibitor of 5 alpha-reductase.  
 5-α-Reductase converts testosterone to dihydrotestosterone (DHT) 
 DHT is much more active than testosterone and binds more avidly to cytoplasmic receptors 
 DHT stimulates prostate growth and may be responsible for benign prostatic hyperpl asia in the elderly 
 
 benign prostatic hyperplasia 
 male-pattern baldness

 impotence 
 decrease libido 
 ejaculation disorders 
 gynaecomastia and breast tenderness 
Finasteride causes decreased levels of serum prostate specific antigen 
____ ______________________________________________________________  
Acetazolamide 
Action 
 carbonic anhydrase inhibitor , hence causing the accumulation of carbonic acid 
 Inhibits proximal tubule  bicarbonate reabsorption  in a similar fashion to type-2 renal tubular acidosis

(RTA)  associated with metabolic acidosis 
 By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation with deep  
respiration (Kussmaul respiration), increasing levels of oxygen and decreasing level s of carbon dioxide 
in the blood. Hence used in  treatment of high altitude sickness.  
 intracranial hypertension  
 post-haemorrhagic hydrocephalus (often with furosemide)

 primary idiopathic pseudotumour cerebri (benign intracranial hypertension) 
 reducing intraocular pressure 
 prevent acute mountain sickness  
 preventative agent for contrast nephropathy 
 metabolic acidosis, due to bicarbonate loss in the proximal and distal tubules through inhibition of 
 hyperchloraemic, normal anion gap metabolic acidosis . 
 Acute interstitial nephritis (AIN)  
 Agranulocytosis and thrombocytopenia 
 hyponatremia,

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  112 
   hyperglycemia, hypoglycemia, glycosuria,  
 crystalluria  (and hematuria), and polyuria.  
 peripheral paresthesiae 
carbonic anhydrase works to control the equilibrium between carbon dioxide and carbonic acid in order  to 
maintain proper blood pH. Through which mechanism does carbonic anhydrase  exert its influence on

reaction kinetics? 
 Lowers the activation energy  
 Enzymes like carbonic anhydrase  lower the energy of activation that is needed to initiate a 
reaction.  
 Inhibition of carbonic anhydrase prevents the conversion of carbon dioxide (CO 2) and 
water (H2O) to carbonic acid (H2O3) thus affecting the blood pH.  
 
Bicarbonate therapy

Bicarbonate therapy  
 Can increase extracellular pH only if the carbon dioxide (CO 2) produced can be removed by adequate 
 Indeed, if hypercapnia occurs then as CO 2 crosses cell membranes easily, intracellular pH may 
decrease even further with further deterioration of cellular function. 
 Bicarbonate has a negative inotropic effect, 
  reducing cerebral blood flow; 
  It shifts the oxygen dissociation curve to the left, inhibiting oxygen rel ease to tissues.

 Exacerbates intracellular acidosis   in cardiorespiratory arrest 
Bisphosphonates 
 
Bisphosphonates are analogues of pyrophosphate, a molecule which decreases demineralisation in bone. 
They inhibit osteoclasts  by reducing recruitment and promoting apoptosis. 
 
The mechanism of action  of bisphosphonates involves the inhibition of farnesyl diphosphate synthase within

osteoclasts. In doing this they interfere with geranylgeranylation (attachment of the lipid t o regulatory proteins), 
which causes osteoclast inactivation. This leads to reduced bone turnover, increased bone mass and i mproved 
mineralisation. 
 
Clinical uses  
 prevention and treatment of osteoporosis 
 Bisphosphonates licensed for the prevention and treatment of osteoporosis  include  
alendronate, risedronate and ibandronate. 
 hypercalcaemia 
 Paget's disease

 Paget's disease 
 pain from bone metastases 
 The bisphosphonates zoledronate and pamidronate are used for the treatment of metast atic 
bone disease and short term management of hypercalcaemia. 
 
 oesophageal reactions: oesophagitis, oesophageal ulcers (especially alendronate) 
 osteonecrosis of the jaw: 
 This is a consequence of potent anti-resorptive action of the nitrogen contai ning 
bisphosphonates. 
1769

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  113 
  Most cases have been associated with zoledronic acid  and pamidronate given intravenously 
for metastatic bone disease. 
  The reported incidence in patients with malignancy treated with these drugs i s between 1.3-
4.0%. 
 Dental disease is a recognised predisposing factor.

 The lesions usually heal with minimal surgical debridement, chlorhexidine mouthwashes, 
antibiotics and analgesia. 
 Bisphosphonate infusions can lead to hypocalcaemia  although it is more common when using 
larger doses in malignancy induced hypercalcaemia as oppose to the smaller dose used in 
 increased risk of atypical stress fractures of the proximal femoral shaft in patients tak ing alendronate

The BNF suggests the following counselling for patients taking oral bisphosphon ates 
 'Tablets should be swallowed whole with plenty of water while sitting or standing; to  be given on an 
empty stomach at least 30 minutes before breakfast (or another oral medication); patien t should stand 
or sit upright for at least 30 minutes after taking tablet' 
Botulinum toxin

Botulinum toxin 
As well as the well publicised cosmetic uses of Botulinum toxin ('Botox') ther e are also a number of licensed 
indications:  
 blepharospasm 
 hemifacial spasm 
 focal spasticity including cerebral palsy patients, hand and wrist disability associated wi th stroke 
 spasmodic torticollis 
 severe hyperhidrosis of the axillae 
 achalasia 
Immunoglobulins: Therapeutics

Immunoglobulins: Therapeutics  
The Department of Health issued guidelines on the use of intravenous immunoglob ulins in May 2008  
Uses  
 Primary and secondary immunodeficiency 
 Idiopathic thrombocytopenic purpura (ITP) 
 Myasthenia gravis 
 Toxic epidermal necrolysis (TEN) 
 Pneumonitis induced by CMV following transplantation 
 Low serum IgG levels following hematopoietic stem cell transplant for malignancy  
 Dermatomyositis

 Dermatomyositis 
 Chronic inflammatory demyelinating polyradiculopathy 
Basics  
 Formed from large pool of donors (e.g. 5,000) 
 Half-life of 3 weeks 
Malignant hyperthermia (MH) 
Overview 
 condition often seen following administration of anaesthetic agents

 characterised by increased temperature and muscle rigidity during anaesthesia, which result s from 
abnormal skeletal muscle contraction and increased metabolism. 
 caused by excessive release of Ca2+ from the sarcoplasmic reticulum of skeletal muscle 
 associated with defects in a gene on chromosome 19 encoding the ryanodine receptor, which contr ols 
Ca2+ release from the sarcoplasmic reticulum 
 neuroleptic malignant syndrome may have a similar aetiology 
Causative agents

Causative agents 
 halothane ( volatile anaesthetic agents) 1770

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  114 
  suxamethonium 
 other drugs: antipsychotics (neuroleptic malignant syndrome) 
 Serum creatine kinase(CK) elevation and myoglobinuria are suggestive but not diagnostic of M H.(both 
known to increase after giving suxamethonium to normal patients)

 Contracture tests with halothane and caffeine  are the investigations of choice.  
 Muscle biopsies may appear histologically normal. 
 dantrolene - prevents Ca2+ release from the sarcoplasmic reticulum 
 Intravenous dantrolene (up to 10 mg/kg) is the only available specific treatment   
 Care must be taken when administering as the solution has a pH of 9- 10. 
Prognosis 
 The prognosis of malignant hyperpyrexia is good when the appropriate treatment  is instigated early,

mortality being less than 5% (prior to dantrolene the mortality was 80%).  
Intravenous fluid therapy  
 
Intravenous fluid therapy in adults in hospital ( NICE guidelines 2013)  
 Indicators for urgent fluid resuscitation : 
 systolic blood pressure is less than 100 mmHg 
 heart rate is more than 90 beats per minute 
 capillary refill time is more than 2 seconds or peripheries are cold to touch

 respiratory rate is more than 20 breaths per minute 
 National Early Warning Score (NEWS) is 5 or more 
 passive leg raising suggests fluid responsiveness 
  Resuscitation 
 If patients need IV fluid resuscitation, use crystalloids that contain sodium in the rang e 130 –154 mmol/l, 
with a bolus of 500 ml over less than 15 minutes. 
 Consider human albumin solution 4 –5% for fluid resuscitation only in patients with severe sepsis. 
 Routine maintenance

 Routine maintenance 
 If patients need IV fluids for routine maintenance alone, restrict the initial prescription to: 
 25–30 ml/kg/day of water and 
 approximately 1 mmol/kg/day of potassium, sodium and chloride and 
 approximately 50 –100 g/day of glucose to limit starvation ketosis. (This quantity will not address 
patients' nutritional needs) 
1771

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  115 
 (patients rarely need more than a total of 3 litres of fluid per day)   
 Consider prescribing less fluid (for example, 20 –25 ml/kg/day fluid) for patients who: 
 are older or frail 
 have renal impairment or cardiac failure 
 are malnourished and at risk of refeeding syndrome

 When prescribing for routine maintenance alone, consider using 25 –30 ml/kg/day sodium chloride 
0.18% in 4% glucose with 27 mmol/l potassium on day 1. 
  Prescribing more than 2.5 litres per day increases the risk of hyponatraemia. These are initial 
prescriptions and further prescriptions should be guided by monitoring.  
 Consider delivering IV fluids for routine maintenance during daytime hours t o promote sleep and 
wellbeing.

wellbeing.  
 
British Consensus Guidelines on Intravenous Fluid Therapy (2011) 
Recommendation  
• Because of the risk of inducing hyperchloraemic acidosis  in routine practice, when crystalloid 
resuscitation or replacement is indicated, balanced salt solutions e.g. Ringer ’s lactate/acetate or 
Hartmann ’s solution should replace 0.9% saline , except in cases of hypochloraemia e.g. from 
vomiting or gastric drainage.

vomiting or gastric drainage. 
• Hypochloraemia is an indication for the use of 0.9% saline, with sufficient additi ons of potassium and 
care not to produce sodium overload.  
• Losses from diarrhoea/ileostomy/small bowel fistula/ileus/obstruction should be repl aced volume for 
volume with Hartmann ’s or Ringer-Lactate/acetate type solutions.  
• “Saline depletion, ” for example due to excessive diuretic exposure, is best managed with a balanced 
electrolyte solution such as Hartmann's.

electrolyte solution such as Hartmann's. 
Daily requirement  
 The typical daily requirement is: 
 1.5 ml/kg/hr fluid - for a 80kg man around 2-3 litres/day 
 70-150mmol sodium 
 40-70mmol potassium 
 This is why the typical regime prescribed for patients is: 
 1 litre 5% dextrose with 20mmol potassium over 8 hours 
 1 litre 0.9% normal saline with 20mmol potassium over 8 hours 
 
The table below shows the electrolyte concentrations (in millimoles/litre) of plasma and the most

commonly used fluids : 
Na+ Cl- K+ HCO3- Ca2+ 
Plasma  135-145 98-105 3.5-5 22-28 2.3-2.6 
0.9% normal saline  150 150 - - - 
5% dextrose  - - - - - 
Hartmann's solution  131 111 5 29 2 
 
Normal saline has a pH of 5 and may produce a mild metabolic acidosis with significant i nfusions.  
 
Lactulose   
 Lactulose MOA  Osmotic laxative 
 Causes hypomagnesaemia associated with diarrhoea 
 Is not absorbed

 Is not absorbed 
 Does not affect the absorption of spironolactone and 
 May be used in diabetics. 
 It reduces proliferation of ammonia producing bacteria 1772

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  116 
 It is used in patients with cirrhosis/hepatic encephalopathy to limit the proliferation o f ammonia-
forming gut organisms and increase the clearance of protein load in the gut. 
 lactulose  broken down by colonic bacteria  production of lactic acid and other organic

acids  contents of the gut become more acidic  (Ļ PH)  ↓↓ absorption of ammonia   
↑↑ ammonia in the gut    ↑↑ water drawn into the lower bowel  
 
laxative abuse  
Features 
 most commonly seen in young female patients complaining of chronic diarrhoea.  
 The diarrhoea is frequently high volume  
 underweight  girl with calluses on her knuckles may point towards induced vomiting and a di agnosis of 
bulimia, which would fit with possible laxative abuse.  

 Hypokalaemia  
 Due to increased GI potassium loss  
 symptoms of fatigue which are consistent with hypokalaemia.  
 GI loss leads to renal conservation of potassium, a urinary concentration of potassium of 
less than 1 mmol/l being highly suggestive of laxative abuse.  
Bismuth   
 subsalicylate is a colloidal substance frequently included in over-the-counter treatments  for 
gastrointestinal discomfort.

gastrointestinal discomfort. 
 It has anti-secretory, anti-inflammatory, and antibacterial properties.  
 It may be included in multidrug regimens against H. pylori .  
 Its most unique side-effect is the appearance of black stool or a black t ongue, both secondary to the 
drug's interaction with sulfur. 
Non-steroidal an ti-inflammatory drugs (NSAID) 
 
Non-steroidal anti-inflammatory drugs (Nice 2015)

• If an NSAID is needed, use ibuprofen (1200 mg a day or less) or naproxen (10 00 mg a day or less). 
• Naproxen (1000 mg a day or less) and low-dose ibuprofen (1200 mg a day or less) are con sidered to 
have the most favourable thrombotic cardiovascular safety profiles of all NSAI Ds. 
• Co-prescribe gastroprotective treatment (a proton pump inhibitor) with NSAIDs  
• In October 2012, a European Medicines Agency (EMA) review on the cardiovascu lar safety of NSAIDs

confirmed that diclofenac is associated with cardiovascular risks that are higher  than ibuprofen and 
naproxen, and similar to the COX-2 inhibitors. 
• etoricoxib should not be prescribed to people whose blood pressure is persistently above 140/90 
mmHg 
• the arterial thrombotic risk with diclofenac is similar to that of COX -2 inhibitors. 
• diclofenac is now contraindicated in patients with established:  
 peripheral arterial disease 
 cerebrovascular disease

 cerebrovascular disease 
 congestive heart failure (New York Heart Association [NYHA] classification II –IV) 
 
1773

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  117 
 Indometacin  is an inhibitor of both prostaglandin synthase and lipoxygenase enzymes 
 
 Current evidence suggests that naproxen, a nonselective NSAID, is associated with t he lowest risk 
of cardiovascular events. Therefore, naproxen is the NSAID of choice in patients w ith high 
cardiovascular risk.

cardiovascular risk.  
 Optic neuritis is described as being rarely associated with diclofenac therapy. 
 A range of other CNS side effects has also been noted on the summary of product charact eristics, these 
include headache, dizziness, vertigo and in rare circumstances drowsiness.  
 gastrointestinal bleeding occurs due to depletion of mucosal prostaglandin E (PGE) levels  
 Endoscopic evidence of peptic ulceration is found in 20% of NSAID users even in the absen ce of 
symptoms

symptoms 
 The relative risk of causing Gl bleeds differs with different preparations: 
 ibuprofen has a low risk  
 piroxicam and azapropazone have the highest risk 
 While all NSAIDs may contribute to anaemia, usually via gastrointestinal blee ding,  mefenamic acid is 
particularly associated with immune haemolytic anaemia . 
 
Non-steroidal anti-inflammatory drugs are contraindicated in chronic liver disease  for a variety of 
reasons:

reasons: 
 their gastrointestinal side effects increase the risk of bleeding, particularly in those with varices. 
 Additionally due to systemic vasodilatation renal circulation is very dependent upon prostaglandin 
production to maintain glomerular filtration. Inhibition of this mechanism by non-steroi dals, in addition to 
their other nephrotoxic effects, means that their use in patients with chron ic liver disease, especially

where there is pre-existing renal impairment, can precipitate renal failure. 
 
Overdose with (NSAIDs) 
Presentation and aetiology 
 GIT upset (epigastric tenderness, nausea, vomiting and diarrhea) 
These effects are mainly due to the inhibition of cyclo-oxygenase 
 convulsions   (10-20%)  more common in mefenamic acid over dose  
Large overdoses can present with: 
 acidosis 
 gastrointestinal haemorrhage 
 CNS effects (drowsiness, coma, cerebellar signs) 

 Activated charcoal in patients presenting within the first hour 
 Supportive care 
 Oral H2-histamine blockers and proton-pump inhibitors may reduce the symptoms o f gastrointestinal 
toxicity 
Celecoxib (COX)-2 inhibitor ) 
Celecoxib  is an NSAID that is safe to use in patients with gastritis or gastric ulcers as it does not affect 
COX1 action at the stomach. 
Action

Action 
 Celecoxib is a selective cyclo-oxygenase(COX)-2 inhibitor   
 differing from the other non-steroidal anti-inflammatory drugs (NSAI Ds) such as naproxen which 
affects both COX-1 and COX- 2. 
 COX-1 is involved in platelet aggregation and inhibition of this by the NS AIDs produces its 
beneficial cardiovascular effects.  
 platelet aggregation is not affected by COX- 2. 
 Celecoxib has a lower level of anti-platelet activity than naproxen  
Advantages

 Naproxen and celecoxib have been shown to be as effective at reducing inflammation.  
 One of the benefits of celecoxib is its reduced incidence of upper gastrointes tinal side effects. 
 As with the non-specific NSAIDS,  hepatotoxicity  may occur with the COX-2 specific inhibitors resulting 1774

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  118 
 in cholestatic, hepatocellular or mixed liver injury. Rates seem to be comparable between the t raditional 
NSAIDs and the COX-2 selective inhibitors. 
 The cardiovascular effects  of the COX-2 inhibitors remains under study, and care should be taken

before prescribing them to patients with a past medical history of significant cardiov ascular disease. 
 Rofecoxib (Vioxx) has been withdrawn due to its increased cardiovascular events compared with 
naproxen.  
 What is the mechanism of celecoxib-induced deterioration in renal function? 
 inhibition of afferent arteriole vasodilatation 
 
 Co-administration of diuretics  and COX-2 inhibitors should be avoided if possible, as COX- 2

inhibitors may reduce the antihypertensive and diuretic effects of diuretics. This may be  due to impaired 
prostaglandin synthesis, which results in salt and water retention. In addition, COX-2 inh ibitors have 
nephrotoxic effects which can be exacerbated by diuretics. 
Aminosalicylate drugs 
 5-aminosalicyclic acid (5-ASA) is released in the colon and is not absorbed. It acts locally  as an anti-

inflammatory. The mechanism of action is not fully understood but 5-ASA  may inhibit prostaglandin 
synthesis 
 The safety of the 5-aminosalicylic acid (5-ASA) drugs in pregnancy is be st supported by the data on 
Salazopyrin which have been available for the longest.  
 
Sulphasalazine  
 a combination of sulphapyridine (a sulphonamide) and 5- ASA 
 many side-effects are due to the sulphapyridine moiety: rashes, oligospermia, heada che, Heinz body 
anaemia, megaloblastic anaemia

anaemia, megaloblastic anaemia 
 other side-effects are common to 5-ASA drugs (see mesalazine) 
Mesalazine 
 a delayed release form of 5- ASA 
 sulphapyridine side-effects seen in patients taking sulphasalazine are avoided 
 side-effects: GI upset, headache, agranulocytosis, pancreatitis, interstitial nephritis 
- pancreatitis is 7 times more common in patients taking mesalazine than sulfasa lazine 
Olsalazine

Olsalazine 
 two molecules of 5-ASA linked by a diazo bond, which is broken by colonic bacteria 
Anti-TNF therapy (NICE January 2016)  
 
Drugs   
 adali mumab , Goli mumab ,  inflixi mab,  certoli zumab , tocilizumab  
 etaner cept, abata cept,  
Action 
 tumour necrosis factor alpha (TNF- α) inhibitors  
 Refractory Crohn's disease,

 Refractory Crohn's disease,  
 rheumatoid arthritis : for adults who have both the following characteristics:  
 Active rheumatoid arthritis  as measured by disease activity score  (DAS 28) greater than 5.1 
confirmed on at least two occasions, 1 month apart. 
 Have undergone trials of two disease-modifying anti-rheumatic drugs (DMARDs), including 
methotrexate (unless contraindicated).  
 A trial of a DMARD is defined as being normally of 6 months, with 2 months at standard

dose, unless significant toxicity has limited the dose or duration of treatm ent. 
1775

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  119 
  Use of the TNF- α inhibitors for  rheumatoid arthritis in adults not previously treated 
with methotrexate or other DMARDs is not recommended. 
 Follow up  
 Continue treatment only if there is a moderate response measured using European 
League Against Rheumatism (EULAR) criteria at 6 months after starting therapy .

 monitored 6-monthly   
 withdraw treatment if a moderate EULAR response is not maintained. 
 Plaque psoriasis   
 Adalimumab is recommended for adults with plaque psoriasis  only if:  
 condition is severe  and 
 not improved with other treatments  such as ciclosporin, methotrexate and PUVA 
(psoralen and long-wave ultraviolet radiation), or they have had side effects with t hese in 
the past or there is a medical reason why they should not be given these t reatments. 
 Follow up

 Follow up  
 Adalimumab treatment should be continued beyond 16 weeks  only if the psoriasis has 
clearly improved within this time.  
 ankylosing spondylitis  
 NICE states that adalimumab, etanercept and golimumab may be used for ankyl osing 
spondylitis (AS) only if:  
 treatment with two or more NSAIDs for four weeks at the highest possible dose has not 
controlled the symptoms 
 confirms that condition has not improved  by 2 methods:

1) level of pain is assessed twice  (using a simple scale to fill in) 12 weeks apart 
and confirms that condition has not improved  
2) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)  is tested 
twice, 12 weeks apart, and confirms that condition has not improved   
 BASDAI is a set of measures to evaluate condition, by asking a number 
of questions about symptoms 
 Reactions  
 Injection site reactions 
 Cutaneous reactions, including psoriasis

 Cutaneous reactions, including psoriasis 
 Infusion reactions 
 Infusion reactions with infliximab are classified as one of two types: 
 Acute reactions : occur within 24 hours.  
 Delayed reactions: develop between 1 and 14 days   
 risk of reactivation of tuberculosis or new infection 
 including miliary TB and some unusual extra-pulmonary TB  
 If patient had previous active TB, the optimal TB screening test in this situa tion

Interferon gamma release assay  
 Demyelinating disease  exacerbation of neurologic disorders associated with demyelination, such as 
multiple sclerosis. 
 Given the evidence to date, patients with symptomatic HF should be treated with stra tegies 
other than TNF-alpha inhibitors. 
  In a patient who develops HF while on a TNF-alpha inhibitor, a drug-induced cause should be 
 Malignancy 
 Induction of autoimmunity 
 
Usage

Usage 
 Prior to initiating  a TNF-alpha inhibitor, all patients should be screened for : 
 tuberculosis ,  
 hepatitis B, and  
 hepatitis C. 1776

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  120 
  All forms of anti-TNF therapy are given by injection. 
 Etanercept  is given as subcutaneous  injection twice per week. 
 Infliximab is given as an infusion (intravenous).   
 requires intravenous infusion in a hospital setting.  
 It is given 2-4 weekly initially and then on a 6-8 weekly basis and as per protocol.

 Infliximab monotherapy induces the production of anti-infliximab antibodies , which 
may reduce its effectiveness. Adding methotrexate to infliximab therapy may 
prevent this response.  
 Adalimumab is given as ( subcutaneous injection ) on alternate weeks (every second week). 
 Unlike methotrexate ,  
 there is little problem with nausea.  
 Nor is there the same concern for effects on blood cells and the liver which means less blood 
tests are required.

tests are required. 
 TNF- α inhibitors should normally be used in combination with methotrexate.  
 If methotrexate is intolerant, adalimumab and etanercept may be given as monot herapy. 
 
Some other monoclonal antibodies in clinical use include: 
monoclonal antibodies Action Indication 
Digibind Digoxin-binding antibody  for treatment of overdoses 
(increases clearance). 
Abciximab Glycoprotein IIb,IIIa receptor  for unstable angina. 
Pexelizumab  Anti- C5 (complement) - anti-

 reduces myocardial infarction 
and death following coronary 
artery bypass graft (CABG) and 
angioplasty.  
Proton pump inhibitors 
 The proton pump is only contained in the tubo-vesicles of the parietal cell  secrete acid.  
 Proton-pump inhibitors (e.g omeprazole)  binds to gastric K+/H+-ATPase proton pump irreversibly

 However, as the half-life of the pump is 24-36 hours, the duration of t he effect of proton-pump inhibitors 
is limited by the degradation of these pumps.  
Sildenafil 
 
Action 
 Sildenafil is a phosphodiesterase type V inhibitor ( PDE-5 inhibitors ) used in the treatment of 
impotence.  
 It increases  intracavernosal cGMP  levels, thereby competitively inhibiting the PDE-5 enzyme , and

allowing nitric oxide-induced vasodilation . 
 it blocks cGMP phosphodiesterase , which is normally responsible for the breakdown 
of cGMP. Sildenafil therefore leads to increased levels of cGMP, which has vasodilator y effects 
to relax smooth muscle. 
1777

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  121 
  patients taking nitrates and related drugs such as nicorandil 
 recent stroke or myocardial infarction (NICE recommend waiting 6 mont hs) 
 non-arteritic anterior ischaemic optic neuropathy 
 visual disturbances e.g. blue discolouration, non-arteritic anterior ischaemic neuropathy

Sildenafil is a PDE-5 inhibitor, but at high doses it also inhibits PDE-6, which leads to blue 
discoloration of vision.This can often be managed by reducing the dose of Sildenafil.  
 nasal congestion   
 flushing 
 gastrointestinal side-effects 
 headache 
Anaesthetic drugs  
halothane hepatitis (medical-masterclass.com 2017 mrcp part 2)

 There are many causes of post-operative jaundice , but the fact that the surgery was 
uncomplicated, the time course, the presence of joint / muscle pains and an eosinophilia , all 
suggest halothane hepatitis as the most likely diagnosis. This is thought to result as a 
hypersensitivity reaction. Treatment is supportive. 
Effects on the liver 
 Halothane  
 Halothane undergoes ∼25% metabolism by oxidative phosphorylation via hepatic cytochrome 
P450 systems.

P450 systems.  
 The major metabolite is trifluoroacetic acid (TFA), which is protein-bound and this T FA–protein 
complex can induce a T-cell-mediated immune response resulting in hepatitis rangin g from mild 
transaminitis to fulminant hepatic necrosis and possibly death.  
 the risk of fatal hepatic necrosis  one in 10 000 anaesthetics.  
 Adult females are more commonly affected.  
 Repeated exposure increases the risk of hepatitis. 
 Halothane and hepatitis

 Halothane and hepatitis 
 Halothane can cause a mild liver dysfunction in approximately 30% of patients, due to 
the binding of reactive halothane metabolites to hepatocytes 
 Halothane oxidation by cytochrome P450 enzymes leads to the synthesis of 
trifluoroacetyl chloride, which covalently binds to hepatic molecules and causes an 
immune reaction Fulminant hepatitis results from the reactive metabolite, 
trifluoroacetyl chloride

trifluoroacetyl chloride  
 Further exposure to halothane anaesthesia may lead to a fulminant hepatitis, where the 
mortality is approximately 90%. 
 Less commonly hepatitis has been described after exposure to en flurane > iso flurane > desflurane .  
 Sevo flurane  is not metabolized to antigenic TFA –protein complexes.  
 Inhaled anaesthetic-like agent

Inhaled anaesthetic-like agent  
 If patient was markedly comatose on arrival but quickly regains consciousness.  This suggests a 
short acting (probably) inhaled anaesthetic-like agent  e.g Inhaled solvent glue.  
 The inhaled solvents, due to their lipophilicity, are rapidly absorbed through the  lungs and then quickly 
distributed to the brain and other organs. The effects therefore appear within m inutes of inhalation.

 Typical substances that are inhaled include toluene, aromatic hydrocarbons and buta ne. 
Pseudocholinesterase deficiency  (emedicine.medscape.com & medical-masterclass.com 2017 part 2 )  
 Pseudocholinesterase is a glycoprotein enzyme, produced by the liver.  
 It specifically hydrolyzes exogenous choline esters. 
 most common in European; rare in Asians.

 most common in European; rare in Asians.  
 Pseudocholinesterase deficiency results in delayed metabolism of the following:  
1. Succinylcholine.  depolarizing neuromuscular blocking agent (the most clinically important 
drug)  
 Suxamethonium  is a depolarising neuromuscular blocking agent,  metabolised by 
plasma pseudocholinesterases.   
 Approximately 1 in 2500 individuals have deficiency of this enzyme, resulting in 
prolonged neuromuscular blockade if they are given suxamethonium.

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  122 
 4. cocaine.  
 After an intravenous dose of succinylcholine in individuals with normal plasma levels of normally 
functioning pseudocholinesterase enzyme: 
 hydrolysis and inactivation of 90-95% of i.v succinylcholine occurs before it reaches the 
neuromuscular junction.

neuromuscular junction.  
 The remaining 5-10% of the dose acts as an acetylcholine receptor agonist at the 
neuromuscular junction, causing prolonged depolarization of the postsynaptic junction of the 
motor-end plate.  
 This depolarization initially triggers fasciculation of skeletal muscle.  
 As a result of prolonged depolarization, endogenous acetylcholine released from the 
presynaptic membrane of the motor neuron does not produce any additional change in

membrane potential after binding to its receptor on the myocyte.  
 Flaccid paralysis of skeletal muscles develops within 1 minute. 
 In normal subjects, skeletal muscle function returns to normal approximately 5 minutes after a single 
bolus injection of succinylcholine as it passively diffuses away from the neuromuscular jun ction.  
 Pseudocholinesterase deficiency can result in higher levels of intact succinylcholine mol ecules reaching

receptors in the neuromuscular junction, causing the duration of paralytic effec t to continue for as long 
as 8 hours. 
 This condition is recognized clinically when paralysis of the respiratory and other sk eletal muscles fails 
to spontaneously resolve after succinylcholine is administered as an adjunctive paralytic agen t during 
anesthesia procedures. 
 by plasma assays of pseudocholinesterase enzyme activity.  
 
 prolonged ventilation until the action of the drug wears off.  
 Relatives of affected patients should be screened. 
Prognosis 
 exposed to succinylcholine excellent when close monitoring and respiratory support measures.  
 exposed to cocaine, sudden cardiac death can occur. 
 
Succinyl choline  
 Depolarizing  Skeletal  muscle relaxants  
 Also called suxamethonium

 Also called suxamethonium 
 Analogue of acetyl choline, acts on nicotinic Nm receptors 
 Only depolarizing skeletal muscle relaxant 
 Fastest onset of action , Shortest duration of action 
 can stimulate autonomic ganglia 
 Side effect and contraindications (CI) 
 Cause hyperkalemia  in patients with nerve and muscular disorders so CI in : 
 nerve disorders (Paraplegia, hemiplegia, GBS) and  
 muscular disorders(muscular dystrophy, Myasthenia, crush injury, burns , 
rhabdomyolysis)

rhabdomyolysis) 
 Increases all pressures  so CI in:  
 head injury, 
 increase BP,  
 nausea and vomiting due to intragastric pressure. 
 Trigger malignant hyperthermia when used with halothane  
Local spinal anesthetics 
Hypotension and bradycardia  following spinal anesthesia suggest  neurogenic shock. 
 Local spinal anesthetics, can interrupt the transmission of nerve impulses in spinal sympat hetic

pathways, causing a loss of sympathetic vascular tone  that ultimately results in neurogenic shock.  
 Neurogenic shock is a type of distributive shock characterized by: 
 generalized vasodilation (causing diaphoresis and flushed skin ).  
 This vasodilation leads to decreased preload and subsequently reduced cardiac output, which 
results in hypotension  and bradycardia .  
 Consequently, cerebral perfusion is impaired, leading to a loss of consciousness . 
 
 1779

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  123 
Fentanyl  
 Large, rapidly given doses of specific opioids such as fentanyl, sufentanil , remifentanil, and alfentanil 
are associated with systemic skeletal muscle rigidity.

 Of most concern to the anesthesiologist is chest wall rigidity  (which impairs mask and bag 
ventilation ) and rigidity of the jaw muscles which can prevent the insertion of an 
advanced airway . 
Ketamine 
 Ketamine is commonly used as a recreational drug.  
adverse effects include: 
 stimulation, euphoria , depersonalisation, floating feeling

 synaesthesia (a sensory stimulus in one modality is perceived as a sensation in another), eg:  being 
able to 'smell sounds'   
 delirium,  
 vivid dreams  
 hallucinations. 
Topoisomerase inhibitors 
  (topoisomerase I and II) are enzymes that control the changes in DNA structure du ring the normal cell 
cycle. 
 By what mechanism does topoisomerase catalyse DNA replication?  
 Helix torsion release

 Helix torsion release  
 Topoisomerase releases torsion in the DNA helix during replication. 
 It accomplishes this by cutting the DNA helix at specific points to allow it to unravel 
and then ligates the ends together again.  This allows large proteins such as DNA 
polymerase to replicate DNA  along the sequence. 
 Topoisomerase is therefore an important target for chemotherapeutic agents such as 
topotecan which can arrest cells in S-phase and induce apoptosis.

 Topoisomerase inhibition leads to apoptosis and cell death. 
 Used in: 
 chemotherapy treatments.  
 as antibacterial agents :Quinolones (including nalidixic acid and ciprofloxacin)  
classification: 
 Topoisomerase I inhibitors: irino tecan , topo tecan , camptothecin  
 Topoisomerase II inhibitors: 
 anti-cancer: eto poside , teniposide , dox orubicin , daun orubicin ,  
 anti-bacterial : Quinolones (nalidixic acid and ciprofloxacin) 
 
Irinotecan

Irinotecan 
 Irinotecan is in topoisomerase inhibitor. 
 It works by blocking topoisomerase 1  which results in DNA  damage and cell death.  
 Its main use is in colon cancer 
 This includes the regimen FOLFIRI which consists of infusional 5-fluorouracil, l eucovorin, and 
irinotecan. 
 The most significant adverse effects of irinotecan are: 
 severe diarrhea 
 extreme suppression of the immune system 

Sodium aurothiomalate   (gold) 
 used for rheumatoid arthritis. 
 has been superceded by newer and less toxic DMARDs.  
 commonly causes trace proteinuria, and if present on its own is unimportant,  
 dermatitis, stomatitis,  
 
Antivenom 
 The adder ( Vipera berus ) is the only poisonous indigenous snake in the United Kingdom.  
 Most adder bites occur in the summer months to people walking in long grass or heathland and

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  124 
  Only 50% of bites are associated with true envenomation as snakes do not always inject v enom when 
they bite. 
 Local symptoms and signs include: 
 pain, swelling and bruising at the site of the bite and  
 painful regional lymphadenopathy. 
 Systemic features of envenomation may be divided into two types:

 Early anaphylactoid symptoms that include: 
 nausea, vomiting, abdominal pain, diarrhoea,  
 transient hypotension with syncope,  
 angioedema or urticarial 
 Some patients later have: 
 persistent hypotension,  
 ECG abnormalities,  
 coagulopathy or spontaneous bleeding,  
 adult respiratory distress syndrome, and  
 acute renal failure. 
 There is frequently a leukocytosis (WBC > 15 ×109/L)  
 serum creatine kinase may be elevated.  

 Fatalities are rare following adder bites, though they may be associated with si gnificant 
morbidity especially tissue necrosis at the site of the bite in adults. 
 usually supportive.  
 The bitten limb should be immobilised and a ligature is not necessary unless a delay is 
anticipated before admission to hospital.  
 Any patient who shows signs of envenomation needs to be admitted to hospital and monitored 
for 24 hours.

for 24 hours.  
 Regular monitoring should consist of measurement of pulse, blood pressure, urine output and 
the degree of swelling of the bitten limb should be recorded.  
 Early anaphylactoid symptoms may be treated with adrenaline. 
 European viper venom antiserum is available and should be considered in the following 
situations: 
 Persistent hypotension 
 ECG abnormalities 
 Haemostatic abnormalities 
 Marked local tissue swelling extending proximally (extending above the ankle or

wrist [if bitten on the hand/foot] within four hours of the bite). 
 Antivenom administration 
 given by intravenous injection over 10-15 minutes or by intravenous infusion over 30 
minutes 
 may be repeated after 12 hours if symptoms of systemic envenoming persist. 
 Anaphylactic reactions occur in 1% of patients during administration of antivenom  
 history of asthma or other allergy is a relative contraindication to its use.

 Adrenaline should be available for immediate use while the antivenom is infused in case 
a severe anaphylactic reaction occurs. 
 
Weeverfish ( Trachinus vipera )  
 The weeverfish ( Trachinus vipera ) lives in shallow waters around the coast of the United Kingdom. 
 This small, sandy-coloured fish has sharp dorsal opercular spines that are attached to subcutaneous 
poison glands.  
 Most stings from the weeverfish occur in the summer months in bare-footed bat hers who step on the

fish in shallow water, but stings also occur in anglers who attempt to grasp the fish whe n caught on a 
line. 
 The sting of the fish causes intense pain at the site of the wound.  
 The toxin produced by the fish is heat-labile and is denatured at temperatures above 40°C.  
 Treatment of a weeverfish sting should include cleansing of the wound and immersion in hot water  
(as hot as can be borne), ideally around 45°C. 
 
 Jellyfish sting

Jellyfish sting 
 The jellyfish with the most severe sting in British waters is the Portug uese man- of-war.  
 The Portuguese man- of-war (Physalia physalis ) - actually a form of plankton and not a jellyfish - can 
give a fatal sting in susceptible individuals.  
 A slurry of sodium bicarbonate  has been shown to be of benefit in treating stings from all 
UK species - and is therefore a better choice when it is uncertain which species is 1781

Notes & Notes for MRCP                                                                                               By Dr. Yousif Abdallah Hamad  125 
 responsible.  
 1782