Extrahepatic manifestations of hepatitis C.It is well established that chronic hepatitis Chronic hepatitis
Long lasting inflammation of the liver due to viruses or other causes.
Mentioned in: Tube Compression of the Esophagus and Stomach
chronic hepatitis C virus (HCV HCV
hepatitis C virus
HCV 1 Hepatitis C virus, see there 2. Human coronavirus. See Coronavirus. ) infection may lead to the development of progressive liver disease Liver Disease Definition
Liver disease is a general term for any damage that reduces the functioning of the liver.
The liver is a large, solid organ located in the upper right-hand side of the abdomen. and cirrhosis of liver. For example, chronic HCV leads to cirrhosis in 20% of patients over 20 to 30 years. (1) This has lead to considerable focus on the hepatic manifestations of the HCV. However, there are research studies indicating that HCV is associated with various extrahepatic ex·tra·he·pat·ic
Originating or occurring outside the liver. manifestations including mixed cryoglobulinemia mixed cryoglobulinemia Mixed polyclonal-polyclonal cryoglobulinemia Nephrology A form of cryoglobulinemia characterized by a IgG & IgM, ± IgA cryoglobulins, evoked by to rheumatoid arthritis, SLE, Sjögren syndrome, EBV, CMV, subacute bacterial (MC), membranoproliferative glomerulonephritis mem·bra·no·pro·lif·er·a·tive glomerulonephritis
Chronic glomerulonephritis characterized by mesangial cell proliferation, increased lobular separation of glomeruli, thickening of glomerular capillary walls, and low serum levels of complement. (MPGN MPGN Membranoproliferative glomerulonephritis, see there ), non-Hodgkin lymphoma, Sjogren syndrome Sjögren syndrome Rheumatology An autoimmune disorder more common in older ♀, associated with rheumatoid arthritis, SLE, scleroderma, polymyositis, and other connective tissue diseases Clinical Dry eyes, dry mouth Lab SS-A, SS-B antibodies Management , porphyria Porphyria
comes in a winter storm to show her devotion, and her lover strangles her with her own tresses. [Br. Poetry: Browning Porphyria’s Lover in Magill IV, 247]
See : Love, Unrequited cutaneous cutaneous /cu·ta·ne·ous/ (ku-ta´ne-us) pertaining to the skin.
Of, relating to, or affecting the skin.
Pertaining to the skin. tarda, lichen planus Lichen Planus Definition
Lichen planus is a skin condition of unknown origin that produces small, shiny, flat-topped, itchy pink or purple raised spots on the wrists, forearms or lower legs, especially in middle-aged patients. , leukocytoclastic vasculitis, and various endocrine and neurologic manifestations. (1-5) Approximately 40% of patients with HCV have cryoglobulinemia with or without specific extrahepatic manifestation. (4-6) It has been suggested that focus on comorbid extrahepatic disorders may lead to better detection of HCV, improvement in these disorders due to antiviral treatment of HCV, and early diagnosis and treatment of these disorders. (7) More importantly, these manifestations can complicate the course and treatment of HCV-related liver diseases. For example, MC associated with HCV has been linked to increased fibrosis and cirrhosis of liver. Furthermore, it is possible that drug treatment of extrahepatic disorders may cause hepatotoxicity hepatotoxicity (hepˑ··tō·t including liver failure. Hence, recognition of type and magnitude of extrahepatic disorders, including their pathophysiology pathophysiology /patho·phys·i·ol·o·gy/ (-fiz?e-ol´ah-je) the physiology of disordered function.
1. , are very important to aid in awareness, early diagnosis, and specifically targeted therapy for HCV-related extrahepatic diseases.
MC is an autoimmune disease associated with chronic HCV. MC has frequently been implicated im·pli·cate
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.
2. in increased fibrosis or cirrhosis in chronic HCV-infected patients. (6,8-11) The pathophysiologic mechanism of MC can also explain other extrahepatic syndromes such as MPGN, non-Hodgkin lymphoma, and leukocytoclastic vasculitis. (12-14) It has been postulated that HCV infects circulating B lymphocytes and can stimulate them to produce monoclonal immunoglobulin M (IgM) rheumatoid factor (Type II) and polyclonal polyclonal /poly·clo·nal/ (-klon´'l)
1. derived from different cells.
2. pertaining to several clones.
derived from different cells; pertaining to several clones. IgM rheumatoid factor (Type III) leading to mixed cryoglobulinemia. (15-16) These IgM rheumatoid factors bind with anti-HCV immunoglobulin G (IgG) or to the IgG-HCV immune complex leading to a deposition of circulating immune complexes in small- or medium-sized blood vessels ultimately resulting in essential MC, MPGN, MPGN and leukocytoclastic vasculitis. (17-18)
The exact nature of the relationship between MC and progressive liver disease remains unclear. It has been hypothesized that the association between cirrhosis and MC may be due to the association of cryoglobulin cryoglobulin /cryo·glob·u·lin/ (-glob´u-lin) an abnormal globulin that precipitates at low temperatures and redissolves at 37° C.
n. with longstanding HCV infection and older age. (10) However, fibrosis progression rate is clearly shown to be related to duration of infection rather than MC. (19) Furthermore, Siagris et al reported no significant correlation of duration of infection or older age with prevalence of MC in HCV-infected patients. (10) Hence, it is still not clear from the findings that the development of MC is cause or effect of progressive liver fibrosis or cirrhosis in chronic HCV infection. Further prospective longitudinal studies with histologic evaluation of liver biopsies comparing chronic HCV patients with or without cryoglobulinemia are warranted to clarify molecular and clinical relationship between MC and liver fibrosis.
Various neurologic manifestations have been reported in patients with chronic hepatitis C. (20-21) The most common peripheral neurologic deficit is mononeuropathy multiplex, which is clearly related to cryoglobulinemia, vasculitis Vasculitis Definition
Vasculitis refers to a varied group of disorders which all share a common underlying problem of inflammation of a blood vessel or blood vessels. The inflammation may affect any size blood vessel, anywhere in the body. , and thrombosis. (20-21) Other neurologic disorders associated with HCV include acute inflammatory syndromes, such as encephalitis encephalitis (ĕnsĕf'əlī`təs), general term used to describe a diffuse inflammation of the brain and spinal cord, usually of viral origin, often transmitted by mosquitoes, in contrast to a bacterial infection of the meninges , and encephalomyelitis encephalomyelitis /en·ceph·a·lo·my·eli·tis/ (en-sef?ah-lo-mi?e-li´tis) inflammation of the brain and spinal cord.
acute disseminated encephalomyelitis . It has been postulated that, since HCV belongs to a family of Flaviviridae, which is characterized by neurotropism neurotropism /neu·rot·ro·pism/ (ndbobr-rot´ro-pizm)
1. the quality of having a special affinity for nervous tissue.
2. , it has the ability to invade the nervous system. HCV RNA RNA: see nucleic acid.
in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic is seen in affected brain tissue or cerebrospinal fluid (22-24) of patients with certain acute inflammatory central nervous system syndromes. Negative-strand HCV was identified in brain tissue of two patients with post-transplantation recurrent HCV and three of six autopsied patients with chronic HCV infection. (25-26) These findings support the idea that HCV may cause neurologic deficits or symptoms directly by invading and replicating in the nervous system. However, due to lack of suitable methodologies for in situ detection, it is unclear whether HCV has the same abilities of infection of the nervous system as its class. As of yet, the pathogenesis of nervous system involvement remains unclear because it can be attributed to in situ HCV replication, toxicity of HCV-encoded proteins, or immune-mediated antiviral response. Further basic virologic and clinical studies will be necessary to fully understand the viral interaction with the nervous system and the resulting neurologic symptoms.
Type II diabetes Type II diabetes
Type II diabetes is the most common form of diabetes and usually appears in middle aged adults. It is often associated with obesity and may be delayed or controlled with diet and exercise.
Mentioned in: Diabetic Ketoacidosis mellitus (DM) has been implicated as an important endocrine manifestation of chronic HCV. (27-30) Even though there is no formal proof for the infectious disease model for type II DM, it has been hypothesized that HCV mediates type II DM in genetically susceptible individuals. Thuluvath et al provided support for both racial and environmental factors for infectious disease model for the development of DM in chronic HCV. (31) They reported an increased prevalence of type II DM in black patients with HCV compared with controls matched for race, severity of liver disease, and body mass index. This finding is significant since both HCV infection and black race have been reported as independent risk factors for type II DM. (32-33) It has been noted that HCV-positive diabetics have beta-islet cell dysfunction with decreased C-peptide levels and limited acute insulin responses. (11,32) In addition, an improvement of glucose metabolism have been observed after antiviral therapy in patients with chronic HCV even though there is no animal or in vitro models to test the hypothesis that HCV directly damage beta islet cells or disturbs their synthetic function. (11) Therefore, further genetic, animal model, tissue culture media, and mechanistic studies are needed to determine the role of HCV on glucose metabolism and pancreatic disease that leads to type II DM. In addition, prospective longitudinal studies are needed in chronic HCV patients on antiviral therapy to determine whether DM is a reversible process in patients who clear HCV infection.
In conclusion, HCV may lead to various extrahepatic manifestations. The majority of extrahepatic manifestations can be explained in terms of an immune-mediated syndrome related to MC even though the exact mechanism by which HCV may result in MC is still not clear. Furthermore, MC is associated with increased fibrosis and cirrhosis. Hence, early treatment of HCV infection in patients with MC may decrease the rate of fibrosis and may prevent cirrhosis including its complications. Mechanisms of other extrahepatic manifestations such as neurologic manifestations and DM related to chronic HCV are unclear and necessitate further research to clarify pathophysiology and clinical course of extrahepatic manifestations of chronic HCV.
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pertaining to or emanating from serology.
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It includes amongst others:
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A watery or thin mucous discharge from the eyes or nose.
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polymerase chain reaction
Polymerase chain reaction (PCR) detected hepatitis C virus genome in the brain of a case with progressive encephalomyelitis with rigidity. Clin Neurol Neurosurg 1996;98:305-308.
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A diffuse inflammation of the brain and spinal cord usually caused by a perivascular hypersensitivity response. associated with hepatitis C virus infection. Arch Neurol 2001;58:1679-1681.
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29. Zein zein
the principal protein in maize. Has low nutritive value, being deficient in lysine and tryptophan. NN, Abdulkarim AS, Wiesner RH, et al. Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol or cholestatic disease. J Hepatol 2000;32:209-17.
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One of the two major types of diabetes mellitus, characterized by late age of onset (30 years or older), insulin resistance, high levels of blood sugar, and little or no need for supple-mental insulin. among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000;133:592-599.
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The employees of the Southern Medical Journal wish to extend our heartfelt sympathies to the victims of Hurricane Katrina and Hurricane Rita.
We would also like to thank the members of the medical profession who assisted in the relief efforts throughout the Gulf Coast. Your professionalism, courage and tenacity have been an inspiration. Your compassion has reminded us of the true meaning of the avocation to which we have devoted our lives.
The purpose of human life is to show compassion and the will to help others. --Albert Schweitzer
Smruti R. Mohanty, MD
From the Center for Liver Diseases, Department of Medicine, Section of Gastroenterology, the University of Chicago, Chicago, IL.
Reprint Requests to Smruti R. Mohanty, MD, Assistant Professor of Medicine, Center for Liver Diseases, Department of Medicine, Section of Gastroenterology, the University of Chicago, 5841 South Maryland Avenue, MC 7120, Chicago, IL 60637. Email: email@example.com
Accepted April 19, 2005