amyloidosis is a clinical disorder caused by extracellular deposition of insoluble abnormal fibrils , derived from aggregation of misfolded normally soluble protein.1 ) cardiac infiltration of amyloid fibril results in progressive cardiomyopathy with a grave prognosis.2)3 ) a prominent clinical feature of cardiac amyloidosis is a syndrome of heart failure , characterized by restrictive hemodynamics and progressive deterioration of systolic function . pleural effusion can develop as a consequence of heart failure , but sometimes it is disproportionate to the degree of heart failure and is resistant to conventional diuretic therapy . the latter complication occurs most often in primary systemic ( al ) amyloidosis.4 ) refractory pleural effusions are difficult to manage and associated with a poor prognosis.4 ) recently , vascular endothelial growth factor ( vegf ) has been implicated to play a role in both malignant and nonmalignant pleural effusions through its ability to regulate vascular permeability.5 - 8 ) thus , a therapeutic approach employing anti - vegf agent might emerge as a potential alternative for managing refractory pleural effusions complicating systemic amyloidosis . here , we report a case of cardiac amyloidosis in which recurrent pleural effusion could be managed by therapy with bevacizumab , an anti - vegf antibody . a 53 year - old female patient was transferred to our cardiology department for the evaluation of hypotension and dyspnea after successful treatment for recombinant tissue - type plasminogen activator for acute right middle cerebral artery infarction . she reported previous episodes of dyspnea and had been diagnosed with cardiac hypertrophy one year previously . but she denied any prior history of coronary heart disease , hypertension , diabetes , or pulmonary diseases . she had not been taking any medication for her cardiac condition . on transfer , examination revealed blood pressure 90/60 mmhg , heart rate 100/min , body temperature 36.4 , and respiration rate 22/min . her face was puffy , and her jugular vein was distended with an estimated pressure of 18 cm h2o . the electrocardiography showed low voltage in the limb leads and a small r wave amplitude across the precordial leads ( fig . 1 ) . the chest film demonstrated moderate cardiomegaly , interstitial congestion and marked pleural effusion in the right lung field ( fig . initial laboratory studies revealed normal ranges of renal function test and liver function test , mildly elevated troponin - i ( 0.52 ng / ml : normal < 0.1 ng / ml ) , and markedly elevated bnp ( 1,867 pg / ml : normal < 100 pg / ml ) . serum protein was 6.2 g / dl ( normal 6.6 - 8.4 g / dl ) , albumin 3.5 g / dl ( normal 3.8 - 5.2 g / dl ) , and 24 hours urine protein 4.5 g / day ( normal 0.03 - 0.12 g / day ) . on echocardiography , the septal and free walls of the left ventricle were both moderately thickened ( 13 mm and 14 mm , respectively ) , but the left ventricular cavity dimension was not enlarged . left ventricular wall motion was active , with an estimated ejection fraction in the 65 - 69% range . two - dimensional evaluation of the inferior vena cava and doppler estimation of tricuspid regurgitation revealed elevated right atrial pressure ( > 20 mmhg ) and systolic pulmonary artery pressure ( > 54 mmhg ) . doppler analysis of transmitral inflow showed restrictive pattern with high e / a ratio ( 2.3 ) and short deceleration time ( 119 m / s ) . tissue doppler of mitral annular diastolic velocity ( e ' ) was markedly reduced ( 2.5 cm / s ) , and estimated left ventricular filling pressure was consequently high ( 50 mmhg ) ( fig . 3 ) . cardiac magnetic resonance imaging ( mri ) revealed a late enhancement of gadolinium over the entire subendocardial circumference with varying degree of extension into the neighboring myocardium ( fig . this particular pattern of late gadolinium enhancement is regarded as a unique and sensitive feature of cardiac amyloidosis.9 ) taken together , these electrocardiographic , echocardiographic , and mri findings strongly suggested a diagnosis of cardiac amyloidosis . congo - red stain of the specimen revealed apple green birefringence under polarized microscopy ( fig . serum free - light - chain assay revealed excessive increase in lambda free light chain , resulting in low kappa - to - lambda ratio { free kappa (  ) light chain 18.6 mg / l : reference value 3.3 - 19.4 mg / l , free lambda (  ) light chain 168.9 mg / l : reference value 5.71 - 26.3 mg / l , / ratio 0.11 : reference value 0.26 - 1.65}. therefore , the patient was diagnosed with primary ( al ) cardiac amyloidosis , with manifestations of heart failure , nephrotic syndrome , and massive pleural effusion . she was initially treated with high dose loop diuretics ( intravenous furosemide 120 mg / day ) which improved dyspnea symptoms and lower leg edema . however , the accumulation of pleural effusion showed no signs of abatement on her chest film . for the drainage , analysis of pleural fluid revealed protein 0.6 g / dl , albumin 0.3 g / dl , ldh 74 iu / l , and 21 nucleated cells ( 46% polymorphonuclear leukocyte , 27% lymphocyte , 20% monocyte and 7% histiocytes ) , consistent with transudative effusion . pleural biopsies were performed , but pathological examination revealed only fibrosis without signs of amyloid deposit . she was then started on chemotherapy with melphalan ( 6 mg / m for 4 days ) and prednisolone ( 60 mg / m for 4 days ) . three cycles of chemotherapy elicited the improvement of the kappa - to - lambda ratio ( free  light chain 25.8 mg / l , free  light chain 51.7 mg / l , / ratio 0.50 ) , but failed to reduce the accumulation of pleural fluid ( fig . 6 ) . following discussion of the risk and benefits , bevacizumab , an anti - vegf antibody , bevacizumab was scheduled to be administered by intravenous infusion , 5 mg / kg / day over 90 minute every 3 weeks . after 1 cycle of bevacizumab therapy , the amount of pleural drainage was markedly decreased to an average of 441 ml / day . however , 8 weeks after the completion of the second bevacizumab therapy , the amount of pleural effusion was reduced to nearly zero despite a similar degree of nephrosis on follow - up ( fig . her general condition was also improved , and she was encouraged to ambulate . with respect to adverse effects of bevacizumab , there were no signs of bleeding or thrombosis , nor aggravation of proteinuria during subsequent follow - up . chest film taken 1 year after initial admission showed no sign of pleural effusion in the right hemithorax ( fig . this case represents a challenging case of refractory pleural effusion associated with primary ( al ) amyloidosis involving cardiac tissue . in this case , the diagnosis of cardiac amyloidosis was established based upon the characteristic findings on echocardiography and cardiac mri , together with histology obtained from renal tissue , and the result of serum free - light - chain assay . recent mri technique of late gadolinium enhancement generates distinct images for cardiac amyloidosis with a great sensitivity and specificity , so histologic demonstration of amyloid deposit in extracardiac tissue would obviate the need for cardiac biopsy.9 ) pleural effusion in cardiac amyloidosis can occur as a consequence of heart failure , but in some patients with primary ( al ) systemic amyloidosis , large pleural effusion develops , which is refractory to diuretic therapy and thoracentesis.4 ) presence of large , persistent pleural effusion among those patients is clinically significant , not only because it deteriorates the quality of life but also because it is associated with poor prognosis.4 ) the prevalence of pleural effusion has not been clearly defined , but in one study 6% of 636 amyloid ( al ) patients were inflicted with this complication.10 ) in contrast , no cases of pleural effusion were reported in 233 patients with secondary ( aa ) amyloidosis.11 ) mechanisms underlying pleural effusions in al amyloidosis remain poorly understood . unlike the transudative nature observed in usual heart failure , the chemistry of pleural effusions in al amyloidosis varied ; about one third to one half of the cases were found to be exudative.4)10 ) the extraordinarily high rate of exudative effusion suggests that altered hydrostatic forces may not be the principal mechanism driving pleural fluid accumulation . indeed , in a study comparing 35 al amyloidosis patients with pleural effusion versus 120 patients without effusion , no significant differences were found in left ventricular indices , pulmonary pressure , or degree of nephrosis.10 ) furthermore , both gross and microscopic examination of pleural surface identified the presence of amyloid deposit,10)12 ) lending strong support to amyloid infiltration being a major factor . in our case , nevertheless , the effusion did not respond to high dose loop diuretics , even after signs of pulmonary congestion had cleared . the development of transudative effusion indicates that the integrity of pleural membranes is mostly intact.13 ) therefore , it is conceivable that impaired pleural fluid absorption is a contributing mechanism . the presence of mesothelial stomata , intercellular openings , and rich networks of submesothelial lymphatics and blood vessels identify parietal pleura as the principal drainage system of the pleural space.14 ) blockage of these drainage components by amyloid deposit could lead to the loss of its ability to remove fluid . however , increased fluid secretion is the principal underlying abnormality in the genesis of most effusions , even if obstruction of fluid drainage co - exists.15 ) one candidate mediator for altered pleural secretion might be vegf , which enhances permeability of vascular and mesothelial barriers.5)16 ) vegf increases capillary and venular leakage by opening the endothelial intracellular junctions and by inducing fenestration development in endothelia.5 ) additionally , vegf increases microvascular permeability by enhancing the activity of vesicular vacuolar organelles , through which macromolecules extravasate.17 ) increased vegf levels have been observed in both the serum and pleural fluid from patients with malignant and non - malignant pleural effusions.6 ) although a role of vegf has been emphasized mostly in exudative effusions,5 ) it is conceivable that vegf might also contribute to formation of transudative effusion via the mechanisms cited above.5)17 ) management of large pleural effusion in primary ( al ) amyloidosis is a challenging task . aggressive diuresis or invasive measures like repeated thoracentesis , pleurodesis , and thoracoscopic interventions have only limited efficacy and risk potential adverse effects . recently , with increasing appreciation of the vital role of vegf in the formation of pleural effusion , strategic targeting inhibition of vegf activity is being employed as an alternative measure for managing refractory effusions . in a case report published in 2005 , bevacizumab , an anti - vegf antibody , successfully reduced pleural effusion for the first time in a patient with primary al cardiac amyloidosis.7 ) following this report , 4 cases of successful management of refractory pleural effusions with bevacizumab were described in patients with primary systemic amyloidosis.8 ) in the present case , recurrence of large pleural effusions was not affected by chemotherapy , but the amount of effusion was remarkably reduced after introduction of bevacizumab therapy . it is unlikely that this benefit was due to the reduction of oncotic pressure , because the degree of nephrosis and proteinuria remained similar throughout the follow - up . regarding the safety issue , bleeding complications or venous thrombosis thus , bevacizumab therapy improved the pleural effusion in this patient , and appeared clinically beneficial . however , the duration of observations presented in this report was relatively short , and further follow - up will be needed to assess the effect of the therapy . for patients with similar overall clinical presentations , this case , together with previous reports,7)8 ) suggests the potential of bevacizumab therapy as a novel strategy in patients with systemic amyloidosis and refractory pleural effusions who have few management options .
cardiac amyloidosis describes a clinical disorder caused by infiltration of abnormal insoluble fibrils in the heart , characterized by progressive heart failure and a grave prognosis . 
 pleural effusion in cardiac amyloidosis may represent a sign of heart failure , but it can also result from pleural infiltration of amyloid , manifested by recurrent large fluid accumulations . 
 recently , the role of vascular endothelial growth factor ( vegf ) has been implicated in the pathogenesis of refractory pleural effusion . 
 we report a case of a 53 year - old female patient with cardiac amyloidosis who presented with recurrent accumulation of large pleural effusions . 
 she was initially treated with high dose loop diuretics , but the pleural effusion persisted , with the daily amount of drainage averaging 1 l / day . 
 accumulation of pleural fluid did not subside after 3 cycles of melphalan / prednisolone therapy . 
 after the introduction of bevacizumab , an anti - vegf antibody , the amount of pleural effusion decreased significantly . 
 efficacy of anti - vegf therapy for refractory pleural effusions needs to be defined through further studies .