Case Discussion < Brief history >      A 61-year-old male patient was admitted due to progressive dyspnea on exertion for 2 months.      One year before the admission, this patient found ecchymosis at the peri-orbital and mouth angle. In addition, he felt fatigue and shortness of breath on exertion. Chest roentgenogram at local clinics revealed a moderate to large amount of pleural effusion bilaterally. He had undergone a thoracentesis to yield transudative effusion. He was referred to a cardiovascular specialist in a medical center with a tentative diagnosis of congestive heart failure. Echocardiography revealed good left ventricular systolic function (ejection fraction, 66%), moderated mitral regurgitation, moderated aortic regurgitation, and left ventricular diastolic dysfunction. Coronary angiogram revealed patent coronary arteries. His symptoms improved after treatment with diurestics. He was discharged 2 weeks later with furosemide(Lasix).      However, his symptoms became worse after discharge. He took some Chinese herb medicine, without improvement. Two months later, because of the intractable symptoms, he was brought to our hospital. On physical examination, the blood pressure was 131/80 mmHg, the temperature was 36.2℃, the pulse was 125 beats per minute and the respirations were 20 breaths per minute. The conjunctiva was pink and the sclera was anicteric. Oral cavity revealed macroglossia (figure 1 ). There was no jugular vein engorgement or lymphadenopathy. The chest inspection was normal and expansion was symmetric in palpation. Increasing dullness was noted at bilateral lower lungs by percussion. The auscultation showed decrease of breath sounds at bilateral lower lobes and bi-basilar rales without wheezes or crackles. The heart sounds were regular with grade II/VI systolic murmurs at the apex. No friction rub was noted. The abdomen was prominently distended and nontender. The bowel sounds were normoactive. The edge of the liver descended at least 5 cm below the right costal margin and crossed the midline by 3 cm. The spleen was impalpable. No shift dullness was noted. The extremities were freely movable without edema or cyanosis. Several purpura lesions were noted on his eyelids, face and neck (figure 2). On neurological examination, the cranial-nerve functions were intact. Motor power was 5/5 in his arms and leg with normal muscle tone and tendon reflex. Sphincter was intact.       Chest roentgenogram performed revealed a moderate to large amount of pleural effusion bilaterally (figure 3 ). A repeat thoracentesis showed transudative effusion. In electrocardiogram (figure 4), broad P wave was noted in lead II and a prominent negative vector of P wave was also noted in V1. Left deviation of QRS axis was also identified. Besides, T wave inversion was noted in V4-6, lead I and aVL.      After admission, echocardiography revealed borderline left ventricle contractility (ejection fraction, 52%), mild mitral, and aortic regurgitation. In Doppler analysis of mitral flow, it characterized as a restrictive pattern without respiratory variation. Restrictive cardiomyopathy (RCM) with congestive heart failure was highly suspected. Cardiac catheterization 2 days later confirmed the diagnosis of RCM.      Serum protein and immunofixation electrophoresis revealed IgG/κλ bi-clonal gammopathy which leaded to the diagnosis of AL amyloidosis. To confirm the diagnosis, tissue biopsies of his right ventricular endomyocardium, skin, bone marrow, rectum, gingival and abdominal subcutaneous fat were performed, but all were negative for amyloid deposition.      During the hospitalization, his symptoms progressed with intractable pleural effusion accumulation. The renal function was also deteriorating. Cardiac transplantation for this patient was advised after the cardiovascular surgeon consultation. He underwent heart transplantation 3 weeks later. The specimen from the failing heart confirmed the diagnosis of amyloidosis pathologically. The post-operative course was smooth and was discharged one month after operation. < Lab Data > CBC/DC: WBC K/μL Hb g/dL Hct % MCV fL Plt k/μL Seg ％ Eos ％ Baso ％ Mon ％ Lym ％ 5.6 14.8 42.6 85.7 242 48.2 2.0 0.2 5.9 48.4  Biochemistry/Electrolyte: Bil-T mg/dL Bil-D mg/Dl AST U/L ALT U/L ALP U/I BUN mg/dL Cr mg/dL Alb g/dL TP g/dL  0.67 0.26 35 33 389 13.5 1.0 * 6.3*    LDH U/L CK U/L CK-MB U/L Tn-I ng/ml Na mmol/L K mmol/L Ca mmol/L Glu mg/dL 349 88 8.5  0.118 135 4.2 2.12 95 TSH 3.45 Ref. 0.1 ~ 4.5 (μIU/mL) FT4 1.03 Ref. 0.6 ~ 1.75 (ng/dL)   Bone Marrow Aspiration: Hematological Diagnosis of BM: Plasmacytosis, mild  Serology/Blood: IgA 82.2 Ref. 259.34 ± 82.84 (mg/dl) IgG 1010.0 Ref. 1419.63 ± 279.84 (mg/dl) IgM 61.4 Ref. 160.57 ± 72.2 (mg/dl)    CEA 0.87 Ref. <3.0 (ng/ml) AFP 2.95 Ref. <20 (ng/ml) Serolgies: negative for S.T.S, Anti-HIV, HBsAg, HBeAg, IgM-Anti-HAV, Anti-hepatitis C Virus, CMV Ab, HSV Ab, VZV Ab, Toxoplasma IgG Ab, EBV-VCA IgG Antibody Acid-fast smear of pleural effusion, negative Culture of pleural effusion, negative for bacteria, fungi, mycobacteria PT/PTT: PT Sec PT cont sec PTT sec PTT cont sec INR 11.4 11.9 38.5 35.5 1.0 11.6 11.8 25.8 29.6 1.1  Peripheral blood smear: WBC and Platelet are adequate, no Rouleaux formation of RBC Serum electrophoresis: Low albumin and increased alpha 1 & alpha 2 globulins Serum immunofixation electrophoresis (IFE) Two bands of IgG/lambda gammopathy Pleural Effusion: Appearance Sp. Gr. Rivalta's WBC RBC Sediment L:N:M Glu AC mg/dL TP g/dL LDH U/L Y, C 1.013 - 500 <10000 59:15:26 120 1.5 103 Urinalysis: Outlook Sp.Gr PH Pro Sugar Ket OB Uro Bil WBC RBC Epi Crys Cast Y, C 1.01 6.5 - - - - 0.1 - 0-1 0-1 0-1 - -   Urine IFE: Quant. of Kappa 316 Ref. 598 ~ 1329 (mg/dl) Quant. of Lamda 450 Ref. 280 ~ 665 (mg/dl)  24 hr. Urine: 24hr protein loss = 0.588g/day Pleural Effusion Cytology: All negative for malignant cells       Pathology: Endomyocardial biopsy Myocardial hypertrophy with enlarged and hyperchromatic nuclei. Some fibrin and leukocytes are seen covered on the surface. Mild increase in interstitial cellularity is also present. No evidence of amyloidosis is seen under H&E and Congo-red stains. Bone marrow Hypocellularity with hemopoietic components accounting for about 20 % of the marrow spaces Skin Biopsy Hemorrhage and red blood cell extravasation, no amyloid deposition at perivascular area is found by congo red stain. Gingiva Punch Biopsy No evident amyloid deposition can be found in H & E and Congo red stains.  Endoscopic Biopsy Chronic colitis, focal fatty infiltration in lamina propria. Subcutaneous fat There is no eosinophilic deposition around vessels and nerves Congo red stain is also negative under polarized light Heart Specimen after orthotopic transplantation Variable hypertrophy and degeneration of the myocardial fiber with vacuolar degeneration and focal interstitial fibrosis. The endocardium is thickened. The aortic valve, pulmonary valve, mitral valve, and tricuspid valve reveal myxomatous degeneration. Mild to moderate atherosclerosis is found in the coronary arteries (LAD, LCX, and RCA). In the pericardial fat tissue and epicardium, amorphous hyalinized materials are noted around small arteries, fat lobules (adjacent myocardium, and in the nerve fibers). Under Congo-red stain and polar microscopic examination, there amorphous hyalinized materials reveal apple-green birefrigence. Therefore, amyloidosis is considered.         < Discussion >      Restrictive cardiomyopathy (RCM) refers to a group of disorders in which the heart chambers are unable to fill with blood properly because of stiffness of the heart. Restrictive cardiomyopathy is often caused by diseases in other parts of the body. One known cause is cardiac amyloidosis. In restrictive cardiomyopathy, the heart is normal in size or only slightly enlarged, but it cannot relax normally during diastole. Later in the disease, the heart may not pump blood efficiently.      Cardiac amyloidosis is a disorder caused by deposits of an abnormal protein (amyloid) in the heart tissue, resulting in decreased heart function. Fibrils are proteins produced in excess that are deposited in different organs and slowly replace normal tissue. Cardiac amyloidosis is classified by the protein precursor as primary, secondary (reactive), senile systemic, hereditary, isolated atrial, and hemodialysis-associated amyloidosis. Cardiac amyloidosis usually occurs during primary amyloidosis. Primary amyloidosis usually accompanies multiple myeloma, a blood disorder in which too much of a certain type of protein is produced. Primary amyloidosis is rare, with an incidence of 8.9 per million population. It affects more men than women (3:2), usually around the sixth decade of life.      The typical picture of cardiac amyloidosis is that of a rapidly progressive congestive heart failure (CHF) due to restrictive cardiomyopathy, but systolic dysfunction occurs later in the course of the disease. Dilated cardiomyopathy is seen in only 5% of the patients and occasionally cardiac amyloidosis may masquerade as hypertrophic cardiomyopathy. Sudden cardiac death accounts for 30% to 50% of all cardiac deaths in systemic amyloidosis and may be due to ventricular arrhythmias, atrioventricular block, or acute electromechanical dissociation. Atrial fibrillation is found in 10-20% of cardiac amyloidosis, due to atrial enlargement, atrial infiltration or congestive heart failure. Atrial thrombi are described even in sinus rhythm related to an impairment of atrial emptying or deranged clotting factors.      The diagnosis of cardiac amyloidosis is difficult to make. The findings from physical examination are not specific and may indicate cardiac enlargement heart and pulmonary or systemic congestion. Auscultations may reveal lung crackles, heart murmurs, or other abnormal sounds. The liver may be enlarged and neck veins may be distended. The blood pressure may be low or may drop when rising to a standing position (orthostatic hypotension).      Electrocardiogram may reveal conduction disturbances, arrhythmias such as atrial fibrillation, ventricular tachycardia, or premature and ectopic beats. Low voltage in the limb leads on electrocardiogram in the presence of increased left ventricle mass is highly suggestive of cardiac amyloidosis.      Echocardiogram is a very important tool for the diagnosis of amyloidosis. Typically, increased thickness of left ventricular walls and a granular sparkling appearance of myocardium are seen. Transmitral and pulmonary venous Doppler findings may reveal the nature of impaired relaxation (restrictive pattern). Tissue Doppler imaging, strain rate imaging, and ultrasonic tissue characterization may be useful in the early diagnosis of cardiac amyloidosis.       If cardiac amyloidosis is suspected, serum and urine protein and immunofixation electrophoresis are the next diagnostic steps. The presence of abnormal light chain suggests the diagnosis of primary amyloidosis. A negative immunofixation test alone will not rule out amyloidosis, as it can occur in non-secretory amyloidosis or in other forms of amyloidosis (familial or senile amyloidosis).       The confirmation of amyloidosis requires some tissue biopsy (fat pad aspirate or other tissues). A bone marrow biopsy is required to characterize the monoclonal gammapathy and usually more than 5% plasma cells are found in primary amyloidosis. Endomyocardial biopsy is sensitive, and is always required in isolated cardiac involvement.      The prognosis of cardiac amyloidosis is poor, with a median survival of one to two years. The major cardiac prognostic factors are heart failure syptoms, LV ejection fraction less than 50% and ventricular septal thickness more than 15 mm. Recently, brain natriuretic peptide have been utilized as a good serum marker. A N-terminal pro-BNP level of 152 pmol/L indicates heart involvement, and is a marker of myocardial dysfunction and of heart toxicity caused by amyloidogenic light chains. Cardiac troponins (I and T) are modestly elevated in patients with advanced cardiac amyloidosis.      Management of cardiac failure in patients with amyloidosis is difficult. Usually larger doses of diuretics are required careful monitoring. Digitalis should only be used in selected patients in atrial fibrillation to control heart rate. Angiotensin-converting enzyme inhibitors should be used cautiously because of orthostatic hypotension and associated renal disease. Calcium channel blockers bind to amyloid fibrils, and may result in exacerbation of heart failure. Utility of β- blockers is not known in amyloidosis. Patients with symptomatic bradyarrhythmia should receive a permanent pacemaker implantation.      With better understanding of the mechanisms of amyloidosis, several chemotherapy and immunotherapy are being tried. However, the majority of patients with cardiac amyloidosis do not benefit from these therapies. An earlier diagnosis, when the disease burden is not high and the organ damage is not severe, may allow greater benefits of treatment. In conclusion, increased awareness of cardiac amyloidosis is warranted for early diagnosis. 繼續教育考題 1. (A)  What kind of cardiomyopathy is most related to cardiac amyloidosis? A  restrictive cardiomyopathy B  dilated cardiomyopathy C  hypertrophic cardiomyopathy D  none of above 2. (D)  Which is the cause of sudden cardiac death in amyloidosis? A  ventricular arrhythmias B  atrioventricular block C  acute electromechanical dissociation D  all of above. 3. (D)  Which is useful in diagnosis of cardiac amyloidosis in echocardiogram? A  2D (B-mode) assessment of ventricular wall and function B  Transmitral and pulmonary venous Dopplor C  ultrasonic tissue characterization D  all of above 4. (D)  Which serum marker is not useful in predicting prognosis of cardiac amyloidosis? A  N-terminal pro-BNP B  Troponin I C  Trponin T D  CK-MB 5. (C)  Which is not a useful diagnostic tool in diagnosing cardiac amyloidosis ? A  Electrocardiogram B  Echocardiogram C  Chest X ray D  Endomyocardial biopsy 6. (A)  Which hematological malignancy is associated with cardiac amyloidosis ? A  Multiple myeloma B  Acute lymphoblastic leukemia C  Chronic myeloblastic leukemia D  Non-Hodgkin lymphoma 答案解說 (A)The typical picture of cardiac amyloidosis is that of a rapidly progressive congestive heart failure (CHF) due to restrictive cardiomyopathy, but systolic dysfunction occurs later in the course of the disease. Dilated cardiomyopathy is seen in only 5% of the patients and occasionally cardiac amyloidosis may masquerade as hypertrophic cardiomyopathy. (D)Sudden cardiac death accounts for 30% to 50% of all cardiac deaths in amyloidosis and may be due to ventricular arrhythmias, atrioventricular block, or acute electromechanical dissociation. (D)Echocardiogram is a very important tool for the diagnosis of amyloidosis. Typically, increased thickness of left ventricular walls and a granular sparkling appearance of myocardium are seen. Transmitral and pulmonary venous Doppler findings may reveal the nature of impaired relaxation (restrictive pattern). Tissue Doppler imaging, strain rate imaging, and ultrasonic tissue characterization may be useful in the early diagnosis of cardiac amyloidosis. (D)The prognosis of cardiac amyloidosis is poor, with a median survival of one to two years. The major cardiac prognostic factors are heart failure symptoms, LV ejection fraction less than 50% and ventricular septal thickness more than 15 mm. Recently, brain natriuretic peptide have been utilized as a good serum marker. A N-terminal pro-BNP level of 152 pmol/L indicates heart involvement, and is a marker of myocardial dysfunction and of heart toxicity caused by amyloidogenic light chains. Cardiac troponins (I and T) are modestly elevated in patients with advanced cardiac amyloidosis. (C)Electrocardiogram may reveal conduction disturbances, arrhythmias such as atrial fibrillation, ventricular tachycardia, or premature and ectopic beats. Echocardiogram is a very important tool for the diagnosis of amyloidosis. Endomyocardial biopsy is sensitive, and is always required in isolated cardiac involvement. (A)Cardiac amyloidosis usually accompanies multiple myeloma, a blood disorder in which too much of a certain type of protein is produced.