Systemic light-chain amyloidosis presenting with rapid progressive heart failure

Abstract

Systemic amyloid light-chain (AL) amyloidosis is caused by deposition of immunoglobulin light-chain proteins. AL amyloidosis is a rapidly progressive disease that affects multiple organs. Cardiac involvement is frequent (50%) and the median survival is 5 months following diagnosis. Although transthoracic echocardiography can show characteristics findings, further diagnostic modalities are required for diagnosis. The gold standard of the diagnosis is presence of the amyloid in a tissue biopsy specimen. We present here a case of AL amyloidosis with presenting rapid progressive heart failure. Despite improvements in diagnostic and therapeutic modalities, diagnosis is difficult and prognosis is still poor in patients with cardiac involvement as in the present case.

Case

A 53-year-old man was admitted to our clinic with severe exertional dyspnea, fatigue and peripheral edema for 6 months. He had an effort capacity of class 3 on the New York Heart Association (NHYA) classification. Physical examination revealed a heart rate of 75 beats/min, blood pressure of 100/70 mmHg, 2/6 apical pan-systolic murmur, bilateral inspiratory crackles up to the middle fields of the lungs and palpable liver. The patient has no complaints until 6 months before presentation. He had no family history of cardiovascular disease or sudden cardiac death.

Surface electrocardiogram (ECG) showed sinus rhythm with occasional premature supraventricular beats, left axis deviation and intraventricular conduction delay. Chest X-ray showed cardiomegaly. On admission, laboratory findings were normal except for elevated N terminal brain natriuretic peptide (NT-proBNP) at 6826 pg/ml. Transthoracic echocardiography revealed thickened left ventricular wall (the interventricular septum 21 mm and posterior wall 18 mm), moderate depressed left ventricular systolic function (ejection fraction: 40%) with global hypokinesis, left ventricular diastolic dysfunction (restrictive pattern), severe mitral and tricuspid regurgitation (Figure 1). Coronary angiography showed normal coronary arteries. Right heart catheterization displayed the following findings: mean right atrial pressure 14 mmHg, right ventricular end-diastolic pressure 18 mmHg, mean pulmonary artery pressure 24 mmHg, pulmonary capillary wedge pressure 22 mmHg and left ventricular end-diastolic pressure 25 mmHg. On late gadolinium-enhanced images, cardiac magnetic resonance imaging (MRI) showed intramyocardial patchy enhancement in the basal lateral segments and diffuse left ventricular subendocardial enhancement was detected (Figure 2A and B). Right ventricular subendocardial enhancement was also found. The inversion time of the myocardium was earlier than the blood in a Look–Locker sequence. Progression of the enhancement was detected according to the previous MRI examination. All of these findings suggested restrictive cardiomyopathy. Amyloidosis was considered as a possible cause because of the MRI characteristics. Storage diseases such as Fabry’s were considered for differential diagnosis.

Figure 1.

(A) Transthoracic echocardiography, parasternal long axis view. Thickened interventricular septum and posterior wall. (B) Transthoracic echocardiography, apical four-chamber view. Thickened interventricular septum and posterior wall, biatrial dilatation. (C)Transthoracic echocardiography, apical four-chamber view. Left end right atrial area size. (D)Transthoracic echocardiography, parasternal short axis view. Thickened interventricular septum, anterior and posterior wall. (E) Transmitral Doppler imaging, restrictive filling pattern with E/A >2 and reduced deceleration time. (F) Tissue Doppler imaging of the mitral annulus, reduced early diastolic velocity (E’).

Figure 2.

(A, B) Cardiac MRI showing late gadolinium-enhanced images; intramyocardial patchy enhancement in the basal lateral segments and diffuse left ventricular subendocardial enhancement are detected. (C) Perivascular proteinaceous material in hypocellular bone marrow biopsy (Congo red, ×100). (D) Fibrillar material accompanied with fibrosis in colonic mucosa (Congo red, ×100). (E) Extracellular deposition of amorphous proteinaceous material in renal parenchyma (Congo red, ×200).

We performed a dermal biopsy for the diagnostic differentiation but no amyloid deposition was obtained with Congo red and cresyl violet. Serum protein electrophoresis showed no monoclonal band. Urine protein electrophoresis showed a lambda light chain and different types of protein bands. We performed bone marrow, rectal and renal biopsy for diagnostic differentiation. All of these biopsies showed amyloid of AL (lambda) type (Figure 2C, D and E).

Once the diagnosis of amyloidosis was established by biopsy findings, cyclophosphamide, bortezomib and dexamethasone therapies were added. The patient was treated with ramipril 2.5 mg, carvedilol 6.25 mg, furosemide 120 mg, spironolactone 50 mg daily and enoxaparin 0.6 ml. During the first chemotherapy cure, cardiopulmonary arrest developed and he died of electromechanical dissociation despite cardiopulmonary resuscitation.

Discussion

Amyloidosis is a systemic disorder characterized by extracellular deposition of pathologic, insoluble, fibrils in many organs. Classification of amyloidosis is dependent on proteins that form amyloid fibrils. AL amyloidosis is the most common form of systemic amyloidosis and caused by deposition of immunoglobulin light-chain proteins that aggregate and deposit as unique fibrils [Merlini and Bellotti, 2003]. AL amyloidosis is a rapidly progressive disease that affects multiple organs. Cardiac involvement is an important prognostic factor in amyloidosis. Cardiac involvement is frequent (50%) and the median survival is 5 months following diagnosis [Dubrey et al. 1998]. Other forms of amyloidosis are senile, familial, secondary and isolated atrial amyloid. Cardiac involvement is also encountered in transthyretin-associated (hereditary/familial and senile) amyloidosis, but the disease course is indolent compared with AL amyloidosis. Diagnosis of amyloidosis is very difficult. Therefore, the diagnosis might require ECG, echocardiography, scintigraphy, MRI, endomyocardial biopsy, serum and urine protein electrophoresis.

Treatment of cardiac amyloidosis is dependent on the underlying cause. Therapeutic approaches for senile systemic amyloidosis are largely supportive. Liver and cardiac transplantation is the treatment of choice in familial amyloidosis which is due to mutation of transthyretin protein. The aim of treatment is to eradicate monoclonal plasma cell production by chemotherapy and stem cell transplantation while using supportive measures because of AL amyloidosis is a plasma cell dyscrasia [Cibeira et al. 2011]. The mainstay of supportive treatment is salt restriction and diuretics given cautiously. Angiotensin-converting enzyme (ACE) inhibitors should be used carefully because of hypotension. Low-dose beta-blockers can be given to the patient, but they can worsen heart failure. In ventricular arrhythmia, amiodarone and artificial implantable cardiac defibrillators should be used. In conduction abnormalities pacemakers can be used. Heart transplantation can be considered in end-stage cardiac amyloidosis, but in AL amyloidosis the 5-year survival rate is only 20–30% with heart transplantation [Dubrey et al. 2001].

In conclusion, cardiac amyloidosis is a rare disease which develops on the basis of different pathologic conditions in systemic amyloidosis. Despite improvements in diagnostic and therapeutic modalities, diagnosis is difficult and prognosis is still poor in patients with cardiac involvement as in the present case.