ABSCRACT: Immunoglobulin light-chain amyloidosis needs to be considered in any patient presenting with cardiomyopathy with preserved systolic function, heavy albuminuria, an unexplained sensorimotor peripheral neuropathy, hepatomegaly, or atypical MGUS (monoclonal gammopathy of undetermined significance) or myeloma. The prognosis of the disease is determined by the levels of cardiac biomarkers and the pretreatment levels of immunoglobulin free light chains. All patients with systemic light-chain amyloid require therapy. There is no presymptomatic phase that warrants observation. Stem-cell transplantation produces a high response rate but is a viable option in only 20% of patients. Corticosteroids, alkylating agents, immunomodulatory drugs, and proteasome inhibitors all have shown activity in this disorder, and combinations are currently being explored in clinical trials. Despite advances in the past decade, 30% of patients still die within a year of diagnosis, suggesting that failure to recognize this disorder prior to advanced organ dysfunction remains a major impediment to improving outcomes.
Light-chain (AL) amyloidosis occurs when a clonal population of bone marrow plasma cells secretes an immunoglobulin light chain that undergoes misfolding. The resulting insoluble light-chain or heavy-chain fragments deposit in tissues in a β-pleated sheet configuration and lead to organ dysfunction. There is no diagnostic blood test or imaging study for AL amyloidosis. Recognition requires a high index of suspicion and a tissue biopsy that demonstrates green birefringence when a Congo red–stained specimen is viewed under polarized light.
A 79-year-old male had symptomatic dyspnea on exertion and lower extremity edema for 1 year. The patient had CT imaging of the abdomen that showed small retroperitoneal nodes. This finding led to a laparoscopic biopsy. Sinus histiocytosis was found; no malignancy was present. He underwent echocardiography that showed concentric left ventricular hypertrophy. His ECG demonstrated an anterior infarction pattern. The ECG finding led to a cardiac catheterization that showed both a normal ejection fraction and normal coronary arteries. Following the catheterization, the patient was informed that his dyspnea did not have a cardiac cause, and he was referred to the Mayo Clinic Division of Thoracic Diseases for evaluation.
When the patient came to the Mayo Clinic, a serum protein electrophoresis was performed (Figure 1). The protein electrophoretic finding led to a 24-hour urine protein electrophoresis (Figure 2). The echocardiogram was repeated and was reinterpreted as showing thickening of the heart walls and valves consistent with an infiltrative cardiomyopathy with restrictive hemodynamics. A subcutaneous fat aspiration was performed, which demonstrated amyloid. The original retroperitoneal node biopsy was obtained from the local hospital. It was stained with Congo red and was positive.
Comments on Patient 1
This patient had an ECG that showed a pseudo-infarction pattern; considered in conjunction with his dyspnea, it was felt to represent silent ischemic heart disease. The presence of a pseudo-infarction pattern on ECG is a post-hoc diagnosis that requires knowledge of the correct process in order to be interpreted. The thickening of the ventricular walls was assumed to be hypertrophy rather than infiltration, presumably because hypertrophy secondary to hypertension is so much more common in the US population. The performance of cardiac catheterization without a right ventricular biopsy indicated a failure to recognize an important cause of heart failure with preserved systolic function. The key diagnostic test was the serum protein electrophoresis, which showed an extremely small (size, 0.5 g/dL) monoclonal protein migrating in the gamma fraction. The 24-hour urine protein measurement demonstrated only 220 mg for the 24-hour period, which is quantitatively insignificant; however, the electrophoresis demonstrated that all of the protein was monoclonal immunoglobulin light chain and not albumin. Most physicians assume that proteinuria equates to albuminuria, but this was not the case here. This patient had a 1-year delay in diagnosis, reducing the likelihood of chemotherapy being effective.
Light-chain amyloidosis should be considered in any patient who has symptoms consistent with cardiomyopathy. These may be as subtle as mild dyspnea on exertion or modest edema in the lower extremities. Exertional fatigue is a common presentation of cardiac amy-loidosis; to arrive at the correct diagnosis requires a careful physical examination that could reveal distention of the jugular veins. This finding reflects restriction to flow and high filling pressures on the right side of the heart. An assessment of cardiac biomarkers, particularly brain natriuretic peptide (BNP) or N-terminal prohormone-BNP (NT-proBNP), and an echocardiogram with Doppler studies that can recognize changes in diastolic flow patterns, will reveal infiltrative cardiomyopathy.
A 47-year-old male was found to have 9.7 grams of protein in a 24-hour urine collection. The patient received a trial of high-dose corticosteroids, which produced no reduction in urinary protein. Because of increasing edema and fatigue, an echocardiogram was performed; this showed a ventricular septal thickness of 18 mm. The cause of the thickening was not commented on. A renal biopsy was performed, and amyloid deposits were detected. Subsequent testing with serum and urine electrophoresis with immunofixation and serum immunoglobulin free light chains revealed monoclonal free λ light chains in the serum and urine (Bence-Jones proteinemia and proteinuria). The κ free light chain was 9.7 mg/L (normal, 3.3-19.4 mg/L), and the λ free light chain was 137 mg/L (normal, 5.7-26.3 mg/L), with a ratio of 0.07 (normal, 0.26-1.65), reflecting excess production of λ immunoglobulins.
Comments on Patient 2
All patients with heavy albuminuria that is not attributable to an obvious cause such as long-standing diabetes mellitus should be screened for amy-loidosis. Frequently, these patients are assumed to have minimal-change glomerulonephropathy or membranoproliferative glomerulonephropathy and undergo an empiric trial of corticosteroids, which delays more effective interventions. Screening with the combination of a serum protein electrophoresis with immunofixation and a serum immunoglobulin free light chain has a sensitivity of 96% for detection of a monoclonal protein in patients with AL amyloidosis. The addition of a urine immunofixation increases sensitivity to 98%. The detection of a monoclonal protein reduces the differential diagnosis to myeloma cast nephropathy, ĸ light chain deposition disease, cryoglobulin-emia, and light-chain amyloidosis. In this instance, the patient had an 8-month delay between the first recognition of proteinuria and the initiation of effective therapy. This patient underwent stem-cell transplantation and is alive with normal renal function at 180 months. His lowest recorded urinary protein post-transplant was 0.27 g/day.