AL amyloidosis usually occurs in persons of middle-age or older, but can also occur in the third or fourth decade of life. It has a wide spectrum of organ system involvement and presenting features reflect the organs most prominently affected. Initial symptoms of fatigue and weight loss are frequent, but the diagnosis is rarely made until symptoms referable to a specific organ appear. The kidneys are commonly affected; renal amyloidosis is manifested by proteinuria, sometimes massive with edema and hypoalbuminemia. Mild renal dysfunction is frequent, but rapidly progressing renal failure is rare. Cardiac involvement, often with congestive heart failure, is a common presentation.
The electrocardiogram may show low voltage with a pattern of myocardial infarction. The echocardiogram frequently shows concentrically thickened ventricles and a normal or mildly reduced ejection fraction. Nervous system features include peripheral sensory neuropathy, carpal tunnel syndrome, and autonomic dysfunction with gastrointestinal motility disturbances (early satiety, diarrhea, constipation) and orthostatic hypotension. Macroglossia, a classic feature pathognomonic of AL amyloidosis, is found in 10 percent of patients. Hepatomegaly may be massive with mild cholestatic abnormalities of liver function, although liver failure is uncommon, even when hapatomegaly is massive.
The spleen is frequently involved and there may be functional hyposplenism even in the absence of significant splenomegaly. Cutaneous ecchymoses are common, particularly around the eyes giving the “raccoon-eyes” sign, and appear spontaneously or when provoked by minor trauma. Other findings include nail dystrophy, alopecia, and amyloid arthropathy with thickening of synovial membranes. Timely diagnosis of AL amyloidosis is critical, and patients with any of these clinical syndromes should have immunofixation electrophoresis performed; the sensitivity of serum or urine protein electrophoresis without immunofixation is inadequate for diagnosis.
Extensive multisystem involvement typifies AL amyloidosis, and median survival with no treatment is usually only about a year from diagnosis.
Current therapies target the clonal bone marrow plasma cells using chemotherapy approaches employed for multiple myeloma. Cyclic oral melphalan and prednisone can decrease the plasma cell burden but produce complete hematologic remission in only a few percent of patients and modestly increases median survival. High-dose intravenous melphalan followed by autologous stem cell transplantation appears to be far more effective than oral melphalan and prednisone. Of more than 300 patients treated on such protocols at Boston Medical Center, half of evaluable patients achieve a hematologic complete response, and most of these enjoy significant improvement or stabilization of organ function.
Median survival in the treated patients exceeds 4 1/2 years. Smaller series from other centers have found similar results. Unfortunately, only about half of AL amyloidosis patients are eligible for such aggressive treatment, and even at specialized treatment centers, peritransplant mortality is high in these patients because of underlying impaired organ function (10% in the Boston Medical Center series). Some of the factors that contribute to mortality are amyloid cardiomyopathy, nutritional status as measured by weight loss, performance status, and in some studies, number of involved organs. The bleeding diathesis due to absorption of clotting factor X to amyloid fibrils also confers high mortality during myelosuppressive therapy. However, age alone, or renal insufficiency, should not exclude patients from such treatment.
For patients with impaired cardiac function or arrhythmias due to amyloid involvement of the myocardium, median survival is only about 6 months without treatment, and stem cell mobilization and high dose chemotherapy are extremely morbid. In a few such patients, cardiac transplantation has been performed followed by treatment with intravenous melphalan and stem cell rescue to prevent fibrillogenesis in the transplanted heart or other organs.
Alternative chemotherapy approaches are being investigated. Innovative approaches target the amyloid fibrils themselves or accessory binding proteins. The anthracycline derivative 4’-iodo-4’-deoxydoxorubicin (IDOX), was serendipitously noted to cause resorption of amyloid deposits in model systems but preliminary trials with single agent IDOX have not produced clinically significant responses. R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) binds serum amyloid P protein and accelerates clearance from the circulation and from amyloid fibrils; its potential efficacy in promoting fibril resorption and reducing amyloid disease is under study.
Supportive treatment is recommended for patients with all types of amyloidosis. At times, supportive treatments are lifesaving (e.g., heart or kidney transplantation, renal dialysis, cardiac pacemaker, and nutritional support). It is important to note that digitalis, calcium-channel blockers and beta-blockers are relatively contraindicated as toxicity has been observed at therapeutic levels.