A contemporary classification of systemic amyloidosis (AL), based on the nature of the amyloid protein that is deposited in tissue, is given in Table 33–2. Amyloidosis is a disorder of abnormal protein folding in which normally soluble proteins are deposited in tissues as fibrillar structures that disrupt organ function and produce disease. The proteins are folded into a β-pleated sheet form that results in a high affinity for Congo red and several other metachromatic dyes. Only one variety of amyloidosis is also a paraprotein, namely AL amyloidosis, in which the fibrils are composed of one or the other of the immunoglobulin LCs. Although this discussion will focus on only this form of systemic amyloidosis, it should be recalled that amyloid may also occur in a localized form. Identification of the precise biochemical nature of the amyloid fibril requires the examination of a tissue specimen with a combination of immunofluorescence or immunoperoxidase and often biochemical tests. Genetic testing may also be needed in the case of the hereditary amyloidoses.
Table 33–2. Classification and Nomenclature for the Systemic Amyloidoses. ||Download (.pdf)
Table 33–2. Classification and Nomenclature for the Systemic Amyloidoses.
Ig light chain
Ig heavy chain
Serum amyloid A
Hereditary, autosomal dominant (AD)
Fibrinogen α chain
Amyloidosis is an uncommon disease affecting about 12 patients per million population per year, with about 15% representing hereditary forms and the remaining consisting of acquired, nongenetic forms. Any race, sex, or ethnicity can be affected.
AL amyloid fibrils are derived from the N-terminal region (variable domain) of monoclonal immunoglobulin LCs, more commonly λ than κ. The AL amyloid fibrils can deposit in almost any tissue except the brain. Certain LCs are more “amyloidogenic” than others. Furthermore, differences in the variable region of the LC (λ) may determine the sites of amyloid deposition. VλVI results in dominant renal involvement while others (VλII or III) are more likely to have dominant cardiac or other organ involvement. AL amyloidosis is also known as primary amyloidosis, largely a holdover from the older literature. A truncated monoclonal heavy chain may rarely cause amyloid (known as AH amyloid).
The fibrils in AL amyloidosis are composed of fragments of the variable portion of monoclonal LCs (λ more frequently than κ). In AA amyloidosis the fibrils are composed of the serum Amyloid A protein. In hereditary Amyloidosis the fibrils are composed of the mutant protein (e.g., Fibrinogen alpha chain). These can be differentiated by appropriate immunohistological studies of biopsy tissue (see below). As monoclonal LCs may deposit in tissue and result in another disease (see monoclonal immunoglobulin deposition disease), it is clear that an additional factor is necessary to form the characteristic morphologic features of amyloid. It is likely that the LCs need to be phagocytized by macrophages where the LCs are metabolized to preamyloid fragments that are secreted and precipitate in the tissues. In the kidneys, the major site of accumulation is the glomeruli, with arterioles, arteries, interstitium, and tubular basement membranes involved to somewhat lesser degrees.
Almost any B cell dyscrasia can be associated with AL amyloidosis, which develops in about 10–15% of cases of MM. Most cases of AL amyloidosis are not associated with MM, but rather develop in association with MGUS or as a “primary” disorder. A monoclonal paraprotein of free LCs can be detected in the serum or urine of the majority of patients. Because older patients may not infrequently (5–10%) have an MGUS, it is necessary to be cautious not to overinterpret the significance of a small paraprotein “spike” in a serum protein electrophoresis.
Bone marrow aspirates or biopsies may reveal frank MM, but frequently do not. The disorder develops equally in men and women, but is quite uncommon in individuals <40 years of age. The clinical manifestations, which depend on the site or sites of amyloid deposition, can be quite varied. Cardiac [heart failure due to restrictive cardiomyopathy, atrioventricular (AV) nodal disease, or “pseudoinfarct” or low-voltage patterns on EKG], renal (nephrotic syndrome, symptomatic proteinuria, renal failure), tongue (macroglossia), gastrointestinal (malabsorption, motility disorders), peripheral nerve [sensory (“stocking and glove”) and motor neuropathies, carpal tunnel syndrome], autonomic nerves (orthostatic hypotension, impotence, gastroparesis), skin (papules, nodules, purpura, ecchymoses with minimal trauma), joints (polyarthritis of the shoulder girdle), and coagulation (Factor IX and X deficiency with bleeding) are among the most common. Macroglossia is almost pathognomonic of AL amyloidosis. Patients presenting with unexplained proteinuria (including nephrotic syndrome), nonischemic cardiac failure, peripheral neuropathy, or hepatomegaly after age 40 years should always be suspected of having AL amyloidosis. Hypertension and hematuria are said to be uncommon in renal amyloidosis, but severe hypertension may be present when renal failure ensues, and normomorphic hematuria due to bladder involvement with amyloid may occur. Renal involvement is principally heralded by proteinuria, which sometimes can be massive (>20 g/day) and lead to problems of protein malnutrition, severe edema, and volume depletion.
The diagnosis of AL amyloidosis can be suspected on the basis of history and physical examination, but the diagnosis requires tissue confirmation. Biopsies of kidney (when proteinuria is present), abdominal fat pad aspiration, or rectal mucosal biopsies are preferred. Biopsy of an enlarged and firm liver in AL amyloidosis should be avoided because of the risk of bleeding. No such excessive bleeding risk appears to occur with a renal biopsy, unless the patient has a severe Factor IX or X deficiency.
Nonhistologic studies may be helpful but are not diagnostic. Cardiac ultrasound may reveal “sparkling” echogenicity and impaired contractility or relaxation of the ventricles in cardiac amyloidosis. Abdominal ultrasound studies often reveal normal sized or enlarged echogenic kidneys. Renal vein thrombosis may be detected by computed tomography (CT) or magnetic resonance imaging (MRI) in patients with the nephrotic syndrome.
Since serum amyloid P (SAP) component is universally present in amyloid (AL as well as other types), radioisotope-labeled SAP (125I) has been used to detect amyloid deposits and to quantitate their changes or resolution with treatment; however, this test has very limited availability. Highly sensitive and specific assays for circulating free LCs have also been developed and should be used for both diagnosis and follow-up of patients with AL amyloidosis to assess the “burden” of LCs.
The light microscopic features of amyloid are characterized by the infiltration of extracellular sites by pale-staining acellular amorphous material that is Congo red positive and displays apple-green birefringence when viewed with polarized optics (Figure 33–1). By electron microscopy, amyloid is composed of fibrils that are nonbranching, usually randomly arranged, of indefinite length, and approximately 10 nm in thickness. By immunofluorescence (IF), AL amyloid most commonly stains for the λ LC (approximately 75%) and less frequently for the κ LC; the pattern is of continuous amorphous or smudgy positivity. While these IF findings are generally the experience of many laboratories, a recent report has indicated that IF has a low degree of sensitivity for detecting a monoclonal LC.
Congo red stain with polarized optics; amyloid is in several segments in the glomerulus and in the wall of the arteriole.
The glomeruli are almost always involved. The amyloid deposits in mesangial regions, infiltrating and replacing mesangial matrix and compressing and displacing cells, and sometimes results in a nodular appearance; it also infiltrates and replaces capillary basement membranes.
Once a tissue diagnosis of amyloidosis is established, there is no differential diagnosis of the type of kidney disease. However, the precursor protein needs to be established. Once an abnormal LC (or heavy chain) is documented in the tissue deposits and/or in serum, urine, or in bone marrow or other plasma cells, there are no further diagnostic considerations.
Treatment of AL amyloidosis is generally quite disappointing, but the outlook may be improving. In addition to supportive and symptomatic therapy, an attempt should be made to reduce the amount of amyloidogenic LC being produced. Oral melphalan (0.15 mg/kg/day for 7 days) and prednisone oral melphalan (20 mg three times per day for the same 7 days), repeated every 6 weeks depending on leukocyte counts, can slow the progression of the disease with a median survival of over 7 years in “responders” (reduced proteinuria, decreased amyloid “burden” in organs, and reduced circulating LC or monoclonal protein, if present).
All long-term survivors of AL amyloidosis have shown some objective response to chemotherapy, but unfortunately the majority of patients do not respond to melphalan-prednisone therapy. α-Tocopherol and interferon do not appear to be effective. High-dose dexamethasone plus interferon may yield some responses. 4′-Iodo-4′-deoxydoxorubicin has been effective in small studies, but the improvement in visceral amyloid deposits (VAD) has not been impressive. VAD regimens (previously described) have also been used in patients with AL amyloidosis (with and without MM) with benefits that seem to exceed those of the “standard” melphalan-prednisone therapy, at least in some studies. Thalidomide and its congeners, which are being evaluated for efficacy and safety in the treatment of MM, might also be effective in AL amyloidosis.
The most encouraging results have been seen with high-dose intravenous melphalan therapy followed by autologous bone marrow or peripheral stem cell transplantation; this may now be the treatment of choice for younger patients with limited organ system involvement, especially without cardiac involvement. However, recent controlled trials seem to indicate that the advantage of high-dose melphalan-prednisone plus autologous bone marrow transplantation therapy over high-dose melphalan-prednisone therapy alone for Systemic AL Amyloidosis is not as great as it was believed. Melpalan-prednisone plus autologous stem cell transplantation was not superior to high-dose melphalan-prednisone alone in this pivotal advanced study of advanced AL Amyloidosis. Stem cell transplants are very risky, with fatal outcomes common in patients with multisystem involvement and those with cardiac disease. Fractional survival for patients with two or fewer systems involved is about 75% at 5 years and is 25% or less at 2 years in those with cardiac involvement or more than two systems involved. Unfortunately, at present, the eligibility criteria for transplantation are such that only a minority of patients actually receive transplants. The best results are in patients with renal involvement as the sole or major manifestation of amyloidosis. Response duration and survival posttransplantation are superior to melphalan-prednisone treatment. A retrospective survey of over 700 patients with AL amyloidosis deemed “eligible” for high-dose intravenous melphalan and autologous stem cell transplantation revealed that only 44% actually received transplants and the median survival was 4.6 years; a complete hematologic response (disappearance of any evidence of a plasma cell dyscrasia) was achieved in 40% of patients. Mortality in the first 100 days was about 13% and was highest in those with cardiac involvement. The overall quality of life was greatly improved in those who achieved a complete hematologic and biochemical remission. Cardiac and/or renal allotransplantation has been performed, with anecdotal reports of prolonged survival. In the absence of specific therapy for the production of LC, recurrence of disease in the allograft can be anticipated.
General supportive therapy includes diuretics (for edema of nephrotic syndrome). Antihypertensive (angiotensin II inhibitors) agents should be used with great caution. Analgesics may be needed for neuropathic pain. Postural hypotension may limit the use of agents for hypertension present in the supine position. Midoridine and antigravity stocking may be of some benefit for severe postural hypotension. Cardiac glycosides (digoxin) and calcium channel antagonists are contraindicated, as they may worsen the cardiac manifestations.
The prognosis of AL amyloidosis, either in association with MM or as a “primary” disease, is poor, especially in the presence of clinically overt renal and/or cardiac involvement. In patients with renal involvement, the median time from diagnosis to end-stage renal disease (ESRD) is about 1 year and survival after dialysis is commenced is short, usually also less than 1 year. With current management, the principal cause of death is cardiac. In patients with restrictive myocardial disease (as determined by Doppler echocardiography), the 1-year survival is <50%. A low κ/λ ratio in bone marrow plasma cells may indicate a poor prognosis.
Novak L et al: AL-amyloidosis is underdiagnosed in renal biopsies. Nephrol Dial Transplant 2004;19:3050.