Amyloidosis is not a single disease but a heterogeneous group of diseases that share in common the extracellular deposition of insoluble fibrillar proteins in tissues and organs. These protein deposits derive from diverse and unrelated serum precursor proteins, yet have similar beta-pleated sheet structural conformations. Furthermore, all forms of amyloid display apple-green birefringence when stained with the cotton-wool dye Congo red and viewed under polarized light. Indeed, this observation (via tissue biopsy) remains the primary means of establishing the diagnosis of amyloidosis. Accumulation of amyloid deposits leads to tissue and organ dysfunction, which in turn causes clinical symptoms and, for some patients, death.

Amyloid diseases are classified by the biochemical composition of the serum precursor proteins that form the amyloid fibrils and deposits. Indeed, once amyloid deposition has been identified, it is important to identify the precursor protein because the prognoses and treatments of the various amyloid diseases depend on the underlying cause. To date, more than 20 amyloid fibril precursor proteins and their associated diseases have been identified. Of these, the most common amyloid diseases are (1) primary or immunoglobulin light-chain protein–related (AL) amyloidosis; (2) secondary (AA) amyloidosis associated with chronic inflammatory disease; (3) dialysis-associated β2-microglobulin (β2-m) amyloidosis; and (4) hereditary amyloidosis. Notably, the clinical manifestations of these forms of amyloidosis are not identical (Table 57–1). Hence, each is discussed in detail.

Essentials of Diagnosis

• AL amyloidosis should be suspected in all patients with unexplained heart failure, nephrotic syndrome, neuropathy, and hepatomegaly.
  
• Approximately 98% of patients with AL amyloidosis have detectable serum or urine monoclonal immunoglobulin light-chain protein. However, this finding alone is insufficient to establish the diagnosis of AL amyloidosis.
  
• AL amyloid, like all forms of amyloid, displays apple-green birefringence when viewed under polarized light after staining with Congo red.
  
• Bone marrow examination almost always reveals a monoclonal population of plasma cells.
  
• Tissue immunohistochemical analysis or protein sequencing by mass spectroscopy is necessary to identify the light-chain origin of AL amyloid fibrils. If inconclusive, other diagnostic testing (eg, ultrastructural fibril characterization) should be done.

General Considerations

AL amyloidosis is a plasma cell dyscrasia associated with multisystem involvement, rapid progression, and short survival. It is a rare disease with an incidence of 8 patients per 1 million persons per year. It usually affects people older than 40 years and men (65%) more than women. Amyloid fibrils derive from the N-terminal region of immunoglobulin light-chains (λ more often than κ) produced by a monoclonal population of plasma cells in the bone marrow. Notably, 5% of patients with multiple myeloma have AL amyloidosis, and it is unusual for patients with AL amyloidosis to develop multiple myeloma. AL amyloidosis affects most organs and the vascular system.

Clinical Findings

Symptoms and Signs

The symptoms and signs of AL amyloidosis are nonspecific. For example, the most common symptoms are fatigue and involuntary weight loss. Other symptoms and signs of AL amyloidosis reflect the organs and tissues involved. Hence, clinicians should suspect AL amyloidosis when seeing patients with syndromes associated with the disease. The syndromes associated most commonly with AL amyloidosis are nephrotic syndrome, congestive heart failure, idiopathic peripheral neuropathy, carpal tunnel syndrome, and hepatomegaly.

One third to one half of patients with AL amyloidosis have symptoms related to kidney involvement. Nephrotic syndrome (urinary excretion of more than 3 g of protein in 24 hours) with hypoalbuminemia and edema is the most frequent initial manifestation of kidney involvement. Symptomatic cardiac involvement affects up to 40% of patients with AL amyloidosis. Amyloid involvement of the myocardium, intramural coronary arteries, and conduction system may cause congestive heart failure, ischemic syndromes (eg, angina, myocardial infarction), and rhythm disturbances. Nearly 20% of patients with AL amyloidosis have neuropathy. These patients usually have lower extremity paresthesias. Pain and temperature senses are lost before light touch and vibratory senses. Motor neuropathy is rare. Patients may also have autonomic neuropathy, the manifestations of which include diarrhea, bladder control problems, erectile dysfunction, and orthostatic hypotension. Fifteen percent of patients have hepatomegaly.

Rheumatic manifestations also develop in some patients with AL amyloidosis. For example, one quarter of patients have carpal tunnel syndrome. Sensory abnormalities caused by amyloid neuropathy may lead to neuropathic joint destruction (Charcot joint). Joint disease resembling rheumatoid arthritis (RA) develops in some patients with AL amyloidosis. These patients have bilateral symmetric arthritis of the large and small joints characterized by pain, stiffness, swelling, and palpable nodules. However, unlike patients with RA, those with amyloid arthropathy do not experience fevers, joint tenderness on palpation, or evidence of inflammation on synovial fluid analysis. Patients with muscle involvement (amyloid myopathy) complain of stiffness, weakness, and enlargement of muscles (pseudohypertrophy). Amyloid involvement of joints, muscles, and nerves may also lead to debilitating contractures. Finally, AL amyloidosis may masquerade as giant cell arteritis. Symptoms suggestive of giant cell arteritis (eg, jaw claudication) are present. However, rather than revealing giant cell arteritis, temporal artery biopsy reveals amyloid involvement of the temporal artery.

In fact, most patients with AL amyloidosis have vascular involvement, and for some, this involvement may be symptomatic (eg, angina pectoris, orthostatic hypotension, and purpura). Pathologic enlargement of the tongue (macroglossia), commonly associated with amyloidosis, is actually an uncommon finding, seen in less than 20% of patients.

Laboratory Findings

No laboratory findings are pathognomonic of AL amyloidosis. Instead, laboratory abnormalities reflect the organs and tissues involved. For example, renal insufficiency, hypoalbuminemia, hyperlipidemia, and proteinuria suggest kidney involvement. Hematologic abnormalities are relatively uncommon. However, peripheral blood smear may reveal Howell-Jolly bodies suggestive of hyposplenism, which is caused by amyloid infiltration of the spleen.

Immunoelectrophoresis of the serum or urine detects a monoclonal immunoglobulin light-chain protein in 90% of patients with AL amyloidosis. Use of the immunoglobulin free light chain (FLC) ratio raises the sensitivity to 98%. For those who do not have detectable monoclonal light chain in the serum or urine (nonsecretory AL amyloidosis), bone marrow examination usually reveals a monoclonal population of plasma cells. Patients with AL amyloidosis usually have increased plasma cells (approximately 5%) in the bone marrow.

Imaging Studies

In general, imaging studies do not reveal findings specific for AL amyloidosis. Some patients with kidney involvement may have enlarged kidneys when viewed by ultrasonography, but most have normal-sized kidneys. Echocardiography usually reveals wall thickening due to amyloid infiltration of the myocardium, evidence of diastolic dysfunction, and a misleadingly normal left ventricular ejection fraction. Reported radiographic findings in patients with AL amyloidosis include osteoporosis, pathologic fractures, osteonecrosis, soft tissue nodules and swelling, subchondral cysts and erosions, joint contractures, and neuropathic osteoarthropathy.

Quantitative scintigraphy with radiolabeled serum amyloid P (SAP) component is useful in determining the extent and total body burden of amyloid deposits in patients with AL amyloidosis. Serial studies reveal uptake of the radiolabeled SAP component that correlates with regression or progression of disease. This test, however, is not widely available.

Cardiac involvement is frequent in AL amyloidosis but can be diagnostically challenging. Echocardiography is frequently used but has limitations, especially if hypertrophy from other causes is present. There are also limitations with the use of other noninvasive modalities, such as electrocardiography and quantitative scintigraphy. The gold standard for diagnosis is cardiac biopsy but cardiovascular MRI has been evaluated in cardiac amyloidosis and has a very high positive predictive value (95%) for the diagnosis of cardiac amyloid involvement. This may be used as an alternative to the invasive method of cardiac biopsy to assess for cardiac involvement. The cornerstone of diagnosis using cardiac MRI is the presence of late gadolinium enhancement, related to the expansion of the interstitial compartment by the infiltrating amyloid protein, which is seen histologically.

Tissue Biopsy

Tissue biopsy is necessary to establish the diagnosis of amyloidosis. All forms of amyloid display apple-green birefringence when viewed under polarized light after staining with Congo red. The least invasive method is aspiration of subcutaneous abdominal fat, which reveals amyloid in 70–80% of patients with AL amyloidosis. Bone marrow biopsy (usually done to evaluate a monoclonal protein) reveals amyloid in one-half of patients. Together, fat aspirate and bone marrow biopsy reveal amyloid in 85% of patients. If analyses of aspirated subcutaneous fat and bone marrow do not reveal amyloid, yet suspicion for amyloidosis remains high, other tissue must be obtained. An effective approach is to obtain tissue specimens from organs suspected of having amyloid involvement (eg, kidney, heart, liver). The presence of a monoclonal light-chain protein in a patient with biopsy-proven amyloidosis strongly suggests AL amyloidosis, but it is not sufficient to establish the diagnosis. For example, monoclonal gammopathies are not uncommon in the general population, and detecting a monoclonal protein in a patient with a form of amyloidosis other than AL amyloidosis (eg, hereditary amyloidosis) may be misleading. Rarely, patients with AL amyloidosis do not have a detectable monoclonal protein. Hence, tissue immunohistochemical analysis is necessary to identify the light-chain origin of AL amyloid fibrils. If the diagnosis remains inconclusive, other testing (eg, electron microscopy or immunoelectrophoresis) may be necessary.

Treatment

A major goal of treating AL amyloidosis is the reduction or elimination of the monoclonal plasma cells that produce the amyloidogenic proteins. Therapeutic options have evolved from the use of melphalan and prednisone in the 1960s, to high-dose chemotherapy and stem cell transplantation in the late 1980s and 1990s, to the introduction of small novel molecules within the past decade.

The standard treatment of AL amyloidosis is the combination of melphalan and prednisone. This combination is superior to placebo and colchicine. Compared with placebo, treatment with melphalan and prednisone increases median survival time from 6 months to 12 months. This treatment, however, is less effective if the disease involves the heart or kidneys. While high-dose melphalan followed by autologous stem cell support results in higher response rates than that of conventional chemotherapy alone, this strategy is associated with high treatment-associated mortality (10–25%) and therefore must be used only in selected patients (eg, those without significant amyloid cardiomyopathy or involvement of three or more other major organs). However, of the patients who can tolerate this treatment, many experience the disappearance of monoclonal light chains from the serum and urine and the normalization of the number of bone marrow plasma cells. Furthermore, the function of organs involved with amyloid may improve (eg, reduced proteinuria). The treatment options for patients with severe amyloid cardiomyopathy or involvement of three or more other major organs include standard melphalan and prednisone or high-dose dexamethasone (with or without melphalan).

More recently, within the past decade, the management of the monoclonal gammopathies, including AL amyloidosis, has seen the introduction of targeted therapies. These include thalidomide, lenalidomide, and bortezomib. Thalidomide has been shown to be a feasible and effective treatment option. Lenalidomide has also been reported to be active, especially when combined with dexamethasone. Bortezomib is a reversible proteasome inhibitor that may be used in the treatment of AL amyloidosis, with or without dexamethasone. It has been shown to induce responses in 68% of pretreated patients and in 64% of patients with disease refractory to previous therapy. Bortezomib with dexamethasone has also been shown to be active in previously untreated patients with high-risk features. Furthermore, responses were rapid (median of 28 days), compared with those in dexamethasone- or thalidomide-based regimens (median, 2–4 months). Further trials have been proposed to compare the combination of bortezomib, melphalan, and dexamethasone to the current standard of melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis.

In addition to treatment directed at the specific form of amyloidosis, most patients with amyloidosis, including those with AL amyloidosis, require supportive treatment (Table 57–2). The aims of supportive treatment are to relieve symptoms caused by amyloid involvement of various organ systems and to prolong survival. Organ transplantation (eg, heart) has been used successfully to treat organ failure in selected patients with AL amyloidosis. Organ transplantation, however, does not prevent amyloid deposition in other organs or in the transplanted organ.