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.
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.
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.
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 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.
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.
Table 57–2. Supportive Measures for All Forms of Amyloidosis. ||Download (.pdf)
Table 57–2. Supportive Measures for All Forms of Amyloidosis.
- Salt restriction
- ACE inhibitors
- Heart transplantation
- Avoidance of digoxin, calcium channel blockers, and β-blockers
- Salt restriction
- Elastic stockings
- Adequate dietary protein
- ACE inhibitors
- Kidney transplantation
|Autonomic neuropathy||Orthostatic hypotension|
|Peripheral neuropathy||Sensory neuropathy|
- Physical therapy
- Braces, other devices
|Macroglossia||Maintenance of airway|
- Factor X deficiency
- Avoidance of trauma
- Factor replacement before surgery and other invasive procedures
- Splenectomy for massive splenomegaly
Patients with AL amyloidosis should be referred to a hematologist who has experience managing this uncommon disease. Managing organ failure caused by amyloidosis can be challenging and often requires the assistance of a subspecialist (eg, nephrologist, cardiologist). Furthermore, many patients with amyloidosis have daunting psychosocial and spiritual challenges. Under these circumstances, referral to an appropriate allied health colleague (eg, social worker, chaplain) or support group may be helpful.
Prognosis in AL amyloidosis is highly variable, as there are several factors that may individually predict survival. These include the number of organ systems involved and degree of involvement, level of bone marrow plasmacytosis, circulating plasma cells in the peripheral blood and β2-m level, among others. Integrating all these parameters to accurately predict survival is challenging and is limited by subjectivity. The presence and severity of cardiac involvement has been found to be the most important determinant of prognosis in patients with AL amyloidosis. There have been several proposed definitions of cardiac involvement, including reduction in the left ventricular ejection fraction, increased interventricular septal wall thickness, hypotension, presence of cardiac failure and cardiac rhythm disturbances. Each of these parameters can be assessed individually. However, studies have shown that cardiac biomarkers provide the strongest prognostic information. Using two simple measurements, namely serum troponins and N-terminal pro brain natriuretic peptide (NT-proBNP), survival in patients with AL amyloidosis can be accurately stratified into three risk groups. Patients are stratified to stage I if both markers are less than a defined threshold value, stage II if either marker is above threshold, and stage III if both are above threshold. This corresponds with median survivals of 26, 11, and 4 months, respectively (Figure 57–1). This staging system does not directly supply information about other organ involvement, but it is an accurate predictor of survival because cardiac involvement is the primary determinant of prognosis.
Stratification of AL amyloidosis into three risk groups—stages I, II, and III—based on serum troponin and N-terminal pro brain natriuretic peptide (NT-proBNP) measurements. Patients are considered to be in stage I if both markers are within the normal range; stage II if either marker is above its respected threshold for normal; and stage III if both are above normal. These stages correspond to median survival lengths of 26, 11, and 4 months, respectively. (Used with permission from Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22(18):3751–3757. [PMId: 15365071])
The other major determinant of survival in AL amyloidosis is the response to therapy as measured by the FLC assay. Given that AL amyloid deposits are derived from circulating monoclonal immunoglobulin light chains, it is not surprising that the FLC response to therapy is a key determinant of outcome. Indeed, the main goal of therapy is suppression of FLC production. It has been shown that reduction in amyloidogenic FLC concentration by more than 50% portends better prognosis, with associated regression of amyloid and a survival advantage. In one study, 5-year survival was 88% in patients whose abnormal FLC concentration fell by more than 50% following therapy, compared with only 39% among those whose FLC did not fall by at least half.
Plasma cell burden is usually low in patients with AL amyloidosis, which makes monitoring difficult. Clinicians should assess the level of organ dysfunction, but apart from measuring troponins and NT-proBNP, there is no consensus regarding the ideal parameters to follow for continued assessment of each involved organ system. The development of the FLC assay has also been a major advance in this regard and has been shown to be the single most important parameter for monitoring the hematologic response in patients with AL amyloidosis. Typical monitoring during therapy includes measurement of FLCs after each treatment cycle (often monthly) to document response.