AL Amyloidosis
Etiology and Incidence
AL amyloidosis is most frequently caused by a clonal expansion of plasma cells in the bone marrow that secrete a clonal Ig LC that deposits as amyloid fibrils in tissues. It may be purely serendipitous whether the clonal plasma cells produce an LC that misfolds and produces AL amyloidosis, or folds properly, allowing the cells to inexorably expand over time and develop into multiple myeloma. It is also possible that the two processes have differing molecular etiologies. AL amyloidosis can occur in multiple myeloma and other B lymphoproliferative diseases, including non-Hodgkin’s lymphoma and Waldenstrom’s macroglobulinemia. AL amyloidosis is the most common type of systemic amyloidosis in North America. Its incidence has been estimated at 4.5 per 100,000; however, ascertainment continues to be inadequate, and the true incidence may be much higher. AL amyloidosis, like other plasma cell diseases, usually occurs after age 40 and is often rapidly progressive and fatal if untreated. It occurs in about 15% of myelomas. About 20% of all patients with AL amyloidosis have myeloma; the rest have other B cell disorders.
Diagnosis
Identification of a clonal plasma cell dyscrasia distinguishes AL from other types of amyloidosis. More than 90% of patients have a serum or urine monoclonal Ig protein that can be detected by immunofixation electrophoresis (Fig. 15-2^) or free light chain assay.
FIGURE 15-2
Laboratory features of AL amyloidosis. A. Serum immunofix-ation electrophoresis reveals an IgGK monoclonal protein; the serum protein electrophoresis is often normal. B. Bone marrow biopsy specimen in another patient, stained with antibody to λ light chain and developed with horseradish peroxidase, exhibits clonotypic λ-positive plasma cells (400x); antibody staining for κ would reveal few or no κ-positive cells.
The standard serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are not useful screening tests because the clonal Ig in AL amyloidosis, unlike in multiple myeloma, is often not present in sufficient quantity in the serum to produce a monoclonal “M-spike”by these tests.A commercially available nephelometric assay accurately quantifies abnormal LCs that circulate free of heavy chains in both multiple myeloma and AL amyloidosis. In AL, elevated levels of free LCs with a shift in the normal ratio of free kappa to lambda is seen in 75% of patients. Lambda LCs are more common than kappa LCs in AL amyloidosis. Examining the ratio is essential because in renal failure free light chain clearance is reduced, and both types of LCs will be elevated. In addition, an increased percentage of plasma cells in the bone marrow is noted in about 90% of patients; those cells are monoclonal by immunohisto-chemical staining for kappa and lambda (Fig. 15-2B), or by fluorescence-activated cell sorter. However, a monoclonal serum protein by itself is not diagnostic of amyloidosis, since monoclonal gammopathy of uncertain significance (MGUS) is common in older patients. However, when MGUS is present in a patient with biopsy-proven amyloidosis, the AL type is strongly suspected. Immunohistochemical staining of the amyloid deposits is useful if they bind one light chain antibody in preference to the other; some AL deposits bind many antisera nonspecifically. Immunoelectron microscopy can be more reliable but is not widely available. Mass spectrometry-based microsequencing of small amounts of protein extracted from fibril deposits may ultimately be the most reliable way to identify the components of the fibrils. In ambiguous cases, other forms of amyloidosis should be thoroughly excluded.
Pathology and Clinical Features
Amyloid deposits are usually widespread in AL amyloidosis and can be present in the interstitium of any organ except the central nervous system. The amyloid fibril deposits are composed of intact 23 kDa monoclonal Ig LCs or smaller fragments, 11-18 kDa in size, representing the variable (V) region alone, or the V region and a portion of the constant (C) region. Although all kappa and lambda LC subtypes have been identified in AL amyloid fibrils, lambda subtypes predominate, and the lambda VI subtype appears to have unique structural properties that predispose it to fibril formation, often in the kidney.
AL amyloidosis is usually a rapidly progressive disease that presents with characteristic clinical syndromes, recognition of which is key to making the diagnosis. Initial symptoms of fatigue and weight loss are common, but the diagnosis is rarely made until symptoms referable to a specific organ appear.The kidneys are the most frequently affected organ (80%). Renal amyloidosis is usually manifested by proteinuria, which is often in the nephrotic range and associated with significant hypoal-buminemia and edema or anasarca; rarely, tubular rather than glomerular deposition of amyloid can produce azotemia without significant proteinuria. Cardiac symptoms are the second most common presentation (40%), but cardiac dysfunction is associated with death in 75% of patients. The electrocardiogram may show low voltage with a pseudo-infarct pattern. With significant cardiac involvement, the echocardiogram will display concentrically thickened ventricles (the interventricular septal thickness is a useful parameter to monitor) and diastolic dysfunction; however, systolic function is preserved until late in the disease.
FIGURE 15-3
Clinical signs of AL amyloidosis. A. Macro-glossia. B. Periorbital ecchymoses. C. Fingernail dystrophy.
Nervous system features include a peripheral sensory neuropathy (18%), carpal tunnel syndrome (25%), and/or autonomic dysfunction with gastrointestinal motility disturbances (early satiety, diarrhea, constipation) and orthostatic hypotension (16%). Macroglossia, with an enlarged, indented, or immobile tongue, is pathognomonic of AL amyloidosis and is seen in 10% of patients. Hepatomegaly, seen in 34% of patients, may be massive with cholestatic liver function abnormalities, although liver failure is uncommon. The spleen is frequently involved, and there may be functional hyposplenism in the absence of significant splenomegaly. Many patients report “easy bruising” due to amyloid deposits in capillaries and deficiency of clotting factor X; cutaneous ecchymoses appear, particularly around the eyes, giving the “raccoon-eyes” sign. Other findings include nail dystrophy, alopecia, and amyloid arthropathy with thickening of synovial membranes (Fig. 15-3).
Treatment:
AL Amyloidosis
Extensive multisystem involvement typifies AL amyloidosis, and median survival with no treatment is usually about one year from the time of diagnosis. Current therapies target the clonal bone marrow plasma cells using approaches employed for multiple myeloma. Treatment with cyclic oral melphalan and prednisone can decrease the plasma cell burden but produces complete hematologic remission in only a few percent of patients and minimal organ responses and improvement in survival (median 2 years). The substitution of pulses of high-dose dexamethasone for prednisone produces a higher response rate and more durable remissions, although dexamethasone is not always well tolerated by patients with significant edema or cardiac disease. High-dose intravenous melphalan followed by autologous stem cell transplantation is far more effective than oral melphalan and prednisone. Complete hematologic response rates are about 40%, as measured by complete loss of clonal plasma cells in the bone marrow and disappearance of the monoclonal LC by immunofixation electrophoresis. In patients without a complete hematologic response,a significant improvement is often seen in hematologic parameters. Similar rates of improvement are seen in organ function and quality of life, with an extended survival exceeding that previously seen in this disease. The complete hematologic responses appear to be more durable than those seen in multiple myeloma and may even signal cure, as remissions of more than 10 years are documented. Unfortunately, only about half of AL amyloidosis patients are eligible for such aggressive treatment, and even at specialized treatment centers, peritransplant mortality is higher than for other hematologic diseases because of impaired organ function. Amyloid cardiomyopathy, poor nutritional status, impaired performance status, and multiple-organ disease contribute to excess morbidity and mortality. The bleeding diathesis due to adsorption of clotting factor X to amyloid fibrils also confers high mortality during myelosuppressive therapy; however, this syndrome occurs in only a few percent of patients. Age alone, or renal insufficiency, does not have a major impact on morbidity or outcome, and these factors alone should not exclude patients from such treatment. In selected patients, tandem transplantation may offer an even higher rate of hematologic response.
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 highdose chemotherapy are dangerous. In these patients, cardiac transplantation can be performed, followed by treatment with high-dose melphalan and stem cell rescue to prevent amyloid deposition in the transplanted heart or other organs. Thalidomide and lenalidomide have activity; lenalidomide is reasonably well tolerated and, particularly in combination with dexamethasone, produces complete hematologic remissions and improvement in organ function. Novel agents such as the proteasome inhibitor bortezomib are also under investigation for AL amyloidosis.
Supportive care is important for patients with any type of amyloidosis. For nephrotic syndrome, diuretics and supportive stockings can ameliorate edema; angiotensin-converting enzyme inhibitors should be used with caution and have not been shown to slow renal disease progression. Congestive heart failure due to amyloid cardiomyopathy is also best treated with diuretics; it is important to note that digitalis, calcium channel blockers, and beta blockers are relatively contraindicated as they can interact with amyloid fibrils and produce heart block and worsening heart failure.Amio-darone has been used for atrial and ventricular arrhythmias. Automatic implantable defibrillators have reduced effectiveness due to the thickened myocardium. Atrial ablation is another effective approach for atrial fibrillation. For conduction abnormalities, ventricular pacing may be indicated. Atrial contractile dysfunction is common in amyloid cardiomyopathy,and is an indication for anticoagulation.Autonomic neuropathy can be treated with α agonists such as midodrine to support the blood pressure; gastrointestinal dysfunction may respond to motility or bulk agents. Nutritional supplementation, either orally or parenterally, is also important.
In localized AL,amyloid deposits can be produced by clonal plasma cells infiltrating local sites in the airways, bladder,skin,or lymph nodes (Table 15-1). Deposits may respond to surgical intervention or radiation therapy; systemic treatment is generally not appropriate. Patients should be referred to a center familiar with management of these rare manifestations of amyloidosis.
AA Amyloidosis
Etiology and Incidence
AA amyloidosis can occur in association with almost any of the chronic inflammatory states (e.g., rheumatoid arthritis, lupus, Crohn’s disease) or chronic infections such as tuberculosis or subacute bacterial endocarditis. In the United States and Europe, AA amyloidosis has become uncommon, occurring in <1% of patients with these diseases, perhaps because of advances in antiinflammatory and antimicrobial therapies. Nonetheless, in Finland AA amyloidosis was reported to be the most common cause of nephrotic syndrome in patients with rheumatoid arthritis. AA amyloidosis is more common in Turkey and the Middle East, where it occurs in association with familial Mediterranean fever. It is the only type of systemic amyloidosis that occurs in children.
Pathology and Clinical Features
Deposits are more limited in AA amyloidosis than in AL amyloidosis; they usually begin in the kidneys. Hepatomegaly, splenomegaly, and autonomic neuropathy can occur as the disease progresses; cardiomyopathy occurs rarely. The symptoms and signs are similar to those described for AL amyloidosis. The AA amyloid fibrils are usually composed of an 8-kDa, 76 amino acid N-terminal portion of a 12-kDa precursor protein, serum amyloid A (SAA). SAA is an acute-phase apoprotein synthesized in the liver and transported by high-density lipoprotein, HDL3, in the plasma. Several years of an underlying inflammatory disease causing chronic elevation of SAA usually precedes fibril formation, although infections can produce AA deposition more quickly. In mouse models and perhaps in people, AA fibril formation can be accelerated by an amyloid enhancing factor present in high concentration in the spleen (which may be early SAA aggregates or deposits), by basement membrane heparan sulfate proteoglycan, or by seeding with AA or heterologous fibrils.
Treatment:
AA Amyloidosis
The primary therapy in AA amyloidosis is treatment of the underlying inflammatory or infectious disease.Treat-ment that suppresses or eliminates the inflammation or infection also decreases the SAA protein concentration. For familial Mediterranean fever, colchicine in a dose of 1.2—1.8 mg/d is the appropriate treatment. Colchicine has not been helpful for AA amyloidosis of other causes or for other amyloidoses. A multicenter randomized phase III trial has recently been completed using eprodisate,designed to interfere with the interaction of AA amyloid protein with glycosaminoglycans in tissues and thus prevent or disrupt fibril formation.This drug is well tolerated and appears to markedly delay progression of AA renal disease, regardless of the underlying inflammatory process. Eprodisate is the first targeted inhibitor for diseases of protein misfolding and deposition to become available to patients.
AF amyloidoses
The inherited AF amyloidoses are autosomal dominant diseases in which a variant plasma protein forms amyloid deposits, beginning in midlife. These diseases are rare, with an estimated incidence of <1 per 100,000. The most common form of AF is caused by mutation of the abundant plasma protein transthyretin (TTR, also known as prealbumin). More than 100 TTR mutations are known, and most are associated with ATTR amyloidosis. One variant, Ile122, has a carrier frequency that may be as high as 4% in the African-American population and is associated with late-onset cardiac amyloidosis. The actual incidence of disease in the African-American population is the subject of ongoing clinical research, but it would be wise to consider this in the differential diagnosis of African-American patients who present with concentric cardiac hypertrophy and evidence of diastolic dysfunction, whether or not they have a history of hypertension. Even wild-type TTR can form fibrils, leading to so-called senile systemic amyloidosis (SSA) in older patients. It can be found in up to 25% of autopsies in patients over age 80, and it can produce a clinical syndrome of amyloid cardiomyopathy that is similar to that occurring in younger patients with mutant TTR. Other familial amyloidoses, caused by variant apolipoproteins AI or AII, gelsolin, fibrinogen Aa, or lysozyme, are reported in only a few families worldwide.
In ATTR and in other forms of familial amyloidosis, the variant structure of the precursor protein is the key factor in fibril formation. The role of aging is intriguing, since patients born with the variant proteins do not have clinically apparent disease until middle age, despite the lifelong presence of the abnormal protein. Further evidence of an age-related “trigger” is the occurrence of SSA in the elderly, caused by the deposition of fibrils derived from normal TTR.
Clinical Features
AF amyloidosis has a variable presentation but is usually consistent within affected kindreds with the same mutant protein. A family history makes AF more likely, but many patients present sporadically with new mutations. ATTR usually presents as a syndrome of familial amyloidotic polyneuropathy or familial amyloidotic cardiomyopathy; within a family, the age of disease onset is usually consistent. Peripheral neuropathy begins as a lower-extremity sensory and motor neuropathy and progresses to the upper extremities. Autonomic neuropathy is manifest by gastrointestinal symptoms of diarrhea with weight loss and orthostatic hypotension. Patients with TTR Met-30, the most common mutation, have normal echocardiograms but may have conduction defects and require a pacemaker. Patients with TTR Ala-60 and several other mutations have myocardial thickening similar to that caused by AL amyloidosis, although heart failure is less common and the prognosis is better. Vitreous opacities caused by amyloid deposits are pathognomonic ofATTR amyloidosis.
Other AF syndromes include those associated with inherited mutations in apolipoprotein AI (AApoAI), apolipoprotein AII (AApoAII), fibrinogen (AFib), lysozyme (ALys), and gelsolin (AGel) that cause amyloid fibril deposition. These are very rare disorders with slowly progressing dysfunction of kidneys, liver, gastrointestinal tract, and, in the case of gelsolin, abnormalities of the cranial nerves and cornea.
Patients with AF amyloidosis can present with clinical syndromes that mimic those of patients with AL. Patients who do not have a plasma cell disorder should be screened for AF. This is particularly important in ethnic populations with a high carrier frequency of AF alleles (e.g., patients of Portuguese decent,African Americans). Variant TTR proteins can usually be detected by isoelectric focusing, but DNA sequencing is the gold standard for diagnosis for ATTR and the other AF mutations.
Treatment:
ATTR amyloidoses
Without intervention, survival after ATTR disease onset is 5-15 years. Orthotopic liver transplantation removes the major source of variant TTR production and replaces it with a source of normal TTR; it also arrests disease progression and leads to improvement in autonomic and peripheral neuropathy in some patients. Cardiomyopathy often does not improve, and in some patients it can worsen after liver transplantation, perhaps due to deposition of wild-type TTR as seen in SSA.Compounds have been identified that stabilize TTR in a nonpathogenic tetrameric conformation.The first of these, diflunisal, is being studied in a multicenter phase III trial,and screens for other agents are ongoing.
Aß2M amyloidosis
Aß2M amyloidosis is composed of ß2-microglobulin, the invariant chain of class I human leukocyte antigens, and produces rheumatologic manifestations in patients on long-term hemodialysis. ß2-microglobulin is excreted by the kidney, and levels become elevated in ESRD. The molecular mass of ß2M is 11.8 kDa, above the molecular mass cutoff of some dialysis membranes. The incidence of this disease appears to be declining with newer dialysis techniques.
Aß2M amyloidosis usually presents with carpal tunnel syndrome, persistent joint effusions, spondyloarthropathy, and cystic bone lesions. Carpal tunnel syndrome is often the first symptom of disease. In the past, persistent joint effusions accompanied by mild discomfort had been seen in up to 50% of patients on dialysis for more than 12 years. Involvement is bilateral, and large joints (shoulders, knees, wrists, and hips) are more frequently affected. The synovial fluid is noninflammatory, and ß2M amyloid deposits can be found if the sediment is stained with Congo red.Although less common, visceral ß2M amyloid deposits do occasionally occur in the gastrointestinal tract, heart, tendons, and subcutaneous tissues of the buttocks. There is no specific therapy for Aß2M amyloidosis, but cessation of dialysis after renal allograft may lead to symptomatic improvement.
Summary
A diagnosis of amyloidosis should be considered in patients with unexplained nephropathy, cardiomyopathy (particularly with diastolic dysfunction), neuropathy (either peripheral or autonomic), enteropathy, or the pathognomonic soft tissue findings of macroglossia and periorbital ecchymoses. Pathologic identification of amyloid fibrils can be made; Congo red staining of aspirated abdominal fat is the initial test of choice in most cases. Accurate typing using a combination of immunologic, biochemical, and genetic testing is essential to choosing the appropriate therapy (see algorithm for workup, Fig. 15-1). For difficult cases, referral centers can provide specialized diagnostic techniques and access to clinical trials.
