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Etiology and Incidence
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AL amyloidosis is most frequently caused by a clonal expansion of bone-marrow plasma cells that secrete a monoclonal immunoglobulin LC depositing as amyloid fibrils in tissues. Whether the clonal plasma cells produce a LC that misfolds and leads to AL amyloidosis or an LC that folds properly, allowing the cells to inexorably expand over time and develop into multiple myeloma (Chap. 107), may depend upon primary sequence of the clonal LC or other genetic or epigenetic factors. AL amyloidosis can occur with multiple myeloma or other B lymphoproliferative diseases, including non-Hodgkin’s lymphoma (Chap. 104) and Waldenström’s macroglobulinemia (Chap. 107). AL amyloidosis is the most common type of systemic amyloidosis diagnosed in North America. Its incidence has been estimated at 4.5 cases/100,000 population; 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.
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Pathology and Clinical Features
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Amyloid deposits are usually widespread in AL amyloidosis and can be present in the interstitium of any organ outside the central nervous system. The amyloid fibril deposits are composed of full-length 23-kDa monoclonal immunoglobulin LCs as well as fragments. Accessory molecules co-deposited with LC fibrils (as well as with other amyloid fibrils) include serum amyloid P component, apolipoproteins e and AIV, glycosaminoglycans, and metal ions. Although all kappa and lambda LC subtypes have been identified in AL amyloid fibrils, lambda subtypes predominate. The lambda 6 subtype appears to have unique structural properties that predispose it to fibril formation, often in the kidney.
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AL amyloidosis is often a rapidly progressive disease that presents as a pleiotropic set of clinical syndromes, recognition of which is key for initiation of the appropriate workup. Nonspecific symptoms of fatigue and weight loss are common; however, the diagnosis is rarely considered until symptoms referable to a specific organ develop. The kidneys are the most frequently involved organ and are affected in 70–80% of patients. Renal amyloidosis usually manifests as proteinuria, often in the nephrotic range and associated with hypoalbuminemia, secondary hypercholesterolemia and hypertriglyceridemia, and edema or anasarca. In some patients, interstitial rather than glomerular amyloid deposition can produce azotemia without proteinuria. The heart is the second most commonly affected organ (50–60% of patients), and cardiac involvement is the leading cause of death from AL amyloidosis. Early on, the electrocardiogram may show low voltage in the limb leads with a pseudo-infarct pattern. Echocardiographic features of disease include concentrically thickened ventricles and diastolic dysfunction with an abnormal global longitudinal strain pattern; a “sparkly” appearance has been described but is often not seen with modern high-resolution echocardiographic techniques. Poor atrial contractility occurs even in sinus rhythm, and patients with cardiac amyloidosis are at risk for development of atrial thrombi and stroke. Cardiac MRI can show increased wall thickness, and characteristic delayed enhancement of the subendocardium has been described following injection of gadolinium contrast. Nervous system symptoms include peripheral sensorimotor neuropathy and/or autonomic dysfunction manifesting as gastrointestinal motility disturbances (early satiety, diarrhea, constipation), dry eyes and mouth, impotence, orthostatic hypotension, and/or neurogenic bladder. Macroglossia (Fig. 108-2A), a pathognomonic sign of AL amyloidosis, is seen in only ~10% of patients. Liver involvement causes cholestasis and hepatomegaly. The spleen is frequently involved, and there may be functional hyposplenism in the absence of significant splenomegaly. Many patients experience “easy bruising” due to amyloid deposits in capillaries or deficiency of clotting factor X due to binding to amyloid fibrils; cutaneous ecchymoses appear, particularly around the eyes, producing another uncommon but pathognomonic finding, the “raccoon-eye” sign (Fig. 108-2B). Other findings include nail dystrophy (Fig. 108-2C), alopecia, and amyloid arthropathy with thickening of synovial membranes in the wrists and shoulders. The presence of a multisystemic illness or general fatigue along with any of these clinical syndromes should prompt a workup for amyloidosis.
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Identification of an underlying clonal plasma cell or B lymphoproliferative process and a clonal LC are key to the diagnosis of AL amyloidosis. Serum protein electrophoresis and urine protein electrophoresis, although of value in multiple myeloma, are not useful screening tests if AL amyloidosis is suspected because the clonal LC or whole immunoglobulin often is not present in sufficient amounts to produce a monoclonal “M-spike” in the serum or LC (Bence Jones) protein in the urine. However, more than 90% of patients with AL amyloidosis have serum or urine monoclonal LC or whole immunoglobulin detectable by immunofixation electrophoresis of serum (SIFE) or urine (UIFE) (Fig. 108-3A) or by nephelometric measurement of serum “free” LCs (i.e., LCs circulating in monomeric form rather than in an immunoglobulin tetramer with heavy chain). Examining the ratio as well as the absolute amount of serum-free LCs is essential, as renal insufficiency reduces LC clearance, nonspecifically elevating both isotypes. In addition, an increased percentage of plasma cells in the bone marrow—typically 5–30% of nucleated cells—is found in ~90% of patients. Kappa or lambda clonality should be demonstrated by flow cytometry, immunohistochemistry, or in situ hybridization for LC mRNA (Fig. 108-3B).
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A monoclonal serum protein by itself is not diagnostic of amyloidosis, since monoclonal gammopathy of uncertain significance is common in older patients (Chap. 107). However, when monoclonal gammopathy of uncertain significance is found in patients with biopsy-proven amyloidosis, the AL type should be ruled out. Similarly, patients thought to have “smoldering myeloma” because of a modest elevation of bone-marrow plasma cells should be screened for AL amyloidosis if they have signs or symptoms of renal, cardiac, or neurologic disease. Accurate tissue amyloid typing is essential for appropriate treatment. Immunohistochemical staining of the amyloid deposits is useful if they selectively bind one LC antibody in preference to the other; some AL deposits bind antibodies nonspecifically. Immunoelectron microscopy is more reliable, while mass spectrometry–based microsequencing of small amounts of protein extracted from fibril deposits has become the diagnostic standard. In ambiguous cases, other forms of amyloidosis should be thoroughly excluded with appropriate genetic and other testing.
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TREATMENT AL Amyloidosis
Extensive multisystemic involvement typifies AL amyloidosis, and the median survival period without treatment is usually only ~1–2 years from the time of diagnosis. Current therapies target the clonal bone-marrow plasma cells, using approaches employed for multiple myeloma. Treatment with oral melphalan and prednisone can decrease the plasma cell burden but rarely leads to complete hematologic remission, meaningful organ responses, or improved survival and is no longer widely used. The substitution of 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 IV melphalan followed by autologous stem cell transplantation (HDM/SCT) produces complete hematologic responses in ~40% of treated patients, as determined by loss of clonal plasma cells in the bone marrow and disappearance of the amyloidogenic monoclonal LC, as determined by SIFE/UIFE and free LC quantitation. Six to 12 months after achieving a hematologic responses, improvements in organ function and quality of life may occur. Hematologic responses appear to be more durable after HDM/SCT than in multiple myeloma, with remissions continuing in some patients beyond 15 years without additional treatment. Unfortunately, only about 30–40% of all AL amyloidosis patients are suitable for aggressive treatment, and, even at specialized treatment centers, transplantation-related mortality rates are higher than those for other hematologic diseases because of impaired organ function at initial presentation. Amyloid cardiomyopathy, poor nutritional and performance status, and multiorgan disease contribute to excess morbidity and mortality. A bleeding diathesis resulting from adsorption of clotting factor X to amyloid fibrils also increases mortality rates; however, this syndrome occurs in only 5–10% of patients. A randomized multicenter trial conducted in France compared oral melphalan and dexamethasone with HDM/SCT and failed to show a benefit of dose-intensive treatment, although the transplantation-related mortality rate in this study was very high. It has become clear that careful selection of patients and expert peritransplantation management are essential in reducing transplantation-related mortality.
For patients with AL amyloidosis and impaired cardiac function or arrhythmias due to involvement of the myocardium, the median survival period is only ~6 months without treatment. In these patients, cardiac transplantation can be performed and followed by HDM/SCT to eliminate the noxious LC clone and prevent amyloid deposition in the transplanted heart or other organs.
Novel anti–plasma cell agents have been investigated for treatment of plasma cell diseases. The immunomodulators thalidomide, lenalidomide, and pomalidomide display activity; dosing may need to be adjusted compared to their usage for myeloma. The proteasome inhibitor bortezomib has also been found to be effective in single-center and multicenter trials. Anti-fibril small molecules and humanized monoclonal antibodies are also being tested. Clinical trials are essential in improving therapy for this rare disease.
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. Effective diuresis can be facilitated with albumin infusions to raise intravascular oncotic pressure. Congestive heart failure due to amyloid cardiomyopathy is 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. Amiodarone has been used for atrial and ventricular arrhythmias. Automatic implantable defibrillators appear to have reduced effectiveness due to the thickened myocardium, but they may benefit some patients. Atrial ablation is an effective approach for atrial fibrillation. For conduction abnormalities, ventricular pacing may be indicated. Atrial contractile dysfunction is common in amyloid cardiomyopathy and associated with increased thromboembolic complications, prompting considerations of anticoagulation even in the absence of atrial fibrillation. Autonomic neuropathy can be treated with α agonists such as midodrine to support postural blood pressure; gastrointestinal dysfunction may respond to motility or bulk agents. Nutritional supplementation, either oral or parenteral, is also important.
In localized AL amyloidosis, amyloid deposits can be produced by clonal plasma cells infiltrating local sites in the airways, bladder, skin, or lymph nodes (Table 108-1). These deposits may respond to surgical intervention or elimination of the responsible plasma cell clone by low-dose radiation therapy (typically only 20 Gy); systemic treatment generally is not appropriate. Patients should be referred to a center familiar with management of these rare manifestations of amyloidosis.