AL amyloidosis is most frequently caused by a clonal expansion of plasma cells in the bone marrow that secrete a monoclonal immunoglobulin LC that deposits as amyloid fibrils in tissues. It may be purely serendipitous whether the clonal plasma cells produce a LC that misfolds and leads to AL amyloidosis or folds properly, allowing the cells to inexorably expand over time and develop into multiple myeloma (Chap. 17). It is also possible that the two processes have diverse molecular etiologies. AL amyloidosis can occur with multiple myeloma or other B lymphoproliferative diseases, including non-Hodgkin's lymphoma (Chap. 15) and Waldenström's macroglobulinemia (Chap. 17). 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 years and is often rapidly progressive and fatal if untreated.
PATHOLOGY AND CLINICAL FEATURES OF AL AMYLOIDOSIS
Amyloid deposits are usually widespread in AL amyloidosis and can be present in the interstitium of any organ outside of 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. The lambda 6 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 a pleiotropic set of clinical syndromes, recognition of which is key to initiating 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 affected organ, in 70–70% of patients. Renal amyloidosis is usually manifested as proteinuria, often in the nephrotic range and associated with significant hypoalbuminemia, secondary hypercholesterolemia, and edema or anasarca. In some patients, tubular rather than glomerular deposition of amyloid can produce azotemia without significant proteinuria. The heart is the second most commonly affected organ, in 50–50% of patients, and the leading cause of death. Early on, the electrocardiogram may show low voltage in the limb leads, with a pseudo-infarct pattern. Eventually, the echocardiogram will display concentrically thickened ventricles and diastolic dysfunction, leading to a restrictive cardiomyopathy; systolic function is preserved until late in the disease. A "sparkly" appearance is usually not seen using modern high-resolution echocardiography equipment. Cardiac magnetic resonance imaging can show an increased wall thickness and a characteristic subendocardial enhancement with gadolinium. Nervous system symptoms include a peripheral sensory neuropathy and/or autonomic dysfunction with gastrointestinal motility disturbances (early satiety, diarrhea, constipation) and orthostatic hypotension. Macroglossia, with an enlarged, indented, or immobile tongue, is pathognomonic of AL amyloidosis but is seen only in ~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 have "easy bruising" due to amyloid deposits in capillaries or to deficiency of clotting factor X, which can bind to amyloid fibrils; cutaneous ecchymoses appear, particularly around the eyes, giving the "raccoon-eye" sign. Other findings include nail dystrophy, alopecia, and amyloid arthropathy with thickening of synovial membranes in the wrists and shoulders (Fig. 18-2). The presence of a multisystem illness or general fatigue along with any of these clinical syndromes should prompt a workup for amyloidosis.
Clinical signs of AL amyloidosis. A. Macroglossia. B. Periorbital ecchymoses. C. Fingernail dystrophy.
Identification of the underlying B lymphoproliferative process and clonal LC is key to the diagnosis of AL amyloidosis. The serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are NOT useful screening tests if AL amyloidosis is suspected because the clonal LC or whole immunoglobulin, unlike in multiple myeloma, is often not present in sufficient quantity in the serum to produce a monoclonal "M-spike" or in the urine to cause LC (Bence Jones) proteinuria. However, more than 90% of patients have a serum or urine monoclonal LC or whole immunoglobulin that can be detected by immunofixation electrophoresis of serum (SIFE) or urine (UIFE) (Fig. 18-3A). Assaying for free immunoglobulin LCs circulating in the serum unbound to heavy chains using commercially available nephelometric (FreeLite©) assay demonstrates an elevation and abnormal free kappa:lambda ratio in more than 75% of patients. Examining the ratio as well as the absolute amount is essential, because in renal insufficiency LC clearance is reduced, and both types of LCs will be elevated. In addition, an increased percentage of plasma cells in the bone marrow, typically 5–30% of nucleated cells, is noted in about 90% of patients. Kappa or lambda clonality can be demonstrated by flow cytometry, immunohistochemical staining, or in situ hybridization for LC mRNA (Fig. 18-3B).
Laboratory features of AL amyloidosis. A. Serum immunofixation electrophoresis reveals an IgGκ monoclonal protein in this example; the serum protein electrophoresis is often normal. B. Bone marrow biopsy sections from another patient, stained with antibody to CD138 (syndecan, highly expressed on plasma cells) by immunohistochemistry (left panel). The middle and right panels are stained using in situ hybridization with fluorescein-tagged probes (Ventana Medical Systems) binding to κ and λ mRNA, respectively, in plasma cells. SPEP, serum protein electrophoresis. (Photomicrograph courtesy of C. O'Hara; with permission.)
A monoclonal serum protein by itself is not diagnostic of amyloidosis, since monoclonal gammopathy of uncertain significance (MGUS) is common in older patients (Chap. 17). However, when MGUS is present in patients with biopsy-proven amyloidosis, the AL type should be strongly suspected. Similarly, patients thought to have "smoldering myeloma" because of modest elevation of bone marrow plasma cells should be screened for AL amyloidosis if they have evidence of organ dysfunction. Accurate typing is essential for appropriate treatment. 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 is more reliable, and mass-spectrometry-based microsequencing of small amounts of protein extracted from fibril deposits can also be done. In ambiguous cases, other forms of amyloidosis should be thoroughly excluded with appropriate genetic and other testing.
TREATMENT: AL Amyloidosis
Extensive multisystem involvement typifies AL amyloidosis, and the median survival time with no treatment is usually only about 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 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), and it 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 intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) produces complete hematologic responses in about 40% of treated patients, as measured by complete loss (CR) of clonal plasma cells in the bone marrow and disappearance of the monoclonal LC by IFE and assay for free LCs. Hematologic responses can be followed in the subsequent 6–12 months by improvement in organ function and quality of life. The CRs after HDM/SCT appear to be more durable than those seen in multiple myeloma, with remissions continuing in some patients beyond 15 years without additional treatment. Unfortunately, only about half of AL amyloidosis patients are eligible for such aggressive treatment, and even at specialized treatment centers, the peritransplant mortality rate 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. The single randomized multicenter trial comparing oral melphalan and dexamethasone with HDM/SCT to date failed to show a benefit to dose-intensive treatment, although the transplant-related mortality rate in this study was very high.
For patients with impaired cardiac function or arrhythmias due to amyloid involvement of the myocardium, the median survival time is only about 6 months without treatment, and stem cell mobilization and high-dose chemotherapy are dangerous. In these patients, cardiac transplantation can be performed followed by treatment with HDM/SCT to prevent amyloid deposition in the transplanted heart or other organs.
Recently, novel agents have been investigated for treatment of plasma cell diseases. The immunomodulators thalidomide and lenalidomide have activity; lenalidomide is well tolerated in doses lower than those used for myeloma and, in combination with dexamethasone, produces complete hematologic remissions and improvement in organ function. The proteasome inhibitor bortezomib has also been found to be effective in single- and multicenter trials. Combination therapy trials are now under development, and studies are examining the as yet unproven role of induction and maintenance treatment. Clinical trials are essential for 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. 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. Amiodarone has been used for atrial and ventricular arrhythmias. Automatic implantable defibrillators have reduced effectiveness due to the thickened myocardium, but they can 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 is an indication for anticoagulation even in the absence of atrial fibrillation. 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 18-1). 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.