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Primary systemic amyloidosis is a light-chain immunoglobulin disorder that causes nonlocalized or multisystem symptoms. Patients with cardiac involvement have a poor prognosis. Fortunately, many effective treatments have become available in recent years. Early diagnosis and institution of treatment is critical to improving survival rates and quality of life. In this article, the authors highlight common clinical presentations, suggest diagnostic workup techniques, and discuss treatment options, including autologous stem cell transplantation.

Amyloidosis is a rare disorder characterized by deposition of amorphous hyaline-appearing material in the intercellular space. Congo red staining of amyloid produces character-istic red-green birefringence under polarized light.1 At the ultrastructural level, amyloid protein consists of fibrillar, nonbranching material deposited in a distinct ƒÀ-pleated configur-ation.2

Amyloidosis is characterized by the type of protein deposited. The most common of several types of systemic amyloidosis, primary systemic amyloidosis (also called light-chain amyloidosis, or AL) is caused by deposition of monoclonal light chains or light-chain fragments as amyloid. These chains are derived from a monoclonal plasma cell popu-lation, although it may not always be evident. The incidence of primary systemic amyloidosis is estimated to be 1 in 100,000 adults in the United States. Like other plasma cell dyscrasias, primary systemic amyloidosis affects older adults (median age at presentation, 65 years).3 No risk factors or sex or racial predispositions have been de-scribed.

The incidence of primary systemic amyloidosis is similar to that of Hodgkin's disease, Myco-bacterium avium complex infection, and polycythemia vera. Therefore, primary care physicians can expect to see patients with primary systemic amyloidosis in their practice. However, primary care physicians are often not very familiar with amyloidosis. Patients frequently present with nonspecific or vague symptoms, and it may be several months before diagnosis is made. Early diagnosis and treatment are crucial to achieving a satisfactory outcome.

Here, we present an illustrative case followed by a review of clinical features and diag-nostic and management approaches. We also highlight recent advances in treatment of primary systemic amyloidosis. The availability of potentially life-prolonging treatments underscores the importance of timely diagnosis so that therapy can be instituted before the pa-tient's condition irreversibly deteriorates.

Clinical features

Being alert to the possibility of amyloidosis is the most important factor in diagnosis of the disorder. Patients with amyloidosis present with signs and symptoms related to dysfunction of the involved organ or organs. Because the kidneys are the most commonly involved organs, proteinuria and nephrotic syndrome are seen in up to 90% of patients4 (table 1). Amyloidosis should be considered in any adult with nephrotic syndrome in the absence of hypertension or diabetes. It is important to note that renal amyloidosis may predominantly involve renal vessels and tu-bules, causing tubular dysfunction and only modest protein-uria.

The next most commonly involved organ is the heart. Cardiac involvement carries a poor prognosis.5 Cardiac amyloidosis should be considered in any patient with CHF or cardiomyopathy in the absence of isch-emic or valvular heart disease. Patients who present with conduction defects or arrhythmias are at risk for sudden death.6 Typically, patients with cardiac amyloidosis have low-voltage complex on the electrocardiogram (figure 1).

A pseudoinfarction pattern may be seen, which may mislead the physician into diagnosing ischemic heart disease. An echo-cardiogram can help differentiate ischemic heart disease from cardiac amyloidosis.7 Patients with amyloidosis have concentric thickening of the ventricle wall or septum, or both, with reduced or normal chamber size. Abnormal left ventricular relaxation and diastolic dysfunction or restrictive hemodynamics may be seen. A speckled appearance of the myocardium on echo-cardiogram is a very suggestive but insensitive sign. More detailed echocardiographic evaluation with tissue Doppler imaging and myocardial strain rate have emerged as important tools that may help lead to early diagnosis.8 Endomyocardial biopsy may be necessary for diagnosis in certain patients.

Amyloidosis may present with neuropathic symptoms, such as carpal tunnel syndrome, peripheral neuropathy, or autonomic neuropathy. Peripheral neuropathy usually is axonal in nature at the beginning, and demyelination occurs later. The lower extremities are typically more involved than the upper extremities, and patients may present with pain as the main or only symptom. Unexplained orthostasis, nausea, emesis, diarrhea, or bowel dysmotility should raise the possibility of autonomic neuropathy. Gastrointestinal (GI) involvement with amyloid may be silent or manifest in symptoms of nausea, abdominal bloating, diarrhea, emesis, or pain. Impaired GI motility may lead to blind loop syndrome and bacterial overgrowth, resulting in malabsorption syndrome.9 GI bleeding, which may be subtle or catastrophic, sometimes is the only evidence of GI involvement.

Amyloidosis may cause a bleeding tendency as a result of infiltration of blood vessels, liver dysfunction, or coagulation factor deficiency unrelated to hepatic impairment.10 Characteristic factor X deficiency secondary to absorption by amyloid deposit may be seen in up to 50% of affected patients, although clinical bleeding is less common.

Other than these major organ-specific manifestations, patients may present with rather nonspecific and vague symptoms. Unexplained fatigue, weakness, or weight loss may lead to a search for occult malignancy. Painless lymphadenopathy, liver function abnormality, or an incidental finding of palpable hepatomegaly may be the only findings. Characteristic physical findings, such as macroglossia (figure 2), periorbital purpura (figure 3), or cutaneous amyloid deposits (typically on flexural areas) may provide valuable diagnostic clues on examination. However, they often develop later and are seen in only a minority of patients.

Diagnostic evaluation

The source of amyloid protein in primary systemic amyloidosis is a population of monoclonal plasma cells. Diagnostic evaluation of suspected amyloidosis should start with immunoelectrophoresis and immunofixation of the serum and urine to detect intact monoclonal immunoglobulin or immunoglobulin light chains, or both. Protein electrophoresis alone is insufficient for diagnosis because the monoclonal protein in amyloidosis is often small and may be obscured by normal serum or urine proteins. Immunofixation of serum and urine detects monoclonal protein in about 90% of patients. Recently, a serum free immunoglobulin light chain assay has become available. It is extremely sensitive and can detect the presence of monoclonal protein in nearly all patients.

Because monoclonal gammopathy is much more common than amyloidosis (prevalence, 2% to 3% of persons over age 65 years), the significance of the presence of monoclonal protein should be carefully evaluated and taken as supportive evidence of primary systemic amyloidosis only in the appropriate clinical context. If monoclonal protein is found in a patient with suggestive clinical features, the likelihood of amyloidosis is high, but the mere presence of monoclonal protein is not sufficient for diagnosis. Demonstration of amyloid on tissue biopsy is required.

Biopsy of the affected organ is the most direct way to establish the diagnosis, but depending on the organ in question, the procedure may carry substantial risk. Because primary systemic amy-loidosis is a systemic disease, demonstration of amyloid in easily obtainable tissue may be sufficient to establish the diagnosis. Subcutaneous fat aspirate and bone marrow are the preferred tissues for biopsy because of the ease and simplicity of the procedure.11,12 Congo red staining demonstrates amyloid deposition in 90% or more of patients with systemic amyloidosis.

If results of biopsy of fat or bone marrow are negative and primary systemic amyloidosis is strongly suspected, biopsy of the affected organ should be obtained; these results can be expected to establish the diagnosis in virtually all patients.

Amyloid deposit can be analyzed immunohistochemically to differentiate immunoglobulin light-chain amyloid from other types of systemic amyloidosis. Amino acid sequencing or mass spectroscopic analysis may be needed for adequate characterization of amyloid protein in some cases. Bone marrow biopsy also allows for assessment of the plasma cell population. However, plasmacytosis is often minimal and not morphologically apparent in most patients with amyloidosis. Immunophenotyping may be helpful in detecting a small light-chain?|restricted (clonal) plasma cell population.

Treatment

Treatment of amyloidosis is based on the observation that arresting the production and deposition of amyloidogenic light chains can result in gradual resolution of amyloid and improvement in organ function. Contrary to general belief, amyloid deposition is not irreversible. Experimental and clinical data show that deposits can be reabsorbed if the supply of amyloidogenic protein is interrupted.13 However, if organ damage has occurred, reabsorption of the amyloidal deposit may not restore organ function. Thus, one of the keys to successful treatment is early diagnosis and institution of therapy.

Appropriate supportive care directed toward specific organ dysfunction and clinical manifestations is an important component of management. Therapy is targeted at suppressing or eliminating the underlying amyloidogenic plasma cell clone. Treatment methods are modeled after treatment of multiple myeloma. However, compared with myeloma, treatment of amyloidosis remains less effective and therefore unsatisfactory. Moreover, the efficacy of treatment is difficult to evaluate because there are no reliable and readily available ways to assess the total amount of amyloid protein in the body.

Melphalan (Alkeran) combined with prednisone has been the mainstay of treatment for many years on the basis of early studies showing superiority over colchicine or supportive care alone.14?|16 Typically, several months of treatment are needed.

Responses, including improvement of renal and cardiac function and correction of coagulation factor X deficiency, have been reported and are associated with increased survival rates. Attempts to intensify chemo-therapy by using intravenous multidrug combinations in the hope of improving responses and increasing survival rates have not been successful and are associated with increased toxicity more so than melphalan and prednisone combination. High-dose or intermediate-dose dexamethasone (Decadron) alone or in combination with melphalan has been used and has resulted in responses in a significant proportion of patients.

Although the treatment of amyloidosis is often ineffective and frustrating, there have been many advances and there is reason for optimism. Newer drugs, such as thalidomide (Thalidomid) alone or in combination with dexamethasone, have shown efficacy in treatment of amyloidosis. However, thalidomide treatment is associated with significant toxic effects, such as neuropathy, somnolence, constipation, bradycardia, and thromboembolic complications. Therefore, many patients are unable to tolerate this therapy.17 Other drugs, such as lenalidomide (a thalidomide analogue) and bortezomib (Velcade), have shown efficacy in multiple myeloma and hold promise for amyloidosis treatment. Their role in amyloidosis treatment is being actively investigated.

High-dose chemotherapy followed by autologous stem cell transplantation has emerged as a treatment option for some patients with amyloidosis. Initial studies of this approach were associated with high transplant-related mortality, but more recent case series from high-volume centers report significantly improved outcomes. Although randomized trials have not been performed, phase 2 and case-control studies suggest that transplantation may result in better survival and quality of life than conventional chemotherapy.18,19

Appropriate patient selection is critical to optimizing the chances of a good outcome. Patients with symptomatic cardiac involvement are not appropriate candidates. Transplantation is not curative, and it is unknown whether patients may be at risk for delayed transplant-related complications. Regardless, high-dose chemotherapy and transplantation are an important advancement in treatment of patients with this frustrating disease.

Summary

Primary systemic amyloidosis is a rare disease with protean manifestations. Presence of nephrotic syndrome in the absence of diabetes and hypertension, cardio-myopathy in the absence of isch-emia, restrictive cardiac defect, demyelinating polyneuropathy, or unexplained hepatomegaly should alert the physician to the possibility of amyloidosis.

Initial steps in the diagnostic evaluation of patients with suspected amyloidosis include serum and urine immunoelectro-phoresis and immunofixation studies. Demonstration of amyloid material on tissue biopsy (eg, subcutaneous fat) is required for diagnosis. Availability of effective treatments has improved the outlook of patients with primary systemic amyloidosis. Early diagnosis is critical to optimizing the chances of effective therapy.

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Dr Archana Roy is assistant professor, division of hospital medicine, Mayo Clinic Jacksonville, Jacksonville, Florida. Dr Vivek Roy is assistant professor, department of internal medicine, division of hematology and oncology, Mayo Clinic Jacksonville, Jacksonville, Florida.
Correspondence: Archana Roy, MD, Mayo Clinic Jacksonville, Division of Hospital Medicine, 4500 San Pablo Rd, Jacksonville, FL 32224. E-mail: roy.archana@mayo.edu.

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