Secondary Disease

Amyloidosis refers to a group of disease states characterized by the extracellular deposition of amyloid protein in single or multiple organ systems. Amyloid is an insoluble proteinaceous material whose presence may interfere with the functional integrity of involved organs. Amyloid deposits may be present in small amounts without any pathologic consequences, or there may be gross, widespread involvement with resultant symptomatic disease. Amyloidosis is usually far advanced by the time the diagnosis is considered clinically. Amyloid infiltration may affect many various organ systems with multiple nonspecific manifestations; therefore, it is often overlooked early on in the differential as other etiologies are considered. Amyloid deposits show a characteristic green birefringence when biopsy specimens are stained with Congo red and viewed under polarized light.

Primary amyloidosis refers to the presence of pathologic amyloid deposition without any underlying disease process; however, amyloidosis associated with multiple myeloma, Waldenstroms macroglobulinemia, and agammaglobulinemia are also considered primary forms. Secondary amyloidosis occurs as a result of some underlying disease process that results in the formation of serum amyloid A. Serum amyloid A is an acute phase reactant that then serves as the precursor for amyloid fibrils. Secondary amyloidosis is seen in conjunction with such diseases as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and familial Mediterranean fever. Familial, or hereditary, amyloidosis has an autosomal dominant inheritance except in amyloidosis associated with familial Mediterranean fever, in which inheritance is autosomal recessive.

Another form of disease classification is based on the type of plasma proteins which serve as amyloid precursors. Based on this classification, the more common forms of disease include immunoglobulin-light-chain related (AL) and familial transthyretin-associated (ATTR) disease. The AL form of disease is more common than ATTR. ATTR is not an uncommon cause of congestive heart failure (CHF) in elderly black patients.

As stated, amyloidosis often presents with multiple, vague manifestations. The many forms of disease presentation based on the affected organ system are detailed in the following:

RENAL: Disease may manifest with mild proteinuria or nephrotic syndrome, and the presence of nephrotic syndrome is an ominous finding. Renal vein thrombosis is also a common complication of renal amyloid involvement and may result in pulmonary emboli. Chronic renal failure is the result of progression of renal involvement and is the leading cause of death. Patients with chronic renal failure on long-term hemodialysis may develop hemodialysis-associated amyloidosis, which usually involves only articular and periarticular structures or may result in carpal tunnel syndrome. Dialysis membranes made of cuprophane or cellulose are unable to clear the amyloid protein, serum concentrations of the protein then become elevated and result in the aforementioned symptoms.

HEPATIC: Amyloid deposits result in hepatomegaly. Liver chemistries often reveal no abnormalities or an isolated elevation of the alkaline phosphatase. When there is concomitant renal involvement in the form of nephrotic syndrome, hypoalbuminemia will also be noted. Signs of chronic liver disease (spider angiomas, palmar erythema, gynecomastia, decreased axillary and pubic hair, ascites) are usually absent.

CARDIAC: Cardiomegaly, congestive heart failure (CHF), murmurs, arrhythmias, and conduction disturbances can all result from myocardial infiltration by amyloid. The endocardium and pericardium may also be affected, although less commonly. Electrocardiographic abnormalities include poor R wave progression in the precordial leads and low voltage conduction. Echocardiography or angiography may demonstrate left ventricular wall thickening, dyskinetic myocardium, decreased ventricular mobility and compliance, and the absence of rapid ventricular filling during early diastole. Echocardiography may display a refractile appearance of the myocardium referred to as granular sparkling plus concentrically thickened ventricles with a fairly normal ejection fraction. The use of digitalis for the treatment of amyloid-induced CHF may result in fatal conduction defects and arrhythmias; therefore, caution should be exercised when administering this medication to this class of patients. When the coronary arterial walls are involved, ischemia with resultant angina is present. ATTR has been noted to be a common cause of congestive heart failure (CHF) among the elderly of the black population.

CUTANEOUS: Petechiae, papules, nodules, tumors, plaques, skin tags, bullous lesions, and taut skin are all potential cutaneous manifestations of amyloidosis. The above-mentioned lesions are not associated with pruritus. Purpura secondary to vessel fragility is common and may be induced by gentle pinching or Valsalvas maneuver. Minor trauma such as sneezing or manipulation of the periorbital area may result in local trauma which manifests as raccoon eyes.

GASTROINTESTINAL: Involvement may manifest as dysphagia, obstruction, ulcers, malabsorption, diarrhea, hemorrhage (melena or hematochezia), and a protein-losing enteropathy. Macroglossia may result from amyloid infiltration of the tongue and may manifest as difficulty in chewing, difficulty in swallowing, or an inability to retain saliva. Macroglossia is seen most often in primary and multiple myeloma-associated amyloidosis.

NEUROLOGIC: Amyloidosis often results in peripheral and autonomic neuropathies with resultant postural hypotension, impotence, an inability to sweat, nocturnal diarrhea, and sphincter dysfunction. The peripheral neuropathy is commonly a lower extremity sensory polyneuropathy. Fifty percent of patients are afflicted with carpal tunnel syndrome. Late manifestations include upper extremity and motor impairment. The central nervous system is usually spared except in some forms of hereditary amyloidosis that may manifest cranial nerve involvement. Amyloid deposition in muscle tissue may cause a pseudomyopathy with weakness.

ENDOCRINE: When the adrenal glands are infiltrated, Addisons disease may result with all of its clinical symptoms and laboratory abnormalities. Hypothyroidism indicates involvement of the thyroid gland.

RHEUMATOLOGIC: A chronic, symmetric arthropathy of the shoulders, wrists, knees, and fingers often results when amyloid infiltration involves articular structures. The shoulder pad sign refers to infiltration of the glenohumeral articulation and surrounding soft tissues.

GENERAL: Fatigue and weight loss are common but are usually too nonspecific to indicate the proper diagnosis. Macroglossia is a classic feature of the AL form of disease and may be associated with swelling of the submandibular glands. Other oropharyngeal symptoms include taste disturbance and a change in voice, which is the result of vocal cord infiltration.

The diagnosis of amyloidosis should be considered in all patients with unexplained proteinuria, cardiomyopathy, CHF, peripheral neuropathy, carpal tunnel syndrome, macroglossia, or hepatosplenomegaly. The diagnosis is established by demonstrating green birefringence when biopsy specimens are stained with Congo red and viewed through a polarizing microscope. Rectal biopsy, skin biopsy, and abdominal-fat-pad biopsy are diagnostic in a majority of cases. Affected target organs may also be biopsied to establish the diagnosis. Serum and urine protein electrophoresis may reveal a monoclonal light chain in the majority of cases.

Once the diagnosis is established, the next step is to determine the type of amyloidosis. AL is the most common type of disease; therefore, a search for clonal plasma-cell dyscrasia is warranted. This may be accomplished by immunofixation electrophoresis of samples of serum and urine for the presence of monoclonal immunoglobulins or light chains (positive in 90% of patients with AL disease). If immunofixation electrophoresis is negative and AL disease is still suspected, immunohistochemical staining of bone marrow specimens may show a clonal dominance of plasma cells. When there is a lack of plasma cell dyscrasias, the search should be directed toward finding a variant transthyretin. This may be accomplished by isoelectric focusing of the serum. Once a variant has been found, specific genetic testing will help identify the site of mutation. If the workup is negative for AL or ATTR disease, the diagnosis of AA amyloidosis may be established by immunohistochemical staining for the abnormal protein.

Amyloid is usually considered incurable; however, current therapeutic options include thalidomide, lenalidomide, bortezomib, stem cell transplantation, and combination melphalan and dexamthasone. In some forms of secondary amyloidosis, treatment of the primary disease is beneficial. Treatment of amyloidosis associated with familial Mediterranean fever with colchicine may result in prolonged survival as does chlorambucil in juvenile rheumatoid arthritis associated amyloidosis. Symptomatic therapy may be offered for different manifestations of the disease such as nephrotic syndrome, renal failure, CHF, and gastrointestinal dysmotility.