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Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of various insoluble proteins. These proteins may accumulate locally, causing relatively few symptoms, or widely, involving multiple organs and causing severe multiorgan failure. Amyloidosis can be primary or be secondary to various infectious, inflammatory, or malignant conditions. Rarely, it results from any of several inherited metabolic defects. Diagnosis is by biopsy of affected tissue. Treatment varies with the type of amyloidosis.
Amyloid deposits may be formed from at least 18 different proteins, including immunoglobulin fragments. Amyloid deposits are metabolically inert but interfere physically with organ structure and function. All stain positive with Congo red dye, stain pink with hematoxylin and eosin, and have apple-green birefringence under polarized light after Congo red staining. Amyloid deposits have a fibrillar, usually rigid, and nonbranching ultrastructure. They form a β-pleated sheet that can be seen by x-ray diffraction. In addition to the fibrillar amyloid protein, the deposits also contain serum amyloid P component and glycosaminoglycans. On gross inspection, affected organs appear waxy and translucent.
Etiology
There are 3 major systemic forms of amyloidosis: primary, secondary, and familial. Also, there are 2 major localized forms, A β (associated with Alzheimer's disease) and AIAPP (which occurs in the pancreas of patients with type 2 diabetes), as well as several miscellaneous forms (eg, A β2-microglobulin associated with chronic hemodialysis).
Primary amyloidosis (AL):
AL is a monoclonal plasma cell disorder in which the abnormal protein is an immunoglobulin, usually a light chain fragment (Bence Jones protein) but occasionally a heavy chain fragment (AH amyloidosis). These chains either have an aberrant structure or are processed abnormally so that some form insoluble deposits. Common sites for deposition include the skin, nerves, heart, GI tract (including tongue), kidneys, liver, spleen, and blood vessels. A mild plasmacytosis occurs in the bone marrow, which is suggestive of multiple myeloma, but most patients do not have true multiple myeloma (with lytic bone lesions, renal tubular casts, and anemia). However, about 10 to 20% of patients with multiple myeloma also develop amyloidosis.
Secondary amyloidosis (AA):
This form can occur secondary to several infectious, inflammatory, and malignant (eg, renal cell carcinomas and others) conditions and is caused by the degradation of the acute-phase reactant serum amyloid A (SAA). Common causative infections include TB, bronchiectasis, osteomyelitis, and leprosy. Inflammatory conditions include RA, juvenile idiopathic arthritis (formerly juvenile RA), Crohn's disease, and familial Mediterranean fever. Inflammatory cytokines (eg, IL-1, tumor necrosis factor, IL-6) that are produced in these disorders cause increased hepatic production of the precursor protein SAA, which circulates in the serum.
AA amyloidosis shows a predilection for the spleen, liver, kidneys, adrenals, and lymph nodes. The liver, spleen, and kidneys are often enlarged, firm, and rubbery. Involvement of the heart and peripheral or autonomic nerves is rare. However, no organ system is spared, and vascular involvement may be widespread.
Familial amyloidosis:
The familial form results from accumulation of a mutated version of a plasma protein (most commonly transthyretin [TTR], hence ATTR). Nearly all of the abnormal protein is produced by the liver. Over 80 mutations of the gene for TTR have been identified, all inherited in an autosomal dominant pattern.
Age at onset of symptoms is highly variable, ranging from the teens to the 70s. ATTR amyloidosis causes peripheral sensory and motor neuropathy, often with an autonomic neuropathy. Carpal tunnel syndrome is common. Later in the illness, cardiovascular and renal involvement occurs. Vitreous abnormalities may also develop.
Other very rare hereditary amyloidoses result from mutations of other physiologic proteins, including apolipoprotein A-1, lysozyme, fibrinogen, gelsolin, and cystatin C. These amyloidoses have various systemic and localized effects.
A β2-microglobulin (dialysis-related) amyloidosis:
This form occurs in patients with chronic renal failure who have been on hemodialysis or peritoneal dialysis for long periods, usually > 8 yr. The amyloid deposits consist of β2-microglobulin, a component of the class I major histocompatibility complex, which is normally cleared by the kidneys but cannot be removed by dialysis membranes. Deposits preferentially occur in and around bones and joints and in the carpal tunnel and have been found in the GI tract and in other organs.
A β-protein amyloidosis:
This form occurs in patients with Alzheimer's disease. Although the exact role of amyloid deposits is unclear, the neuritic plaques characteristic of Alzheimer's disease contain amyloid deposits consisting of a β-protein fragment of β-amyloid precursor protein (a transmembrane glycoprotein). The β-protein fragment is sometimes complexed with apolipoprotein E. Within the plaques, nonfibrillar forms of the β protein are intermixed with fibrillar amyloid forms.
β-Protein amyloid deposition may also occur around cerebral blood vessels, which is thought to be a cause of nonhypertensive cerebral hemorrhage (cerebral amyloid angiopathy). The angiopathy may occur sporadically or as a hereditary syndrome (Dutch hereditary cerebral hemorrhage).
Symptoms and Signs
Symptoms and signs are nonspecific and relate to the organ or system affected. Symptoms in AA amyloidosis are often obscured by the underlying disease.
When the kidneys are affected, nephrotic syndrome is the most striking early manifestation. Initially, only slight proteinuria may occur; later, the distinctive symptom complex develops with anasarca, hypoproteinemia, and massive proteinuria.
Hepatic involvement causes painless hepatomegaly, which may be massive (liver weight > 7 kg). Except for occasional elevation of alkaline phosphatase, liver function tests remain normal. Jaundice is rare. Occasionally, portal hypertension develops, with resulting esophageal varices and ascites.
Cardiac involvement causes a restrictive cardiomyopathy, eventually leading to heart failure. Cardiomegaly and various degrees of heart block or arrhythmia may occur.
Peripheral neuropathy, with paresthesias of the fingers and toes, is a common presenting manifestation in AL and ATTR amyloidoses. Autonomic neuropathy may cause orthostatic hypotension, erectile dysfunction, sweating abnormalities, and GI motility disturbances.
Rheumatologic symptoms in patients with A β2-microglobulin amyloidosis include carpal tunnel syndrome and chronic pain in the shoulder, wrist, and fingers. Pathologic fractures, particularly of the humerus and femur, may occur.
GI amyloid may cause motility abnormalities of the esophagus and small and large intestines. Gastric atony, malabsorption, bleeding, or pseudo-obstruction may also occur. Macroglossia is common in AL amyloidoses.
A firm, symmetric, nontender goiter resembling that found in Hashimoto's thyroiditis may result from amyloidosis of the thyroid gland. Lung involvement (mostly in AL amyloidosis) can be characterized by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits. In several hereditary amyloidoses, amyloid vitreous opacities and bilateral scalloped pupillary margins develop.
Diagnosis
Amyloidosis is suspected clinically but can be diagnosed only by biopsy. Subcutaneous abdominal fat pad aspiration and biopsy of rectal mucosa are the best approaches. Other useful biopsy sites are the gingiva, skin, nerves, kidneys, and liver. Tissue sections are stained with Congo red dye and examined with a polarizing microscope for characteristic birefringence. Isotopically labeled serum AP (in which AP represents the pentagonal component of amyloid) can be used in a scintigraphic test to confirm the diagnosis.
Prognosis
Prognosis depends on the type of amyloidosis and the organ system involved. AL amyloidosis with multiple myeloma has the poorest prognosis: death within 1 yr is common. Untreated ATTR amyloidoses are fatal within 10 to 15 yr. Prognosis in other familial amyloidoses varies. In general, renal or cardiac involvement in patients with any type of amyloidosis is of particular concern.
Prognosis in AA amyloidosis depends on successful treatment of the underlying disorder, although rare patients undergo spontaneous regression of the amyloid deposits without such treatment.
Treatment
Management is generally symptomatic, although treatment of the underlying disorder can sometimes arrest amyloidosis. In patients with renal amyloid, kidney transplantation provides long-term survival comparable to that in other renal diseases, although mortality is higher in the early years. Amyloid ultimately recurs in a donor kidney, but several recipients have done very well and have survived up to 10 yr. Heart transplantation has been successful in carefully selected patients with AL amyloidosis and severe cardiac involvement.
Patients with AL amyloidosis are often treated with chemotherapy. A common protocol uses melphalan 0.075 mg/kg po bid and prednisone 0.2 mg/kg po qid. Melphalan with autologous stem cell transplantation achieves good short-term success and apparent cures in some cases.
In patients with ATTR amyloidosis, liver transplantation—which removes the site of synthesis of the mutant protein—is very effective.
For AA amyloidosis with familial Mediterranean fever, colchicine 0.6 mg po once/day or bid is effective. Underlying infections in patients with AA amyloidosis of infectious origin must be treated aggressively. Treatment of amyloid resulting from cancer (eg, renal cell carcinoma) is directed at the cancer.
Last full review/revision April 2008 by Alan S. Cohen, MD
Content last modified April 2008
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