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  1. 1. Amyloidosis Amyloidosis comprises a group of diseases characterized by extracellular deposition of insoluble, fibrous amyloid proteins in various body tissues. ETIOLOGY. Amyloid material is composed of microscopic fibrils that are biochemically heterogeneous, with at least 20 different types of protein fibril compositions. All amyloid deposits contain the same nonfibrillar component, serum amyloid P. Amyloid fibril deposition may have no apparent consequences, or it may ultimately interfere with organ function. The traditional amyloidosis classification system uses the descriptive terms systemic and localized, which do not designate the etiology or associated clinical manifestations. The systemic, or multisystem, amyloidoses correspond to clinical patterns of primary, secondary, familial, and dialysis- related amyloidosis. The localized, or organ-limited, amyloidoses are associated with aging and diabetes and occur in isolated organs such as endocrine glands without systemic involvement. The newer nomenclature of amyloidoses is based on biochemical analysis and uses A for amyloid followed by the abbreviation for the type of fibril protein. The most common type of amyloidosis in the United States, which was known as primary idiopathic amyloidosis or myeloma-associated amyloidosis, has deposition of amyloid composed of pieces of monoclonal immunoglobulin light-chain (abbreviated to L) and is now referred to as AL amyloidosis. Amyloidosis in persons with familial Mediterranean fever (FMF), chronic infection, and chronic inflammatory diseases involve amyloid A protein and was formerly known as secondary or reactive amyloidosis, and is
  2. 2. now referred to as AA amyloidosis. AA amyloidosis is the most common serious complication of FMF (see Chapter 162 ). Amyloid conditions associated with aging (Alzheimer disease) as well as several rare autosomal dominant forms of amyloidoses have fibril protein composed of variants of the transport protein transthyretin (TTR) and are now referred to as TTR amyloidosis. EPIDEMIOLOGY. AL amyloidosis is extremely rare in children and usually occurs in persons of middle age or older. It represents a plasma cell dyscrasia and can occur in isolation or along with multiple myeloma. Only AA amyloidosis affects children in appreciable numbers, occurring in some persons with FMF, chronic inflammatory diseases including juvenile rheumatoid arthritis (JRA), ankylosing spondylitis, inflammatory bowel disease, chronic infections such as tuberculosis, cystic fibrosis, and, less commonly, systemic lupus erythematosus and juvenile dermatomyositis. The factors that determine the risk for amyloidosis as a complication of inflammation are not clear, as many individuals with long-standing inflammatory disease do not develop tissue amyloid deposition. AA amyloidosis affects as many as 10% of children with JRA in some European countries but is rarely seen as a complication of seemingly similar disease in children in the United States and Canada. Additionally, Armenians with FMF living in Armenia are reported to have a significantly higher incidence of amyloidosis than do their Armenian counterparts in North America. There is also ethnic variability in the frequency of amyloidosis, which among patients with FMF occurs in up to 60% of Turks, 27% of Sephardic Jews, and 1–2% of Armenians living in the United States. Reasons for these
  3. 3. differences are unknown, although environmental and genetic factors in addition to the underlying inflammatory disease appear to have a role. PATHOGENESIS. The AA protein isolated from AA amyloidosis is the 76-amino acid N-terminus fragment of serum amyloid A (SAA). SAA, a polymorphic protein synthesized in the liver, is an acute- phase reactant. Chronic inflammation results in elevated levels of SAA, which is the precursor to the fibril formation of AA amyloidosis. Three protein isoforms of SAA exist. SAA1 is the precursor of AA amyloidosis in majority of cases and has 5 variants that differ from each other by amino acid substitutions. The factors responsible for determining the site of amyloid deposition in any form of amyloidosis are unknown. AA amyloidosis fibrils have been generated in tissue cultures by incubating SAA with macrophages, which may explain amyloid depositions in tissues such as the liver and spleen. The increased deposition in the kidneys is related to a different mechanism, possibly the glyco-oxidative modification of the AA protein itself. Amyloid deposits are composed of seemingly homogeneous eosinophilic material that stains with Congo red dye and in polarized light demonstrates the pathognomonic apple-green birefringence. Amyloid can be recognized also by routine hematoxylin and eosin(H&E)–staining. CLINICAL MANIFESTATIONS. Various patterns of organ dysfunction result from deposition of different types of amyloid fibril protein material. Regardless of the cause of amyloidosis, clinical symptoms
  4. 4. usually begin >10 yr after the onset of inflammatory disease. The diagnosis is not usually established until the disease is far advanced. The most common clinical presentation of AA amyloidosis is renal dysfunction, ranging from proteinuria to nephrotic syndrome and eventual renal failure. Involvement of the gastrointestinal system is also frequent and usually manifests as chronic diarrhea, gastrointestinal bleeding, abdominal pain, and malabsorption. Anemia, hepatomegaly, and splenomegaly may be present. DIAGNOSIS. The diagnosis of amyloidosis is established by biopsy demonstrating amyloid fibril proteins in affected tissues. In the presence of amyloidosis, renal biopsies are contraindicated because of potential bleeding. The liver and spleen are often affected but are not suitable sites for biopsy. Biopsy sites that are more accessible include the rectal mucosa, gingival tissue, and abdominal fat aspirate. A method of microradiographic scintigraphy using serum amyloid P component has been described as a useful tool for the diagnosis as well as for the monitoring of the status of amyloidosis. LABORATORY FINDINGS. Patients with JRA and AA amyloidosis usually show elevated acute-phase reactants and high levels of immunoglobulins. Specific laboratory testing is only possible for AL amyloidosis. Most of these patients show increased plasma cells in the bone marrow, and serum or urine monoclonal Ig or free light chain. A biopsy showing amyloid deposition along with a monoclonal serum protein distinguishes AL amyloidosis from monoclonal gammopathy of uncertain significance (MGUS), which is common in older adults.
  5. 5. TREATMENT. The primary means of treatment of AA amyloidosis is aggressive management of the underlying inflammatory or infectious disease, which decreases levels of SAA protein. Colchicine is effective in controlling the attacks of FMF and also in preventing the development of amyloidosis associated with FMF. Children with FMF who are homozygous for M694V are at greater risk of developing amyloidosis and should receive colchicine for life. Unlike AA amyloidosis associated with FMF, AA amyloidosis associated with JRA does not respond to colchicine therapy but instead does respond to chlorambucil, which reverses renal findings and prolongs the life of treated patients. Chlorambucil is associated with chromosome breakage and an unknown risk of subsequent malignancy. There is little experience with other cytotoxic agents or with the therapy for AA amyloidosis associated with other conditions. Anti–tumor necrosis factor-α (TNF-α) therapy, with etanercept or infliximab, is well tolerated and effective in reducing proteinuria in patients with AA amyloidosis secondary to inflammatory arthritides. Drugs that specifically prevent fibril development are in development. COMPLICATIONS AND PROGNOSIS. End-stage renal failure is the underlying cause of death in 40–60% of cases of amyloidosis, with a median survival time from diagnosis of 2–10 yr. PREVENTION. The primary means of preventing AA amyloidosis is treatment of the underlying inflammatory or infectious
  6. 6. disease, which decreases levels of SAA protein and the risk of amyloid deposition.