Etiology

Amyloid material is composed of microscopic fibrils that are biochemically heterogeneous, with at least 20 different types of protein fibril composition. All amyloid deposits contain the same nonfibrillar component, serum amyloid P. Amyloid fibril deposition may have no apparent consequences or 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 for 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 USA has deposition of amyloid composed of pieces of monoclonal immunoglobulin light-chain (abbreviated as L) and is referred to as AL amyloidosis (formerly known as idiopathic amyloidosis or myeloma-associated amyloidosis). Amyloidosis in patients with the hereditary periodic fever syndromes (including familial Mediterranean fever [FMF], tumor necrosis factor receptor–associated periodic syndrome [TRAPS], CAPS, and hyperimmunoglobulinemia D syndrome [HIDS]), other autoinflammatory disorders, chronic infection, and chronic inflammatory diseases involving amyloid A protein is referred to as AA amyloidosis (formerly referred to as secondary or reactive amyloidosis). AA amyloidosis is the most common serious complication of FMF and TRAPS (Chapter 157). 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, usually occurring in middle-aged or older individuals. 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 individuals with hereditary periodic fever syndromes, chronic inflammatory diseases (such as juvenile idiopathic arthritis, ankylosing spondylitis, and inflammatory bowel disease), chronic infections (such as chronic osteomyelitis and 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, because many individuals with long-standing inflammatory disease do not demonstrate tissue amyloid deposition. AA amyloidosis affects approximately 10% of children with juvenile idiopathic arthritis in some European countries but is rarely seen as a complication of this condition in children in the USA and Canada. Additionally, Armenians with FMF living in Armenia are reported to have a significantly higher incidence of amyloidosis than their Armenian counterparts in North America. There is also ethnic variability in the frequency of amyloidosis, which occurs in up to 60% of Turks, 27% of Sephardic Jews, and 1-2% of Armenians with FMF living in the USA. Reasons for these differences are still unknown, although environmental and genetic factors in addition to the underlying inflammatory disease appear to have a role.

Pathogenesis

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