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GENERAL PRINCIPLES

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Amyloidosis is the term for a group of protein folding disorders characterized by the extracellular deposition of insoluble polymeric protein fibrils in tissues and organs. A robust cellular machinery exists to chaperone proteins during the process of synthesis and secretion, to ensure that they achieve correct tertiary conformation and function, and to eliminate proteins that misfold. However, genetic mutation, incorrect processing, and other factors may favor misfolding, with consequent loss of normal protein function and intracellular or extracellular aggregation. Many diseases, ranging from cystic fibrosis to Alzheimer’s disease, are now known to involve protein misfolding. In the amyloidoses, the aggregates are typically extracellular, and the misfolded protein subunits assume a common antiparallel, β-pleated sheet–rich structural conformation that leads to the formation of higher-order oligomers and then of fibrils with unique staining properties. The term amyloid was coined around 1854 by the pathologist Rudolf Virchow, who thought that these deposits resembled starch (Latin amylum) under the microscope.

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Amyloid diseases, defined by the biochemical nature of the protein composing the fibril deposits, are classified according to whether they are systemic or localized, whether they are acquired or inherited, and their clinical patterns (Table 137-1). The standard nomenclature is AX, where A indicates amyloidosis and X represents the protein present in the fibril. This chapter focuses primarily on the systemic forms. AL refers to amyloid composed of immunoglobulin light chains (LCs); this disorder, formerly termed primary systemic amyloidosis, arises from a clonal B cell or plasma cell disorder and can be associated with myeloma or lymphoma. AF refers to the familial amyloidoses, which are most commonly due to mutations in transthyretin (TTR), the transport protein for thyroid hormone and retinol-binding protein. AA amyloid is composed of the acute-phase reactant protein serum amyloid A (SAA) and occurs in the setting of chronic inflammatory or infectious diseases; for this reason, this type was formerly known as secondary amyloidosis. Aβ2M amyloid results from misfolded β2-microglobulin, occurring in individuals with long-standing renal disease who have undergone dialysis, typically for years. Aβ, the most common form of localized amyloidosis, is found in the brain of patients with Alzheimer’s disease after abnormal proteolytic processing and aggregation of polypeptides derived from the amyloid precursor protein.

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Table Graphic Jump Location
TABLE 137-1Amyloid Precursor Proteins and Their Clinical Syndromes

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