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The amyloidoses are disorders caused by extracellular protein misfolding and tissue deposition. A soluble protein secreted into the serum or extracellular space aggregates into insoluble, fibrillar tissue deposits, leading to organ dysfunction. The site and rate of protein deposition determine the clinical presentation. Amyloid deposits contain a single major fibrillar component and many minor associated protein and glycosaminoglycan components. To date, 27 different fibril proteins have been isolated in human amyloidosis; the major form associated with hematologic diseases is made up of immunoglobulin light chains. Light-chain amyloidosis (AL amyloidosis) is caused by a monoclonal plasma cell or lymphoproliferative disorder in which the secreted immunoglobulin, either because of its amino acid sequence or some other structural feature, is predisposed to fibrillogenesis under physiologic conditions. AL amyloidosis is characterized by fatigue, weight loss, purpura, heart failure, proteinuria, renal failure, gastrointestinal dysfunction, neuropathy, and various other symptoms, depending upon the organ(s) involved. Diagnosis of amyloidosis (of any type) is made by biopsy of an affected organ or subcutaneous fat aspiration followed by Congo red staining. In the face of similar clinical features, distinguishing AL amyloidosis from the other systemic amyloidoses, in which AL-specific treatment would be inappropriate, is critical. Chemotherapy reduces the size of the plasma cell clone that produces the amyloidogenic light chain and prolongs survival.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: AA, amyloid A; Aβ2M, amyloid β2-microglobulin; AF, familial amyloid; AL, light-chain amyloid; CPHPC, 6-R-2-carboxy-pyrrolidin-1-yl-6-oxo-hexanoyl pyrrolidine-2-carboxylic acid; HDM/autoSCT, high-dose melphalan and autologous stem cell transplantation; IDOX, 4-iodo-4-deoxydoxorubucin; IEF, isoelectric focusing; IMiDs, immunomodulatory drugs; MIDD, monoclonal immunoglobulin deposition disease; NT-proBNP, N-terminal probrain natriuretic peptide; SAP, serum amyloid P component; TTR, transthyretin; VAD, infusional vincristine, doxorubicin (Adriamycin), and dexamethasone.

Amyloidosis is a term for diseases that have in common the extracellular deposition of insoluble fibrillar proteins in tissues and organs. These diseases are a subset of a growing group of disorders recognized to be caused by misfolding of proteins; these disorders include Alzheimer disease and other neurodegenerative diseases, prion diseases, serpinopathies, and some cases of cystic fibrosis. A unifying feature of the amyloidoses is that the deposits share a common β-pleated sheet structural conformation that confers unique staining properties. The term amyloid is attributed to the pathologist Rudolf Virchow (1821–1902), who, in 1854, thought such deposits in autopsy livers were starch-like because of their peculiar staining reaction with iodine and sulfuric acid.1 One hundred years later “amyloid” was found to be a proteinaceous fibrillar deposit in tissues.2 Biochemical characterization of the fibril proteins from clinical cases proved the “amyloidoses” to be a spectrum of diseases, often with a fatal outcome because of progressive deposition of amyloid fibrils in major organs. A growing list of treatments are available to target the source of the abnormal protein and, for some types, to inhibit the amyloidogenic protein misfolding process.

In the past, the amyloidoses were classified according to ...

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