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Pathology Lecture 18 Amyloidosis 1) To understand the biochemistry and structure of amyloid proteins. Amyloid proteins are composed of nonbranching fibrils of indeterminate length and 7.5-10nm in diameter. The proteins can aggregate into an insoluble beta-pleated sheet conformation. Chemically, they are made up of 95% fibrillary protein and 5% glycoprotein (P component). There are 15 biologically distinct forms known to exist. Extracellular in distribution, they mostly accumulate near basement membranes and stain as amorphous eosinophilic structures. 2) To be able to classify amyloid proteins. Major Classes of Amyloid AL (amyloid light chain) – derived from plasma cells. Contains Ig light chains AA (amyloid-associated) – unique liver protein derived from serum-amyloid associated protein (SAA), also known as secondary amyoidosis Minor Classes of Amyloid Amyloid transthyretin (ATTR) is deposited in tissues. Transthyretin (TTR) is a normal serum protein that transports thyroxine and retinol Beta2-microglobulin – a component of MHC class I molecules and amyloid fibril (Aβ2m) Beta-amyloid protein (Aβ) derived from the transmembrane amyloid precursor protein A-Cal, derived from the hormone procalcitonin AIAPP – islet amyloid peptide AANF – atrial naturitic factor Associated Diseases Multiple myeloma and other monoclonal B-cell proliferations Chronic inflammatory conditions such as rheumatoid arthritis; also in heroin abusers, chronic skin infections from skin-popping Associated Diseases Several familial amyloidotic neuropathies and Senile cardiac amyloidosis Chronic renal disease/hmoialysis-associated amylidosis Alzheimer’s disease Medullary carcinoma of the thyroid Type II diabetes Isolated atrial amyloidosis 3) To know which diseases are associated with amyloid accumulation. (See above) a. Systemic Amyloidosis: Immunocyte dyscrasias (primary amyloidosis), Reactive systemic amyloidosis (secondary amyloidosis), Hemodialysis-associated amyloidosis, and Hereditary amyloidosis. b. Localized Amyloidosis: Senile cardiac, Senile cerebral (Alzheimer’s disease), Endocrine (medullary carcinoma of thyroid and type II diabetes), and Isolated atrial amyloidosis. 4) To appreciate the clinical manifestations of amyloid accumulation in organs. Amyloidosis primarily affects the kidneys, liver, spleen, lymph nodes, adrenals, and thyroid. The affected organs become enlarged, firm, and have a waxy appearance. Kidneys – amyloid primarily in glomeruli. Spleen – two patterns are seen: “sago spleen” amyloid is limited to splenic follicules and “lardaceous spleen” amyloid involves splenic sinus walls. Liver – deposits in the space of Disse (liver basement membranes). Heart – subendothelial accumulations expanding into the myocardium. Symptoms vary depending on site of deposition. Diagnosis is made by biopsy.