[Fibril-forming proteins: the amyloidosis. New hopes for a disease that cardiologists must know]

Eloisa Arbustini, Antonello Gavazzi, Giampaolo Merlini
Italian Heart Journal. Supplement: Official Journal of the Italian Federation of Cardiology 2002, 3 (6): 590-7
Several proteins share the property of conforming as antiparallel beta-sheets, and forming insoluble amyloid fibrils that deposit in the interstitium of organs/tissues and cause systemic amyloidosis. Cardiac involvement is frequent and constitutes a major predictor of poor outcome. Its typical phenotype is that of restrictive cardiomyopathy. The biochemical classification of the amyloidogenic proteins provides the bases for innovative therapeutic approaches. Primary systemic amyloidosis (AL) is a protein conformation disorder in which monoclonal immunoglobulin light chains (kappa or lambda) produced by clonal plasma cells, are deposited as amyloid in kidneys, heart, liver, and other organs. The recent evidence that chemotherapy reduces or even eradicates the amyloidogenic clone with consequent functional improvement of the affected organs raises new hopes for a treatment, whose key of success is early diagnosis. Heart transplantation can be proposed in patients < 60 years of age in association with autologous stem cell transplantation. In serum amyloid A amyloidosis, fibrils are constituted of the acute phase serum amyloid A protein that is produced in excess in chronic inflammatory diseases such as familial mediterranean fever, autoimmune disorders and chronic infections. The strategy is to treat the underlying inflammatory disease, but new molecules inhibiting amyloid formation and promoting amyloid resorption are facing the clinical scenario and trials are in progress. In transthyretin (TTR) amyloidosis, the non-senile forms are autosomal dominant diseases caused by defective proteins synthesized by mutated TTR genes (more than 70 known mutations with different genotype-phenotype correlations). The treatment is based on transplantation of the TTR-producing liver; exceptionally, liver plus heart or kidney are transplanted. Apolipoprotein A1 amyloidosis is an inherited autosomal dominant disease that benefits from the transplantation of the most impaired organs, usually heart, liver or kidney, either single or combined. The diagnosis of apolipoprotein A1 and TTR amyloidosis relies on positive family history, immunocharacterization of the amyloid fibrils in a tissue biopsy, gene defect detection and absence of light chains in serum and urines. Vice versa, non-familial primary amyloidoses are diagnosed when kappa or lambda light chains are identified with immunofixation in serum or urines. Tissue studies provide the gold standard for the diagnosis and immunocharacterization of amyloid protein. Heart involvement is diagnosed with a multiparametric approach that includes clinical, electrocardiographic and echocardiographic evaluation. The fine-needle biopsy of the periumbilical fat is the preferral procedure for amyloid detection and immunocharacterization of amyloid protein. This approach excludes, with a few exceptions, the need of endomyocardial biopsy.

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