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Fibrinogen Gamma375 Arg→Trp Mutation (Fibrinogen Aguadilla) Causes Hereditary Hypofibrinogenemia, Hepatic Endoplasmic Reticulum Storage Disease and Cirrhosis

2006; Lippincott Williams & Wilkins; Volume: 30; Issue: 7 Linguagem: Inglês

10.1097/01.pas.0000209848.59670.2c

1532-0979

Laura Rubbia‐Brandt, Marguerite Neerman‐Arbez, Anne‐Laure Rougemont, Pierre‐Jean G. Malé, Laurent Spahr,

Lipid metabolism and disorders

Hypofibrinogenemia is a rare inherited disorder characterized by low levels of circulating fibrinogen, caused by mutations within 1 of the 3 fibrinogen genes. We report here the case of a 61-year-old man with chronic liver function test alterations. Liver biopsy examination revealed chronic hepatitis complicated by cirrhosis and weakly eosinophilic globular cytoplasmic inclusions within the hepatocytes, faintly stained with PAS-diastase. On immunohistochemistry, the inclusions reacted strongly with human antifibrinogen antibodies. Coagulation investigations of the propositus and his 2 sons showed low functional and antigenic fibrinogen concentrations that were indicative of hypofibrinogenemia. A liver biopsy performed on the 28-year-old son demonstrated the same globular cytoplasmic inclusions, albeit without associated chronic liver disease. PCR amplification followed by sequencing showed that all 3 were heterozygous for a CGG>TGG mutation at codon 375 of the fibrinogen gamma-chain gene (FGG), corresponding to an Arg>Trp substitution. This is the first in an adult male and the second published case with a discernible hepatic fibrinogen endoplasmic reticulum storage disease due to an FGG Arg375Trp (fibrinogen Aguadilla) mutation. Our results suggest that familial hypofibrinogenemia should be considered in the differential diagnosis of a progressive liver disease associated to hepatocellular intracytoplasmic globular inclusions.