Genetic basis of progressive familial intrahepatic cholestasis.

oo~~ssrvn familial intrahepatic cholestasis (PFIC), P originally known as Byler disease, was first described in an Amish kindred (1,2). It is an inherited disorder of childhood in which cholestasis of hepatocellular origin often presents in the neonatal period or the first year of life and leads to death from liver failure at ages ranging from infancy to adolescence. Cholangiograms show normal extraand intrahepatic bile ducts. The pattern of appearance of affected children within families is consistent with autosomal recessive inheritance. On the basis of clinical, biochemical and histological features, several studies have provided support for the heterogeneity of this clinical entity, suggesting the existence of different types due to different disorders affecting the hepatocyte and related to a defect of bile secretion or bile acid metabolism (Table 1) (3-10). Recent molecular and genetic studies have allowed the identification of genes responsible for three types of PFIC (11-16) and have shown that PFIC was related to mutations in hepatocellular transport system genes involved in bile formation (Fig. 1) (17). These findings now provide specific diagnostic tools for the investigation of children with PFIC. This review summarizes the molecular defects that are associated with PFIC. Liver diseases resembling PFIC that have recently been identified as inborn errors in primary bile acid synthesis will not be considered (9,lO).