Genetic cholestasis: lessons from the molecular physiology of bile formation.

[benign recurrent intrahepatic cholestasis]

Progressive familial intrahepatic cholestasis (PFIC ) is a group of severe genetic cholestatic liver diseases of early life . PFIC types 1 and 2 are characterized by cholestasis and a low to normal serum gamma-glutamyltransferase (GGT ) activity , whereas in PFIC type 3 , the serum GGT activity is elevated . PFIC types 1 and 2 occur due to mutations in loci at chromosome 18 and chromosome 2 , respectively . The pathophysiology of PFIC type 1 is not well understood . PFIC types 2 and 3 are caused by transport defects in the liver affecting the hepatobiliary secretion of bile acids and phospholipids , respectively . Benign recurrent intrahepatic cholestasis (BRIC ) is linked to a mutation in the same familial intrahepatic cholestasis 1 locus at chromosome 18 . Defects of bile acid synthesis may be difficult to differentiate from these transport defects . Intrahepatic cholestasis of pregnancy (ICP ) appears to be related to these cholestatic diseases . For example , heterozygosity in families with PFIC type 3 is associated with ICP , but ICP has also been reported in families with BRIC . In Dubin-Johnson syndrome there is no cholestasis ; only the hepatobiliary transport of conjugated bilirubin is affected . This , therefore , is a mild disease , and patients have a normal lifespan .