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Progressive familial intrahepatic cholestasis (PFIC) is a group of diseases characterised by cholestasis and biliary cirrhosis. Byler disease, the best known member of this group, is now also known as PFIC type 1. Byler disease is named after Jacob Byler, a farmer of Amish ancestry, who settled in Pennsylvania in the late 18th century. Patients have recurrent and later persistent cholestasis.1The recurrent disease pattern is reminiscent of benign recurrent intrahepatic cholestasis (BRIC). In contrast to BRIC, Byler disease eventually evolves into biliary cirrhosis. Clinically the disease is characterised by jaundice, steatorrhoea, reduced growth, and a relatively low to normal serum γ-glutamyltranspeptidase (γGT) activity despite an elevated alkaline phosphatase. Positional cloning studies in a large Byler kindred revealed a mutation in a locus at chromosome 18q21-q22, the FIC1 locus.2-4 In their recent paper in Nature Genetics Bull et al suggest that this mutation affects a member of a subfamily of P-type ATPases; other members of this subfamily seem to be involved in ATP dependent aminophospholipid transport. FIC1 is expressed in several epithelial tissues and more strongly in the intestine than in the liver. Patients with this disease have high serum bile salt concentrations. Disturbed hepatobiliary (and perhaps intestinal) transport of bile salts is the most likely cause. How this relates to a P-type ATPase, possibly mediating aminophospholipid transport, is currently unknown. As expected, BRIC is genetically related to Byler disease as FIC1 is also mutated in BRIC patients, confirming earlier reports.4-6
Another form of PFIC, PFIC type 2, is characterised by persistent neonatal cholestasis with …