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Progressive familial intrahepatic cholestasis type 1
PFIC1, a type of progressive familial intrahepathic cholestasis (PFIC, see this term), is an infantile hereditary disorder in bile formation that is hepatocellular in origin and associated with extrahepatic features.
ORPHA:79306Classification level: Subtype of disorder
Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000 births. PFIC1 is the less frequent type of PFIC.
Its onset occurs mostly during infancy. Clinical signs of cholestasis (discolored stools, dark urine) usually appear in the first months of life with recurrent or permanent jaundice associated with hepatomegaly and severe pruritus. Patients usually develop fibrosis and end-stage liver disease before adulthood. Extrahepatic features have been reported including persistent short stature, watery diarrhea, pancreatitis and sensorineural deafness.
PFIC1 is due to mutations in the ATP8B1 gene (18q21-22) encoding the FIC1 protein expressed at the canalicular membrane of hepatocytes as well as in other epithelia. In hepatocytes, abnormal protein might indirectly disrupt biliary bile acid secretion, explaining the low biliary bile acid concentration found in PFIC1 patients. Extrahepatic features of the disease are probably related to the extrahepatic expression of FIC1.
PFIC1 should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of the other main causes of cholestasis presenting with normal serum gamma-GT activity and high serum bile acid concentration. Usually, serum alpha-fetoprotein level is normal and alanine aminotransferase values are below five times the upper limit of normal. Liver ultrasonography is usually normal but may reveal a huge gallbladder. Liver histology reveals canalicular cholestasis and the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes. When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals mildly decreased biliary bile salt concentration. Genotyping confirms the diagnosis.
In the scope of cholestasis with normal gamma-GT, differential diagnosis includes mainly primary bile acid synthesis defects and PFIC2 (see these terms).
Prenatal diagnosis can be proposed if a mutation has been identified in each parent.
Transmission is autosomal recessive.
Management and treatment
Ursodeoxycholic acid therapy (UDCA) should be initiated in all patients to prevent liver damage but is not fully effective. Rifampicin is helpful to control pruritus. Nasobiliary drainage may help to select potential responders to biliary diversion. However, because of severe cholestasis, half of patients are ultimately candidates for liver transplantation (LT). Diarrhea often worsens after LT and might be favorably managed by bile adsorptive resin treatment. LT does not prevent extrahepatic progression of the disease, and does not lead to catch-up growth. Furthermore, severe steatohepatitis of the liver graft has been reported. Specialized follow-up is mandatory lifelong. FIC1 defect predisposes to development of intrahepatic cholestasis of pregnancy (see this term).