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Progressive familial intrahepatic cholestasis type 2
Progressive familial intrahepatic cholestasis type 2 (PFIC2), a type of progressive familial intrahepatic cholestasis (PFIC, see this term), is a severe, neonatal, hereditary disorder in bile formation that is hepatocellular in origin and not associated with extrahepatic features. Initially, PFIC2 was reported under the name Byler syndrome.
ORPHA:79304Classification level: Subtype of disorder
Estimated prevalence at birth of PFIC types 1-3 varies between 1/50,000 and 1/100,000. PFIC2 represents half of PFIC cases.
Onset occurs in the neonatal period. 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. Early appearance of liver failure and/or progression to hepatocellular carcinoma within the first years of life may complicate the course of PFIC2. Patients usually develop fibrosis and end-stage liver disease before adulthood.
PFIC2 is due to mutations in the ABCB11 gene (2q24) encoding the bile salt export pump (BSEP) protein resulting in impaired biliary bile acid secretion which leads to decreased bile flow and bile salt accumulation in hepatocytes with ongoing severe hepatocellular damage. BSEP is only expressed in hepatocytes, and extrahepatic features are not present in PFIC2.
PFIC2 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 elevated and alanine aminotransferase values are over five times the upper limit of normal. Liver ultrasonography is usually normal but may reveal a huge gallbladder and sometimes biliary stones. Liver histology reveals canalicular cholestasis, the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes, pronounced lobular and portal fibrosis and inflammation, hepatocellular necrosis and giant cell transformation. BSEP immunostaining is helpful for diagnosis. When performed, cholangiography shows a normal biliary tree and allows bile collection. Biliary lipid analysis reveals dramatically 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 PFIC1 (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, liver failure or hepatocellular carcinoma, half of patients are ultimately candidates for liver transplantation (LT). Close monitoring of hepatocellular carcinoma should be offered from the first year of life. Due to hepatocellular carcinoma and rapid liver failure, the course in patients with PFIC2 appears to be more severe than in patients with PFIC1.
Early treatment with UDCA or biliary diversion may prevent significant morbidity and mortality from end-stage liver disease. Furthermore, patients may develop biliary stones, drug-induced cholestasis, and/or intrahepatic cholestasis of pregnancy (see this term) further in the disease course. Specialized follow-up is mandatory and lifelong.