Progressive familial intrahepatic cholestasis: Genetic disorders of biliary transporters

ANZAC Research Institute, University of Sydney and Center for Education and Research on Aging, Concord Repatriation General Hospital, Sydney, NSW, Australia.
Journal of Gastroenterology and Hepatology (Impact Factor: 3.5). 07/2005; 20(6):807-17. DOI: 10.1111/j.1440-1746.2005.03743.x
Source: PubMed


Progressive familial intrahepatic cholestasis types 1, 2 and 3 are childhood diseases of the liver. Benign recurrent intrahepatic cholestasis is predominantly an adult form with similar clinical symptoms that spontaneously resolve. These genetic disorders have significantly helped to unravel the basic mechanisms of the canalicular bile transport processes. Progressive familial intrahepatic cholestasis type 1 involves a gene also linked to benign recurrent intrahepatic cholestasis. The gene codes for an aminophospholipid translocase protein that maintains the integrity of the membrane. How a mutation in this protein causes cholestasis is unknown but is thought to involve the enterohepatic recirculation of bile acids. Progressive familial intrahepatic cholestasis types 2 and 3 involve the canalicular bile salt export pump and a phospholipid translocase, respectively, both of which are fundamental to bile secretion. This review covers the clinical manifestations, genetics, treatment and mechanism of each disease.
© 2005 Blackwell Publishing Asia Pty Ltd

  • Source
    • "Progressive familial intrahepatic cholestasis (PFIC), known as a group of heterogeneous autosomal recessive disorders, hit liver hepatocellular bile salt secretion as a cholestasis of hepatocellular origin appearing in infants and leading to death from liver failure. Three types of PFIC have been defined from the hepatocellular transport system defects and related genes, which involved in bile formation.[123] Main clinical manifestations include cholestasis, pruritus and jaundice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Progressive familial intrahepatic cholestasis is an autosomal recessive liver disorder caused by (biallelic) mutations in the ATP8B1 of ABCB11 gene. A nine-year-old girl with cholestasis was referred for genetic counseling. She had a family history of cholestasis in two previous expired siblings. Genetic analysis of the ABCB11 gene led to the identification of a novel homozygous mutation in exon 25. The mutation 3593- A > G lead to a missense mutation at the amino acid level (His1198Arg). This mutation caused PFIC2 due to abnormal function in the bile salt export pump protein (BSEP).
    Full-text · Article · Jul 2013 · Indian Journal of Human Genetics
  • Source
    • "Progressive familial intrahepatic cholestasis is an autosomal recessive disorder of intrahepatic cholestasis of metabolic and genetic origin [27] [12]. It begins in infancy and usually progresses to cirrhosis or may progress relatively slowly with minimal Figure 5 Three months extraoral and intraoral recall photographs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Progressive familial intrahepatic cholestasis refers to a heterogenous group of autosomal recessive disorders in which children develop severe intrahepatic cholestasis progressing to biliary cirrhosis and chronic liver failure, usually during the first decade of life. The clinical features include jaundice, hepatomegaly, splenomegaly, growth retardation and severe pruritus. The laboratory tests demonstrate elevated bilirubin, bile acids and liver function enzymes. The only curative treatment of progressive familial intrahepatic cholestasis is liver transplantation.This article presents the medical and dental history along with a comprehensive dental management and prognosis of a 6 years old male patient with progressive familial intrahepatic cholestasis type I and liver cirrhosis 5 years post living related liver transplant in Riyadh, Saudi Arabia. The patient demonstrated improved oral hygiene performance during the course of treatment, and continued to demonstrate a low caries rate up to 7 months following treatment. Based upon the apparent success of the preventive programme, the patient was judged to have a very good prognosis.
    Full-text · Article · Jan 2013
  • Source
    • "Other investigators, however, failed to reproduce these observations (Cai et al, 2009). Nevertheless, multiple studies in patients with PFIC/BRIC-1 and -2 support a critical role for both ATP8B1 and ABCB11 on bile secretion (Davit-Spraul et al, 2010; Harris et al, 2005; Kubitz et al, 2005; Morotti et al, 2011; van der Woerd et al, 2010). Since SREBP-2/miR-33 are transcriptionally induced following treatment with statins (Marquart et al, 2010; Najafi- Shoushtari et al, 2010; Rayner et al, 2010), we hypothesized that miR-33 might account for some of the (side) effects of these drugs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bile secretion is essential for whole body sterol homeostasis. Loss-of-function mutations in specific canalicular transporters in the hepatocyte disrupt bile flow and result in cholestasis. We show that two of these transporters, ABCB11 and ATP8B1, are functional targets of miR-33, a micro-RNA that is expressed from within an intron of SREBP-2. Consequently, manipulation of miR-33 levels in vivo with adenovirus or with antisense oligonucleotides results in changes in bile secretion and bile recovery from the gallbladder. Using radiolabelled cholesterol, we show that systemic silencing of miR-33 leads to increased sterols in bile and enhanced reverse cholesterol transport in vivo. Finally, we report that simvastatin causes, in a dose-dependent manner, profound hepatotoxicity and lethality in mice fed a lithogenic diet. These latter results are reminiscent of the recurrent cholestasis found in some patients prescribed statins. Importantly, pretreatment of mice with anti-miR-33 oligonucleotides rescues the hepatotoxic phenotype. Therefore, we conclude that miR-33 mediates some of the undesired, hepatotoxic effects of statins. →See accompanying article
    Full-text · Article · Sep 2012 · EMBO Molecular Medicine
Show more