Progressive familial intrahepatic cholestasis: Genetic disorders of biliary transporters

ArticleinJournal of Gastroenterology and Hepatology 20(6):807-17 · July 2005with24 Reads
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
    • "Compared with BSEP, however, inhibition of MDR3 has received relatively little attention to date, and only one report has described the inhibition of MDR3 by a drug (itraconazole) (Yoshikado et al., 2011). The second transporter, ATP8B1 (ATPase-aminophospholipid transporter), is associated with progressive familial intrahepatic cholestasis type 1 (Harris et al., 2005; Groen et al., 2011). Unlike MDR3, canalicular ATP8B1 acts as a " flippase " and mediates the translocation of phosphatidylserine from the outer to the inner leaflet of the canalicular membrane. "
    [Show abstract] [Hide abstract] ABSTRACT: The bile salt export pump (BSEP) is located on the canalicular plasma membrane of hepatocytes and plays an important role in the biliary clearance of bile acids (BAs). Therefore, any drug or new chemical entity that inhibits BSEP has the potential to cause cholestasis and possibly liver injury. In reality, however, one has to consider the complexity of the BA pool, BA enterohepatic recirculation (EHR), extrahepatic (renal) BA clearance, and the interplay of multiple participant transporters and enzymes (e.g., sulfotransferase 2A1, multidrug resistance-associated protein 2, 3 and 4). Moreover, BAs undergo extensive enzyme-catalyzed amidation and are subjected to metabolism by enterobacteria during EHR. Importantly, the expression of the various enzymes and transporters described above is governed by nuclear hormone receptors (NHRs) that mount an adaptive response when intracellular levels of BAs are increased. The intracellular trafficking of transporters, and their ability to mediate the vectorial transport of BAs, is governed by specific kinases also. Finally, bile flow, micelle formation, canalicular membrane integrity, and BA clearance can be influenced by the inhibition of MDR3 (multidrug resistant protein 3)- or ATP8B1 (ATPase-aminophospholipid transporter)-mediated phospholipid flux. Consequently, when screening compounds in a discovery setting, or conducting mechanistic studies to address clinical findings, one has to consider the direct (inhibitory) effect of parent drug and metabolites on multiple BA transporters, as well as inhibition of BA sulfation and amidation, and NHR function. Vectorial BA transport, in addition to BA EHR and homoeostasis, could also be impacted by drug-dependent modulation of kinases and enterobacteria.
    Full-text · Article · Oct 2013
    • "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
    • "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 minimalFigure 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
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