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Semin Liver Dis 2010; 30(2): 134-146
DOI: 10.1055/s-0030-1253223
© Thieme Medical Publishers

The Spectrum of Liver Diseases Related to ABCB4 Gene Mutations: Pathophysiology and Clinical Aspects

Anne Davit-Spraul1 , Emmanuel Gonzales2 , 3 , Christiane Baussan1 , Emmanuel Jacquemin2 , 3
  • 1Biochemistry, University of Paris – Sud 11, Assistance Publique – Hôpitaux de Paris, Le Kremlin Bicêtre, France
  • 2Pediatric Hepatology and National Reference Centre for Biliary Atresia, Bicêtre Hospital, Faculty of Medicine Paris – Sud, University of Paris – Sud 11, Assistance Publique – Hôpitaux de Paris, Le Kremlin Bicêtre, France
  • 3INSERM, UMR-S757, University of Paris – Sud 11, Orsay, France
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Publication Date:
26 April 2010 (online)

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ABSTRACT

Class III multidrug resistance P-glycoproteins, Mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an ABCB4 gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation. Several ABCB4 mutations have been identified in children with PFIC3 and are associated with low level of phospholipids in bile leading to a high biliary cholesterol saturation index. ABCB4 mutations are associated with loss of canalicular MDR3 protein and /or loss of protein function. There is evidence that a biallelic or monoallelic ABCB4 defect causes or predisposes to several human liver diseases (PFIC3, low phospholipid associated cholelithiasis syndrome, intrahepatic cholestasis of pregnancy, drug-induced liver injury, transient neonatal cholestasis, adult biliary fibrosis, or cirrhosis). Most patients with MDR3 deficiency have a favorable outcome with ursodeoxycholic acid (UDCA) therapy, but some PFIC3 patients who do not respond to UDCA treatment still require liver transplantation. The latter should be good candidates for a targeted pharmacologic approach and/or to cell therapy in the future.

KEYWORDS

Multidrug resistance 3 - ABCB4 - progressive familial intrahepatic cholestasis type 3 - cholesterol gallstone - cholestasis of pregnancy - biliary cirrhosis - low phospholipid associated cholelithiasis - transient neonatal cholestasis - drug-induced cholestasis - ursodeoxycholic acid - adult ductopenia