title: The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects.
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.
authors.affiliation: Biochemistry, University of Paris - Sud 11, Assistance Publique - Hôpitaux de Paris, Le Kremlin Bicêtre, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Davit-Spraul
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gonzales
authors.forename: Christiane
authors.initials: C
authors.lastname: Baussan
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jacquemin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D019450:Genes, MDR / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007231:Infant, Newborn; D007567:Jaundice, Neonatal / Q000503:physiopathology; D008107:Liver Diseases / Q000503:physiopathology*; D016031:Liver Transplantation; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense; D010641:Phenotype; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics / Q000503:physiopathology; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D014580:Ursodeoxycholic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3