title: ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults.
abstract: OBJECTIVE
  Adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) mutations have not been investigated in patients with unexplained cholestasis. We aimed to investigate ABCB4 mutations in adult patients with unexplained anicteric cholestasis and to describe liver injury associated with ABCB4 mutations.
  
  
  METHODS
  Between February 2004 and March 2007, all adults with unexplained cholestasis despite multiple investigations including liver biopsy and 124 healthy volunteers had ABCB4 sequencing. Fibrosis, bile duct lesions, inflammatory infiltrate, activation of myofibroblasts and multidrug-resistant P-glycoprotein 3 (MDR3) immunostaining were assessed on patients' liver biopsy specimens.
  
  
  RESULTS
  Thirty-two patients were included (23 females, 16-69 years of age). Eight different ABCB4 heterozygous mutations were found in 11 patients (34%). Seven of these mutations (exons 4, 6, 14, 18, 23) were never detected in the control group. One mutation (exon 15) was detected in 4 patients (12.5%) and 4 controls (3%). At the time of liver biopsy, the main clinical and biologic characteristics were similar in the 32 patients regardless of ABCB4 mutation. The histologic pattern in patients with a mutation consisted of portal fibrosis with ductular reaction and strong macrophagic infiltrate of portal tracts without significant periportal and lobular necroinflammatory lesions or cholangitis. Fibrosis score and macrophagic infiltration of portal tracts were significantly increased in patients with ABCB4 mutation (P = .01). Absence or reduced MDR3 canalicular immunostaining was demonstrated in all patients with ABCB4 mutations tested.
  
  
  CONCLUSIONS
  Heterozygous ABCB4 mutations were detected in 34% of adults with unexplained cholestasis, for the most part without biliary symptoms, and could result in significant liver fibrosis.
authors.affiliation: Laboratoire d'anatomie et de cytologie pathologique, AP-HP Hôpital Jean Verdier, Bondy, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbu
authors.forename: Olivier
authors.initials: O
authors.lastname: Rosmorduc
authors.forename: Annonciade
authors.initials: A
authors.lastname: Frassati-Biaggi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Barget
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hermelin
authors.forename: Georges L
authors.initials: GL
authors.lastname: Scheffer
authors.forename: Selma
authors.initials: S
authors.lastname: Bennouna
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Trinchet
authors.forename: Michel
authors.initials: M
authors.lastname: Beaugrand
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ganne-Carrié
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000473:pathology*; D001706:Biopsy; D002780:Cholestasis, Intrahepatic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002908:Chronic Disease; D005260:Female; D005355:Fibrosis; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; C095122:multidrug resistance protein 3