ABSTRACT
BACKGROUND & AIMS: 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.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , Bile Ducts, Intrahepatic/pathology , Cholestasis, Intrahepatic/genetics , Cholestasis, Intrahepatic/pathology , ATP Binding Cassette Transporter, Subfamily B/metabolism , Adolescent , Adult , Aged , Bile Ducts, Intrahepatic/metabolism , Biopsy , Cholestasis, Intrahepatic/metabolism , Chronic Disease , Female , Fibrosis , Heterozygote , Humans , Immunohistochemistry , Male , Middle Aged , Phenotype , Point MutationABSTRACT
The ABCB4 gene codes for a protein involved in the transport of phosphatidylcholine across the canalicular membrane of the hepatocyte. ABCB4 gene defects have been associated with progressive familial intrahepatic cholestasis type 3, intrahepatic cholestasis of pregnancy, adult biliary cirrhosis and the more recently described low phospholipid associated cholelithiasis syndrome. The present paper describes 2 probands with a long history of recurrent pancreatitis and cholelithiasis and the same heterozygous, as yet undescribed del 3683>3688 within exon 28 of the ABCB4 gene resulting in a loss of function. This report shows that ABCB4 mutations may cause acute recurrent biliary pancreatitis.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , ATP-Binding Cassette Transporters/genetics , Cholelithiasis/genetics , Mutation , Pancreatitis/genetics , Acute Disease , Adult , Cholelithiasis/complications , Cholelithiasis/diagnosis , Cholelithiasis/therapy , Female , Gene Deletion , Humans , Male , Middle Aged , Pancreatitis/diagnosis , Pancreatitis/etiology , Pancreatitis/therapy , Pedigree , Polymerase Chain Reaction , Treatment OutcomeSubject(s)
Cataract/blood , Cataract/genetics , Ferritins/blood , Ferritins/genetics , Adult , Apoferritins , Family Health , Female , Genetic Predisposition to Disease/genetics , Humans , Iron/blood , Iron-Regulatory Proteins/blood , Iron-Regulatory Proteins/genetics , Pedigree , Point Mutation/genetics , Syndrome , Transferrin/genetics , Transferrin/metabolismABSTRACT
BACKGROUND & AIMS: We recently put forward arguments in favor of ABCB4 gene (adenosine triphosphate-binding cassette, subfamily B, member 4) defects as a risk factor for symptomatic cholelithiasis in adults. In this study, we characterized ABCB4 gene mutations in a series of patients with symptomatic cholelithiasis to determine the genetic basis and the clinical phenotype of ABCB4 gene mutation-associated cholelithiasis. METHODS: We analyzed the entire ABCB4 gene coding sequences in a first group of 32 patients who had a clinical history compatible with the syndrome previously described, in a second group of 28 patients who presented with a classic gallstone disease that justified a cholecystectomy, and in a third group of 33 patients without a history of cholelithiasis. RESULTS: We identified both heterozygous and homozygous ABCB4 gene point mutations in 18 of 32 (56%) patients who presented with clinical criteria of the syndrome, whereas no mutation was detected in the 2 other groups of patients (P < 0.001). Three independent clinical features were strongly associated with point mutations: recurrence of symptoms after cholecystectomy (odds ratio, 8.5); intrahepatic hyperechoic foci, intrahepatic sludge, or microlithiasis (odds ratio, 6.1); and age <40 years at the onset of symptoms (odds ratio, 3.0). ABCB4 gene point mutations were detected exclusively in the patients who showed 2 or 3 of these clinical features. CONCLUSIONS: Our results show that ABCB4 gene mutations represent a major genetic risk factor in a symptomatic and recurring form of cholelithiasis in young adults.
