title: Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.
abstract: OBJECTIVE
  Progressive familial intrahepatic cholestasis (PFIC), an inherited liver disease of childhood, is characterized by cholestasis and either normal or increased serum gamma-glutamyltransferase activity. Patients with normal gamma-glutamyltransferase activity have mutations of the FIC1 locus on chromosome 18q21 or mutations of the BSEP gene on chromosome 2q24. Also, patients with bile acid synthesis defects have low gamma-glutamyltransferase activity. We investigated expression of the bile salt export pump (BSEP) in liver samples from patients with a PFIC phenotype and correlated this with BSEP gene mutations.
  
  
  METHODS
  BSEP and multidrug resistance protein 2 (MRP2) expressions were studied by immunohistochemistry in liver specimens of 28 patients and BSEP gene mutation analysis in 19 patients. Bile salt kinetics were studied in 1 patient.
  
  
  RESULTS
  Sixteen of 28 liver samples showed no canalicular BSEP staining. Staining for MRP2 showed a normal canalicular pattern in all but 1 of these samples. Ten of 19 patients showed BSEP gene mutations; BSEP protein expression was lacking in all 10 patients. No mutations were found in 9 of 19 patients, and in all except 1, BSEP protein expression was normal. Bile salt concentration in bile of BSEP-negative/MRP2-positive PFIC patients was 0.2 +/- 0.2 mmol/L (n = 9; <1% of normal) and in BSEP-positive PFIC patients 18.1 +/- 9.9 mmol/L (n = 3; 40% of normal). The kinetic study confirmed the dramatic decrease of bile salt secretion in BSEP-negative patients.
  
  
  CONCLUSIONS
  The findings show a close correlation between BSEP gene mutations and canalicular BSEP expression. Biliary secretion of bile salts is greatly reduced in BSEP-negative patients.
authors.affiliation: Department of Gastroenterology, University Hospital Groningen, Groningen, The Netherlands. P.L.M.Jansen@int.azg.nl
authors.forename: P L
authors.initials: PL
authors.lastname: Jansen
authors.forename: S S
authors.initials: SS
authors.lastname: Strautnieks
authors.forename: E
authors.initials: E
authors.lastname: Jacquemin
authors.forename: M
authors.initials: M
authors.lastname: Hadchouel
authors.forename: E M
authors.initials: EM
authors.lastname: Sokal
authors.forename: G J
authors.initials: GJ
authors.lastname: Hooiveld
authors.forename: J H
authors.initials: JH
authors.lastname: Koning
authors.forename: A
authors.initials: A
authors.lastname: De Jager-Krikken
authors.forename: F
authors.initials: F
authors.lastname: Kuipers
authors.forename: F
authors.initials: F
authors.lastname: Stellaard
authors.forename: C M
authors.initials: CM
authors.lastname: Bijleveld
authors.forename: A
authors.initials: A
authors.lastname: Gouw
authors.forename: H
authors.initials: H
authors.lastname: Van Goor
authors.forename: R J
authors.initials: RJ
authors.lastname: Thompson
authors.forename: M
authors.initials: M
authors.lastname: Müller
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D002887:Chromosomes, Human, Pair 18; D018076:DNA, Complementary / Q000032:analysis; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D016623:Ion Pumps / Q000096:biosynthesis / Q000276:immunology; D007700:Kinetics; D008297:Male; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: C093491:ABCB11 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D018076:DNA, Complementary; D016623:Ion Pumps; C095122:multidrug resistance protein 3; D005723:gamma-Glutamyltransferase