title: Characterization and treatment of persistent hepatocellular secretory failure.
abstract: OBJECTIVE
  Hepatocellular secretory failure induced by drugs, toxins or transient biliary obstruction may sometimes persist for months after removal of the initiating factor and may then be fatal without liver transplantation. We characterized patients with severe persistent hepatocellular secretory failure (PHSF) and treated them with the pregnane X receptor (PXR) agonist, rifampicin. We also studied the effect of rifampicin on PXR-dependent expression of genes involved in biotransformation and secretion in vitro.
  
  
  METHODS
  Thirteen patients (age 18-81 years, 6 male) with hepatocellular secretory failure that persisted after removal of the inducing factor (drugs/toxin: 9) or biliary obstruction (4) were identified over 6 years. Six of these patients were screened for ATP8B1 or ABCB11 mutations. All were treated with rifampicin (300 mg daily) for 1-10 weeks. Expression of genes involved in biotransformation and secretion was determined by rtPCR in human hepatocytes and intestinal cells incubated with rifampicin (10 μmol/L).
  
  
  RESULTS
  Serum bilirubin of patients with PHSF ranged from 264 to 755 μmol/L. Normal γGT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 μmol/L after 1-10 weeks of rifampicin treatment. In vitro, rifampicin PXR-dependently upregulated biotransformation phase 1 (CYP3A4), phase 2 (UGT1A1) and phase 3 (MRP2) enzymes/carriers as well as the basolateral bile salt exporter OSTβ.
  
  
  CONCLUSIONS
  Persistent hepatocellular secretory failure may develop in carriers of transporter gene mutations. In severe cases, rifampicin may represent an effective therapeutic option of PHSF. PXR-dependent induction of CYP3A4, UGT1A1, MRP2 and OSTβ could contribute to the anticholestatic effect of rifampicin in PHSF.
authors.affiliation: Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: van Dijk
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kremer
authors.forename: Wouter
authors.initials: W
authors.lastname: Smit
authors.forename: Bram
authors.initials: B
authors.lastname: van den Elzen
authors.forename: Thomas
authors.initials: T
authors.lastname: van Gulik
authors.forename: Dirk
authors.initials: D
authors.lastname: Gouma
authors.forename: Johan S
authors.initials: JS
authors.lastname: Lameris
authors.forename: Hennie
authors.initials: H
authors.lastname: Bikker
authors.forename: Valentine
authors.initials: V
authors.lastname: Enemuo
authors.forename: Pieter C F
authors.initials: PC
authors.lastname: Stokkers
authors.forename: Mark
authors.initials: M
authors.lastname: Feist
authors.forename: Piter
authors.initials: P
authors.lastname: Bosma
authors.forename: Peter L M
authors.initials: PL
authors.lastname: Jansen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001663:Bilirubin / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D002779:Cholestasis / Q000150:complications / Q000628:therapy; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017093:Liver Failure / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012293:Rifampin / Q000627:therapeutic use*; D012307:Risk Factors; D012720:Severity of Illness Index; D016896:Treatment Outcome; D015854:Up-Regulation; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D001663:Bilirubin; D051544:Cytochrome P-450 CYP3A; D065701:Cytochrome P-450 CYP3A Inducers; D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012293:Rifampin; D000099148:UGT1A1 Enzyme; C093491:ABCB11 protein, human; C000715087:ABCC2 protein, human; C476577:SLC51B protein, human; C510163:CYP3A4 protein, human; C111067:ATP8B1 protein, human
keywords: ABCB11; ATP8B1; cholestasis; pregnane X receptor; rifampicin