Characterization and treatment of persistent hepatocellular secretory failure

Liver Int. 2015 Apr;35(4):1478-88. doi: 10.1111/liv.12603. Epub 2014 Jul 4.

Abstract

Background & aims: 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.

Conclusion: 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.

Keywords: ABCB11; ATP8B1; cholestasis; pregnane X receptor; rifampicin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / genetics
  • Adenosine Triphosphatases / genetics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Bilirubin / blood
  • Chemical and Drug Induced Liver Injury / diagnosis
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / physiopathology
  • Cholestasis / complications
  • Cholestasis / therapy
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Cytochrome P-450 CYP3A Inducers / pharmacology
  • Female
  • Genetic Predisposition to Disease
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism
  • HT29 Cells
  • Hep G2 Cells
  • Humans
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / metabolism
  • Liver Failure / diagnosis
  • Liver Failure / drug therapy*
  • Liver Failure / etiology
  • Liver Failure / physiopathology
  • Male
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Middle Aged
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Mutation
  • Pregnane X Receptor
  • Receptors, Steroid / agonists
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Rifampin / therapeutic use*
  • Risk Factors
  • Severity of Illness Index
  • Treatment Outcome
  • Up-Regulation
  • Young Adult

Substances

  • ABCB11 protein, human
  • ABCC2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Cytochrome P-450 CYP3A Inducers
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Protein 2
  • Multidrug Resistance-Associated Proteins
  • Pregnane X Receptor
  • Receptors, Steroid
  • SLC51B protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Adenosine Triphosphatases
  • ATP8B1 protein, human
  • Bilirubin
  • Rifampin