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Characterization and treatment of persistent hepatocellular secretory failure
Author(s) -
Dijk Remco,
Kremer Andreas E.,
Smit Wouter,
Elzen Bram,
Gulik Thomas,
Gouma Dirk,
Lameris Johan S.,
Bikker Hennie,
Enemuo Valentine,
Stokkers Pieter C. F.,
Feist Mark,
Bosma Piter,
Jansen Peter L. M.,
Beuers Ulrich
Publication year - 2015
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12603
Subject(s) - pregnane x receptor , rifampicin , cyp3a4 , secretion , medicine , pharmacology , bilirubin , gastroenterology , chemistry , biology , gene , antibiotics , cytochrome p450 , microbiology and biotechnology , metabolism , biochemistry , nuclear receptor , transcription factor
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 ATP 8B1 or ABCB 11 mutations. All were treated with rifampicin (300 mg daily) for 1–10 weeks. Expression of genes involved in biotransformation and secretion was determined by rt PCR 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 γ GT was found in 10/13 patients of whom 3/6 tested positive for ATP 8B1/ ABCB 11 mutations. Serum bilirubin declined to <33 μmol/L after 1–10 weeks of rifampicin treatment. In vitro, rifampicin PXR ‐dependently upregulated biotransformation phase 1 ( CYP 3A4), phase 2 ( UGT 1A1) and phase 3 ( MRP 2) enzymes/carriers as well as the basolateral bile salt exporter OST β. 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 CYP 3A4, UGT 1A1, MRP 2 and OST β could contribute to the anticholestatic effect of rifampicin in PHSF .