Characterization and treatment of persistent hepatocellular secretory failure

Van Dijk R, Kremer A, Smit W, Van Den Elzen B, Van Gulik T, Gouma D, Lameris JS, Bikker H, Enemuo V, Stokkers PCF, Feist M, Bosma P, Jansen PLM, Beuers U (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Liver International Wiley-Blackwell

Book Volume: 35

Pages Range: 1478-88

Journal Issue: 4

DOI: 10.1111/liv.12603

Abstract

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.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 ?mol/L).Serum bilirubin of patients with PHSF ranged from 264 to 755 ?mol/L. Normal ?GT was found in 10/13 patients of whom 3/6 tested positive for ATP8B1/ABCB11 mutations. Serum bilirubin declined to <33 ?mol/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 OST?.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 OST? could contribute to the anticholestatic effect of rifampicin in PHSF.

Authors with CRIS profile

Andreas Kremer Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology

Involved external institutions

University of Amsterdam NL Netherlands (NL) Louisiana State University US United States (USA) (US) Sint Lucas Andreas Hospital NL Netherlands (NL) Covenant Pediatric Gastroenterology Group US United States (USA) (US)

How to cite

APA:

Van Dijk, R., Kremer, A., Smit, W., Van Den Elzen, B., Van Gulik, T., Gouma, D.,... Beuers, U. (2015). Characterization and treatment of persistent hepatocellular secretory failure. Liver International, 35(4), 1478-88. https://doi.org/10.1111/liv.12603

MLA:

Van Dijk, Remco, et al. "Characterization and treatment of persistent hepatocellular secretory failure." Liver International 35.4 (2015): 1478-88.

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