Pharmacogenetics of drug-induced liver injury

Authors

  • Stefan Russmann,

    1. Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland
    2. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
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  • Alexander Jetter,

    1. Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland
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  • Gerd A. Kullak-Ublick

    Corresponding author
    1. Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland
    2. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland
    • Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland
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    • fax: +41 44 255 4411


  • Potential conflict of interest: All authors declare that they have no conflict of interest in relation to this work. Dr. Kullak-Ublick is a member of the investigative Liver Expert Team at the Novartis Institutes for BioMedical Research, Basel, Switzerland.

Abstract

Recent progress in research on drug-induced liver injury (DILI) has been determined by key developments in two areas. First, new technologies allow the identification of genetic risk factors with improved sensitivity, specificity, and efficiency. Second, new mechanistic concepts of DILI emphasize the importance of unspecific “downstream” events following drug-specific initial “upstream” hepatocyte injury and of complex interactions between environmental and genetic risk factors. The integration of genetic and mechanistic concepts is essential for current research approaches, and genetic studies of DILI now focus on targets that affect the function and transcriptional regulation of genes relating not only to drug metabolism but also to human leukocyte antigens (HLAs), cytokines, oxidative stress, and hepatobiliary transporters. Risk factors affecting unspecific downstream mechanisms may be identified using pooled DILI cases caused by various drugs. The power to detect variants that confer a low risk can be increased by recruitment of strictly selected cases through large networks, whereas controls may also be obtained from genotyped reference populations. The first genomewide studies of DILI identified HLA variants as risk factors for hepatotoxicity associated with flucloxacillin and ximelagatran, and their design has defined a new standard for pharmacogenetic studies. From a clinical and regulatory point of view, there is a need for genetic tests that identify patients at increased hepatotoxic risk. However, DILI is a rare complex disease, and pharmacogenetic studies have so far not been able to identify interactions of several risk factors defining a high population-attributable risk and clinically relevant absolute risk for DILI. (HEPATOLOGY 2010)

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