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Recent advances in clinical practice
Drug-induced liver injury: recent advances in diagnosis and risk assessment
  1. Gerd A Kullak-Ublick1,2,
  2. Raul J Andrade3,
  3. Michael Merz4,
  4. Peter End4,
  5. Andreas Benesic5,6,
  6. Alexander L Gerbes5,
  7. Guruprasad P Aithal7
  1. 1Department of Clinical Pharmacology and Toxicology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
  2. 2Drug Safety and Epidemiology, Novartis Pharma, Basel, Switzerland
  3. 3Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain
  4. 4Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
  5. 5Department of Medicine II, Klinikum Grosshadern of the University of Munich (KUM), University of Munich, Munich, Germany
  6. 6MetaHeps GmbH, Planegg/Martinsried, Germany
  7. 7National Institute for Health Research (NIHR), Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
  1. Correspondence to Dr Gerd A Kullak-Ublick, Department of Clinical Pharmacology and Toxicology, University Hospital Zurich and University of Zurich, Rämistrasse 100, Zurich 8091, Switzerland; gerd.kullak{at}usz.ch

Abstract

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption–distribution–metabolism–elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public–private partnerships.

  • HEPATOBILIARY DISEASE
  • DRUG INDUCED HEPATOTOXICITY
  • BILE ACID
  • PHARMACOGENETICS
  • ADVERSE DRUG REACTIONS

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/gutjnl-2016-313369

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    Footnotes

    • Contributors GAK-U planned and wrote parts of the manuscript and contributed table 2; RJA wrote parts of the manuscript and contributed table 1 and figure 3; MM and PE wrote parts of the manuscript; AB contributed figures 1, 2 and 4; ALG wrote parts of the manuscript and GPA wrote parts of the manuscript and contributed table 3 and figure 5.

    • Funding This work was supported by Swiss National Science Foundation grant no. 320030_144193 (to GAK-U).

    • Competing interests AB and ALG have equity in the company MetaHeps GmbH. PE and MM are employees and GAK-U is a contractor of Novartis Pharma.

    • Provenance and peer review Not commissioned; externally peer reviewed.