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Drug-induced liver injury

Nature Reviews Disease Primers volume 5, Article number: 58 (2019) Cite this article

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Abstract

Drug-induced liver injury (DILI) is an adverse reaction to drugs or other xenobiotics that occurs either as a predictable event when an individual is exposed to toxic doses of some compounds or as an unpredictable event with many drugs in common use. Drugs can be harmful to the liver in susceptible individuals owing to genetic and environmental risk factors. These risk factors modify hepatic metabolism and excretion of the DILI-causative agent leading to cellular stress, cell death, activation of an adaptive immune response and a failure to adapt, with progression to overt liver injury. Idiosyncratic DILI is a relative rare hepatic disorder but can be severe and, in some cases, fatal, presenting with a variety of phenotypes, which mimic other hepatic diseases. The diagnosis of DILI relies on the exclusion of other aetiologies of liver disease as specific biomarkers are still lacking. Clinical scales such as CIOMS/RUCAM can support the diagnostic process but need refinement. A number of clinical variables, validated in prospective cohorts, can be used to predict a more severe DILI outcome. Although no pharmacological therapy has been adequately tested in randomized clinical trials, corticosteroids can be useful, particularly in the emergent form of DILI related to immune-checkpoint inhibitors in patients with cancer.

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Fig. 1: Hepatocyte transporters and cellular mechanisms of DILI.
Fig. 2: Molecular mechanisms of idiosyncratic and intrinsic DILI.
Fig. 3: Proposed algorithm to suspect, diagnose and manage idiosyncratic DILI.
Fig. 4: Traditional and investigational biomarkers of DILI.
Fig. 5: Proposed detection and management of hepatotoxicity due to ICIs in patients with cancer.

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Acknowledgements

We acknowledge the support of the European Cooperation in Science & Technology (COST) Action CA17112 Prospective European Drug-Induced Liver Injury Network. R.J.A., N.C., E.S.B., A.S., G.A.K.-U, H.D., M.M., M.I.L. and G.P.A. are members of COST Action CA17112.

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Authors and Affiliations

  1. Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Malaga, Spain

    Raul J. Andrade

  2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain

    Raul J. Andrade & M. Isabel Lucena

  3. Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA

    Naga Chalasani

  4. Department of Gastroenterology, Landspitali University Hospital Reykjavik, University of Iceland, Reykjavík, Iceland

    Einar S. Björnsson

  5. Faculty of Medicine, University of Iceland, Reykjavík, Iceland

    Einar S. Björnsson

  6. Gastroenterology, Duke University, Durham, NC, USA

    Ayako Suzuki

  7. Gastroenterology, Durham VA Medical Centre, Durham, NC, USA

    Ayako Suzuki

  8. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

    Gerd A. Kullak-Ublick & Michael Merz

  9. Mechanistic Safety, CMO & Patient Safety, Global Drug Development, Novartis Pharma, Basel, Switzerland

    Gerd A. Kullak-Ublick

  10. UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    Paul B. Watkins

  11. University of North Carolina Institute for Drug Safety Sciences, Research Triangle Park, Chapel Hill, NC, USA

    Paul B. Watkins

  12. Department of Gastroenterology and Hepatology, St. John’s Medical College Hospital, Bangalore, India

    Harshad Devarbhavi

  13. Patient Safety, AstraZeneca, Gaithersburg, MD, USA

    Michael Merz

  14. Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, UICEC SCReN, Universidad de Málaga, Málaga, Spain

    M. Isabel Lucena

  15. Division of Gastroenterology and Liver Diseases, Department of Medicine, Keck School of Medicine, Los Angeles, CA, USA

    Neil Kaplowitz

  16. National Institute for Health Research (NIHR) Nottingham Digestive Diseases Biomedical Research Centre, Nottingham University Hospital NHS Trust and University of Nottingham, Nottingham, UK

    Guruprasad P. Aithal

Authors
  1. Raul J. Andrade
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  2. Naga Chalasani
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  7. Harshad Devarbhavi
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Contributions

Introduction (R.J.A.); Epidemiology (N.C., E.S.B. and H.D.); Mechanisms/pathophysiology (N.K., G.A.K.-U. and A.S.); Diagnosis, screening and prevention (R.J.A., G.P.A., H.D., M.I.L., P.B.W. and M.M.); Prognosis (E.S.B.); Management (N.C.); Quality of life (A.S. and M.I.L.); Outlook (N.K., G.P.A. and R.J.A.); Overview of Primer (R.J.A. and M.I.L.).

Corresponding authors

Correspondence to Raul J. Andrade or M. Isabel Lucena.

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Nature Reviews Disease Primers thanks M. Chen, H. Jaeschke, J. Lewis, T. Yokoi, and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Andrade, R.J., Chalasani, N., Björnsson, E.S. et al. Drug-induced liver injury. Nat Rev Dis Primers 5, 58 (2019). https://doi.org/10.1038/s41572-019-0105-0

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