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Immune-Mediated Drug-Induced Liver Injury

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Liver Immunology

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Abstract

Drug-induced liver injury (DILI) has previously been classified into an immunologic or metabolic idiosyncrasy. Metabolic idiosyncrasy implies that a subject developing adverse reaction metabolizes the drug in a different way in most individuals or lacks adequate protective mechanisms to neutralize reactive metabolites formed. An immunologic idiosyncrasy implies that the susceptible individual has an immune system that would more readily recognize the formed neoantigens. Alternatively, immune system through cytokines and chemokines may modulate the degree of hepatic inflammation secondary to toxic injury. However, this classification derived from clinical observations, such as latent period, presence or absence of manifestations attributable to hypersensitivity, and pattern of response to rechallenge, is too simplistic to be accurate. Increasingly, it is evident that the development of idiosyncratic DILI is a multistep process involving both metabolic and immunologic factors.

Superimposition of drug-metabolizing enzymes and the immune system within the liver which may act both as a lymphoid organ and a target for toxicity creates a setting suitable for interaction between variety of factors that influence the rate and extent of pathogenic process leading to liver injury. Liver is involved in 80% of cases of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, a severe form of idiosyncratic reaction involving multiple organ systems. This syndrome has been associated with drugs, such as phenobarbital, carbamazepine, phenytoin, lamotrigine, minocycline, sulfonamides, allopurinol, modafinil, and dapsone. In patients with DRESS syndrome, drug-reactive T cells are in a pre-activated state and, therefore, may have a lower threshold for activation by drugs. Evidence for the involvement of immune system in the pathogenesis of idiosyncratic DILI have existed for decades; family studies performed over 30 years ago have revealed that the lymphocytes from first-degree relatives of patients with amineptine-induced liver injury demonstrated increased sensitivity to the drug metabolites. Consistent with this, several candidate gene and genome-wide association studies involving well characterized patient cohorts conducted in the past decade have indicated that immune mechanisms may underlie the pathogenesis of a range of clinically diverse DILI secondary to therapeutically and structurally unrelated compounds.

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Authors and Affiliations

  1. Landspítali – The National University Hospital of Iceland and the Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Einar S. Björnsson

  2. National Institute for Health Research (NIHR) at the Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham Digestive Diseases Centre, School of Medicine, Nottingham, UK

    Guruprasad Padur Aithal

Authors
  1. Einar S. Björnsson
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  2. Guruprasad Padur Aithal
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Correspondence to Einar S. Björnsson .

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Editors and Affiliations

  1. Division of Rheumatology, Allergy and Clinical Immunology, The University of California School of Medicine, Davis, CA, USA

    M. Eric Gershwin

  2. Departments of Medicine and Surgery, Baylor College of Medicine, Houston, TX, USA

    John M. Vierling

  3. Department of Medicine, Teikyo University School of Medicine, Itabashi, Tokyo, Japan

    Atsushi Tanaka

  4. President, Hannover Medical School, Hannover, Germany

    Michael P. Manns

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Björnsson, E.S., Aithal, G.P. (2020). Immune-Mediated Drug-Induced Liver Injury. In: Gershwin, M.E., M. Vierling, J., Tanaka, A., P. Manns, M. (eds) Liver Immunology . Springer, Cham. https://doi.org/10.1007/978-3-030-51709-0_30

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