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Hepatotoxicity related to antirheumatic drugs

Nature Reviews Rheumatology volume 7, pages 139–150 (2011)Cite this article

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Abstract

Antirheumatic agents are among commonly used drugs associated with adverse hepatic reactions. Sulfasalazine and azathioprine are among the most important causes of acute hepatotoxicity. Because such a large number of people take NSAIDs, even the rare occurrence of hepatotoxicity from these agents might contribute substantially to the total burden of drug-induced liver disease. A wide spectrum of hepatotoxic effects is described with antirheumatic drugs. Studies investigating genetic susceptibility to diclofenac hepatotoxicity have expanded our understanding of the potential drug-specific, class-specific and general factors involved in its pathogenesis, and methotrexate-associated liver disease demonstrates the interaction between drug, host and environmental factors that determines the likelihood and magnitude of liver disease. Infliximab therapy is associated with typical drug-induced autoimmune hepatitis. Although validated causality assessment methods have been used to objectively assess the strength of the association between a drug and a clinical event, in practice the diagnosis of drug-induced liver injury (DILI) involves a clinical index of suspicion, pattern recognition, the establishment of a temporal relationship between drug exposure and the adverse event, and the exclusion of alternative explanations for the clinical presentation. Detailed understanding of genetic and environmental factors underlying an individual's susceptibility would enable risk reduction and potentially primary prevention of hepatotoxicity.

Key Points

  • Antirheumatic agents are among commonly used drugs associated with hepatotoxic effects ranging from acute drug-induced liver injury (DILI) to chronic drug-associated liver disease and drug-induced autoimmune hepatitis

  • Diclofenac hepatotoxicity demonstrates that the pathogenesis of acute 'idiosyncratic' DILI is a multistep process involving interaction between metabolic and immunologic factors

  • Drug regimen and genetic susceptibility contribute to the pathogenesis of methotrexate-associated chronic liver disease; however, environmental factors are the major determinants of the extent of liver injury

  • Avoiding the use of a particular drug in those with recognized risk factors (e.g. methotrexate in those with diabetes, obesity or excessive alcohol consumption) whenever clinically feasible, could reduce the risk of serious DILI

  • Novel serum markers and imaging techniques can detect evidence of liver fibrosis non-invasively and their use in the monitoring of methotrexate-associated chronic liver disease should be evaluated

  • The strong association between a common HLA haplotype and lumiracoxib-induced liver injury raises the possibility of pre-prescription testing and primary prevention of acute idiosyncratic DILI

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Figure 1: Mechanisms of diclofenac hepatotoxicity, an archetype of idiosyncratic DILI.
Figure 2: Mechanisms underlying methotrexate hepatotoxicity, an archetype of chronic drug-associated liver disease.
Figure 3: Nodular regenerative hyperplasia associated with long-term azathioprine therapy.

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Acknowledgements

The author is grateful to Dr. Charles Paulding, Novartis Institutes for BioMedical Research and Dr. Muhammad F. Dawwas, Nottingham University Hospitals, for allowing him to discuss their unpublished data in this Review. The author also thanks Dr. Philip Kaye, Nottingham University Hospitals NHS Trust, for providing histology slides used in this article. C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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    Guruprasad P. Aithal

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Aithal, G. Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol 7, 139–150 (2011). https://doi.org/10.1038/nrrheum.2010.214

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