Drug-induced liver injury (DILI) ascribed to non-steroidal anti-inflammatory drugs (NSAIDs) in the USA-Update with genetic correlations

Herbert L Bonkovsky; Marwan Ghabril; Paola Nicoletti; Andrew Dellinger; Robert J Fontana; Huiman Barnhart; Jiezhun Gu; Ann K Daly; Guruprasad P Aithal; Elizabeth J Phillips; David E Kleiner; US DILIN Investigators

doi:10.1111/liv.15892

Drug-induced liver injury (DILI) ascribed to non-steroidal anti-inflammatory drugs (NSAIDs) in the USA-Update with genetic correlations

Liver Int. 2024 Mar 7. doi: 10.1111/liv.15892. Online ahead of print.

Authors

Affiliations

¹ Department of Internal Medicine, Wake Forest University School of Medicine and Atrium Health Wake Forest Baptist, Winston-Salem, North Carolina, USA.
² Department of Internal Medicine, Indiana University School of Medicine and IU Hospital, Indianapolis, Indiana, USA.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁴ Duke Molecular Physiology Institute, Durham, North Carolina, USA.
⁵ Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
⁶ Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, Durham, North Carolina, USA.
⁷ Duke Clinical Research Institute, Durham, North Carolina, USA.
⁸ Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
⁹ Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK.
¹⁰ National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospital NHS Trust, University of Nottingham, Nottingham, UK.
¹¹ Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
¹² Department of Pathology, National Cancer Institute, Bethesda, Maryland, USA.

PMID: 38451034
DOI: 10.1111/liv.15892

Abstract

Objective: To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI.

Methods: In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort.

Results: Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB1*04:03 and HLA-B*35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB1*04:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB1*04:03 could be a drug and/or class risk factor. HLA-B*35:03 but not HLA-DRB1*04:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac.

Conclusions: Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B*35:03 and DRB1*04:03, driven by diclofenac, suggests the importance of immune-mediated responses.

Keywords: HLA (human leucocyte antigen); diclofenac; genetics; ibuprofen; idiosyncratic drug-induced liver injury; immune-mediated liver disease.

Grants and funding

NIDDK