Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor

Urban, Thomas Jacob; Nicoletti, Paola; Chalasani, Naga; Serrano, Jose; Stolz, Andrew; Daly, Ann K.; Aithal, Guruprasad P.; Dillon, John F.; Navarro, Victor; Odin, Joseph; Barnhart, Huiman X.; Ostrov, David; Long, Nanye; Cirulli, Elizabeth Theresa; Watkins, Paul Brent; Fontana, Robert John

Abstract

Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline DILI in a well-phenotyped cohort of patients. Methods: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. Results: Amongst the 25 cases, 80% were female, median age was 19 years and median latency from drug start to DILI onset was 318 days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1077 U/L (range: 63 to 2333), median bilirubin 4.5 mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no subjects died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline-DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (Odds Ratio: 29.6, 95% CI: 7.8-89.8, p=2.5 x 10-8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline-DILI. Conclusion: HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline-DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.

Citation

Urban, T. J., Nicoletti, P., Chalasani, N., Serrano, J., Stolz, A., Daly, A. K., Aithal, G. P., Dillon, J. F., Navarro, V., Odin, J., Barnhart, H. X., Ostrov, D., Long, N., Cirulli, E. T., Watkins, P. B., & Fontana, R. J. (in press). Minocycline hepatotoxicity: clinical characterization and identification of HLA-B∗ 35:02 as a risk factor. Journal of Hepatology, 67(1), 137-144. https://doi.org/10.1016/j.jhep.2017.03.010

• Journal Article Type: Article
• Acceptance Date: Mar 4, 2017
• Online Publication Date: Mar 18, 2017
• Deposit Date: Apr 3, 2017
• Publicly Available Date: Apr 3, 2017
• Journal: Journal of Hepatology
• Print ISSN: 0168-8278
• Electronic ISSN: 1600-0641
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 67
• Issue: 1
• Pages: 137-144
• DOI: https://doi.org/10.1016/j.jhep.2017.03.010
• Keywords: Drug induced liver injury, Single nucleotide polymorphism, Genetic association, Autoimmunity, Human leukocyte antigen
• Public URL: https://nottingham-repository.worktribe.com/output/851329
• Publisher URL: https://doi.org/10.1016/j.jhep.2017.03.010
• Contract Date: Apr 3, 2017