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

Abstract

Background & Aims 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 × 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.

A Pilot Genome‐Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH

“…Genetic variants in the IL28 gene were highly predictive of response to interferon therapy in patients with chronic hepatitis C. (5) Variations in the HLA region are a well-known risk factor for liver injury due to antibacterial agents such as flucloxacillin, amoxicillin-clavulanate, or minocycline. (6)(7)(8)(9) However, pharmacogenomics research within the NAFLD area is somewhat limited. One study showed that genetic variation in cytochrome P450 4F2 was not a significant predictor of response to vitamin E in nondiabetic patients with biopsy-proven NASH.…”

The diagnosis and management of idiosyncratic drug‐induced liver injury

“…More recently, Nicoletti et al demonstrated that HLA‐A * 33:01 was a risk factor for cholestatic and mixed DILI in Caucasians from a number of drugs, including terbinafine, fenofibrate and ticlopidine . Finally, we recently showed that HLA‐B *35:02 was over‐represented in Caucasian patients with minocycline hepatotoxicity . However, due to the small number of minocycline cases, replication cohorts are needed to confirm the value of testing for this allele in minocycline‐treated patients presenting with liver injury.…”

“…21 Finally, we recently showed that HLA-B *35:02 was over-represented in Caucasian patients with minocycline hepatotoxicity. 84 However, due to the small number of minocycline cases, replication cohorts are needed to confirm the value of testing for this allele in minocycline-treated patients presenting with liver injury.…”

Primum non nocere: Minocycline‐induced liver injury in a teenager

“…Urban et al recently demonstrated that individuals who are HLA-B*35:02 carriers are at increased risk of developing minocycline-related liver injury. 8 Re-exposure to hepatotoxic drugs is strongly discouraged, particularly if there is a significant rise in transaminases (>5× upper limit of normal) or jaundice. 3 In our case, an adverse drug reaction report was completed, and she was advised to avoid tetracyclines for life.…”