Associations of gender and a proxy of female menopausal status with histological features of drug-induced liver injury

Abstract

Background & aim: Gender and menopause may contribute to type and severity of drug-induced liver injury (DILI) by influencing host responses to injury. The aim of this study was to assess the associations of gender and female age 50 [a proxy of menopause] with histological features of liver injury in 212 adults enrolled in the Drug-Induced Liver Injury Network (DILIN) registry.

Methods: All participants had a causality score of at least 'probable', a liver biopsy within 30 days of DILI onset, and no prior chronic liver disease. Biochemical and histological injury types were classified as hepatocellular or cholestatic/mixed injury. The cohort was divided into three gender/age categories: men (41.0%), women <50 years (27.4%) and women ≥50 years of age (31.6%). Interaction of gender and age category (≥50 or not) was assessed.

Results: Hepatocellular injury was more prevalent in women <50 years vs. others (P=.002). After adjusting for biochemical injury types, black race and possible ageing effects, more severe interface hepatitis was noted in biopsies of women <50 years compared to those of men and women ≥50 years (P=.009 and P=.055 respectively). Compared to those of men, biopsies of women showed greater plasma cell infiltration, hepatocyte apoptosis, hepatocyte rosettes and lobular disarray but less iron-positive hepatocytes and histological cholestasis (P<.05). These associations persisted after excluding cases of amoxicillin/clavulanic acid, anabolic steroids or nitrofurantoin DILI which showed gender-specific distributions.

Conclusion: Gender and a proxy of menopause were associated with various features of inflammation and injury in DILI.

Keywords: drug-induced liver injury; gender difference; hepatotoxicity; liver histology; menopause.