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

Abstract

Background and 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 histologic 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 histologic 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=0.002). After adjusting for biochemical injury types, black race and possible aging effects, more severe interface hepatitis was noted in biopsies of women < 50 years compared to those of men and women ≥ 50 years (p=0.009 and p=0.055, 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<0.05). 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.

Acetaminophen-induced Acute Liver Failure Is More Common and More Severe in Women

“…Women are more likely to present with DILI-induced ALF (12) and to require subsequent liver transplant (18). While recent studies have questioned whether women are systematically at greater risk of hepatotoxicity (11, 19), it is clear that women are more likely to progress to DILI-induced ALF, and to have increased susceptibility to hepatotoxicity caused by specific medications (11, 20–22).…”

Histopathological challenges in suspected drug‐induced liver injury

“…At the other end of the age spectrum, older patients may be at greater risk of DILI mainly because they take more medications and the histological implications have yet to be studied in detail . Gender differences in histology have been studied in the DILIN . Women were more likely to have biopsies that showed autoimmune‐like histology, including more frequent plasma cell infiltration, hepatocyte rosette formation and lobular disarray, while the men were more likely to show cholestasis on biopsy .…”

“…Gender differences in histology have been studied in the DILIN . Women were more likely to have biopsies that showed autoimmune‐like histology, including more frequent plasma cell infiltration, hepatocyte rosette formation and lobular disarray, while the men were more likely to show cholestasis on biopsy . The differences persisted after excluding agents with gender‐specific prescription patterns.…”

Drug-induced liver injury

“…In vivo animal studies, sex differences in susceptibility to DILI 399 depends on models: male dominance in liver injury induced by acetaminophen [80][81][82] and cocaine 400 (only after the onset of puberty) 83,84 and female dominance in halothane [85][86][87][88] and in another 401 immune-mediated DILI model 89 . In humans, age, sex, and a proxy of women's menopausal status 402 (i.e., 50 years) significantly influence drug-specific reporting frequencies of liver events in the 403 World Health Organization VigiBase™ 90,91 , and influence clinical and histologic phenotypes of 404 DILI 92,93 . Drugs associated with sex-/age-biased reporting frequencies of liver events showed 405 distinct properties 90 .…”