Human Pathology · Nov 22, 2025

Impact of gender and age on the histologic severity of metabolic syndrome associated steatohepatitis

By Acharya EK, Lam R, Lim JK et al.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are leading causes of chronic liver disease. Although clinical studies suggest age and gender may influence disease severity, histologic data remain limited. We investigated the relationship between age, gender, and histologic features of MASH. METHODS: We retrospectively reviewed 407 liver biopsies (2012-2019) with histologic steatosis. Clinical, demographic, and laboratory data were collected. Biopsies were assessed for steatosis, inflammation, ballooning, and fibrosis, and the NAFLD activity score (NAS) was calculated. Patients were divided into four groups: women 18-50 years, men 18-50 years, women >50 years, and men >50 years. Statistical analyses included univariable and multivariable ordinal logistic regression. RESULTS: Younger patients (18-50 years) had higher steatosis and NAS irrespective of gender, while older patients (>50 years) had higher fibrosis scores. Fibrosis was most severe in older men (mean stage 2.41 ± 1.41), compared with younger men (1.21 ± 1.21) and younger women (1.52 ± 1.30). Severe ballooning and lobular inflammation were more frequent in women, particularly younger women. In multivariable regression, age > 50 years remained independently associated with higher fibrosis stage (OR 2.17), while gender was not significant. BMI did not differ between groups. CONCLUSIONS: Older age is strongly associated with higher fibrosis in MASH, independent of BMI and other clinical covariates. Gender-related differences in histologic features contributed to NAS but were not statistically significant. These findings highlight age as a potentially important driver of fibrosis progression in MASH. Hormonal factors may play a role but further investigation is warranted.

doi.org/10.1016/j.humpath.2025.105985 Open access, accepted manuscript PubMed 41276023 Mechanisms