Lower prolactin levels are associated with histological severity of metabolic dysfunction-associated steatotic liver disease

Prolactin, a hormone synthesized by pituitary, was associated with metabolic dysfunction-associated steatotic liver disease (MASLD). Metabolic dysfunction-associated steatohepatitis (MASH) is the more severe manifestation of MASLD. We investigated whether prolactin levels correlate with the severity of MASLD and its histological features. Participants were categorized into non-MASLD, non-MASH, and MASH based on histopathological criteria. Baseline clinical and biological characteristics were compared according to MASLD status. Participants were further classified into tertiles based on prolactin levels, and binary regression analysis was used to assess the association between prolactin levels and MASLD/MASH. Subgroup analyses were performed according to sex, BMI, and glycemic status. Mediation analysis was performed to explore the relationship between prolactin and hepatic pathological features. This study enrolled 742 subjects (median age 31.0 years, median BMI 38.06 kg/m 2 , 64.29% females), of whom 67 had non-MASLD, 190 had non-MASH, and 485 had MASH. Serum prolactin levels were significantly lower in MASH group (median: 9.38 µg/L; IQR: 7.37–11.90) compared with non-MASLD group (median: 11.65 µg/L; IQR: 9.18–15.86) and non-MASH group (median: 9.91 µg/L; IQR: 8.08–13.00). After adjusting for potential confounders, subjects in the lowest prolactin tertile had significantly higher odds of MASLD (OR: 3.117; 95% CI: 1.253–7.757) and MASH (OR: 1.676; 95% CI: 1.110–2.530) compared with those in the highest tertile. Subgroup analyses suggested that this association was consistent across BMI and glycemic subgroups but restricted to females. Furthermore, prolactin levels were inversely correlated with steatosis score (rs = -0.207, p < 0.001) and inflammation score (rs = -0.148, p < 0.001), but not with ballooning score (rs = -0.015, p = 0.682) or fibrosis score (rs = 0.031, p = 0.410). The effects of prolactin on NAFLD activity score, steatosis score, and inflammatory score were mediated by HOMA-IR, with mediation proportions of 17.03%, 16.08% and 17.32%, respectively. Lower prolactin levels are associated with histological severity of MASLD, particularly in terms of hepatic steatosis and inflammation.