Breastfeeding in infancy confers sex-specific, long-term protection against metabolic dysfunction-associated steatohepatitis and adverse liver outcomes

BACKGROUND: It remains unclear whether breastfeeding in infancy is associated with risk of metabolic dysfunction-associated steatohepatitis (MASH) and adverse liver outcomes in adulthood. METHODS: We analyzed data from the prospective UK Biobank. Breastfeeding in infancy was ascertained via self-report. In a cross‑sectional analysis involving 26,850 participants with liver MRI data, metabolic dysfunction-associated steatotic liver disease (MASLD) was defined as PDFF > 5.5%, and MASH as PDFF > 5.5% combined with cT1 > 800 ms. Additionally, a longitudinal analysis of 378,702 participants assessed associations with incident cirrhosis, hepatocellular carcinoma (HCC), and liver‑related mortality. RESULTS: In MRI-based analysis, breastfeeding in infancy was associated with lower odds of MASLD (OR 0.89, 95% CI 0.80-0.99) and MASH (OR 0.79, 95% CI 0.65-0.97) in females but not males, with a significant sex interaction for MASH (P for interaction = 0.023) but not for MASLD (P for interaction = 0.301). Over a median follow‑up of 14.9 years, breastfeeding was associated with reduced risks of cirrhosis (HR 0.71, 95% CI 0.60-0.83), HCC (HR 0.52, 95% CI 0.33-0.82), and liver‑related mortality (HR 0.63, 95% CI 0.46-0.86) in females. No such associations were observed in males (P for interaction = 0.047, 0.030, and 0.008, respectively). Mediation analysis revealed that circulating insulin-like growth factor-1 (IGF-1) mediated the association specifically in females, with a sex difference in the indirect effect (FDR < 0.001). CONCLUSIONS: Breastfeeding in infancy confers a long-term protective effect against MASH and adverse liver outcomes in women, but not in men. This sex-specific protective association was mediated by circulating IGF-1, suggesting a potential underlying mechanism.