Abstract
BACKGROUND: Mediterranean diet (MED) is recommended for managing metabolic dysfunction-associated steatotic liver disease (MASLD). However, associations between MED adherence, related metabolite signatures, and risks of liver-related events (LRE) and mortality in MASLD patients remain unclear. METHODS: We performed a prospective analysis using UK Biobank data, including 47,429 MASLD participants free of LRE at baseline. MED adherence was assessed as alternate Mediterranean Diet (aMED) score through a validated questionnaire. Metabolic biomarkers were measured using high-throughput nucleic magnetic resonance (NMR) spectroscopy. Cox regression and restricted cubic splines assessed the association of aMED, its components, with risk of LRE and mortality. Mediation analysis evaluated the role of metabolites in the relationship between aMED, its components, and MASLD progression. RESULTS: Over a median follow-up of 13.3 years, 296 LRE cases and 3616 deaths occurred. Higher aMED scores (6-9) were associated with lower risks of LRE (HR: 0.553, 95% CI: 0.351-0.874) and mortality (HR: 0.854, 95% CI: 0.762-0.956) compared with the lowest scores (0-3), with linear dose-response relationships. Vegetables and legumes were associated with lower LRE risk, while vegetables, nuts, fish, MUFA:SFA ratio, and moderate alcohol intake were linked to reduced mortality. Of 143 metabolites, 46 were significantly associated with aMED. Omega-3 fatty acids, the omega-3 to total fatty acid ratio, and albumin accounted for 7.9%, 11.9%, and 2.6% of the reduction in LRE, and 19.4%, 23.1%, and 4.7% of the mitigation in mortality, respectively. CONCLUSIONS: Adherence to MED is linked to reduced LRE risk and mortality in MASLD patients. Metabolic biomarkers, particularly small HDL particles and omega-3 fatty acids, may mitigate MASLD progression.