Metabolic dysfunction-associated steatotic liver disease and risk of gallstone disease: A systematic review and meta-analysis

Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly known as non-alcoholic fatty liver disease, NAFLD) and gallstone disease (GD) share common pathophysiological underpinnings of metabolic dysregulation. However, the epidemiological strength of their association, dose-response relationship, and subgroup differences remain incompletely assessed. This study aimed to quantify the association between MASLD/NAFLD and GD, and to explore the influence of sex, age, and study design. Following the PRISMA guidelines, a systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted up to December 2025. Cohort and cross-sectional studies evaluating the risk of GD in relation to MASLD/NAFLD were included. A stratified analysis strategy was employed, pooling odds ratios (ORs), hazard ratios (HRs), and relative risks (RRs) separately. Summary effect estimates with 95% confidence intervals (CIs) were calculated using random-effects models. Study quality was assessed using the Newcastle-Ottawa Scale. Subgroup analyses were performed to explore heterogeneity sources. Twelve studies (6 cohort, 6 cross-sectional) involving 5,405,757 participants were included. The main analysis (7 OR studies) showed that MASLD/NAFLD was associated with increased odds of GD (pooled OR = 1.50, 95% CI: 1.29–1.74, I² = 80%). Additional analyses using other effect measures yielded consistent results (HR = 1.50; RR = 1.32). Subgroup analyses indicated: (i) A single high-quality prospective cohort study reported a stronger association (OR = 2.62) compared to the pooled estimate from cross-sectional studies (OR = 1.39), though this observation is based on only one cohort study and must be interpreted with caution; (ii) The association was statistically significant in females (OR = 1.98, p < 0.00001) but did not reach significance in males (OR = 1.92, p = 0.09), with no statistically significant difference between sexes; (iii) The point estimate was higher in the age < 50 group (OR = 2.53) than in the ≥ 50 group (OR = 1.78), though the inter-subgroup difference was not statistically and the younger-age subgroup was limited by small study numbers and imprecise estimates; (iv) The risk was potentially higher in patients with moderate-to-severe NAFLD. MASLD/NAFLD is associated with an approximately 50% higher odds of GD. The association strength may be greater in younger individuals. A single prospective cohort study yielded a higher risk estimate than cross-sectional studies, highlighting the need for more longitudinal research to validate this pattern. Given the observational nature of the evidence, causal inferences cannot be drawn, and screening recommendations should await further prospective data and cost-effectiveness evaluations.