Multimodal evidence for the association between muscle mass and NAFLD: insights from hospital-based data, NHANES and mendelian randomization

Background Sarcopenia has been suggested as a potential risk factor for non-alcoholic fatty liver disease (NAFLD), but the causal relationship remains unclear. Methods We conducted a multimodal study combining hospital-based data, population survey, and Mendelian randomization (MR). A total of 2,384 patients with acute appendicitis (2016–2025) were analyzed using appendicular skeletal muscle mass index (ASMI) as a sarcopenia marker and CT-defined NAFLD as outcome. Logistic regression and SIMEX correction were applied. The association was validated in 21,696 NHANES participants (1999–2018) using the United States Fatty Liver Index (USFLI) and double-SIMEX correction. Finally, two-sample and multivariable MR were performed using GWAS summary data. Results Higher muscle mass was consistently associated with a lower NAFLD risk in hospital-based (OR = 0.16, 95% CI 0.03–0.82, P = 0.03) and NHANES populations (OR = 0.02, 95% CI 0.01–0.04, P < 0.001). MR analyses suggested a potential causal inverse relationship (OR = 0.91, 95% CI 0.84–0.99, P = 0.01), independent of BMI, cholesterol, and triglycerides (OR = 0.82, 95% CI 0.72–0.94, P = 0.003). Conclusion This multimodal evidence suggested low muscle mass as a causal risk factor for NAFLD. Interventions that maintain or increase muscle mass may reduce NAFLD risk.