Salt intake and the risk of NAFLD and NASH: A prospective cohort and Mendelian randomization study

Background While excess salt intake is known to affect cardiovascular health, its role in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is less established. We aimed to examine the longitudinal association between salt intake and incident NAFLD/NASH. Methods and findings This study included 494,170 UK Biobank participants without NAFLD/NASH at baseline. Salt exposure was assessed via self-reported salt-adding frequency (four-point Likert scale) and estimated 24-hour sodium intake from spot urine. Incident NAFLD/NASH cases were defined by diagnostic codes. Hazard ratios (HRs) and 95%CIs were calculated by using Cox proportional hazards models. Mendelian randomization and mediation analyses were conducted to infer causality and explore underlying mechanisms. Over a mean 14.3-year follow-up, 7,307 NAFLD and 630 NASH cases were identified. Both higher salt-adding frequency and sodium intake were significantly associated with elevated NAFLD/NASH risk. Compared to those who never/rarely added salt, adjusted HRs (aHRs) for NAFLD were 1.02 (95% CI: 0.98–1.10), 1.20 (1.09–1.31), and 1.31 (1.16–1.48) for sometimes, usually, and always, respectively (P-trend < 0.001). Always adding salt was also linked to higher NASH risk (aHR = 1.42; 95% CI: 1.01–1.99). Per 1g increase in estimated 24-hour sodium intake, NAFLD and NASH risks increased (aHRs = 1.82; 95% CI: 1.73–1.92 and 2.17; 95% CI: 1.81–2.61). Genetically predicted salt-adding frequency was also associated with increased NAFLD risk (Odds ratio = 1.54; 95% CI: 1.16–2.05). The salt-NAFLD associations were more pronounced among individuals with normal body-mass index (BMI) or normal alanine transaminase (P-interaction = 0.002, 0.005), with BMI mediating 16.4% (95% CI: 13.1–22.4%) of the salt–NAFLD association. Conclusions Higher salt intake is independently associated with increased NAFLD/NASH risk, particularly in metabolically healthy individuals. These findings support liver-focused strategies in salt reduction policies.