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.

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.

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. Competing Interest Statement The authors have declared that no competing interests exist. Funding Statement Yes Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the UK Biobank, which has ethical approval from the North West Multi-center Research Ethics Committee in the United Kingdom. This analysis was conducted under UK Biobank application number 129053. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability Researchers registered with UK Biobank can apply for access to the UK Biobank Resource via portal (https://www.ukbiobank.ac.uk/). The summary data for all tables and figures are available in the appendix.