Prevalence and long-term outcomes of NAFLD and cardiovascular-kidney-metabolic health in the United States.

Background and aims: To explore non-alcoholic fatty liver disease (NAFLD)'s role within the novel cardiovascular-kidney-metabolic (CKM) syndrome framework, given their overlapping pathophysiological mechanisms. Methods: We analyzed 10,985 U.S. adults from the National Health and Nutrition Examination Survey III (1988-1994), with mortality follow-up until 2019. NAFLD was assessed via ultrasonography, and liver fibrosis was determined by the NAFLD fibrosis score and Fibrosis-4 index. CKM stages and predicted cardiovascular (CVD) event risk were assessed per American Heart Association guidelines. Results: Age-standardized prevalence of NAFLD progressively increased across CKM stages, from 21.8 % at stage 0, 24.1 % at stage 1, 40.0 % at stage 2, and 40.2 % at advanced CKM. NAFLD was significantly associated with CKM progression (odds ratio = 2.01; 95 % confidence interval: 1.84-2.20) in ordinal logistic regression. During a median follow-up of 27.9 years, 3,772 deaths occurred. NAFLD was associated with a 26 % increased risk of all-cause mortality in multivariable Cox models; however, the association became non-significant after adjustment for specific components of CKM. Among participants with NAFLD, mortality risk increased stepwise with advancing CKM. Predicted CVD event risk demonstrated superior prognostic value than NAFLD fibrosis score and Fibrosis-4 score (area under the curve = 0.88). CKM stage significantly mediated the association between NAFLD and mortality, with a mediation proportion of 35.4 %. Conclusions: NAFLD exhibits high comorbidity with CKM syndrome, and the high prevalence of NAFLD at CKM 0 highlights early metabolic risk. NAFLD is not an independent mortality predictor but accelerates CKM progression to increased mortality.