OBJECTIVES: Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), may lead to liver failure, cancer (hepatic and extra-hepatic), and non-liver-related complications such as cardiovascular disease (CVD). The relative contribution of such complications to mortality, and the variation of these associations by age, is not well characterized. This study assessed the association of high-risk NAFLD/NASH with cause-specific and all-cause mortality in US adults, stratified by age.

METHODS: An observational, longitudinal study was conducted using NHANES III (1988-1994) linked to National Death Index (NDI) mortality outcomes through 2019. Presumed NAFLD was identified as presence of steatosis and absence of other liver diseases, and high-vs-low risk NAFLD was determined based on (i) presence of risk factors and (ii) high risk of advanced fibrosis (FIB-4>2.67 or FIB-4≥1.30+NFS>0.675; Kosick 2021, specificity=0.95). The following causes of mortality specified by the NDI were considered: CVD, diabetes, malignancies/cancer, and other specified causes (respiratory diseases, accidents, Alzheimer’s, influenza and pneumonia). Mortality not specified by the NDI as associated with these causes was considered in a “residual-cause” category, expected to include liver-related mortality. Unadjusted cumulative-incidence and adjusted Cox proportional-hazards analyses were conducted.

RESULTS: Of 12,499 participants (median follow-up: 27.1yrs), 210 had high-risk NAFLD. At ages 20-64 (n=78), cumulative incidence of mortality was driven by cancer (42% at 30yrs [95% CI:1%-66%]), residual-cause (32% [9%-48%]), and CVD (27% [4%-44%]). At ages 65-74 (n=132), drivers were CVD (85% [63%-94%]), residual-cause (65% [23%-85%]), and cancer (29% [12%-42%]). Adjusting for demographics, high-risk vs. no-NAFLD was significantly associated (p<0.05) with CVD, diabetes, residual-cause, and all-cause mortality. Additionally adjusting for diabetes, associations were maintained with residual-cause (HR:1.62 [95%CI:1.09-2.41]) and all-cause (1.33 [1.10-1.61]) mortality.

CONCLUSIONS: All-cause mortality risk was significantly elevated in US adults with high-risk vs. no-NAFLD, independent of diabetes. Mortality was driven by CVD, cancer, and other-cause (likely liver-related) complications, with increasing CVD contribution with age.