Time‐Dependent Mortality Risk in Lean Metabolic Dysfunction‐Associated Steatotic Liver Disease During Long‐Term Follow‐Up

Abstract

ABSTRACT Background and Aim The prognosis of lean metabolic dysfunction‐associated steatotic liver disease (MASLD) remains controversial. We investigated the long‐term prognosis of lean MASLD and its time‐dependent associations with all‐cause and cardiovascular mortality. Methods We analyzed 3568 participants with MASLD from the Third National Health and Nutrition Examination Survey. Cox proportional hazards and Fine‐Gray competing‐risk models assessed all‐cause and cardiovascular mortality. Because the proportional hazards assumption was violated for all‐cause mortality, 10‐year landmark and time‐varying coefficient Cox analyses were performed. Restricted cubic splines (RCS) evaluated the association between body mass index (BMI) and early all‐cause mortality, and subgroup analyses identified high‐risk populations. Results During a median 27.7‐year follow‐up, lean MASLD was associated with higher all‐cause mortality within 0–10 years (adjusted hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.29–2.20), but not thereafter (adjusted HR, 1.04; 95% CI, 0.87–1.25). No significant association between lean MASLD and cardiovascular mortality was observed during either pre‐landmark (adjusted subdistribution HR [sHR], 1.45; 95% CI, 0.95–2.22) or post‐landmark (adjusted sHR, 0.97; 95% CI, 0.69–1.36) in the overall population. Time‐specific HR demonstrated a gradual attenuation of the excess mortality association over follow‐up. RCS demonstrated a nonlinear U‐shaped association between BMI and early all‐cause mortality. Excess early mortality risks were particularly evident among males aged ≥ 60 years and participants with baseline FIB‐4 ≥ 1.30. Conclusions Lean MASLD conferred a time‐dependent excess risk of all‐cause mortality, predominantly within the first decade of follow‐up, but was not robustly associated with cardiovascular mortality in the overall population. Older males and patients with elevated FIB‐4 scores represented high‐risk phenotypes.