Differential Cardiometabolic Risk Profiles of Lean and Obese Metabolic Dysfunction-Associated Steatotic Liver Disease: A Longitudinal Health Checkup Cohort Study.
Abstract
Background
Lean metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized. Whether it represents a distinct entity or a phenotype within the MASLD spectrum remains unclear. We examined differences in risk factor contribution and metabolic trajectories.
Methods
In a longitudinal health checkup cohort (2017-2025), we included individuals without hepatic steatosis at baseline and excluded those with alcohol intake at or above the MetALD threshold. Incident MASLD was classified at diagnosis as Obese or Lean MASLD based on obesity status (BMI/WC). Baseline risk factors were evaluated using time-to-event and competing-risk models with interaction testing. Longitudinal metabolic changes were assessed using logistic regression, and repeated trajectories were examined using linear mixed-effects models.
Results
Among 13,624 participants, 1865 developed incident MASLD (Obese MASLD, n = 1469; Lean MASLD, n = 396). Male sex, baseline obesity, glycemic abnormality/diabetes, hypertension, hypertriglyceridemia, and higher baseline ALT were independently associated with incident MASLD. Interaction analyses showed a stronger contribution of male sex and weaker contributions of hypertension and low HDL-C in Lean MASLD. Longitudinal analyses showed Δtriglycerides and ΔALT were consistently associated with incident MASLD in both phenotypes, whereas ΔBMI showed a stronger association with Obese MASLD.
Conclusions
Lean MASLD shared a broadly similar cardiometabolic risk structure with Obese MASLD, whereas the relative contribution of risk factors differed between phenotypes. Male sex showed a stronger association with Lean MASLD, whereas longitudinal changes in triglycerides and ALT were consistently associated with incident MASLD across both phenotypes. These findings provide exploratory evidence of phenotype-specific metabolic associations requiring validation before clinical application.