Revisiting the Obesity Paradox in Metabolic Dysfunction-Associated Steatotic Liver Disease: Longitudinal Trajectory...

Obesity is a key driver of metabolic dysfunction-associated steatotic liver disease (MASLD). Paradoxically, obese patients with MASLD often exhibit better survival than their nonobese counterparts. This study investigates the "obesity-survival paradox" using longitudinal body mass index (BMI) data.

We analyzed 3 large population-based MASLD cohorts, including National Health and Nutrition Examination Survey (NHANES) III (n = 2190), NHANES 1999-2018 (n = 5210), and UK Biobank (n = 8962). We assessed the dose-response associations of BMI at different stages of adulthood/disease with mortality using multivariable-adjusted restricted cubic spline models. Latent class trajectory modeling identified distinct clusters of long-term BMI patterns.

BMI above 30 kg/m² in mid-to-late adulthood or after MASLD diagnosis was associated with decreased overall mortality (P < .001), indicating an obesity-survival benefit. Conversely, higher early-adulthood BMI was associated with increased mortality (P < .001). Pre-diagnostic BMI displayed U-shaped and J-shaped associations with all-cause and cancer-specific mortality, respectively. Trajectory analyses indicated that the cluster with persistent nonobesity throughout adulthood had a low overall mortality risk, whereas persistent obesity (hazard ratio, 1.79; 95% confidence interval, 1.10-2.89) and rapid BMI increase (hazard ratio, 1.93; 95% confidence interval, 1.03-3.64) were associated with significantly higher mortality. Clusters with earlier obesity onset tended toward higher mortality. Among clusters exposed to obesity before age 40, BMI had a tendency to decline during later life, and such BMI declines across adulthood were associated with increased mortality (P < .001).

This study demonstrates that the association between obesity and MASLD outcomes is heterogeneous and depends on the timing of obesity exposure. Long-term BMI trajectory analysis suggests that obesity does not confer a survival advantage in MASLD, whereas maintaining nonobese status throughout adulthood is associated with lower overall mortality.