Weight Changes Differentially Impact Metabolic Dysfunction–Associated Steatotic Liver Disease Incidence, Progression, and Outcomes Based on Genetic and Metabolic Risk Profiles

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises heterogeneous subgroups with liver- vs cardiovascular-related adverse outcomes. Weight management is crucial in MASLD prevention and treatment, but its effect on MASLD subgroups is unclear. METHODS: We assessed the impact of body weight dynamics on incident MASLD, steatosis resolution, fibrosis risk regression, and related cardiovascular diseases from the UK Biobank. Genetic subgroups (ie, hepatic and systemic) were defined by polygenic risk scores, a metabolic risk group by lipid accumulation product. A Cox proportional model evaluated impacts across the general population and sex-stratified subgroups. RESULTS: Among 11,882 participants without MASLD, 1350 developed MASLD during a median follow-up of 4 years. Each 1% reduction in body weight was associated with a 10% lower risk of MASLD (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.89-0.91). Among 6013 participants with MASLD, 753 achieved MASLD resolution; each 1% reduction in weight was associated with a 9% higher rate of resolution (HR, 1.09; 95% CI, 1.08-1.10). Weight loss was also associated with a lower risk of MASLD-related cardiovascular diseases (HR, 0.98; 95% CI, 0.97-0.99). Recommended weight loss for MASLD prevention (male and female) differed across hepatic (8.7% and 13.1%), systemic (8.0% and 11.8%), and metabolic risk (10.9% and 14.4%) groups. Estimated lower weight-loss thresholds associated with MASLD resolution were 5.3% and 13.3% in hepatic risk, 10.2% and 10.7% in systemic risk, and 5.7% and 5.8% in metabolic risk participants (male and female, respectively). For fibrosis risk regression, no robust threshold was identified in participants with hepatic risk, but 7.7% and 5.6% (male and female, respectively) in participants with metabolic risk. CONCLUSIONS: Individualized weight management should be recommended according to the genetic and metabolic risk profiles of individuals.