Intrinsic capacity, genetic susceptibility, and the risks of metabolic dysfunction–associated steatotic liver disease and cirrhosis

Background The World Health Organization (WHO) has introduced a new functional aging framework centered on intrinsic capacity (IC). This study aimed to evaluate the relationship between IC and the risk of incident metabolic dysfunction–associated steatotic liver disease (MASLD) and cirrhosis, and to assess the potential modifying effect of genetic susceptibility. Methods We included 393,355 participants without prior liver disease from the UK Biobank. A comprehensive IC deficit score was constructed using seven indicators across four IC domains. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results Over a median follow-up of 14 years, 5,279 MASLD and 1,782 cirrhosis cases were identified. Compared with individuals with an IC deficit score of 0, those with a score of 4 or more had a significantly higher risk of MASLD (HR: 1.84; 95% CI: 1.63–2.08) and cirrhosis (HR: 2.17; 95% CI: 1.77–2.65). Participants with both a high polygenic risk score (PRS) and an IC deficit score of 4 + had the highest risk of MASLD (HR: 2.78; 95% CI: 2.29–3.36) and cirrhosis (HR: 3.30; 95% CI: 2.44–4.46), compared with those with low PRS and an IC score of 0. Moreover, individuals with an IC deficit score of 3 + had elevated risks of MASLD (HR: 1.23; 95% CI: 1.08–1.40) and non-alcoholic steatohepatitis (HR: 1.37; 95% CI: 1.08–1.72), defined by liver proton density fat fraction >5% or iron-corrected T1 ≥ 800 ms. A greater rate of IC decline over time was associated with increased risks of both MASLD and cirrhosis. Conclusions Lower IC are independently associated with increased risks of MASLD and cirrhosis, regardless of genetic susceptibility. These findings suggest that routine monitoring and early intervention targeting IC may offer a novel strategy to prevent chronic liver disease.