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.