Abstract
Aims To evaluate the association of frailty with mortality and incident extrahepatic diseases in individuals with metabolic dysfunction-associated steatotic liver disease and the interaction between frailty and cardiovascular health. Methods This prospective cohort study included 107,867 participants with metabolic dysfunction-associated steatotic liver disease from the UK Biobank. Metabolic dysfunction-associated steatotic liver disease is defined as hepatic steatosis plus cardiometabolic abnormality. Frailty was assessed as physical frailty based on five components (weight loss, exhaustion, physical activity, gait speed, and grip strength) and the Rockwood frailty index, while cardiovascular health was evaluated using the Life’s Essential 8 score. Results Frailty was associated with increased risks of all-cause mortality (physical frailty: HR 2.01, 95% CI 1.87-2.16; frailty index: HR 1.63, 95% CI 1.54-1.74) and incident extrahepatic diseases with the exception of cancer (physical frailty: HRs ranged from 1.62 to 3.35; frailty index: HRs ranged from 1.34 to 8.07). Among the five components of physical frailty, slow gait speed exhibited the strongest associations with most adverse outcomes. There were significant multiplicative and additive interactions between frailty and cardiovascular health on respiratory disease mortality, heart failure, and peripheral arterial disease. Compared with participants with no frailty and good cardiovascular health, those with both frailty and poor cardiovascular health had the highest risks of all adverse outcomes. Conclusion Frailty was associated with increased risks of mortality and extrahepatic complications in metabolic dysfunction-associated steatotic liver disease, particularly in those with suboptimal cardiovascular health. Early detection and interventions for frailty are needed alongside cardiovascular health promotion to enhance the prognosis of metabolic dysfunction-associated steatotic liver disease.