Subclinical liver disease and incident cardiovascular events.

BACKGROUND AND AIMS: Quantifying the multidimensional risk that subclinical liver disease imposes on cardiovascular health remains a critical unmet need. This study aimed to investigate the independent and synergistic associations of hepatic steatosis, fibrosis, and functional decline with incident cardiovascular disease (CVD). METHODS: In this prospective cohort study of 318 308 participants free of clinical liver and CVD at baseline, this study evaluated the association of three non-invasive liver biomarkers-fatty liver index (FLI) for steatosis, fibrosis-4 index (FIB-4) for fibrosis, and albumin-bilirubin (ALBI) score for functional reserve-with major incident CVD events, including myocardial infarction, heart failure, atrial fibrillation, ischaemic stroke, and cardiovascular death. RESULTS: Over a median follow-up of 14.0 years, 32 637 incident CVD events (10.3%) occurred. Each biomarker independently predicted CVD risk after multivariable adjustment: the highest quartile (Q4) of FLI (adjusted hazard ratio [aHR] 1.46, 95% confidence interval [CI] 1.40-1.52), FIB-4 (aHR 1.66, 95% CI 1.60-1.73), and ALBI (aHR 1.42, 95% CI 1.37-1.47) showed significantly elevated risks compared to Q1. Critically, participants with all three biomarkers in Q4 exhibited a substantially elevated synergistic risk (aHR 2.53, 95% CI 2.38-2.70). Sex-specific analyses revealed FLI was more strongly associated with CVD in women, whereas FIB-4 and ALBI showed greater risk in men. Results were consistent across sensitivity analyses and specific CVD endpoints. CONCLUSIONS: These findings establish subclinical liver disease-through steatosis, fibrosis, and functional impairment-as an independent and synergistic determinant of CVD risk. Incorporation of these non-invasive biomarkers could refine CVD risk stratification and enable targeted prevention strategies.