Stage specific associations between FIB-4 index and cardiovascular kidney metabolic syndrome: a population-based study

Background The fibrosis-4 (FIB-4) index is a classical indicator reflecting liver fibrosis. Previous studies have demonstrated that FIB-4 is closely associated with coronary heart disease, hypertension, and carotid intima-media thickness. However, its relationship with cardiovascular kidney metabolic (CKM) syndrome remains unclear. Purpose This study aimed to comprehensively evaluate the relationship between FIB-4 and CKM syndrome, further investigate possible mediators and interactions, and employ machine learning based approaches to assess their associations. Methods This study included participants aged ≥20 years from the 1999–2018 National Health and Nutrition Examination Survey. The FIB-4 index was calculated based on age, alanine aminotransferase, aspartate aminotransferase, and platelet count. CKM syndrome stages were determined using multiple clinical indicators. Generalized linear models and partial proportional odds models were applied to assess the associations and potential mediating effects between FIB-4 and CKM syndrome stages. Furthermore, double machine learning (DML) was employed to infer the potential causal effect of FIB-4 on advanced CKM stages. Results 23,654 participants were included, with a mean age of 49.92 ± 18.12 years; 11,420 (48.3%) were male. A total of 4,483 participants (19.0%) were diagnosed with advanced CKM syndrome. After multivariable adjustment, FIB-4 remained significantly associated with CKM stages. Mediation analysis indicated that low-density lipoprotein, waist-to-height ratio, and triglyceride-glucose index, and 10-year cardiovascular risk may serve as positive mediators between FIB-4 and advanced CKM syndrome. Subgroup analyses revealed stronger associations in participants without hypertension or diabetes, among nonsmokers, and among non–statin users (all P for interaction < 0.001). DML analysis further supported a robust association between higher FIB-4 levels and advanced CKM syndrome (average treatment effect = 0.108, P < 0.001). Conclusion The FIB-4 index is closely associated with the stages of CKM syndrome and may promote disease progression by influencing lipid metabolism, insulin resistance, and cardiovascular risk. These findings highlight the intrinsic link between cardiovascular liver metabolic health and multi-organ metabolic dysfunction, providing new evidence for the early prevention of systemic metabolic disorders.