Liver fibrosis biomarkers as a prognostic tool beyond the defining components in cardiovascular-kidney-metabolic syndrome

Background: Despite the multisystem nature of Cardiovascular-Kidney-Metabolic (CKM) syndrome, hepatic dysfunction markers are rarely included. We evaluated whether two noninvasive liver fibrosis scores (LFSs)-the Fibrosis-4 Index (FIB-4) and the non-alcoholic fatty liver disease fibrosis score (NFS)-independently predict all-cause mortality (ACM) and cardiovascular mortality (CVM) in CKM, and whether they complement CKM staging to better capture mortality risk heterogeneity. Methods: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 (n=32,197) and the UK Biobank (n=88,590). The least absolute shrinkage and selection operator (LASSO) selected a parsimonious covariate set for the baseline Cox model, to which FIB-4 or NFS was added separately. Incremental prognostic value was assessed by discrimination (C-index, time-dependent area under the receiver operating characteristic curve [AUC]), model fit (likelihood ratio test [LRT]), and clinical utility (decision curve analysis). We also compared the original CKM staging with a CKM-Liver staging that added an intermediate-to-high fibrosis-risk indicator. Results: <0.001), with similar findings for CVM. Time-dependent AUCs were 0.74-0.79 for ACM and 0.75-0.81 for CVM. The CKM-Liver staging yielded modest overall gains but showed steeper risk gradients in advanced stages. Conclusions: FIB-4 and NFS are readily accessible and independent predictors of mortality in CKM. Adding LFSs provides modest but consistent incremental prognostic value and refines risk stratification. LFSs may serve as practical, complementary markers within a multi-organ CKM risk assessment framework.