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: