Stage-Dependent Prognostic Value of the Joint MASLD-NAFLD Fibrosis Score Phenotype Across the Cardiovascular-Kidney-Metabolic Syndrome Continuum: A Retrospective NHANES Cohort Analysis, 1999-2018.

The cardiovascular-kidney-metabolic (CKM) framework and metabolic dysfunction-associated steatotic liver disease (MASLD) describe a shared clinical continuum, but the prognostic value of joint fatty liver index (FLI)-NAFLD fibrosis score (NFS) phenotypes across CKM stages is uncertain. We analyzed 10 National Health and Nutrition Examination Survey cycles (1999-2018) linked to mortality through 2019. Among 31,317 adults, participants were classified as A (no MASLD/NFS-low), B (MASLD/NFS-low), C (no MASLD/NFS-high), or D (MASLD/NFS-high) and stratified by operational CKM Stages 0-4. Survey-weighted survival analyses and Cox models incorporated 20-imputation covariate analysis; exposure, outcome, follow-up, and survey-design fields were not imputed. During 291,392.5 person-years, 4284 all-cause and 1417 cardiovascular deaths occurred. All-cause survival differed across phenotypes in Stages 2-4 (p < 0.001 for each), but not between A and B in Stage 1 (p = 0.695). At Stage 2, adjusted D-versus-A hazard ratios were 1.57 (95% CI 1.30-1.91) for all-cause mortality and 2.09 (1.57-2.79) for cardiovascular mortality; corresponding Stage 4 estimates were 1.44 (1.21-1.70) and 1.25 (0.96-1.64). The full stage interaction was non-estimable, and supported-stage interaction p values were 0.113 and 0.122. Joint-phenotype associations varied across supported CKM stages, but sparse early-stage phenotypes, a small apparent discrimination gain, and nominal subgroup findings support external validation rather than immediate clinical deployment.