Association of the C-reactive protein-triglyceride-glucose index with metabolic dysfunction-associated steatotic liver disease and long-term all-cause and cardiovascular mortality: evidence from two nationwide prospective cohort studies.

Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to cardiometabolic disorders, and cardiovascular disease is the leading cause of death among affected individuals. Identifying simple biomarkers that capture metabolic-inflammatory burden and predict long-term mortality in MASLD remains a clinical priority. The C-reactive protein-triglyceride-glucose index (CTI) integrates inflammation, dyslipidaemia, and glycaemic status, but its relevance to MASLD and long-term mortality has not been fully elucidated.

Methods: We conducted a multi-stage investigation using two nationally representative cohorts from the United States and China. Cross-sectional associations between CTI and MASLD were assessed in the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS). Prospective associations of CTI with cardiovascular and all-cause mortality among participants with MASLD were examined utilising multivariable Cox proportional hazards models, restricted cubic splines, threshold analyses, and competing risk models. Causal mediation analyses were performed to measure the mediating functions of diabetes, hypertension, and body mass index. Extensive sensitivity analyses using alternative MASLD definitions and analytic strategies were conducted to assess robustness. Results from NHANES were externally validated in CHARLS.

Results: Higher CTI levels were strongly and nonlinearly associated with the presence of MASLD in both cohorts. Among individuals with MASLD, elevated CTI was associated with significantly increased risks of all-cause and cardiovascular mortality. Each unit increase in CTI in NHANES was linked to a 57% increased risk of cardiovascular death (HR 1.57, 95% CI 1.24-1.99) and a 47% increased risk of all-cause death (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.28-1.69) in fully adjusted models. A pronounced threshold effect was observed, with mortality risk rising sharply once CTI exceeded approximately 5.6. Consistent associations with all-cause mortality were observed in CHARLS. Mediation analyses indicated that diabetes accounted for a substantial proportion of the association between CTI and mortality, whereas body mass index played a minimal mediating role.

Conclusions: CTI is a robust metabolic-inflammatory marker associated with MASLD and long-term all-cause and cardiovascular mortality across diverse populations. The strong mediating role of diabetes underscores the central importance of glycaemic dysfunction in cardiometabolic risk. As a readily obtainable index, CTI may aid in cardiometabolic risk stratification among individuals with MASLD.