HALP, a routine nutrition-inflammation index, and mortality across the cMetS spectrum: NHANES with supportive external cohort evidence

Background: The continuous metabolic syndrome score (cMetS) quantifies cardiometabolic burden but may not fully capture systemic vulnerability related to nutrition, immunity, and thrombo-inflammation. We examined the prognostic value of the hemoglobin-albumin-lymphocyte-platelet (HALP) index across the cMetS spectrum. Methods: Adults aged ≧ 20 years from NHANES 1999-2010 were followed through 31 December 2019. HALP was assessed using survey-weighted Cox regression with restricted cubic splines, adjusting for cMetS and covariates. Additional analyses included absolute risk, joint HALP-cMetS classification, Harrell's C statistic, decision curve analysis, competing-risk models, and supportive external cohort analysis. Results: Among 10,770 participants, lower HALP was associated with higher all-cause mortality. Compared with the lowest HALP tertile, adjusted HRs were 0.78 (95% CI, 0.69-0.88) for the middle tertile and 0.86 (95% CI, 0.77-0.95) for the highest tertile. Ten-year mortality risk was highest in the lowest HALP tertile: 15.4% versus 11.8 and 12.2% in the middle and highest tertiles. The association was nonlinear and L-shaped. Participants with high cMetS and low HALP had the highest risks of all-cause mortality (HR, 1.32, 95% CI, 1.15-1.52) and cardiovascular mortality (HR, 1.56,95% CI, 1.16-2.09). Adding HALP modestly improved discrimination beyond cMetS and covariates (Harrell's C, 0.8666 to 0.8685; ΔC = 0.0018), with modest net benefit. Competing-risk analyses attenuated cardiovascular mortality associations. A supportive external cohort analysis supported the all-cause mortality association but was limited for cardiovascular mortality. Conclusion: HALP was independently and nonlinearly associated with mortality across the cMetS spectrum and provided modest prognostic information beyond cMetS. As an inexpensive routine index, HALP may complement metabolic burden assessment by identifying systemic vulnerability.