Inverse Association of the Life's Crucial 9 Score With MAFLD: An Exploratory Mediation Analysis of the C-Reactive Protein-Albumin-Lymphocyte (CALLY) Index.

BACKGROUND

Metabolic dysfunction-associated fatty liver disease (MAFLD) is strongly associated with cardiovascular disease. Life's Crucial 9 (LC9), an expanded cardiovascular health metric incorporating psychological health, may provide a multidimensional measure of cardiometabolic health. The CALLY index integrates inflammatory, immune, and nutritional information and has been associated with MAFLD. However, whether ln(CALLY) statistically accounts for part of the association between LC9 and MAFLD remains unclear. This study aimed to examine the association between LC9 and MAFLD and to explore the statistical indirect association through ln(CALLY).

METHODS

Data were obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2016. Weighted logistic regression, restricted cubic spline (RCS) modeling, subgroup analysis, and weighted quantile sum (WQS) regression were used to assess the relationship between LC9 and MAFLD. Exploratory mediation analysis was performed to evaluate the statistical indirect association through ln(CALLY). Sensitivity and supplementary analyses were conducted to assess the robustness of the findings with respect to missing data, alternative disease definitions, definitional overlap, alternative cardiovascular health metrics, individual LC9 components, and mediator choice.

RESULTS

This study included 3841 participants. Higher LC9 scores were significantly associated with lower odds of prevalent MAFLD. Specifically, every 10-point increase in the LC9 score was associated with lower odds of MAFLD (OR = 0.51, 95% CI: 0.47-0.56, p < 0.001). Participants in the highest tertile of the LC9 score had lower odds of MAFLD (OR = 0.16, 95% CI: 0.12-0.22, p < 0.001) compared with those in the lowest tertile. Similarly, ln(CALLY) was inversely associated with MAFLD (OR = 0.57, 95% CI: 0.52-0.64, p < 0.001). Exploratory mediation analysis indicated that ln(CALLY) statistically accounted for approximately 17.7% of the LC9-MAFLD association (p < 0.001). Sensitivity and supplementary analyses showed that the association was attenuated but remained statistically significant after exclusion of overlapping metabolic components from LC9 (OR per 10-point increase in modified LC9 = 0.891, 95% CI: 0.832-0.955, p = 0.002) and remained materially consistent when MASLD was used as an alternative outcome (OR = 0.545, 95% CI: 0.494-0.602, p < 0.001). No significant indirect association was observed using PNI as an alternative mediator (p = 0.988). WQS analysis assigned relatively larger weights to BMI, blood glucose, and psychological health.

CONCLUSION

Higher LC9 scores were associated with lower odds of prevalent MAFLD. Exploratory mediation analysis suggested a statistical indirect association through ln(CALLY), although causal or temporal mediation cannot be inferred. Further prospective studies are needed to confirm these findings.