Impact of cumulative inflammatory burden on the risk of metabolic dysfunction-associated steatotic liver disease

Abstract Background Chronic low-grade inflammation is a core mechanism underlying the development and progression of MASLD. Traditional inflammatory biomarkers, limited by single-timepoint measurements, fail to comprehensively reflect the dynamic cumulative effects of inflammation. This study aimed to investigate the long-term impacts of both comprehensive and individual cumulative inflammatory burdens on MASLD incidence, providing theoretical foundations for early intervention. Methods Based on the prospective "Tongzhou Cohort" in Beijing, 2,126 participants without baseline MASLD who consecutively underwent health examinations from 2016 to 2019 were enrolled and followed until 2022. Cumulative burden scores for both comprehensive and individual inflammation were constructed using five biomarkers (platelet count, neutrophils, lymphocytes, monocytes, and CRP). Multivariable Cox proportional hazards models were employed to analyze their associations with MASLD risk, and restricted cubic spline (RCS) analyses were conducted to assess dose-response relationships. Results During a median follow-up of 4.3 years, each 1-standard deviation (SD) increase in the comprehensive cumulative inflammatory burden score was associated with a 16% elevated MASLD risk (HR, 1.16; 95% CI, 1.08-1.23; P 0.001), while the highest quartile (Q4) group exhibited a 39% increased risk compared to Q1 (HR, 1.39; 95% CI, 1.16-1.68; P 0.001). Among individual biomarkers, cumulative burdens of platelets (HR=1.48, Q4 vs. Q1), neutrophils (HR=1.30), and lymphocytes (HR=1.28) significantly elevated MASLD risk (all P 0.05). RCS analyses revealed linear positive correlations between MASLD risk and comprehensive score, as well as cumulative burdens of platelets, neutrophils, and monocytes (P for nonlinear 0.05), whereas lymphocyte and CRP cumulative burdens demonstrated nonlinear associations (P for nonlinear 0.05). Subgroup analyses confirmed consistent associations across sex, age, and BMI strata (interaction P 0.05). Conclusion Cumulative inflammatory burden serves as an independent predictor of MASLD development. Comprehensive assessment of long-term cumulative effects from multiple inflammatory biomarkers may enhance the precision of high-risk population identification. These findings provide critical evidence for inflammation-targeted early prevention strategies against MASLD.