High systemic inflammation response index and increased cardiovascular risk and mortality in MASLD: A prospective cohort study.

Background & Aims: The correlation between systemic inflammation response index (SIRI) and both cardiovascular disease (CVD, including myocardial infarction and total stroke) and mortality in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. We examined this association in a large Chinese cohort. Methods: A population of 24,340 patients with MASLD from the Kailuan study were observed over a median of 16.0 years. SIRI was calculated based on neutrophil, monocyte, and lymphocyte counts. Cox proportional hazards models were used to estimate hazard ratios (HRs) for CVD and mortality across SIRI quartiles. Net reclassification improvement assessed SIRI's predictive value vs. high-sensitivity C-reactive protein and other indices. Mediation analysis assessed the roles of platelet count (PLT), Chinese visceral adiposity index and triglyceride-glucose index. Results: During follow-up, 4,171 CVD events and 4,510 deaths occurred. Elevated SIRI was significantly linked to higher risks of CVD (HR for Q4 vs. Q1 1.21; 95% CI 1.10-1.31; p <0.001), including myocardial infarction (HR 1.22; 95% CI 1.01-1.48; p = 0.045), total stroke (HR 1.18; 95% CI 1.06-1.31; p = 0.003), and mortality (HR 1.34; 95% CI 1.24-1.46; p <0.001) in MASLD. Associations were stronger among women (HR 1.17; 95% CI 1.07-1.29; p <0.01) and physically inactive individuals (HR 1.09; 95% CI 1.05-1.13; p <0.01). SIRI improved outcome prediction over high-sensitivity C-reactive protein and other indices, with significant reclassification gains (5.84; 95% CI 2.57-9.12; p <0.001). Triglyceride-glucose index partially mediated these associations (5.3% for CVD, p = 0.006; 2.9% for mortality, p = 0.003), whereas PLT exhibited a slight inverse mediation effect on mortality (-3.3%, p = 0.032). Conclusions: High SIRI independently correlates with increased risk of CVD and mortality in MASLD. These findings highlight the role of systemic inflammation and support SIRI as a potential biomarker for risk stratification in these individuals. Impact and implications: This study provides important evidence linking systemic inflammation, as measured by the systemic inflammation response index, to increased cardiovascular disease and mortality in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD), a prevalent condition with rising global burden. The findings underscore the clinical relevance of inflammation markers in cardiovascular risk stratification, particularly for patients and healthcare providers managing MASLD. Physicians and policymakers could incorporate systemic inflammation response index into routine assessments to identify patients with MASLD at higher risk of cardiovascular events, potentially guiding targeted interventions aimed at mitigating systemic inflammation and metabolic dysfunction. Nonetheless, due to the predominantly male, community-based cohort from northern China, further research across diverse populations is warranted to confirm these associations before widespread clinical implementation. Clinical trial number: ChiCTR-TNC-11001489.