Abstract
BACKGROUND: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is increasingly recognized as a systemic immuno-metabolic disorder characterized by chronic low-grade inflammation and dysregulated innate immune activation. Circulating immune-related indices derived from routine blood tests may reflect early immuno-metabolic imbalance and provide accessible markers for identifying disease-associated immune dysregulation. AIM: To investigate the associations of two systemic immuno-metabolic inflammatory indices, namely the neutrophil-to-high-density lipoprotein cholesterol ratio (NHR) and the systemic inflammation response index (SIRI) with MASLD, and to evaluate their combined discriminative performance. METHODS: In this retrospective case-control study, adult participants attending a tertiary hospital between November 2023 and October 2024 were enrolled. After strict eligibility screening, propensity score matching (1:1) was applied to balance demographic characteristics and comorbidities, yielding 522 matched individuals (261 with MASLD and 261 without MASLD). Multivariable conditional logistic regression was used to assess associations between immuno-metabolic inflammatory indices and MASLD. Discriminatory performance was assessed using receiver operating characteristic (ROC) curves. The DeLong test, Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI) were used to evaluate discriminative ability. Model calibration was evaluated using the Hosmer-Lemeshow test, Brier score, and calibration curves. Internal validation was performed using 2,000 bootstrap resamples. RESULTS: After propensity score matching, both NHR and SIRI were independently associated with MASLD in multivariable analysis. The combined model integrating NHR, SIRI, and alanine aminotransferase (ALT) demonstrated optimal discriminative performance (AUC = 0.865, sensitivity = 72.41%, specificity = 84.30%), significantly outperforming the ALT-only model (DeLong test, Z = -8.3083, P < 0.001). The total Net Reclassification Improvement (NRI) was 0.345 (95% CI: 0.245-0.438), and the total Integrated Discrimination Improvement (IDI) was 0.348 (95% CI: 0.282-0.424, P < 0.001). The Hosmer-Lemeshow test (χ² = 11.043, df = 8, P = 0.199) and Brier score (0.151, 95% CI: 0.134-0.168) confirmed good model calibration, and the calibration curve showed excellent agreement between predicted probabilities and actual incidence. Internal validation through 2,000 bootstrap resamples resulted in a corrected AUC of 0.866 (95% CI: 0.836-0.897), with an average optimism of -0.001, indicating good model stability and minimal risk of overfitting. CONCLUSION: Systemic immuno-metabolic inflammatory indices reflecting innate immune activation and lipid-related anti-inflammatory dysfunction (NHR and SIRI) are closely associated with MASLD. The combined assessment of NHR, SIRI, and ALT provides a robust, clinically accessible approach with significant incremental value for identifying immuno-metabolic risk in MASLD, highlighting the central role of systemic immune dysregulation in metabolic liver disease.