S2648 Association of NAFLD Severity With Major Adverse Cardiovascular Events: A Meta-Analysis of Cohort Studies

Introduction: Non-alcoholic fatty liver disease (NAFLD), a primary hepatic manifestation of metabolic syndrome, is now recognized as a significant contributor to cardiovascular disease burden. It is unclear whether advanced NAFLD severity independently predicts major adverse cardiovascular events (MACE) because severity has not been consistently defined, and few considered potential confounding factors. Methods: Following the PRISMA 2020 guidelines, we looked through the Cochrane Library, Web of Science, Embase, and PubMed till January 2025 for longitudinal cohort studies assessing MACE incidence according to NAFLD severity. Eligible studies included adults with biopsy-verified (NASH or fibrosis ≥ F2) or imaging-verified (MRI-PDFF ≥10% or CAP ≥280 dB/m) NAFLD and stratified as mild vs moderate/severe, with an average follow-up of 1 year or greater. Two reviewers separately conducted the data extraction and assessed for bias using the Newcastle-Ottawa Scale. Ninety-five percent confidence intervals (CI) and pooled risk ratios (RR) were determined using a random-effects model. Heterogeneity (I²) and small-study effects (Egger's test) were assessed. Sensitivity analyses were performed to exclude studies at high risk of bias. Results: Three cohort studies met inclusion criteria for MACE outcomes (N = 136,789; mean age: 52–58; duration: 5.2–8.1 years). One study on advanced (F3–F4/NASH) and mild (F0–F1/steatosis) NAFLD calculated a fully adjusted RR of 1.50 (95% CI 0.97–2.32; P = 0.07), indicating a trend towards greater MACE risk. The pooled RR for NAFLD, compared to no NAFLD, was 1.19 (95% CI 0.80-1.79; I² = 94%) with sensitivity analysis RR (95% CI) 1.12 (0.85-1.48). There is a pooled RR for MACE among NAFLD cases across all severity strata of 1.26 (95% CI 0.92-1.73; I² = 88%). Egger's test did not report evidence of publication bias (P = 0.34). Only 1 study controlled for diabetes and dyslipidemia, and none for visceral adiposity. Conclusion: This meta-analysis suggests that histologically or imaging-defined advanced NAFLD may be associated with a clinically meaningful but statistically insignificant increased risk of MACE. Substantial heterogeneity and residual confounding affect definitive interpretations. Future studies should employ standardized severity cutoffs (such as MRI-PDFF ≥10% or fibrosis stage ≥ F2), adjust for cardiometabolic risk factors, and distinguish the atherosclerotic and non-atherosclerotic MACE components to strengthen the prediction of cardiovascular risk in NAFLD.