Evidence From a Systematic Review of Non-alcoholic Fatty Liver Disease (NAFLD)/Metabolic Dysfunction-Associated Fatty...

Non-alcoholic fatty liver disease (NAFLD), now termed metabolic dysfunction-associated steatotic liver disease (MASLD), is increasingly implicated as a key risk factor for cardiovascular disease (CVD). However, its independent contribution remains debated due to confounding metabolic factors and methodological heterogeneity. This review aims to synthesize evidence on the association between NAFLD/MASLD and cardiovascular outcomes, focusing on the influence of liver fibrosis and metabolic dysfunction.  Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, we searched PubMed/MEDLINE, ScienceDirect, Europe PMC, and Cochrane Library (through May 2025) for observational studies and trials assessing NAFLD/MASLD and CVD outcomes in adults. NAFLD required imaging/biopsy or validated scores (fatty liver index (FLI) ≥30, Fibrosis-4 Index (FIB-4)); comparators were non-NAFLD controls. Outcomes included myocardial infarction, stroke, CVD mortality, and atherosclerosis. Two reviewers independently screened records, extracted data, and assessed risk of bias (Newcastle-Ottawa Scale (NOS)/Cochrane RoB 2).  The systematic search identified 21 eligible studies (18 cohort, two cross-sectional, and one RCT). Sample sizes ranged widely, from a few hundred in clinical cohorts to over 9.5 million in a national database study. Observational studies demonstrated good methodological quality (mean NOS score ≥7/9). NAFLD/MASLD showed a consistent dose-dependent association with cardiovascular risk, with effect sizes ranging from modest (adjusted HR=1.2) to substantial (HR=8.0). Risk stratification revealed (i) advanced fibrosis (FIB-4 >2.67) quadrupled CVD risk (HR >4.5) and (ii) metabolic burden significantly amplified outcomes (HR=8.04 for ≥4 risk factors). While the association remained significant in most studies, rigorous adjustment for metabolic covariates attenuated effects in some analyses, suggesting that MASLD represents both an independent pathogenic factor and a metabolic dysfunction marker. NAFLD/MASLD is a significant risk factor for adverse cardiovascular outcomes, with the degree of risk strongly graded by the severity of liver fibrosis and metabolic comorbidity. While evidence is predominantly observational, these findings support integrating non-invasive fibrosis assessment into CVD risk stratification. Future research requires randomized trial testing whether MASLD-targeted therapies can reduce cardiovascular events.