Endothelial dysfunction and cardiovascular risk in non-alcoholic fatty liver disease – a systematic review and meta-analysis

Abstract

Abstract Background Nonalcoholic fatty liver disease (NAFLD) is a prevalent metabolic disorder that has been associated with an increased risk of cardiovascular diseases. Endothelial dysfunction, characterized by impaired flow-mediated dilation (FMD) of the brachial artery, is a known predictor of cardiovascular risk. However, the relationship between NAFLD and endothelial dysfunction, as well as the impact of NAFLD on clinical cardiovascular events, remains unclear. Objective The aim of this systematic literature review was to determine the association between endothelial dysfunction, as measured by FMD of the brachial artery, and NAFLD. Additionally, we aimed to investigate the relationship between NAFLD and clinical cardiovascular events (CVE). Methods A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar for articles published between 2000 and July 2023. The reference lists of the included studies were also searched to retrieve possible additional studies. Original studies published in English focusing on adults with NAFLD and endothelial dysfunction are included. Editorials, commentaries, letters and studies focusing on pediatric populations and non-NAFLD liver diseases were excluded. The quality of included studies was appraised using the Newcastle–Ottawa scale. Meta-analyses were performed using Review Manager 5.4 software. Results The initial search yielded a total of 1792 articles and ultimately only 20 studies met the criteria. A total 6396 NAFLD patients were studied. Meta-analysis showed that individuals diagnosed with NAFLD had significantly lower brachial FMD values compared to their respective control groups (standardized mean difference: -4.63, 95% confidence interval: -5.68 to -3.58, p < 0.0001). Furthermore, NAFLD patients exhibited a significantly higher risk of clinical cardiovascular events compared to controls (odds ratio: 2.61; 95% CI: 1.41–4.83, p < 0.002). Subgroup analysis of studies focusing on non-alcoholic steatohepatitis (NASH) versus pure steatosis demonstrated that individuals with NASH had even lower FMD values than those with pure steatosis (standardized mean difference: -3.84, 95% confidence interval: -7.56 to -0.13, p = 0.03, I2 = 66%). Limitations, bias and heterogeneity The review included studies published in English language, over last 23 years and specified database resulted in language bias and might have missed older pertinent studies from another important database. The overall heterogeneity is attributed to variations in study populations, outcome measurements, differences in methodological approaches among included studies, and diverse diagnostic criteria for NAFLD. Conclusion Individuals with NAFLD exhibited impaired brachial FMD, indicating compromised endothelial function. Furthermore, NAFLD patients had an elevated risk of clinical cardiovascular events.

Keywords

• NAFLD
• NASH
• MASLD
• FMD
• SLD
• CVE