Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis

Abstract

Background: Studies have reported a significant association between non-alcoholic fatty liver disease (NAFLD) and increased incidence of cardiovascular disease (CVD). However, the magnitude of the risk and whether this risk changes with the severity of NAFLD remains uncertain. We performed a meta-analysis of observational studies to quantify the magnitude of the association between NAFLD and risk of incident CVD events. Methods:We systematically searched PubMed, Scopus and Web of Science from database inception to July 1, 2021 to identify eligible observational studies, in which NAFLD was diagnosed by imaging, International Classification of Diseases codes, or liver biopsy. The primary outcomes were CVD death, nonfatal CVD events, or both. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95% CIs. The quality of the evidence was assessed with the Cochrane risk of bias tool. This study is registered on Open Science Framework, number osf.io/5z7gf. Findings:We identified 36 longitudinal studies with aggregate data on 5,802,226 middle-aged individuals of different countries and 99,668 incident cases of fatal and nonfatal CVD events over a median follow-up of 6.5 years. NAFLD was associated with a moderately increased risk of fatal or nonfatal CVD events (pooled random-effects HR 1.45, 95% CI 1.31-1.61; I 2 =86.2%).This risk markedly increased across the severity of NAFLD, especially the stage of fibrosis (pooled random-effects HR 2.50, 95% CI 1.68-3.72; I 2 =73.8%). All risks were independent of age, sex, adiposity measures, diabetes and other common cardiometabolic risk factors. Sensitivity analyses did not modify these results. Funnel plot did not show any significant publication bias.Interpretation: NAFLD is associated with a ~1.5-fold increased long-term risk of fatal or nonfatal CVD events. CVD risk is further increased with more advanced liver disease, especially with higher fibrosis stage. These results provide evidence that NAFLD may be an independent risk factor for CVD morbidity and mortality.Funding: None.

Triglyceride-Rich Lipoproteins and Glycoprotein A and B Assessed by 1H-NMR in Metabolic-Associated Fatty Liver Disease

“…In accordance, given the implications of inflammation in the progression of MAFLD and the chronic inflammatory status present in metabolic syndrome and related conditions (including obesity, insulin resistance and T2DM), the role of these glycoproteins could be of potential interest in the detection of such an inflammatory status in fatty liver disease ( 16 , 19 ). In addition, MAFLD has been reported to be associated with increased CVD morbidity and mortality, making its detection even more clinically important ( 46 ).…”

Non-Alcoholic Fatty Liver Disease and Risk of Macro- and Microvascular Complications in Patients with Type 2 Diabetes

“…Several longitudinal studies and some meta-analyses confirmed that patients with NAFLD (as detected by imaging techniques, ICD codes or liver biopsy) have an increased risk of developing fatal and non-fatal CVD events, even after adjustment for several traditional CVD risk factors, diabetes-related variables, specific medications and other potential confounders (Table 1) [22,23,[54][55][56][76][77][78][79]. In a 2021 meta-analysis of 36 longitudinal studies for a total of 5,802,226 adults and 99,668 incident cases of fatal and non-fatal CVD events over a median follow-up of 6.5 years, our research group reported that NAFLD (as detected by imaging techniques, ICD codes or liver biopsy) was associated with a 45% increased risk of fatal or non-fatal CVD events, independent of age, sex, body mass index, waist circumference, presence of T2DM and other cardiovascular risk factors (random-effects hazard ratio 1.45, 95% confidence interval 1.31-1.61; I 2 = 86.2%) [14]. Such risk further increased in patients with severe forms of NAFLD, especially those with advanced fibrosis [14].…”

“…Importantly, in the last decades, it has also become clear that NAFLD is a "multisystemic" disease [13]. Indeed, several observational studies and some meta-analyses have clearly documented that NAFLD is independently associated with serious hepatic complications (e.g., hepatic decompensation, hepatocellular carcinoma [HCC]) [5], but also with an increased risk of developing cardiovascular disease (CVD) [14], T2DM [15], chronic kidney disease (CKD) [16] and some extra-hepatic cancers [17]. Notably, among the various hepatic and extra-hepatic complications related to NAFLD, CVD is the leading cause of death among NAFLD patients.…”

Serum PCSK9 Correlates with PTX3 and Apolipoproteins B, A1, and C3 Concentrations in Patients with Type 2 Diabetes

“…Increasing number of data indicate that NAFLD is associated with cardiovascular risk [ 20 , 21 ]. In young adult Korean persons, NAFLD was an independent predictor of MI and stroke [ 20 ].…”

“…In young adult Korean persons, NAFLD was an independent predictor of MI and stroke [ 20 ]. According to recent meta-analysis, NAFLD is associated with increased long-term risk of cardiovascular events and might be an independent risk factor [ 21 ].…”