Association of NAFLD with cardiovascular disease and all-cause mortality: a large-scale prospective cohort study based on UK Biobank

Abstract

Objective: Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome, sharing the similar cardiometabolic risk factors with cardiovascular disease (CVD). Whether NAFLD by itself is associated with increased cardiovascular events and death remain an issue to debate. This study aimed to further investigate the association between NAFLD and adverse CVD outcomes. Methods: Participants were followed up until the end of 2020 in current analysis. NAFLD is defined using fatty liver index (FLI). Cox proportional hazard model was used to analyze the association between NAFLD and all-cause mortality, major adverse cardiovascular events (MACEs), CVD mortality, fatal/nonfatal acute myocardial infarction (AMI), and fatal/nonfatal stroke. C-index was calculated to evaluate the model enhancement when adding NAFLD factor. Results: After screening the data of 502,492 participants in the original cohort, 215,245 eligible participants were included in this study for MACEs outcome. Compared with non-NAFLD participants, the multivariable adjusted hazard ratios of NAFLD group was 1.25 (1.14–1.36) for MACEs; 1.14 (1.08–1.20) for all-cause mortality; 1.61(1.42–1.82) for CVD mortality; 1.58(1.19–2.11) for AMI mortality; and 1.18 (0.85–1.64) for stroke mortality. When adding FLI, C-index of NAFLD model improved for all-cause mortality, MACEs, and CVD mortality compared with that in the traditional CVD risk factor model. Conclusion: NAFLD is an independent risk factor for all-cause mortality and adverse CVD outcomes. Based on the traditional CVD risk factor model, additionally screening NAFLD could improve the prediction efficiency for adverse CVD outcomes.

Association between nonalcoholic fatty liver disease and atrial fibrillation and other clinical outcomes: a meta-analysis

“…However, 72 studies were further excluded based on inclusion criteria. A total of 12 studies qualified for the final analysis, [12][13][14]16,17,[26][27][28][29][30][31][32] of which 10 were prospective studies and 2 were retrospective studies (Figure 1).…”

Liver fat as risk factor of hepatic and cardiometabolic diseases

“…Diacylglycerols (DAGs) and ceramides affect also insulin signaling leading to increased glucose production. According to other studies, not the abundance but the compartmentation especially of diacylglycerols in the membrane is an important contributing factor to hepatic insulin resistance 117 . Similarly, not only the concentrations of lipid droplets but their protein and lipid composition, their intracellular localization, and their distribution–zonation in the liver affect their functional properties 132 .…”

“…115 Other studies have suggested that the ratios of aspartate/alanine transaminase 116 representing a marker of liver inflammation or FLI score, representing liver fat content, are predictors of cardiovascular events. 117,118 In this context, a large prospective analysis based on UK Biobank has reported that FLI between 30 and 59 is associated with 16% higher risk and FLI ≥ 60 with 25% increased risk for major cardiovascular events at a median follow-up of 11.62 years after adjusting for multiple factors including transaminases and presence of diabetes, hypertension, and statin therapy. 117 FLI seems also to have an independent prognostic value for cardiovascular events in newly diagnosed, treatment-naïve hypertensive patients.…”

“…117,118 In this context, a large prospective analysis based on UK Biobank has reported that FLI between 30 and 59 is associated with 16% higher risk and FLI ≥ 60 with 25% increased risk for major cardiovascular events at a median follow-up of 11.62 years after adjusting for multiple factors including transaminases and presence of diabetes, hypertension, and statin therapy. 117 FLI seems also to have an independent prognostic value for cardiovascular events in newly diagnosed, treatment-naïve hypertensive patients. 119 Furthermore, in an analysis including more than 5 million young adults aged 20 to 39 years, FLI between 30 and 59 was associated with 28% increased risk of myocardial infarction and 18% of stroke, whereas FLI above 60 was associated with 73% and 41% increased risk, respectively.…”

“…According to other studies, not the abundance but the compartmentation especially of diacylglycerols in the membrane is an important contributing factor to hepatic insulin resistance. 117 Similarly, not only the concentrations of lipid droplets but their protein and lipid composition, their intracellular localization, and their distribution-zonation in the liver affect their functional properties. 132 Consequently, it may not be triglyceride accumulation per se, but rather the exhaustion of "detoxification" and fat storage capacities in the liver that contributes to inflammation, insulin resistance, and elevated cardiovascular risk.…”