Elsevier

Journal of Hepatology

Volume 65, Issue 3, September 2016, Pages 589-600
Journal of Hepatology

Research Article
Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis

https://doi.org/10.1016/j.jhep.2016.05.013Get rights and content

Background & Aims

There have been many studies of the effects of non-alcoholic fatty liver disease (NAFLD) and the risk of cardiovascular disease (CVD), but these have produced conflicting results. We performed a meta-analysis of these studies to quantify the magnitude of the association between NAFLD (and NAFLD severity) and risk of CVD events.

Methods

We searched PubMed, Google scholar, and Web of Science databases using terms “NAFLD”, “cardiovascular events”, “cardiovascular mortality”, “prognosis” and their combinations to identify observational studies published through January 2016. We included only observational studies conducted in adults >18 years and in which NAFLD was diagnosed on imaging or histology. Data from selected studies were extracted and meta-analysis was then performed using random effects modelling.

Results

A total of 16 unique, observational prospective and retrospective studies with 34,043 adult individuals (36.3% with NAFLD) and approximately 2,600 CVD outcomes (>70% CVD deaths) over a median period of 6.9 years were included in the final analysis. Patients with NAFLD had a higher risk of fatal and/or non-fatal CVD events than those without NAFLD (random effect odds ratio [OR] 1.64, 95% CI 1.26–2.13). Patients with more ‘severe’ NAFLD were also more likely to develop fatal and non-fatal CVD events (OR 2.58; 1.78–3.75). Sensitivity analyses did not alter these findings. Funnel plot and Egger’s test did not reveal significant publication bias.

Conclusions

NAFLD is associated with an increased risk of fatal and non-fatal CVD events. However, the observational design of the studies included does not allow to draw definitive causal inferences.

Lay summary

The data on whether NAFLD by itself is associated with increased cardiovascular events and death remains an issue of debate. The findings of this updated and large meta-analysis of observational studies indicate that NAFLD is significantly associated with an increased risk of fatal and non-fatal cardiovascular events. However, the observational design of the studies included does not allow us to prove that NAFLD causes cardiovascular disease. Clinicians who manage patients with NAFLD should not focus only on liver disease but should also consider the increased risk of cardiovascular disease and undertake early, aggressive risk factor modification.

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a clinico-pathological syndrome that ranges from simple steatosis to non-alcoholic steatohepatitis (NASH) with varying amounts of fibrosis, and cirrhosis [1]. NAFLD is becoming the most common cause of chronic liver disease worldwide, affecting up to 30% of the adult population in the United States and Europe [1], [2], [3]. Over the past decade, it has become increasingly clear that NAFLD is not only associated with an increased risk of liver-related morbidity or mortality, but also it is a multisystem disease that affects a variety of extra-hepatic organ systems, including the cardiovascular system [3], [4], [5], [6], [7].

A recent comprehensive meta-analysis involving 27 cross-sectional studies has shown that NAFLD was associated with various markers of subclinical atherosclerosis, such as increased carotid artery intimal-medial thickness, impaired flow-mediated vasodilation, increased arterial stiffness or increased coronary artery calcification [8]. All these associations were independent of multiple cardio-metabolic risk factors across a wide range of patient populations [8].

Several studies have also demonstrated that the prevalence of clinically manifest cardiovascular disease (CVD) was also significantly increased among patients with NAFLD (as reviewed elsewhere) [5], [6]. Worryingly, NAFLD was also associated with a higher prevalence of high risk and vulnerable coronary artery plaques, independently of traditional CVD risk factors and the extent and severity of coronary atherosclerosis [9].

Although the cross-sectional association between NAFLD and increased CVD prevalence is strong and consistent, it remains uncertain whether the presence of NAFLD predicts incident CVD events or whether the more severe forms of NAFLD are associated with an even higher risk of future CVD events. Moreover, the mechanisms linking NAFLD to CVD are controversial and several putative mechanisms have been proposed which, however, are to be traced back to liver histologic changes, insulin resistance and oxidative stress [10].

In this context, we have carried out a comprehensive systematic review and meta-analysis of published observational studies to gauge precisely the nature and magnitude of the association between NAFLD and the risk of incident CVD events. We have also investigated whether the severity of NAFLD is associated with a higher risk of CVD events. Clarification of these issues may have important clinical implications for management of patients with NAFLD.

Section snippets

Registration of review protocol

The protocol for this review was registered in advance with PROSPERO (International Prospective Register of Systematic Reviews, #CRD42016033481).

Type of studies, inclusion and exclusion criteria and definition of severe NAFLD

Studies were included if they were observational, prospective or retrospective studies that reported fatal and/or non-fatal CVD events in adult patients (>18 years old) with NAFLD as compared with adult individuals without NAFLD. Study participants were of either sex with no restrictions in terms of comorbid conditions. We included only studies in which

Characteristics of included studies

Based on the titles and abstracts of 4,569 citations, we identified 33 potentially relevant studies. Of these, we excluded 17 studies for the reasons reported in the MOOSE diagram (Fig. 1). Thus, 16 unique observational studies, including 17 comparisons, were eligible for inclusion in the meta-analysis and were assessed for quality. As shown in Table 1, all the eligible studies had an observational retrospective or prospective design (either community-based or hospital-based or outpatient

Discussion

Several studies have assessed the association between NAFLD and the risk of CVD. The data on whether NAFLD by itself is associated with an increased risk of CVD events and death remains an issue of debate. The results from these studies have been conflicting partly due to variability in NAFLD definition and CVD ascertainment. A prior narrative review published in 2010 by Ghouri et al. concluded that a diagnosis of NAFLD was insufficient to consider patients as being at high risk for CVD, and

Financial support

GT is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. CDB is supported in part by the Southampton National Institute for Health Research Biomedical Research Centre.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Authors’ contributions

Study concept and design: GT, CDB, AL; acquisition of data: GT, GZ; statistical analysis of data: CB; analysis and interpretation of data: GT, CDB, AL; drafting of the manuscript: GT, CB; critical revision of the manuscript for important intellectual content: AL, CDB, GZ.

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