Research ArticleNon-alcoholic fatty liver disease and risk of incident cardiovascular disease: A meta-analysis
Graphical abstract
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.
References (57)
- et al.
NAFLD: a multisystem disease
J Hepatol
(2015) - et al.
A systematic review: burden and severity of subclinical cardiovascular disease among those with non-alcoholic fatty liver; should we care?
Atherosclerosis
(2013) - et al.
Association between non-alcoholic fatty liver disease and the incidence of cardiovascular and renal events
J Saudi Heart Assoc
(2013) - et al.
Impact of non-alcoholic fatty liver disease on myocardial perfusion in nondiabetic patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction
Am J Cardiol
(2015) - et al.
Non-alcoholic fatty liver disease and incident cardiac events: The Multi-Ethnic Study of Atherosclerosis
J Am Coll Cardiol
(2016) - et al.
Progression of carotid vascular damage and cardiovascular events in non-alcoholic fatty liver disease patients compared to the general population during 10 years of follow-up
Atherosclerosis
(2016) - et al.
Independent association between non-alcoholic fatty liver disease and cardiovascular disease in the US population
Clin Gastroenterol Hepatol
(2012) - et al.
In patients with non-alcoholic fatty liver disease, metabolically abnormal individuals are at a higher risk for mortality while metabolically normal individuals are not
Metabolism
(2013) - et al.
Non-alcoholic fatty liver disease: a spectrum of clinical and pathological severity
Gastroenterology
(1999) - et al.
The natural history of non-alcoholic fatty liver disease: a population-based cohort study
Gastroenterology
(2005)
Heart valve calcification in patients with type 2 diabetes and non-alcoholic fatty liver disease
Metabolism
Non-alcoholic fatty liver disease: a systematic review
JAMA
Epidemiological modifiers of non-alcoholic fatty liver disease: focus on high-risk groups
Dig Liver Dis
Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis
Nat Rev Gastroenterol Hepatol
Risk of cardiovascular disease in patients with non-alcoholic fatty liver disease
N Engl J Med
Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease
World J Gastroenterol
Non-alcoholic fatty liver disease is associated with an almost two-fold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis
J Gastroenterol Hepatol
High-risk coronary plaque at coronary CT angiography is associated with non-alcoholic fatty liver disease, independent of coronary plaque and stenosis burden: results from the ROMICAT II trial
Radiology
Non-alcoholic fatty liver disease and risk of cardiovascular disease
Metabolism
Serum gamma-glutamyltranspeptidase distinguishes non-alcoholic fatty liver disease at high risk
Hepatogastroenterology
Noninvasive evaluation of NAFLD
Nat Rev Gastroenterol Hepatol
Accumulation of (18)F-FDG in the liver in hepatic steatosis
AJR Am J Roentgenol
Hepatic glucose uptake is increased in association with elevated serum γ-glutamyltranspeptidase and triglyceride
Dig Dis Sci
Checklists of methodological issues for review authors to consider when including non-randomized studies in systematic reviews
Res Synth Methods
Variance estimators for attributable fraction estimates consistent in both large strata and sparse data
Stat Med
Quantifying heterogeneity in a meta-analysis
Stat Med
Can we individualize the ’number needed to treat’? An empirical study of summary effect measures in meta-analyses
Int J Epidemiol
Cited by (941)
The evil relationship between liver fibrosis and cardiovascular disease in metabolic dysfunction-associated fatty liver disease (MAFLD): Looking for the culprit
2024, Biochimica et Biophysica Acta - Molecular Basis of DiseaseInvited review liver fibrosis in NAFLD/NASH: From pathophysiology towards diagnostic and therapeutic strategies
2024, Molecular Aspects of MedicineCurrent status and future trends of the global burden of MASLD
2024, Trends in Endocrinology and MetabolismNon-invasive testing and risk-stratification in patients with MASLD
2024, European Journal of Internal Medicine