Elsevier

Atherosclerosis

Volume 191, Issue 2, April 2007, Pages 235-240
Atherosclerosis

Review
Non-alcoholic fatty liver disease and increased risk of cardiovascular disease

https://doi.org/10.1016/j.atherosclerosis.2006.08.021Get rights and content

Abstract

Non-alcoholic fatty liver disease (NAFLD) is present in up to one-third of the general population and in the majority of patients with cardio-metabolic risk factors such as abdominal obesity, type 2 diabetes and other components of the metabolic syndrome (MetS). Currently, the importance of NAFLD and its relationship to the MetS is increasingly recognized, and this has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Indeed, the impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening/surveillance strategies in this growing number of patients. Recent evidence suggests that the severity of liver histology in NAFLD patients is closely associated with markers of early atherosclerosis such as greater carotid artery wall thickness and lower endothelial flow-mediated vasodilation independently of classical risk factors and components of the MetS. Moreover, NAFLD is associated with greater overall mortality and independently predicts the risk of future CVD events. Overall, the current body of evidence strongly suggests that NAFLD is likely to be associated with increased CVD risk, and raises the possibility that NAFLD may be not only a marker but also an early mediator of atherosclerosis.

Introduction

For a long time, the presence of hepatic steatosis was considered as a benign manifestation with scarce or no clinical significance. However, recent results indicate a broad spectrum of clinical and pathological manifestations that individuals with non-alcoholic hepatic steatosis develop, which are termed as non-alcoholic fatty liver disease (NAFLD). Interestingly, the manifestations of NAFLD are very similar to those observed in patients with alcoholic liver disease, and range from simple steatosis, steatohepatitis (NASH), liver fibrosis to cirrhosis and, rarely, to hepatocellular carcinoma [1], [2].

The prevalence of NAFLD in Western countries is high and there is a trend towards a further increase, with millions of people at risk of advanced liver disease. NAFLD affects approximately 15–30% of the general population, and its prevalence increases steadily to ∼70–90% in people with obesity or type 2 diabetes [1], [2], [3], [4]. Given the rapid rise of obesity in children globally, NAFLD is now recognized as the most common cause of liver abnormality also in the pediatric population [5].

Abdominal obesity, type 2 diabetes, insulin resistance, hypertension and dyslipidaemia – the typical components of the metabolic syndrome (MetS) [11] – are coexisting pathological conditions frequently associated with NAFLD, and their coexistence within the same individual increases the likelihood of having more advanced forms of NAFLD [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. This strongly supports the notion that NAFLD may be the hepatic manifestation of the MetS.

The importance of NAFLD and its relationship with the MetS is now increasingly recognized, and this has stimulated an interest in the possible role of NAFLD in the development of cardiovascular disease (CVD). Indeed, the possible impact of NAFLD on CVD risk deserves particular attention in view of the implications for screening/surveillance strategies in the growing number of patients with NAFLD. Given the strong associations between NAFLD and MetS risk factors, patients with NAFLD would be expected to have an increased risk of CVD. In theory, however, it is also possible to speculate that NAFLD itself might confer an excess of CVD risk over and above what would be expected due to the increased prevalence of the underlying MetS risk factors.

In this article, we will briefly review the strength of the recent evidence for significant associations between NAFLD and subclinical/clinical CVD. Furthermore, we will discuss some recent follow-up data supporting the possibility that NAFLD might be not only a marker but also an early mediator of CVD.

Recent cross-sectional studies have repeatedly demonstrated a marked increase in carotid artery intima-media thickness (IMT), as a reliable index of subclinical atherosclerosis [12] in patients with NAFLD [13], [14], [15], [16]. This finding has been validated by the results of a population-based study demonstrating increased carotid IMT and higher prevalence of carotid plaques in NAFLD patients [17].

However, in these studies the NAFLD diagnosis was exclusively based on blood testing and ultrasound imaging, but was not confirmed by liver biopsy, which is the best diagnostic tool for confirming NAFLD [1], [2], [3], [4].

Recently, we have shown in a large observational study that patients with biopsy-proven NAFLD had a significant increase in carotid IMT in comparison with age-, sex-, and BMI-matched healthy controls; carotid IMT was significantly higher for individuals with NASH than for those with simple steatosis, and, more importantly, the histological severity of NAFLD (i.e., steatosis, necroinflammation and fibrosis) predicted carotid IMT independently of classical risk factors, HOMA-estimated insulin resistance, and components of the MetS [18]. Previously, O’Leary et al. reported that a carotid IMT value ≤0.86 mm carries a low risk of CVD, whereas an IMT value ≥1.10 carries a high risk of CVD [19]. It is worth emphasizing that the mean carotid IMT values we found among healthy controls and NAFLD patients were of 0.82 and 1.14 mm, respectively [18].

Further accumulating evidence also exists demonstrating that NAFLD is correlated with circulatory endothelial dysfunction, another marker of early atherosclerosis [20]. It has been shown that non-diabetic patients with NAFLD had a significant decrease in brachial artery endothelial flow-mediated vasodilation when compared with matched healthy controls, and that this decrease correlated to histological features of NAFLD independent of age, sex, BMI, HOMA-insulin resistance, and other MetS components [21]. Moreover, the 10-year probability of CVD risk events (as calculated by the Framingham equation) was moderately increased among these patients [21]. Similarly, in metabolically well-controlled patients with type 2 diabetes, mildly elevated liver enzymes, as surrogate markers of NAFLD, were independently associated with decreased brachial artery flow-mediated vasodilation and impaired whole-body insulin sensitivity [22].

Obviously, these findings raise the question as to whether CVD events will occur prior to the development of liver failure in NAFLD patients, and if aggressive treatment of CVD risk factors is an important treatment modality for all patients with NAFLD.

We have recently reported increased prevalence of coronary, cerebrovascular and peripheral vascular disease in people with type 2 diabetes and NAFLD (as diagnosed by blood testing and ultrasound) compared with that found in diabetic patients without NAFLD; the significant relationship between NAFLD and CVD was little affected by adjustment for classical risk factors, diabetes duration and glycaemic control, but additional adjustment for the MetS attenuated this relationship [23].

Consistently, in a large sample of middle-aged male workers, those with NAFLD were more likely to have CVD compared with those without NAFLD; moreover, the presence of NAFLD was associated with CVD independent of obesity and other prognostic factors [24].

Additionally, in a study presented during the recent meeting of the American Association for the Study of Liver Diseases (AASLD), the prevalence of NAFLD was significantly higher in patients with acute myocardial infarction (66 and 50% for women and men, respectively) compared with that found in the general population [25]; moreover, NAFLD was associated with greater severity of coronary artery disease. Both of these findings were independent of age, sex and BMI [25].

Finally, in another study presented during the AASLD meeting, Schwimmer et al. [26] hypothesized that fatty liver is a risk factor for early onset of atherosclerosis and that atherosclerosis begins in childhood and progresses through adulthood to form the lesions that cause symptomatic CVD. Therefore, they reviewed the autopsy findings from 817 children (aged 2–19 years) who died of external causes (accident, homicide, suicide). Fatty liver, defined as ≥5% of hepatocytes affected by steatosis, was present in 15%, mild atherosclerosis of coronary arteries was present in 21%, and more severe atherosclerosis was present in 2% of subjects. Atherosclerosis was two-fold more frequent (odds ratio 1.8, P < 0.001) in children with fatty liver than in those without fatty liver. The investigators reasonably concluded that fatty liver might not only be a marker but also an early mediator of atherosclerosis [26].

Clearly, we must be cautious in making any causal inference given the cross-sectional design of these studies. Further follow-up studies are necessary to determine whether the increased prevalence of CVD among NAFLD patients also affects long-term mortality.

Patients with NAFLD appear to have an increased risk of death compared with the general population (as well reviewed in a recent article by Adams and Angulo) [1]. For example, in a community-based cohort of 420 NAFLD patients, Adams et al. [27] reported that overall mortality was increased during a mean follow-up of 7.6 years among these patients compared to the general population, and was most commonly due to CVD and malignancy; older age and the baseline diagnosis of type 2 diabetes and cirrhosis, but not the MetS, independently predicted overall mortality among NAFLD patients. Matteoni et al. [28] reported that mortality rates from CVD were the second most common cause of death in 132 NAFLD patients followed-up for ∼18 years, with rates equalling those of liver-related deaths and trailing only cancer-related deaths. Previously, Lee [29] reported that CVD was the most common cause of death in 49 NASH patients followed for ∼4 years.

However, it is important to emphasize that the existing studies examining the natural history of NAFLD are limited by relatively small numbers of patients, and originate from tertiary specialist centres, thus limiting the generalizability to the broader community [1].

As regards to this, some large epidemiological studies have prospectively shown strong associations between mildly elevated liver enzymes, as surrogate markers of NAFLD, and increased CVD incidence in both non-diabetic and type 2 diabetic individuals. Among 7613 middle-aged British men followed for 11.5 years, elevated serum gamma-glutamyltransferase (GGT) levels were independently associated with a significant increase in mortality from all causes and from CVD [30]. In a study of 163,944 middle-aged Austrian men and women, GGT levels were independently associated with increased cardiovascular mortality in both genders [31]. Ioannou et al. performed a cross-sectional analysis comparing 7526 participants of the National Health and Nutrition Examination Survey-III with normal and elevated serum alanine aminotransferase (ALT) levels, examining the mean levels of the Framingham coronary risk score; they reported that persons with elevated serum ALT levels in the absence of viral hepatitis or excessive alcohol consumption, most of whom have NAFLD, have an increased calculated CVD risk [32]. Recently, Schindhelm et al. [33] reported a strong positive association between serum ALT levels and incidence of CHD in a large population-based cohort of middle-aged Caucasian individuals. These authors have elegantly demonstrated that persons with mildly elevated ALT levels have an increased risk of future CHD events during a mean follow-up of 10 years independently of classical risk factors and components of the MetS; on the contrary, the association of ALT levels with all-cause mortality became not significant after adjustment for the same prognostic factors [33].

Interestingly, we carried out a prospective, nested case–control, study in 2103 type 2 diabetic patients, who were free of diagnosed CVD and viral hepatitis at baseline [34]. During 5 years of follow-up, 248 participants (case subjects) subsequently developed non-fatal coronary heart disease (myocardial infarction and coronary revascularization procedures) or ischaemic stroke or cardiovascular death. Using risk set sampling, 496 control patients among those who remained free of diagnosed CVD during follow-up were randomly selected in a 2:1 ratio, matched for age and sex to the case subjects. We found that NAFLD, as diagnosed by blood testing and liver ultrasound, was significantly associated with a moderately increased risk of incident CVD even after adjustment for classical risk factors, glycaemic control, and MetS components [34].

Notably, these findings originate from non-specialist centres [31], [32], [33], [34], and might have important clinical and public health implications. These results support the implication that patients with NAFLD have an increased risk of CVD. Thus, the casual detection of NAFLD in a ultrasound examination should alert clinicians to the coexistence of multiple underlying CVD risk factors warranting evaluation and treatment as much as the risk for advancing liver disease.

Currently, it is not known whether improving NAFLD will ultimately prevent the development of CVD. However, it is notable that interventions that are known to be effective in preventing CVD, including weight reduction [35], [36], [37] and treatments with insulin sensitizing agents (metformin and glitazones) [38], [39], [40], [41] or lipid-lowering drugs (statins) [42], [43], [44] may possibly improve NAFLD.

Although the higher risk of CVD associated with NAFLD might be well explained by the close association of NAFLD with the metabolic risk factors making up the MetS, however, recent data from cross-sectional and prospective studies (as referenced above) support the hypothesis that NAFLD itself might contribute to higher risk of CVD independent of other prognostic risk factors. This suggests a more complex picture about the intertwined interrelationships between NAFLD, MetS and atherosclerosis.

The possible biological mechanisms linking NAFLD and accelerated atherosclerosis are still poorly known.

NAFLD in its more advanced forms might act as a stimulus for further increased whole-body insulin resistance and dyslipidaemia (with a characteristic overproduction of triglyceride- and cholesterol-rich remnant particles), leading to accelerated atherosclerosis. This hypothesis is supported by the close, linear, relationship between liver fat content and direct measures of hepatic insulin sensitivity [45], and it is also partly validated by prospective studies demonstrating that raised liver enzymes have been shown to predict type 2 diabetes independent of obesity [46], [47], [48].

Another possible underlying mechanism linking NAFLD and atherosclerosis may be represented by increased oxidative stress and chronic, subclinical inflammation, which are thought to be causal factors in the progression from simple steatosis to more advanced forms of NAFLD [1], [2], [3], [4]. Reactive oxygen species derived from steatosis-stimulated fatty acid oxidation, attendant hepatocyte injury and cytokine release, and the ensuing proinflammatory milieu are likely to perpetuate the liver damage of NAFLD and add further atherogenic stimuli to the already high oxidative/proinflammatory status that is closely related to the MetS [11], especially through the increased hepatic production of C-reactive protein. It has been reported that patients with NAFLD have higher plasma markers of oxidative stress [49], [50], [51] and inflammation [51], [52], [53], [54] than those without NAFLD; most of these inflammatory markers are associated with the severity of histological features of NAFLD independent of classical risk factors and components of the MetS.

Decreased adiponectin concentrations, an adipose-secreted cytokine with anti-atherogenic properties [55], may represent another possible underlying mechanism linking NAFLD and atherosclerosis. Patients with NAFLD have a marked decrease in plasma adiponectin concentrations [53], [56], [57], [58], [59], [60], and this decrease is associated with the histological severity of NAFLD independently of abdominal obesity and other MetS components [53], [57], [60]; this observation may be relevant since hypoadiponectinemia independently predicts both CVD and MetS in large prospective studies [55], [61], and might also directly contribute to the development and progression of NAFLD. Indeed, it has been shown that recombinant adiponectin administration is effective in ameliorating obesity-associated hepatomegaly and fatty liver infiltration in ob/ob mice [62]; the potential mechanisms through which adiponectin can exert its hepato-protective actions include induction of hepatic fatty acid oxidation, inhibition of fatty acid synthesis, and suppression of TNF-alpha production in the liver [62].

Finally, accumulating evidence also exists that NAFLD could be linked to accelerated atherogenesis through the presence of abnormal lipoprotein metabolism, especially during the post-prandial phase [63], [64], [65], [66], [67]. The magnitude of post-prandial triglyceride and LDL conjugated diene responses after oral fat load test has been shown to be higher in NAFLD patients than in healthy controls, and closely correlated with the severity of liver histopathology [64], [65].

Section snippets

Conclusions

This article reviews the growing body of current evidence suggesting that NAFLD is associated with higher overall mortality and increased risk of future CVD events independent of classical risk factors and other prognostic factors. Overall, these novel findings raise the possibility that NAFLD and atherosclerosis share common molecular mediators, and that NAFLD is not merely a marker but also an early mediator of atherosclerosis. On the other hand, the possibility that NAFLD itself might

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