Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: A systematic review☆
Introduction
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide because of the rise of obesity and type 2 diabetes prevalence [1]. NAFLD is present in 10–24% of the general population in various countries [2] and is closely related to insulin resistance and markers of oxidative stress and endothelial dysfunction [3], [4]. In fact, NAFLD is considered the hepatic manifestation of the metabolic syndrome (MS) [3], [5].
People with metabolic syndrome are at risk for cardiovascular disease, including coronary heart disease and stroke [6]. The importance of NAFLD and its relationship with MS is now increasingly recognized as recent data suggest that NAFLD is linked to increased cardiovascular risk independently of the broad spectrum of risk factors of MS [7]. Indeed, it is hypothesized that NAFLD is not merely a marker of cardiovascular disease but may also be involved in its pathogenesis [8].
Various non-invasive markers of early arterial wall alteration are currently available, such as arterial wall thickening and stiffening, endothelial dysfunction and coronary artery calcification [9]. Of them, non-invasive assessment of carotid intima-media thickness (IMT) by high-resolution carotid B-mode ultrasonography (US) is widely used as a proxy end point for cardiovascular disease [10]. In addition, carotid US allows the evaluation – in a simple, safe and reproducible way – of lumen diameter, intima-media thickness, and the presence and extent of carotid plaques.
Recent studies have shown that NAFLD patients have significantly greater carotid IMT than age and sex-matched patients without NAFLD, independently of the classical risk factors of the metabolic syndrome. However, some degree of variability about the mean carotid IMT values’ can be observed among all the published reports that result in a difficult evaluation of the magnitude of the observation. For instance, among the different studies, mean carotid IMT values in NAFLD patients range from 0.64 ± 0.10 mm to 1.24 ± 0.13 mm. The importance of this is to decide if further recommendations with regard to carotid atherosclerosis screening should be implemented in all NAFLD patients, as currently available epidemiological data indicate that a value of carotid IMT at or above 1 mm at any age is associated with a significantly increased risk of myocardial infarction and/or cerebrovascular disease [11].
In view of the evidence mentioned above, our primary purpose was to estimate from the available literature, the strength of the increased carotid IMT and carotid atherosclerosis observed in NAFLD patients. In addition, we systematically evaluated the study characteristics that could be responsible for the association.
Section snippets
Data sources and study selection
For the electronic searches, published studies were found through PubMed at the National Library of Medicine (http://ncbi.nlm.nih.gov/entrez/query) and in Medline databases for the query “(fatty liver or hepatic steatosis or non-alcoholic fatty liver disease) and (intima-media thickness, carotid artery, carotid plaque, cardiovascular disease and atherosclerosis)”. In addition, the references of the articles were checked and the PubMed link ‘related articles’ was used to identify additional
Results
We evaluated seven studies that met the selection criteria and that were identified using the search strategy described in Appendix Fig. A1. Studies characteristics are shown in Table 1. Data on one further study was unavailable because in the paper the authors did not disclose the raw data; the authors were contacted but they were unable to provide the data in the required format for evaluation [16]. In addition, the patients included in this study have fatty liver of unspecified aetiology.
Discussion
Recent epidemiological studies suggested an increased incidence of major cardiovascular events in patients with ultrasound-diagnosed NAFLD independent of traditional risk factors and components of the metabolic syndrome [7], [8], [24]. Moreover, the 14-year risk of cardiovascular mortality was doubled in 129 patients with biopsy-proven NAFLD compared with that of the reference population [25].
A strong association between NAFLD and endothelial dysfunction as measured by brachial artery
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This study was partially supported by grants UBACYT B119 (Universidad de Buenos Aires), PICT 05-25920 and PICT 2006-124 (Agencia Nacional de Promoción Científica y Tecnológica), PIP 5195 (Consejo Nacional de Investigaciones Científicas y Técnicas), Fundación Alfredo Lanari, and Consejo de Investigación de la Ciudad Autonóma de Bs.As. S.S., and C.J.P. belong to Consejo Nacional de Investigaciones Científicas. S.S. belongs to Consejo de Investigacion de la Ciudad de Buenos Aires. The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.