Cardiovascular phenotype of nonalcoholic fatty liver disease: Hanging the paradigm about the role of distant toxic fat accumulation on vascular disease
Authors: Silvia Sookoian, Gustavo O. Castaño, Carlos J. Pirola
Journal: Hepatology (2012)

We read with great interest the article by Kim et al. about the association between nonalcoholic fatty liver disease (NAFLD) and coronary artery calcification (CAC). The authors concluded that NAFLD per se might be a risk factor for coronary artery disease (CAD) as the association was "above and beyond visceral adiposity (VAT)."1 Interestingly, the Framingham Heart Study showed that VAT, body mass index, and pericardial fat (PCF) are associated with CAC, but only PCF remains significant following risk factor adjustment, suggesting a locally toxic effect of PCF on the vasculature.2 Thus, Kim et al. still leave open a key question about whether the contribution of NAFLD to CAC is above and beyond PCF. That would be an interesting hypothesis to test, even though the current evidence linking NAFLD, carotid artery wall thickness, and plaque development strongly suggests so.3 The authors also suggested that the pathogenesis of the association between NAFLD and CAD has not been thoroughly investigated. We would like to add some comments, as we have shown that the contribution of NAFLD to a proatherogenic profile is biologically plausible (Fig. 1), and the atherogenic risk is related to the disease severity. The liver of nonalcoholic steatohepatitis patients showed overexpression of proatherogenic genes such as TGFB1,4 which is associated with a high incidence of coronary events and restenosis after coronary intervention. NAFLD might also participate in the pathogenesis of CAD through the release of molecular mediators of atherogenesis such as sICAM-1, PAI-1, and sCD40L.5 Accordingly, patients with NAFLD showed higher liver expression of ICAM-1 and PAI-1, and a significant correlation was found between both the degree of liver steatosis and the severity of necroinflammatory activity and liver ICAM-1 expression.5 This scenario suggests that NAFLD participates in the crosstalk with target organs, leading to vascular disease and causing a change in the classical paradigm about the role of local versus distant toxic fat accumulation and deleterious vascular effects. Thus, all of us should take notice of the potential secretory/endocrine role of the fatty liver and its impact on the modulation of systemic phenotypes. Cardiovascular risk factors in patients with nonalcoholic fatty liver disease (NAFLD). Leukocyte and platelet counts are significantly higher in NAFLD patients compared with control subjects, suggesting that NAFLD is associated with a proinflammatory and prothrombotic state. Both risk markers are consistently associated with atherosclerosis and increased mortality from cardiovascular disease, and are independent prognostic indicators of future cardiovascular events. Determination of a 10-year risk of developing coronary heart disease outcomes (myocardial infarction and coronary death) was carried out using Framingham risk scoring. This study was partially supported by grants PICT 2008-1521 and 2010-0441 (Agencia Nacional de Promoción Científica y Tecnológica), and UBACYT CM04 (Universidad de Buenos Aires). Silvia Sookoian M.D., Ph.D.* , Gustavo O. Castaño M.D., Ph.D. , Carlos J. Pirola Ph.D. , * Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Buenos Aires, Argentina, Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Buenos Aires, Argentina, Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta and Research Council in Health, Buenos Aires, Argentina.