Epicardial fat in patients with non-alcoholic fatty liver disease
Authors: Salvatore Petta, Antonio Craxì
Journal: Journal of Hepatology (2015)

Epicardial fat, cardiac geometry and cardiac function in patients with non-alcoholic fatty liver disease: Association with the severity of liver diseaseJournal of HepatologyVol. 62Issue 4PreviewNon-alcoholic fatty liver disease (NAFLD) is increasing worldwide, affecting roughly 20–30% of the general population [1]. In addition to an expected risk for disease progression from non-alcoholic steatohepatitis (NASH) to bridging fibrosis, cirrhosis and its complications [1], NAFLD patients are also at higher risk of early asymptomatic cardiovascular alterations and/or frank cardiovascular disease [2]. Specifically, NAFLD, diagnosed either by ultrasonography or by liver biopsy, has been associated with a higher prevalence of low coronary flow reserve [3], coronary calcification [4], and carotid atherosclerosis [5–7], well before the occurrence of cardiovascular events. Full-Text PDF Non-alcoholic fatty liver disease: Severity of fibrosis and its relationships with clinical and biological variablesJournal of HepatologyVol. 62Issue 5PreviewThe paper of Petta et al. [1] throws new light on an important issue. Indeed, no data were previously available on the impact of the severity of liver damage on cardiac function and structural remodeling for patients affected by NAFLD. Moreover, this study partially clarifies the relationship between visceral adiposity and severe liver fibrosis in these patients. However, some comments might be useful for a deeper interpretation of these findings. In fact, some of our previous work shows that various circulating molecules (i.e., adiponectin, TGF β1, e-selectin, and endothelin) play a significant role in left ventricular remodeling [2,3], progression of renal function impairment [4,5], and in the manifestation of left ventricular dysfunction [6–8] in central obese subjects. Full-Text PDF Open AccessEpicardial fat and liver disease; the contribution of cardio autonomic nervous system functionJournal of HepatologyVol. 62Issue 5PreviewWe read with great interest, the recent article by Petta et al. [1]. The authors show a positive relationship between higher epicardial fat thickness and the severity of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), which may indicate a possible pathogenic role of ectopic fat depots in whole body organ damage. They also stated that morphological and functional cardiac alterations were more pronounced according to the severity of fibrosis. In our letter, we would like to highlight another possible mechanism between epicardial fat and liver disease; the contribution of cardio autonomic nervous system function (CAF). Full-Text PDF Open Access We recently reported that epicardial fat thickness is significantly associated with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), and that in this clinical setting, morphological and functional cardiac alterations by echocardiography are inversely related with the severity of liver damage [[1]Petta S. Argano C. Colomba D. Cammà C. Marco V.D. Cabibi D. et al.Epicardial fat, cardiac geometry and cardiac function in patients with nonalcoholic fatty liver disease: association with the severity of liver disease.J Hepatol. 2015; 62: 928-933Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar]. Of note, these associations were maintained after correction for both cardiometabolic and hepatic confounders including visceral adiposity. In their letter [[10]Corrao S. Rinollo C. Scaglione R. Non-alcoholic fatty liver disease: severity of fibrosis and its relationships with clinical and biological variables.J Hepatol. 2015; 62: 1212-1213Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar], Corrao and colleagues suggest that some cytokines/adipocytokines as well as adiponectin, transforming growth factor β1, e-selectin, endothelin, and fibroblast growth factor 21 could explain the link we observed between the severity of liver disease and the presence of cardiac alterations. In this line in our paper we already suggested that "the inflammatory state that characterize NAFLD/NASH might be able to act systemically, affecting the homeostasis of different organs, including the heart, as already demonstrated for systemic atherosclerosis [[2]Targher G. Bertolini L. Padovani R. et al.Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease.Diabetes Care. 2006; 29: 1325-1330Crossref PubMed Scopus (344) Google Scholar] and kidney damage [[3]Targher G. Bertolini L. Rodella S. Lippi G. Zoppini G. Chonchol M. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis.Clin J Am Soc Nephrol. 2010; 5: 2166-2171Crossref PubMed Scopus (171) Google Scholar]". Therefore we are planning to study the relationship between cytokines/adipocytokines levels, liver damage and cardiac alterations in NAFLD, as well as the role of genetic variants associated with NAFLD and its severity on the presence of cardiac alterations. We recently reported that gene variants in the PNPLA3 and TMS6F2 genes, can modulate the risk of atherosclerosis as well as the occurrence of cardiovascular events in patients with NAFLD or at high NAFLD risk [4Dongiovanni P. Petta S. Maglio C. Fracanzani A.L. Pipitone R. Mozzi E. et al.TM6SF2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.Hepatology. 2015; 61: 506-514Crossref PubMed Scopus (359) Google Scholar, 5Petta S. Valenti L. Marchesini G. Di Marco V. Licata A. Cammà C. et al.PNPLA3 GG genotype and carotid atherosclerosis in patients with non-alcoholic fatty liver disease.PLoS One. 2013; 8: e74089Crossref PubMed Scopus (57) Google Scholar]. Corrao and colleagues also question the approach we used for the multivariate model, assessing variables independently associated with severe liver fibrosis. Specifically, they raised concerns about the inclusion in the model of both visceral obesity and epicardial fat, because considered as a phenomenon of collinearity. We thank the authors to correctly explain this phenomenon and the implication that it can produce on data interpretation. However, we respectfully think that our analysis is not biased by collinearity. Epicardial fat [[6]Iacobellis G. Bianco A.C. Epicardial adipose tissue: emerging physiological, pathophysiological and clinical features.Trends Endocrinol Metab. 2011; 22: 450-457Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar], as well as other ectopic fat depots like liver or dorsocervical fat [[7]Cheung O. Kapoor A. Puri P. Sistrun S. Luketic V.A. Sargeant C.C. et al.The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome.Hepatology. 2007; 46: 1091-1100Crossref PubMed Scopus (101) Google Scholar], are obviously strongly related to visceral obesity. However, they do not depend on visceral obesity only, because they can have an independent role in affecting liver and systemic damage. In this line, cross-sectional and prospective studies showed that both liver and visceral fat are independent risk factors for presence and occurrence of cardiovascular events [8Targher G. Bertolini L. Padovani R. Rodella S. Tessari R. Zenari L. et al.Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients.Diabetes Care. 2007; 30: 1212-1218Crossref PubMed Scopus (776) Google ScholarHarrell F.E. Lee K.L. Mark D.B. Stat Med. 1996; 15: 361-387Crossref PubMed Scopus (7074) Google Scholar, 9Targher G. Bertolini L. Rodella S. Tessari R. Zenari L. Lippi G. et al.Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients.Diabetes Care. 2007; 30: 2119-2121Crossref PubMed Scopus (410) Google Scholar]. So, we included both visceral and epicardial fat in the model for fibrosis to demonstrate that the effect of epicardial fat is independent of that of visceral fat. Finally, in response to Ulucan and colleagues [[11]Ulucan S. Katlandur H. Kaya Z. Epicardial fat and liver disease; the contribution of cardio autonomic nervous system function.J Hepatol. 2015; 62: 1214Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar] we agree with the authors that the interference of epicardial fat with the autonomic nervous system could be one of the mechanisms linking this ectopic fat to liver damage. Accordingly, further clinical and experimental studies are needed in this topic. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.