13 33 Intern Emerg Med Suppl (2012) 33-46 Non-alcoholic fatty liver disease (NAFLD): a novel cardiovascular risk factor Stefano Ballestri, Amedeo Lonardo, Fabio Nascimbeni, Enrica Baldelli, Erica Meschiari, Maria Rosaria Odoardi, Paola Loria Unit of Internal Medicine, Department of Internal Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Italy. REVIEW © SIMI Abstract Nonalcoholic fatty liver disease (NAFLD) is a common form of primary fatty liver almost universally asso- ciated with metabolic risk factors. Histologically, NAFLD is categorized as simple steatosis, which follows a benign course, and its potentially progressive counterpart, nonalco- holic steatohepatitis (NASH). Practicing physicians, while relatively aware of liver-related morbidity and mortality of NAFLD, appear to be more reluctant to engage their NAFLD patients in a protocol of screening and surveillance for car- diovascular disease. This occurs contrary to the alert made by scientific societies about the importance of focusing on vas- cular complications in addition to liver-related complications. Aiming to get further insight into such a controversial issue, we critically reviewed all the available literature on this hot topic. Clinical studies have been discussed first; next the pu- tative biological mechanisms involved in the NAFLD-athero- sclerosis association have been reviewed. Finally, recommen- dations issued by hepatological scientific societies have been compared. Data strongly support the association of NAFLD with en- dothelial dysfunction, carotid and coronary atherosclerosis. However, whether it is simple steatosis or NASH or both re- mains to be ascertained by large prospective studies recruiting subjects with biopsy-proven NAFLD and definite cardiovas- cular outcomes. Mechanisms linking NAFLD and early atherosclerosis in- clude subclinical inflammation, insulin resistance/diabetes, dyslipidemia, prothrombotic changes, hyperuricemia and probably chronic kidney disease, all of which appear to be af- fected to a large extent by hepatic histological changes seen in NAFLD, and particularly in NASH. In conclusion, our study confirms that NAFLD patients should be screened and monitored with reference to their car- diovascular risk. Keywords Atherosclerosis · epidemiology · fatty liver · IMT · NASH · Natural history · pathogenesis Abbreviations ALT, Alanine aminotransferase · CAD, Coronary Artery Disease · CRP, C-reactive protein · CV, Cardiovascular · CVD, Cardiovascular Disease · CVR, Cardiovascular Risk · CT, Computed tomography · EASL, European Association for the Study of the Liver · ED, Endothelial dysfunction · FLI, Fatty liver index · FMV, Flow- mediated vasodilation · FRS, Framingham Risk Score · GGT, γ-glutamyltransferase · HDL, High-density lipoprotein · HOMA, Homeostatic model assessment · IMT, Intima-media thickness · IL-6, interleukin-6 · IR, Insulin resistance · LDL, Low density lipoprotein · MS, Metabolic Syndrome · MTH- FR, Methylenetetrahydrofolate reductase · NAFLD, Non-al- coholic fatty liver disease · NASH, Non-alcoholic steatohep- atitis · T2D, Type 2 Diabetes · TNF-α tumor necrosis factor- α · US-FLI, Ultrasound fatty liver indicator · VLDL, Very low–density lipoprotein I. BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is defined by imag- ing/histological evidence of primary fatty liver after ruling out competing etiologies [1]. The only positive diagnostic cri- terion in a negative diagnosis is the finding that, almost uni- Paola Loria ( ✉ ) Department of Internal Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Modena, Nuovo Ospedale Civile S.Agostino-Estense, Via Giardini 1355, 41100 Modena, Italy e-mail: paola.loria@unimore.it