NAFLD Epidemiology: Role of Endothelial Dysfunction

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Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 4731-4741 The epidemiology of non-alcoholic fatty liver disease and its connection with cardiovascular disease: role of endothelial dysfunction A. FEDERICO 1, M. DALLIO 1, M. MASARONE 2, M. PERSICO 2, C. LOGUERCIO 1

1Division of Hepato-Gastroenterology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy 2Department of Medicine and Surgery, University of Salerno, Baronissi, Salerno, Italy

Abstract. – The non-alcoholic fatty liver dis - of this lipid accumulation is completely different ease is considered a predominant hepatopathy from pathogenesis of other nosological entities, worldwide and a component of metabolic syn - such as drug induced steatohepatitis, chemothera - drome. It represents a risk factor for the develop - py associated steatohepatitis, and hepatitis C ment of cardiovascular diseases, independently virus-related steatosis, and it significantly lies on of the presence of diabetes mellitus, hyperten - 3 sion and obesity. For this reason, nowadays an insulin resistance . Insulin resistance may be able epidemiological analysis and a research of the to intervene on all mechanisms responsible for causes that correlate non-alcoholic fatty liver dis - lipid accumulation in hepatocytes : hepatic lipoge - ease and cardiovascular pathologies, are ex - nesis increase, a decrease of lipid export in the tremely useful. There are important epidemiologi - liver, a decrease of hepatic fatty acid oxidation , cal variations in relation to various geographical 3-7 areas, and depending on different population the increase of adipocyte lipolysis . groups, the prevalence of this pathology Depending on histology, NAFLD can be dis - changes. Epidemiological analysis for non-alco - tinguished into a simple lipid accumulation in holic fatty liver disease shows its remarkable rel - hepatocytes, named non-alcoholic fatty liver evance and diffusion, especially in Western ar - (NAFL ), and into a condition characterized by a eas; therefore immediate interventions are neces - cytolitic damage supported by an inflammatory sary for its prevention, diagnosis and therapy. En - dothelial dysfunction could be the joining link be - process based on an imbalance of oxidoreduc - tween non-alcoholic fatty liver diseases and car - tivecell potential, named non-alcoholic steato - diovascular disease risk. Indeed, their correlation hepatitis (NASH ). Even though factors responsi - should be researched in the alterations that meta - ble for the passage from first to second condition bolic hepatopathies are able to induce on en - are not yet clear, scientific community believes dothelial function and viceversa. For this reason, the scientific community may research new thera - that a basic genetic predisposition together with a peutic strategies for non-alcoholic fatty liver dis - negative contribution of different environmental ease, by intervening on the early stage of the causes, is able to trigger lipid peroxidation and pathology and blocking endothelial dysfunction. proinflammatory cytokine production , such as in - Key Words: terleukin (IL) -6, tumour necrosis factor alfa and Non-alcoholic fatty liver disease, Endothelial dysfunc - IL-1 beta, which support the pathology and also tion, Cardiovascular disease, Epidemiology, Endocan. cause the possible progression to more advanced stages, including cirrhosis and hepatocellular car - cinoma 8-15 . In this regard , NAFLD currently rep - Introduction resents the second most common cause of hepa - tocellular carcinoma development, as well as the second most frequent indication for liver trans - The non-alcoholic fatty liver disease (NAFLD) plantation , probably becoming the first cause by is becoming the most predominant hepatopathy in 2020 1,16-19 . Since NAFLD is a pathology without the near future 1. It is characterized by a pathologi - any symptom, with the exception of advanced cal fat accumulation in hepatocytes > 5% in the stages, its incidence and/or prevalence is largely liver tissue , in absence of alcohol consumption, underestimated. The lack of specific pharmaco - drug intake , and viral hepatopathy 2. This last logical therapies , easier to obtain when the diag - point is very important because the pathogenesis nosis is done , complicates the achievement of the

Corresponding Author: Alessandro Federico, MD; e-mail: [email protected] 4731 A. Federico, M. Dallio, M. Masarone, M. Persico, C. Loguercio

Epidemiology consent for the execution of parenchymal biopsy, that is the diagnostic gold standard. Moreover, Geographical Distribution nowadays the number of specialist medical con - sultations related to this pathology is very re - Whatever consideration about incidence and duced, because routine analysis execution, per - prevalence of NAFLD in the general population formed in order to determine transaminase level, corresponds to an estimate of real ones, probably often produces negative response despite the because of a large number of patients affected by presence of the disease , since there is no correla - the pathology who do not know to be diseased. tion between liver damage and aspartate amino - There are remarkable epidemiological variations transferase/alanine aminotransferase levels in in relation to geografichal areas analysed, and in NASH 20,21 . this case, the prevalence of the disease changes if NAFLD is part of metabolic syndrome and is we consider specific population groups. considered a risk factor for the development of In North America the prevalence of NAFLD in cardiovascular diseases independently of the the general population is between 27% and 34% , presence of diabetes, hypertension and obesi - whereas the prevalence of NASH is between 3% ty 22,23 . Indeed , the most of deaths that occur in and 5% 2,28,32-34 . However, if we consider the high- patients with NAFLD could be due to cardiovas - risk population groups, in these areas NAFLD cular causes 24 . prevalence grows exponentially, precisely 75- Currently , there are more than 7 billion people 92% in obese subjects and 60-70% in diabetic worldwide . About 1,5 billion is malnourished, ones 34-40 . This problem has a higher importance if and more than double is overfed and obese, in we consider the diffusion of obesity and diabetes fact obesity is now considered as a real epidemic. in the American population 41 . Indeed, one-third This observation is relevant because this social of the population consists of overweight subjects category represents that with a higher prevalence or obese people showing an increase of type 2 di - of NAFLD 25,26 . With regard to hepatopathy etiol - abetes mellitus incidences doubled in the last ogy, in the near future a complete reversal of the decade. These data seem to be even more discon - ratio between viral and metabolic hepatopathies certing in view of the fact that this increase is will probably occur, with a clear prevalence of mainly related to an increased diffusion of these metabolic ones 1. Because of the high rate of mor - pathological conditions in young and pediatric bility and mortality with a survival, estimated at population , that have a higher life expectancy. ten years , of 60-70% of patients with NASH, in - Consequently, in the absence of an efficient ther - ternational scientific community has wondered apeutic intervention, in the near future it will be whether a screening plan for NAFLD identifica - possible to observe an increase in the prevalence tion were necessary 27-29 . Each screening plan of disease advanced stages and its hepatic and should be direct towards significant and poten - extrahepatic complications 42 . Indeed, both obesi - tially lethal diseases, that are common in the gen - ty and type 2 diabetes mellitus , are considered eral population, have a well identified natural risk factors for the development of NASH and fi - history, benefit from an early therapeutic ap - brosis 2,28,38,43 . proach, are diagnosed in simple and cheap way . In Europe, the estimated NAFLD prevalence NAFLD has two of the features above men - affects, on average, one-fourth of the general tioned, especially in relation to the diffusion of population among the different nations, includ - pathological process in world population. This ing areas with a higher prevalence in Balkan led to believe that in 2015 there were no prereq - Peninsula (40-45%) 44-47 . In Asia it is possible to uisites to start a screening plan for this patholo - observe, on average, a prevalence between 15% gy, even if this concept should be probably re - and 20% with a variable distribution among assessed in the light of epidemiological data, de - China, Japan, Korea, Malaysia, Indonesia and velopment of well defined treatments, and new Sri Lanka, from 3 to 10 percentage points more diagnostic procedures that will be observable in or less 24,47-52 . The increase of prevalence among the near future 29-31 . This review aims to the recent obese subjects and diabetic ones in Europe and epidemiological developments, as well as the Asia, shows what it has already been highlight - connection between NAFLD and cardiovascular ed for the United States. Therefore, it is possi - diseases, taking into consideration a possible ble to observe the existence of a gradient of joining link of these two entities: endothelial NAFLD prevalence in the general population , dysfunction (ED). with higher rates in the Western areas of the

4732 NAFLD epidemiology: role of endothelial dysfunction

Earth, which gradually decrease if we consider ment is also reported. Indeed , there are familial the rates of the Eastern countries. This is proba - clusters in which the copresence of NAFLD bly related to more factors: environmental fac - among lineal relatives can reach 39% 68 . Some - tors, lifestyle and drastic modifications in diet times, the transmission of a mutation developed (i.e. , meat consumption in Western countries and on a regulator gene of lipid metabolism can oc - fish consumption in Eastern ones) , as well as ge - cur, which can produce an increase of fatty acid netic factors transmittable among native people . synthesis, hepatic uptake, export decrease, alter - 69,70 Age, Sex, Ethnicity and Genes ation of oxidative metabolism . However , monogenic mutations able to determine this dis - In the analysis of world population, a lot of ease transmission are very rare in the general studies highlighted some connections among population, for this reason it is impossible to ex - NAFLD prevalence, age, sex and ethnicity. Ac - clusively ascribe the role of this familial predis - cording to some authors, people in advanced age position to them . Rather, there are allelic variants and male gender have a higher risk of developing of some genes, such as I148M for the gene NAFLD, independently of presence or absence patatin-like phospholipase domain-containing 3 of metabolic syndrome 53-58 . In male gender, it is (PNPLA3), involved in triglyceride hydrolisis , possible to observe an increase of the risk of which are associated with a higher risk of devel - NAFLD in the transition between young and me - opment and progression of the disease 71,72 . The dian age, until 50, threshold beyond which a pro - distribution of these allelic variants among differ - gressive decline occurs 59,60 . Whereas female gen - ent ethnicities could explain, at least in part, their der has a higher risk of developing NAFLD from different predisposition to develop this pathology. the age of 45-50, with a progressive decline after However, other studies have put in correlation 70 59-61 . Moreover , the age could have an influ - this allelic variant with the development and pro - ence on the risk of progression of the disease gression of NAFLD in advanced stages, indepen - from NAFL to NASH, until the development of dently of age, sex and ethnicity 72-74 . Another vari - fibrosis in advanced stages and hepatic and ex - ant of PNPLA3 gene, S4531 is associated to a re - trahepatic complications related to the patholo - duced hepatic accumulation of triglycerides. It is gy 43,62,63 . Furthermore , it has been hypothesized more widespread among African Americans than that , in women , oestrogens may have a protective between Caucasian and the Hispanic people, role towards liver fibrosis development: in this which present a smaller expression 75 . way the risk of fibrosis may increase in relation The background of the damage supported by to age progression in the male gender, and it is liver lipid accumulation, is the outbreak of an in - higher if compared to the risk in women of the flammatory reaction related to the generation of same age until 50. From this threshold on, a re - reactive oxygen species (ROS) . Therefore, the duction of this difference may occur, becoming overexpression of genes with proinflammatory weak after menopause 64 . activity, supported by rs12979860 CC genotype As is known, there is a connection between the of IL-28B , together with PNPLA3 rs738409 GG , risk of developing NAFLD and ethnicity 65 . In the is associated to both a higher lobular inflamma - American population there is a clear prevalence tion and fibrosis 76 . Moreover, the minor activity of liver steatosis among Hispanic subjects if com - of superoxide dismutase-2 enzime too, in deter - pared to Caucasian ones, and even less in African mining a reduction of ROS concentration is asso - Americans 66 . This difference is related to a higher ciated to a similar histological response 77 . Other distribution of risk factors responsible for the de - genic variants, related to familial forms of velopment of NAFLD in the Hispanic population, NAFLD in advanced stages are rs780094 of he - if compared to African Americans. Indeed, de - patic glicokinase regulatory protein , rs2228603 spite African Americans show a prevalence of polymorphism of neurocan gene, rs3750861 obesity and insulin resistance similar toHispanic polymorphism of Kruppel-like factor-6, involved people, they have a lower frequency of liver in the activation of liver stellate cells for the de - steatosis 66 . Additionally, at histology, Hispanic posit of fibrotic tissue, and rs58542926 polymor - subjects often present NASH signs, including bal - phism of trans-membrane 6 superfamily member looning hepatocytes and Mallory bodies, if com - 278-83 . The study of genes responsible for the de - pared to Caucasian people and African Ameri - velopment and progression of the pathology may cans 67 . In epidemiological analysis , the evaluation allow the identification of familial groups at risk of familial predisposition to NAFLD develop - to be undergone screening tests aimed at obtain -

4733 A. Federico, M. Dallio, M. Masarone, M. Persico, C. Loguercio ing an early diagnosis of the disease, in order to other cardiovascular risk factors. Carotid intima- avoid its evolution in more advanced and severe media tickness alterations, atherosclerosis, coro - forms, as well as to avoid the development of he - nary calcification and low coronary flow reserve patic or extrahepatic complications. are also associated with NAFLD , and their severi - Endothelial Dysfunction ty in the pejorative sense is directly correlated to the severity of histological liver damage, defined Endothelium can be considered as an organ by lobular inflammation and fibrosis extent 22,92-95 . that has a key role in vascular homeostasis, ED evaluation is one of the most recent research through the release of a large number of sub - areas in the field of NAFLD, and its evaluation stances with autocrine and paracrine activity, may be essential to define patients with a higher such as: nitrix oxide (NO), prostacycline, en - risk of developing cardiovascular diseases. In - dothelium derived hyperpolarizing factor, en - deed, a study by Rubinshtein et al 96 that included dothelin -1, thromboxane A2, prostaglandin A2, 270 symptomatic outpatients with unexplained platelet activating factor and many others 84 . The chest pain, low-risk findings during stress testing processes regulated by these substances include and/or the absence of new obstructive lesions by the maintenance of vascular tone, vasal perme - an invasive coronary angiogram, demonstrated an ability, balance between coagulation and fibrinol - association between ED, evaluated by peripheral ysis, as well as subendothelial matrix structuring arterial tonometry , and the onset of adverse cardio - and proliferation/apoptosis of smooth muscle vascular events, such as: cardiac death, myocar - cells 85 . NO is produced by L-arginine catabolism dial infarction, revascularization or cardiac hospi - due to NO-synthase (NOS )86 . NO production is talization, during the seven years of follow-up . stimulated by both substances, including acetyl - Actually, the association between ED and NAFLD choline , bradykinin , substance P, serotonin , was already highlighted in 2005 , in a study , that which act on specific receptors and mechanical demonstrated a significant reduction of flow medi - stimuli: wall shear stress. NO causes a reduction ated dilatation (FMD) in NAFLD patients if com - of intracellular calcium concentration in smooth pared to controls , after adjusting for sex, age, body muscle cells and consequently their release 87 . mass index, and insulin resistance 97 . Back then, When endothelium is physically and functionally even though NAFLD started to be considered a damaged, these homeostatic mechanisms fail, es - significant problem of hepatology, it did not have pecially those related to NO-dependent vasodila - the same epidemiological relevance that we live tion, determining ED. ED is characterized by a nowadays. In 2013 , Colak et al 98 highlighted in an reduction of bioavailability of vasodilator mole - observational case-control study, a reduction of cules and/or an increase of vasocontrictor stim - FMD in NAFLD patients if compared to controls. uli, such as thromboxane A2, prostaglandin H2 These data did not correlate with classic risk fac - and ROS 86 . ROS cause not only vasocontriction, tors for cardiovascular diseases, neither with the but also NO degradation, reducing its bioavail - presence nor the absence of metabolic syndrome, ability and producing a vicious circle that further and this difference was mainly marked in patients damages endothelium, making it more predis - with NASH . posed to the onset of cardiovascular disease. In 2015 Long et al 99 , with a study in a large NAFLD and Endothelial Dysfunction community-based sample (n. 2284) of patients without apparent cardiovascular diseases, high - NAFLD and its association with other known lighted the association of NAFLD , as defined by risk factors is now considered both a marker of decreased liver attenuation on multidetector cardiovascular diseases and a pathological mani - computed tomography , and abnormalities in both festation able to carry out a pathogenetic role to - the microcirculation and ED. NAFLD correlated wards cardiovascular diseases 88-91 . Nowadays, with measures of microvascular dysfunction: fin - among death causes in patients with NAFLD gertip peripheral arterial tonometry ratio, base - stand out cardiovascular pathologies, for this rea - line brachial artery mean flow velocity, and base - son an intervention in the “metabolic epidemic line peripheral artery pulse amplitude after ad - era” is necessary in order to reduce the number of justing for cardiovascular and metabolic risk fac - deaths 24 . The connection between NAFLD and tors. The possible explanation of this ill-fated as - cardiovascular diseases may be researched in the sociation could derive from the fact that NAFLD , alterations that metabolic hepatopathies are able to inducing proinflammatory cytockine production induce on endothelial function, independently of and low-grade inflammation, would lead to an

4734 NAFLD epidemiology: role of endothelial dysfunction inefficiency of mechanisms that underlie func - the experiment, underlies the process that causes tional endothelial homeostasis 100 . However the the inflammation and fibrosis development . In - pathogenetic connection between NAFLD and deed, they demonstrated the way sinusoidal cap - ED maybe also inversely considered, as different illarization in mice, in L-amino acid-defined diet studies demonstrated: ED would be able to in - model of NAFLD, precedes the development of duce and worsen metabolic hepatopathy, produc - inflammation and consequently the passage from ing a self-feeding vicious circle . NAFL to NASH, as well as fibrosis 109 . The theo - Some investigations have highlighted how ED ry of researchers is that the structural change of may be considered an early alteration in metabolic sinusoids, the loss of fenestrations and the acqui - hepatopathy that develops before the on set of sition of continual basal membrane can be asso - whatever cardiovascular disease or structural alter - ciated with a functional change of endothelial tis - ation of vasal wall 101 . In a paper by Pasarìn et al 102 , sue that , becoming dysfunctional, would be able it has been demonstrated how mice fed for 30 to carry out a role that promotes the activation of days with a “Cafeteria diet” (including 65% of immune cells, with the onset of inflammation, calorie intake made up of fats, especially saturated and hepatic stellate cells for the deposit of extra - ones ) precociously developed ED, before the de - cellular matrix. velopment of structural endothelial alterations, in - The most suggestive hypothesis is to manage flammation and liver fibrosis . They studied hepat - to intervene on ED process, through its early ic microcirculation through an ex-vivo liver perfu - identification, with the use of next-generation sion model, eliminating the possible extrahepatic medicines, which may lead to the interruption of effects on endothelial functionality. They observed pathogenetic chain that leads to the progression an ex-vivo portal perfusion pressure increase in the of hepatocellular damage. liver of mice fed for 30 days with Cafeteria diet , compared to those fed with conventional diet; Serum Markers of Endothelial Dysfunction there was a reduction of this difference using NO, therefore the most likely hypothesis is that it was A possible joining link between NAFLD and due to an increase of vasal tone 102 . Moreover , they cardiovascular diseases has therefore been identi - evaluated the vasodilator response to acetyl - fied in ED. For this reason, the development of choline stimulus (ED standardized evaluation new diagnostic methods able to measure ED method) that was clearly lower in mice fed for 30 should be necessary, in order to predict cardio - days with Cafeteria diet than in mice fed with con - vascular risk in NAFLD patients. In this regard, ventional diet 102 . Lastly, they measured phospho - for ED evaluation it is possible to use invasive rylated protein kinase B and ph osphorylated NOS methods (intravascular injection of acetylcholine (active forms of proteins) levels, which were and the measurement of vasodilation caused by lower in mice fed for 30 days with Cafeteria diet this neurotransmitter ) and non-invasive methods, than in mice fed with conventional diet 102 . Re - that are economically unsustainable for ED garding this last observation, the researchers con - screening (FMD ), up to dosage of ED serum cluded that an early phase of ED development markers. was the onset, induced by Cafeteria diet , of liver Elsheikh et al 110 have tried to correlate endothelial insulin resistance: insulin administra - NAFLD and presence of coronary artery disease tion, that physiologically increases the amount of (CAD) to the level of some ED serum markers . active NOS, did not cause any effect in hepatic Sixty-six patients with NAFLD (diagnosed by ul - capillaries of mice fed with Cafeteria diet, com - trasonography and fatty liver index) and CAD pared to the increase obtained in mice fed with (evaluated by coronary angiography) were en - conventional diet. rolled . The evaluated serum markers were: A suitable NO production due to the correct Endocan (ESM-1): a soluble proteoglycan, operation of NOS stops hepatic stellate cells acti - discovered by Lassalle and co-workers in 1996, vation, prevents sinusoidal thrombosis, a known produced by endothelial cells 111 . It is released by progression mechanism of liver cirrhosis, and it damaged endothelial cells in response to proin - is essential for the correct process of liver regen - flammatory and angiogenetic stimuli 112,113 . eration 102-108 . High mobility group box 1 (HMGB1): a mole - In another study, Miyao et al 109 have highlight - cule that has a role in the regulation of inflamma - ed that structural variation of sinusoids, observed tory response by endothelial cells, inducing the beyond the fourth week from the beginning of dysfunction 114,115 . However, on the contrary, other

4735 A. Federico, M. Dallio, M. Masarone, M. Persico, C. Loguercio scientific proofs demonstrate the role of this mol - tients with simple steatosis, with low-cost meth - ecule in repair process and endothelial homeosta - ods, may provide extra information about pa - sis 116 . tient prognosis, in addition to the evaluation of Anti-endothelial cells antibodies: antibodies conventional risk factors, as regards both car - directed against endothelial cells; they would in - diovascular system and liver. For this reason , crease endothelial expression of leukocyte adhe - the scientific community should research new sion molecules, pro inflammatory cytokine pro - therapeutic strategies for NAFLD, and intervene duction and their apoptosis 117-119 . on an early stage of the pathology, blocking ED . ESM-1 was higher in NAFLD patients with This approach could determine a strong impact CAD than in controls, and its level directly corre - on cardiovascular in these patients, with a clear lated with CAD degree, observed by arteriogra - advantage with regard to public health. phy. ESM-1, together with hyperlipemia, was significantly associated with an increased risk of –A–c–k–n–o––w–l–e–d–g––e–m––e–n–t–s cardiovascular diseases in NAFLD patients. HMGB1 levels were lower in patients with We thank Ms Maddalena Farina (Second cycle degree in NAFLD and CAD than in NAFLD patients with - Linguistics and Translation for Special Purposes) for her out CAD. However, the researcher observed that English assistance. the correlation between HMGB1/ESM-1 ratio was significantly reduced in NAFLD patients C––o–n––f–li–c–t– –o–f– I–n––te– –r-e– s–t– with CAD if compared to controls. A possible explanation of this outcome, as the authors hy - The Authors declare that there are no conflicts of interest. pothesized, could be the alteration of balance be - tween damage (measured by ESM-1 levels) and References endothelial repair (measured by HMGB1 levels). Nevertheless, since the role of this molecule is CHARLTON M 1) . Nonalcoholic fatty liver disease: a re - not clear in endothelial physiopathology, future view of current understanding and future impact. researches are necessary in order to confirm the Clin Gastroenterol Hepatol 2004; 2: 1048-1058. predictive role in ED. Finally, no significant dif - CHALASANI N, Y OUNOSSI Z, L AVINE JE, D IEHL AM, 2) BRUNT EM, C USI K, C HARLTON M, S ANYAL AJ ference about anti-endothelial cells antibodies . The di - levels between NAFLD patients with CAD and agnosis and management of non-alcoholic fatty controls was observed. liver disease: practice Guideline by the American In summary, currently the most reliable serum Association for the Study of Liver Diseases, American College of Gastroenterology, and the markers for ED evaluation are ESM-1 serum lev - American Gastroenterological Association. Hepa - els and HMGB1/ESM-1 ratio . tology 2012; 55: 2005-2023. ALAM S, M USTAFA G, A LAM M, A HMAD N. 3) Insulin re - Conclusions sistance in development and progression of non - alcoholic fatty liver disease. World J Gastrointest Pathophysiol 2016; 7: 211-217. PAREDES AH, T ORRES DM, H ARRISON SA Epidemiological analysis for NAFLD shows , 4) . Nonalcoholic year by year , the huge relevance of this patholo - fatty liver disease. Clin Liver Dis 2012; 16: 397- 419. gy , economically and socially. The large diffu - KARLAS T, W IEGAND J, B ERG T 5) . Gastrointestinal com - sion of risk factors for NAFLD in Western ar - plications of obesity: non-alcoholic fatty liver dis - eas, implicates the necessity of an immediate ease (NAFLD) and its sequelae. Best Pract Res intervention for the prevention, diagnosis and Clin Endocrinol Metab 2013; 27: 195-208. MOORE JB. therapy of this pathology , because it has also 6) Non-alcoholic fatty liver disease: the been identified as an independent cardiovascu - hepatic consequence of obesity and the metabol - ic syndrome. Proc Nutr Soc 2010; 69: 211-220. lar risk factor . A greater awareness of phys - SOUZA MR, D INIZ MDE F, M EDEIROS -F ILHO JE, A RAUJO iopathological steps that lead to the correlation 7) MS. between NAFLD and cardiovascular diseases, Metabolic syndrome and risk factors for nonalcoholic fatty liver disease. Arq Gastroenterol allows us to highlight a new scientific scenario, 2012; 49: 89-96. BUZZETTI E, P INZANI M, T SOCHATZIS EA which is ED may be considered as an early 8) . The multi - phase of pathogenetic process that leads to ple-hit pathogenesis of non-alcoholic fatty liver death due to cardiovascular pathologies in these disease (NAFLD). Metabolism 2016; 65: 1038- patients 24 . Therefore , ED identification in pa - 1048.

4736 NAFLD epidemiology: role of endothelial dysfunction

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