nonalcoholic fatty liver disease ( nafld ) is emerging as an important public health problem across the globe and associated with high risk for cardiovascular disease ( cvd ) for adult and children . nafld refers to a wide spectrum of liver damage , ranging from simple steatosis to steatohepatitis , advanced fibrosis , and cirrhosis . nafld is strongly associated with insulin resistance and is defined by the accumulation of liver fat > 5% per liver weight , in the presence of < 10  g of daily alcohol consumption . nafld is associated with type 2 diabetes , obesity , and hyperlipidemia [ 1 , 2 ] . the prevalence of nafld is estimated to be around 34% of total population , while obesity with nonalcoholic fatty liver disease varies between 30% and 100% , whereas the prevalence of nafld within type 2 diabetes varies between 10 and 75% . interestingly , the prevalence of nafld in usa is around 34% and 90 % of these cases of nafld were attributed to nonalcoholic causes [ 3 , 4 ] . in the dionysos nutrition and liver disease study in italy , we found that the prevalence of nafld was ~25% and was associated with most features of the metabolic syndrome . interestingly , alcohol intake and obesity could both act in a synergistic way to increase risk of in mortality . for instance , the one million women study showed that women who are obese or overweight had an increased risk of liver cirrhosis . the absolute risk of liver cirrhosis with obesity has also been shown to be increased synergistically with only ~15 units of alcohol per week . furthermore , hart et al . found that obesity and alcohol ( consuming 15 or more units per week ) intake are associated with greater risk of dying of liver disease . it is plausible to predict that , with an increase in prevalence of epidemic of diabetes and obesity , it is likely that there will be a marked increase in prevalent nafld with important consequences for health care providers . on the other hand , in nondiabetic and nonobese individuals , insulin resistance , hypertriglyceridemia and hyperuricemia the prevalence of nafld increased from 16.4% among individuals with normal bmi to 75.8% among obese people . the prevalence of nafld is even higher with morbid obesity , and among morbidly obese undergoing bariatric surgery the prevalence may be as high as 96% . for instance , in japan the prevalence of nafld was 25% and in china 24% , while in a small study in diabetic saudi individuals have suggested that the prevalence of nafld is ~55% [ 1114 ] . children are also known to be in risk of developing nafld . in a retrospective review of 742 children between the ages of 2 and 19 years who had an autopsy performed from 1993 to 2003 , fatty liver was present in 13% of subjects . in a small study of 44 obese children , one important concern with silent undiagnosed nafld is that it may progress silently and result in cirrhosis , portal hypertension , and liver - related death in early adulthood . interestingly , nafld is the hepatic component of the metabolic syndrome and is an independent risk factor for cardiovascular disease ( cvd ) . importantly , nafld is associated with an increased risk of all - cause death and predicts future cvd events , independently of the classical risk factors like age , sex , ldl cholesterol , smoking , and features of metabolic syndrome . one significant challenge for mass screening for nafld is the lack of sensitive and specific biochemical marker have studied the impact of nafld on mortality among 337 patients with type 2 diabetes followed for 9 years ( adams et al . 2005 ) . in multivariate analysis to adjust for confounders , overall mortality was significantly associated with a diagnosis of nafld , presence of ischemic heart disease , and duration of diabetes . interestingly , fatty liver and smoking had synergistic effect in metabolic syndrome and it is parameters , especially , low hdl - c and high plasma triglyceride . therefore , individuals with features of the metabolic syndrome , obesity , consume alcohol , and smoking with fatty liver will need aggressive treatment to decrease the risk of cvd . a joint interim statement of the international diabetes federation task force on epidemiology and prevention ; national heart , lung , and blood institute ; american heart association ; world heart federation ; international atherosclerosis society ; and international association for the study of obesity they define an individual with the metabolic syndrome with three of the five criteria  including elevated waist circumference , elevated triglycerides , and reduced high - density lipoprotein ( hdl)cholesterol levels , elevated blood pressure , and elevated fasting - glucose levels . in this new definition , waist circumference is just one of five criteria that physicians can use when diagnosing the metabolic syndrome ( population  and country insulin resistance which is a landmark of metabolic syndrome has been shown to be associated with 95% of individuals with nafld . importantly , both metabolic syndrome and nafld are associated with high incidence of cvd and most features of metabolic syndrome present in subjects with nafld . there is now general agreement in the literature that nafld is another clinical feature of the metabolic syndrome [ 2 , 5 , 8 , 21 ] . a study of 66 patients with nafld showed that 98% were insulin resistant , and 39% of those were diabetic . in another study , 19 nafld patients who were not obese or did not have diabetes and had a normal lipid profile , 47% showed features of the metabolic syndrome . a marked increase in body mass index ( bmi ) and insulin resistance is not dependent on bmi but is related to central obesity , which is a feature of nafld . obesity is associated with a higher incidence of a wide spectrum of liver diseases associated with nafld from steatosis to fibrosis and cirrhosis . recent study carried in 19 european centres showed high association of decreased insulin sensitivity and increased incidence of cvd with nafld . therefore , screening for diabetes is an essential part of the assessment of risk of cvd in individuals with nafld . several studies have shown association of nafld with cardiovascular disease . in individuals with diabetes and no diabetes , nafld is associated with increased risk of cvd [ 27 , 28 ] . in a study of biopsy - proven nafld with followup for around 21 years interestingly , the histological severity of nafld and inflammation is strongly associated with increased risk of cvd and atherogenic lipid profile . in contrast , domanski et al . 2012 conducted a retrospective chart review of patients with biopsy - confirmed nafld : of these , 219 patients had biopsies showing the presence of at least grade i nash . the overall prevalence of cardiovascular disease was 6.63% independent of age , sex , body mass index , and the presence of diabetes . on the other hand , simple hepatic steatosis is being shown to be associated with marked silent carotid atherosclerosis . several cross - sectional studies have reported a relationship between elevated serum activity of liver enzymes ( e.g. , alanine aminotransferase ( alt ) and gamma - glutamyltransferase ( gt ) ) and metabolic syndrome , diabetes , and nafld . raised serum activity of liver enzymes independently predicted the future development of metabolic syndrome and dm as well as cardiovascular ( cv ) events and/or total / cv mortality in prospective studies . importantly , these associations can be partly attributed to nonalcoholic fatty liver disease ( nafld ) and insulin resistance , and there may be additional underlying mechanisms that contribute to the increased cv risk ( e.g. , inflammation and oxidative stress ) . the association of gt with atherosclerotic plaque is of particular importance in individuals with nafld [ 31 , 32 ] . in a study of 14,874 middle - aged finnish men and women , mildly increased ggt levels were independently associated with an increased risk of ischemic stroke in both sexes . among 7,613 middle - aged british men followed for 11.5 years , increased ggt levels were independently associated with a significant increase in mortality from all causes and from chd . showed that serum gamma - glutamyltransferase may represent a link between fatty liver and development of early atherosclerosis . recent epidemiological studies have suggested the increase in alt may be linked to increase in risk of cvd . the hoorn study showed that the association between alt and chd events is significant , suggesting that nafld is associated with chd independently of other features of the metabolic syndrome . interestingly , serum alt is also shown to be positively associated with an increased risk of carotid atherosclerosis in nafld . furthermore , another study examined the association between elevated serum alt activity and the 10-year risk of chd as estimated using the framingham risk score ( frs ) . the alt threshold for increased risk of chd was higher in men ( > 43 recently , the firenze bagno a ripoli ( fibar ) study concluded that increased gamma gt or ast is an independent predictor of cvd . an increase of gamma - gt levels above the reference range , or also in the upper reference , range was also an independent predictor of incident of diabetes . lopez - suarez et al . showed in an observational study , the percentage of cases with hypertension was 21.2% greater in individuals with nafld than those without nafld ( 95% ci , 11.830.6 , p < 0.0005 ) . nafld was independently associated with prevalent hypertension with an adjusted odds ratio of 1.71 ( 95% ci , 1.102.65 , p = 0.017 ) . among nonhypertensive participants , nafld was also independently associated with high - normal systolic bp ( adjusted odds ratio 2.13 , 95% ci , 1.084.20 , p = 0.029 ) but not with high - normal diastolic bp . the authors concluded that the detection of nafld , even with normal alt levels , should serve as an opportunity to identify metabolic and bp abnormalities and intensify lifestyle modification . however , the us third national health and nutrition examination survey ( nhanes iii : 198894 ) study showed that nafld was not associated with an increased risk of death from all causes , cardiovascular disease , cancer , or liver disease . interestingly , data from the national health and nutrition examination survey iii study showed that nafld was associated independently with cvd , after adjusting for major demographic , clinical , and metabolic confounders ( odds ratio , 1.23 ; 95% confidence interval , 1.041.44 ) . however , nafld did not increase cardiovascular mortality over a 14-year period . in individuals with diabetes and nafld for instance , data by targher et al . showed that the unadjusted prevalence of nafld was 69.5% among participants with type 2 diabetes ( n = 2839 ) , and ultrasound detected nafld was the most common cause ( 81.5% ) of hepatic steatosis . nafld patients had a higher age ( p < 0.001 ) , and sex - adjusted prevalence of coronary ( 26.6 versus 18.3% ) , cerebrovascular ( 20.0 versus 13.3% ) , and peripheral ( 15.4 versus 10.0% ) vascular disease than their counterparts without nafld . in logistic regression analysis , nafld was associated with prevalent cvd independent of classical risk factors , glycaemic control , medications , and the metabolic syndrome features . in addition , the valpolicella heart diabetes study is a prospective control study in 2,103 type 2 diabetic patients who were free of diagnosed cvd at baseline . during 5 years of followup , 248 participants ( case subjects ) subsequently developed nonfatal coronary heart disease ( myocardial infarction and coronary revascularization procedures ) , ischemic stroke , or cardiovascular death . after adjustment for age , sex , smoking history , diabetes duration , hba1c , ldl cholesterol , liver enzymes , and the use of medications , the presence of nafld was significantly associated with an increased cvd risk ( odds ratio 1.84 , 95% ci 1.42.1 , p < 0.001 ) . additional adjustment for the metabolic syndrome ( as defined by national cholesterol education program adult treatment panel iii criteria ) appreciably attenuated , but did not abolish , this association ( 1.53 , 1.11.7 , p = 0.02 ) .   of significant is that nafld during childhood is strongly associated with atherosclerosis . in a case - control study of 150 overweight children with biopsy - proven nafld , children with nafld had significantly higher fasting glucose , insulin , total cholesterol , low - density lipoprotein cholesterol , triglycerides , systolic blood pressure , and diastolic blood pressure . subjects with nafld also had significantly lower high - density lipoprotein cholesterol than controls . after adjustment for age , sex , race , ethnicity , body mass index , and hyperinsulinemia , children with metabolic syndrome had 5.0 ( 95% confidence interval , from 2.6 to 9.7 ) times the odds of having nafld as overweight and obese children without metabolic syndrome . therefore , nafld in overweight and obese children is strongly associated with multiple cardiovascular risk factors . the authors concluded that the identification of nafld in a child should prompt global counseling to address nutrition , physical activity , and avoidance of smoking to prevent the development of cardiovascular disease and type 2 diabetes . the association of nafld with metabolic syndrome and diabetes may in part explain the increased risk of cvd with nafld . in addition , several studies showed that nafld in itself might contribute to the increased cvd risk . probably several highly interrelated factors contribute to the enhanced risk of diabetes and metabolic syndrome in persons with nafld . the following factors are possible explanation of mechanisms of the association of cvd with nafld ( figures 1 and 2 ) . it is well documented in the literature that nafld is associated with an increase in insulin resistance [ 16 ] . importantly , insulin resistance in the pathogenesis of nafld and associated with dyslipideamia , carotid atherosclerosis , and endothelial dysfunction . nafld is associated with atherogenic dyslipidaemia ( an increase in ldl - c , tg , apolipoprotein b , and decrease in hdl ) this associated with an increase in risk of cvd [ 16 ] . recent studies show a link between nafld and increased carotid intima - media thickness ( imt ) . ( 2008 ) concluded ( in a series of normal and nafld subjects ) that independent risk predictors of increased intima - media thickness were the presence of hepatic steatosis ( odds ratio ( or ) = 6.9 ) , age ( or 6.0 ) , and increased systolic blood pressure ( or 2.3 ) . more interestingly , targher et al . suggested that the severity of liver histopathology among 85 nafld patients is strongly associated with early carotid atherosclerosis , independent of age , sex , bmi , smoking , ldl cholesterol , insulin resistance , and the presence of metabolic syndrome . in addition , a large population study showed that nafld is associated with increase in imt . on the other hand , in 100 diet - controlled type 2 diabetic individuals , the significant increase of carotid imt in the presence of nafld has largely been explained by insulin resistance . showed that in people with type 2 diabetes fatty liver is not associated with increased risk of cvd . in contrast , nafld is independently associated with carotid atherosclerosis and only in people with multiple features of the metabolic syndrome . nafld in diabetic and nondiabetic individuals is associated with marked impairment in endothelial function [ 52 , 53 ] . inflammation is crucial in pathogenesis of nafld , and fat is now considered a metabolically active endocrine organ producing proinflammatory cytokines including tnf- , il-6 , and il-8 and there is an evidence to support the activation of other inflammatory pathways , oxidative stress , and the de novo pathway by tnf-. inflammation is associated insulin resistance resulting in increased lipolysis in adipose tissue , increased nefa uptake by hepatocytes and increased triglyceride synthesis in the liver . mitochondrial fat oxidation and export of vldl particles are not able to match triglyceride synthesis leading to net fat deposition in the hepatocytes . as a consequence of abnormal fat accumulation in the hepatocytes , there is a marked derangement in the insulin - signalling pathways in the liver [ 54 , 55 ] . inflammation is the link between obesity and insulin resistance and may have an important role in the pathogenesis of hepatic and systemic insulin resistance and cvd . adiponectinhas been shown to decrease de novo fatty acid synthesis and enhance fat oxidation , with levels of adiponectin increasing after dietary fat ingestion . decreased adiponectin is associated with insulin resistance and hyperlipidaemia , and low level of adiponectin was shown in nafld independent of the components of the metabolic syndrome [ 57 , 58 ] . interestingly , matikainen et al . suggested that liver fat content is a close correlate of postprandial lipids predicting the responses of triglyceride ( tg)-rich lipoproteins ( trl ) in chylomicrons and vldl better than measures of glucose metabolism or body adiposity . high liver fat content associated with postprandial lipemia represents potential risk factors for cardiovascular disease . furthermore , high dietary fat intake has been shown to induce perturbations in insulin signaling and rates of lipid synthesis via increased hepatic free fatty acid ( ffa ) flux and triglyceride ( tg ) . ( 2008 )   showed that tg / hdl - c ratio is a independent predictor of coronary heart disease in men . furthermore , 2 prospective large cohort studies with large numbers of individuals showed clearly that elevated nonfasting triglyceride levels were associated with increased risk of mi , ihd , and death in men and women . in woman nonfasting triglyceride levels were associated with higher cardiovascular events , independent of traditional cardiac risk factors . in addition , nonfasting triglyceride is also been shown to be associated with high risk of ischemic stroke . generally speaking postprandial lipaemia may emerge as separate cvd risk factor as is being suggested by mora et al . that nonfasting hdl cholesterol , triglycerides , total / hdl cholesterol ratio , and apolipoprotein a predict cvd better than measured in the fasting state . therefore , postprandial hyperlipidaemia may in part explain why some lean , overweight , and obese individuals with nafld may encounter cvd despite normal fasting lipid profile or being in lipid - lowering medication . several studies have shown the nafld is associated with coronary atherosclerosis , heart valve abnormality , and left ventricular dysfunction . for instance , kim et al . showed that patients with nafld are at increased risk for coronary atherosclerosis independent of classical coronary risk factors , including visceral adiposity . the authors claimed that nafld per se might be an independent risk factor for coronary artery disease . furthermore , biopsy - proven nafld is associated with marked reduction in coronary flow reserve ( marker of the integrity of coronary microvascular circulation ) . liver fibrosis scores are found to be independent predictor of marked decrease in coronary flow reserve . in patients with nafld the absence of morbid obesity , hypertension , and diabetes has mildly altered lv geometry and early features of left ventricular diastolic dysfunction . in patient with diabetes and nafld early features of lv diastolic dysfunction obstructive sleep apnea ( osa ) is characterised by loud and frequent snoring , periods of apnea during sleep , and excessive day somnolence [ 71 , 72 ] . interestingly , osa is also regarded as one of the factors that accelerate the progression of nafld to nash . importantly considerable numbers of studies showed an increase incidence of cvd with osa [ 7476 ] . animal studies showed that osa can lead to increase in insulin resistance and alteration in lipid metabolism with nafld [ 77 , 78 ] . it is possible to suggest that high fat diet in association with osa may aggravate the course of nafld . furthermore , in a rat model of fatty liver ( a choline - deficient high - fat diet ) intermittent hypoxia was shown to induce nash [ 79 , 80 ] . the conclusion of bradley and floras is that an association between osa and cvd exists . their conclusion was that osa is associated with an increased risk of cvd , and this has been demonstrated in epidemiological , clinical and physiological studies . epidemiological studies have shown a significant independent association between osa and hypertension , coronary artery disease , arrhythmias , heart failure , and stroke [ 8288 ] . the complex interaction between obesity , nafld , obesity metabolic syndrome , and cvd will accelerate atherosclerosis development . nafld may also be associated with a detrimental effect on other organs that may have direct or indirect influence on cvd or organs that may accelerate the presentation of cvd , at least in people with type 2 diabetes . for example , nafld patients with type 2 diabetes had higher ( p < 0.001 ) age- and sex - adjusted prevalence rates of both nonproliferative ( 39 versus 34% ) and proliferative / laser - treated retinopathy ( 11 versus 5% ) , and chronic kidney disease ( ckd ) ( 15 versus 9% ) than counterparts with type 2 diabetes but without nafld . furthermore , in this study , nafld was associated with an increased incidence of ckd , independent of gender , age , body mass index , waist circumference , bp , smoking , diabetes duration , glycosylated hemoglobin , lipids , baseline estimated gfr , microalbuminuria , and medications ( hypoglycemic , lipid - lowering , antihypertensive , or antiplatelet drugs ) . interestingly , nafld has been shown to be associated with the development of ckd in korean individuals . the practice guideline by the american association for the study of liver diseases , american college of gastroenterology , and the american gastroenterological association for diagnosis and management of nonalcoholic fatty liver disease recommended that statins can be used to treat dyslipidaemia in patients with nafld and nash . this recommendation is based on lack of evidence that patients with nafld and nash are at increased risk for serious drug - induced liver injury from statins . in addition , the liver expert panel stated that statins can be safely used in nafld and nash without the needs for routine liver enzyme monitoring . nafld is regarded as hepatic component of the metabolic syndrome and associated with high risk of development of cvd . dyslipidemai , insulin resistance , low adiponectin , and postprandial dyslipidaemai and hyperglycaemia are main factors lead to nafld and further aggravate the course of nafld as well as accelerate the progress of atherosclerosis and development of cvd . the mechanism and complex factors involved in the development of cvd in individuals with nafld currently , it is not known how treatment of nafld will modulate the risk of cvd . further research is urgently needed to understand the association between nafld and cvd and how potential treatment of nafld will modulate the risk of cvd .
nonalcoholic fatty liver disease ( nafld ) is prevalent in people with the metabolic syndrome and type 2 diabetes and is present in up to one - third of the general population . 
 evidence is now accumulating that nafld is associated with obesity and diabetes and may serve as a predictor of cardiovascular disease ( cvd ) . 
 the possible mechanisms linking nafld and cvd include inflammation and oxidative stress , hyperlipidaemia , insulin resistance , and direct impact of nafld on coronary arteries and left ventricular dysfunction . 
 in addition , several studies suggest that nafld is associated with high risk of cvd and atherosclerosis such as carotid artery wall thickness and lower endothelial flow - mediated vasodilation independently of classical risk factors and components of the metabolic syndrome . 
 it is not yet clear how treatment of nafld will modulate the risk of cvd . 
 furthermore , studies are urgently needed to establish ( i ) the pathophysiology of cvd with nafld and ( ii ) the benefit of early diagnosis and treatment of cvd in patients with nafld . in the absence of biochemical markers , it is crucial that screening and surveillance strategies are adopted in clinical practice in the growing number of patients with nafld and at risk of developing cvd . 
 importantly , the current evidence suggest that statins are safe and effective treatment for cvd in individuals with nafld .