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Association Between Fatty Liver and Cardiovascular Disease: Mechanism and Clinical Implications

Written By

Nseir W. and Assy N.

Published: 06 September 2011

DOI: 10.5772/21294

From the Edited Volume

Coronary Angiography - The Need for Improvement in Medical and Interventional Therapy

Edited by Branislav Baškot

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1. Introduction

NAFLD is associated with major cardiovascular risk factors including type 2 diabetes mellitus (T2DM), obesity, dyslipidemia, hypertension and insulin resistance and constitutes a new component of the metabolic syndrome (MetS) [1-2].The association of MetS and NAFLD is so strong that NAFLD is considered as the hepatic manifestation of MetS [3]. The clinical implication of NAFLD and nonalcoholic steatohepatitis (NASH) are mainly derived from their common occurrence in the general population (15%-30%) and their potential to contribute to CAD, extra hepatic cancer, diabetes, and progression to fibrosis (30%-40%), cirrhosis (20%-30%) and hepatocellular carcinoma [4-5]. Although the mechanisms underlying liver disease progression remain unclear, insulin resistance and obesity-related inflammation, obesity related ectopic fat and lipotoxicity play a key role, along with possible genetic, dietary and life style factors [6].

Most studies show that MetS is associated with a two-fold increase in CAD risk and a 5-fold increased risk for incidences of T2DM [7-12]. The importance of NAFLD component within the MetS is now increasingly recognized, and this has stimulated an interest in the possible relationship between NAFLD and cardiovascular disease (CVD). This review focuses on the relationship between NAFLD and CAD, the Biological mechanisms linking NAFLD and CAD and a proposed new treatment approach for patients with NAFLD.

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2. The relationship between NAFLD and CAD

Prevalence: NAFLD affects 15-30% of the general population [13]. The prevalence is also high in overweight and obese children [14]. Factors contributing to NAFLD include sedentary life style, and increased consumption of foods with high fat and high fructose corn syrup content (soft drinks). Steatosis is associated with an increased prevalence and incidence of CAD and cardiovascular mortality. [15- 16].

Clinical studies: Targher et al showed a significant increase of carotid intima-media thickness (IMT) in the presence of NAFLD [17]. Brea et al showed that patients with NAFLD had increased intima-media thickness (IMT), independently by the MetS [18]. Lin et al showed that patients with NAFLD were more likely to have CAD compared to patients without NAFLD, independent of obesity and other risk factors [19]. Villanova et al showed that NAFLD patients have a significant decrease in brachial artery flow- mediated vasodilatation, which correlates with the extent of liver disease. Furthermore, the 10-year probability of coronary heart disease (as calculated according to the Framingham risk score) was moderately increased in NAFLD patients, and particularly in patients with NASH [20]. This study and others provide evidence of severe endothelial dysfunction and increased risk of cardiovascular events in NAFLD [21]. Targher et al showed an increased prevalence of CAD in patients with T2DM and NAFLD as compared with diabetic patients without NAFLD [22] and that the severity of liver histology among NAFLD patients is strongly associated with early carotid atherosclerosis, independent of classical risk factors, insulin resistance, and the presence of MetS [23]. Akabame et al showed that NAFLD is a novel risk factor for vulnerable plaques, using a multislice computed tomography (MSCT) [24]. Recently, we showed that patients with NAFLD, even without MetS, have more vulnerable coronary soft plaques than healthy controls. [25] (Figure 1). Pacifico et al demonstrated that obese children with NAFLD have a marked increase in carotid IMT in comparison with control healthy children, and that the carotid IMT was higher for obese children with NAFLD than obese children without liver involvement but with similar body mass index (BMI) [26].

Figure 1.

Presence of coronary plaque in patients with Non Alcoholic Fatty Liver Disease

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3. Cause of death in patients with NAFLD

The mortality rate among patients with NAFLD followed for 8 years was higher than in the general population, [27]. In another study consisting of biopsy-proven, NAFLD patients who were followed for 18 years, CVD was among the common causes of death after all of the cancers combined [28]. In the Valpolicella Heart Diabetes Study, Targher et al showed that NAFLD patients have been associated with an increased incidence of major CVD events after excluding classical risk factors, diabetes duration, glycemic control, medication use, and components of the metabolic syndrome [29-30]. Dunn et al showed that NAFLD patients had significantly increased all-cause mortality and cardiovascular mortality, especially in the 45-54 years age group [31]. A strong association between mildly elevated serum liver enzymes as a surrogate marker of NAFLD and increased risk for CVD mortality and morbidity was reported in several population-based cohort studies [21, 32, 33]. A Swedish study consisting of 129 patients with NAFLD showed that patients with NASH had higher incidences of cardiovascular mortality compared to the reference population [34]. Recently, other studies with 28 years follow up showed that CAD was the leading cause of death in patients with NAFLD, followed by hepatic and extra hepatic malignancy and finally by cirrhosis and its complications [35, 36, Table 1].

% Number of patients Cause of death
35.0 15 CAD
28.0 12 Extra hepatic cancer
18.6 8 Liver cancer, cirrhosis
7.0 3 Diabetes mellitus
6.8 3 Poisoning
2.3 1 Intestinal Perforation
2.3 1 Alcohol abuse

Table 1.

Causes of Death in 143 patients with NAFLD (death= 43)

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4. Classical and emerging risk factors for atherosclerosis

The new risk factors for CAD include markers for inflammation (e.g. CRP, lipoprotein A), homocystine, markers of fibrinolytic and homeostatic function (e.g. fibrinogen, tissue plasminogen activator, and plasminogen activator inhibitor-1). These markers are also associated with NAFLD [37-41]. The classic common risk factors for NAFLD and CAD are age and gender [42, 43], physical inactivity [44- 47], T2 DM [48-52], hyperlipidemia [53- 56], obesity [57-63], and hypertension [64- 66]. These risk factors are well known and beyond the scope of this review.

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5. Mechanisms linking NAFLD and CAD

The biological mechanisms potentially responsible for accelerated atherogenesis in NAFLD patients may either have origin in the liver or have the liver as the target of systemic abnormalities. Here we will discuss the biological mechanisms linking NAFLD and CAD, the novel risk factors for CAD, and the common pathways of both diseases (Figure 2)

A) Oxidative stress

Oxidative stress plays an important role in the progression from simple steatosis to steatohepatitis [67]. The role of oxidative stress is supported by different animal models of

Figure 2.

Biological mechanism of accelerated atherosclerosis in patients with NAFLD. Fat accumulation in the liver induces hyperglycemia, sub clinical inflammation, atherogenic dylipidemia, lipotoxicity, and the secretion of cytokines. Thereby inducing insulin resistance, atherosclerosis, and diabetes mellitus. All contributes to coronary artery diseases.

NASH which show either increased reactive oxygen species (ROS) formation or evidence of extensive lipid peroxidation [68,69]. The association between oxidative stress and NAFLD in humans is supported by the immunohistochemical detection of lipid peroxidation products and 8-hydroxy-deoxyguanosine in the plasma and liver biopsies from patients with NAFLD [70, 71]. The earliest events in the pathogenesis of atherosclerosis are thought to be changes in endothelial functions, in turn triggered by oxidative modification of low-density lipoproteins (LDL), leading to the formation of oxidized LDL in the subintimal space [72]. The expression of chemotactic factors such as monocyte chemotactic protein-1

(MCP-1) is enhanced by oxidative stress and oxidized LDL Endothelial expression of vascular cell adhesion molecule-1 (VCAM-1), which is regulated through a redox-sensitive mechanism, promotes the adhesion of monocytes to the endothelium. The release of macrophage colony-stimulating factor (M-CSF) is also stimulated by modified LDL. Expression of these factors results in the attraction and adhesion of monocytes to the arterial wall and the promotion of their differentiation into tissue macrophages. Exposure to the superoxide ion, a ROS, activates the nuclear factor kappa-B (NF-kappa B) regulatory complex and triggers the transcription of several atherosclerosis-related genes (VCAM-1, MCP-1, tumor necrosis factor (TNF), matrix metalloproteinase (MMP)-9 and procoagulant tissue factor). This series of events leads to the accumulation of macrophages in the arterial wall, which then avidly incorporate oxidized LDL to form foam cells. Oxidized LDL, in turn, stimulates the release of interleukin-1 from macrophages. The activity of MMPs is also regulated by oxidative stress and appears to be closely linked to smooth muscle cell activation and migration. MMPs have also been implicated in the physiopathology of plaque rupture. Furthermore, ROS can lead to platelet activation and thrombus formation. Therefore, oxidative stress appears to be important in both the early and later stages of the atherosclerotic process [73, 74].

B) Insulin resistance

NAFLD is strongly associated with hepatic and adipose tissue insulin resistance (IR), as well as reduced whole-body insulin sensitivity [75]. Previous studies have documented a reduction of 45-50% in glucose disposal, and an impaired ability of insulin to suppress endogenous glucose production (hepatic IR) in subjects with NAFLD [76]. The spectrum of metabolic disturbances associated with IR extends beyond hyperglycemia and includes dyslipidemia, obesity, hypercoagulability, and inflammation. In long-term follow-up of patients with T2DM, IR was independently predictive of CAD, with a 1-unit increase in IR assessed by the homeostasis model assessment (HOMA) associated with a 5.4% increased risk for CAD [77]. Increased levels of fatty acids, (NEFA), lipotoxicity and disturbances in adipokine secretion, are believed to be related to insulin resistance. Increased levels of NEFA might affect the endothelial nitric oxide production, thereby impairing endothelium-dependent vasodilatation. They may increase myocardial oxygen requirements and, therefore. ischemia. Recent evidence in older men with CAD has shown that NEFAs are independently associated with cardiovascular mortality [78]. The Insulin Resistance and Atherosclerosis Study (IRAS) also confirmed the relation between IR and atherosclerosis in the carotid artery [79]. Overall, growing evidence suggests that hepatic insulin resistance is sufficient to induce several components of the metabolic syndrome and promote progression to cardiovascular disease

C) Sub clinical inflammation

Targher et al showed that in healthy non-smoking volunteers, plasma CRP, fibrinogen, von Willebrand factor (v-WF) and plasminogen activator inhibitor-1 (PAI-1) activity levels were markedly higher in subjects with hepatic steatosis than in those without, even after controlling for other confounders such as age, BMI, blood pressure, insulin resistance and triglyceride levels [80]. Recently, Il-6 and CRP have been shown to correlate with higher degrees of fibrosis and inflammation (i.e. NASH) in patients with NAFLD [81]. Thus, NAFLD/NASH should be considered a chronic inflammatory condition. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of atherosclerosis from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis.

Prospective epidemiological studies have found increased vascular risk in association with increased inflammatory markers such as, IL-6, TNF-α, CRP and fibrinogen [82-85]. Elevated values of circulating inflammatory markers commonly accompany acute coronary syndrome (ACS). Such elevations correlate with in-hospital and short-term prognosis [85, 86].Chronic subclinical inflammation is a common finding in NAFLD and in atherosclerosis. Moreover, chronic sub clinical inflammation is strongly involved in IR and MetS, as mainly demonstrated by mechanistic studies in animal models [87]. Ectopic fat deposition in visceral adipose depots, heart and other depots increases the expression of visceral proinflammatory mediators such as monocyte chemotactic protein-1 and IL-6, leading to local macrophage infiltration and associated systemic chronic inflammation [88].

Hepatic steatosis is associated with increased production of pro-inflammatory cytokines by hepatocytes and non-parenchymal cells, including Kupffer cells and hepatic stellate cells. Increased intra-hepatic cytokine expression results from local NF-kB activation, mediated by hepatocellular damage and fat-derived factors, and is likely to play a major role in NAFLD progression and CVD pathogenesis [81, 88-90].

An atherogenic role of liver inflammation is supported by the observation that CAD risk is greater in NASH than in simple hepatic steatosis [27, 28].

D) Adiponectin

Liver fat accumulation, NEFAs, adiponectin, low-grade inflammation in the context of insulin resistance patient with fatty liver, might explain the development of endothelial dysfunction and early cardiovascular disease. Mature adipocytes act as an active endocrine and paracrine organ, secreting an increasing number of growth factors that participate in diverse metabolic processes, particularly IR. Patients with NAFLD exhibit reduced levels of adiponectin, which are inversely correlated with the severity of NAFLD histology [91-93]. The reduced production of adiponectin associated with obesity may contribute to the progression of NAFLD [89]. Adiponectin increases the expression of messenger RNA and protein production of tissue inhibitor of metalloproteinase in macrophages through the induction of IL-10 synthesis and selectively suppresses endothelial cell apoptosis [94, 95]. This suggests that adiponectin protects plaque rupture by the inhibition of matrix metalloproteinase function. Endothelium-dependent vasoreactivity is impaired in people with hypoadiponectinaemia, which might be at least one cause of hypertension in visceral obesity [96]. The protein inhibits the expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), ICAM-1 and E-selectin, through the inhibition of NF-ĸB activation; it also suppresses foam-cell formation. From this, it is clear that adipokines are capable of contributing to remodeling of the myocardial extracellulat matrix [96]

E) Myocardial Lipotoxicity

Increasing plasma free fatty acids for few hours causes endothelial dysfunction and induces the production of systemic inflammation, and pro coagulants in vitro, in animal models and in humans. Of interest, free fatty acid impairs nitric oxide production by endothelial cells through the activation of an IKKb- mediated response. For instance, subjects with either glucose intolerance or T2DM have a significant increase in myocardial triglyceride content. There is a significant correlation between the development of fatty liver and abnormalities in left ventricular energy metabolism. [97]. In Diabetic patients with NAFLD, fatty liver and elevated aminotransferases coexist with myocardial insulin resistance and coronary dysfunction [97]

F) Atherogenic dyslipidemia

Liver fat accumulation originate from peripheral fats stored in adipose tissue that flow to the liver via the plasma nonesterified fatty acid (NEFA, 60%) pool, fatty acids newly made within the liver through de novo lipogenesis (DNL, 30%), and from dietary fatty acid uptake (10%). The fat of lipids entering the liver may be secreted as very low-density lipoprotein (VLDL) triglycerides, oxidized or stored. The major component of dyslipidemia in NAFLD patients is an elevation of serum triglycerides (TG) which comes mainly from increased concentration of VLDL. In addition to increased synthesis of VLDL, there is also decreased clearance of triacylglycerol-rich lipoprotein (TRLs) induced by a decrease in lipoprotein lipase activity [98]. Other components of dyslipidemia, such as formation of small dens low-density lipoprotein (LDL), are closely associated with IR and hypertriglyceridemia [99]. VLDL1 triglyceride is a major predictor of LDL size. It seems that stimulated hepatic lipase activity favors the formation of small dense LDL particles. The increased activity of hepatic lipase in IR conditions such as in NAFLD and obesity produces smaller HDL particles, leading to increased HDL elimination [100]. In addition, increased levels of VLDL1 alter the composition of HDL, leading finally to an increased catabolism of these particles, which explains the inverse correlation of HDL and liver fat [101]. In summary, patients with NAFLD have increased levels of VLDL, TG, and small dense LDL particles and decreased levels of HDL. The presence of small dense LDL particles is associated with increased CVD risk [102]. Small dense LDL particles can move through endothelial fenestrations, entering the subendothelial space where inflammation and transformation into plaque can occur, and leading finally to coronary artery diseases [103]. Further, alterations in smooth muscle ion channels, Ca2+ handling, and cell signaling may be important mechanisms leading to coronary micro vascular dysfunction [103].

G) Postprandial lipemia

Exaggerated postprandial lipemia is an established CVD risk in T2DM [104]. Studies comparing the postprandial response of TG and FFA to a fat rich meal in nondiabetic subjects with biopsy proven NASH to control subjects showed that patients with NASH had significantly higher postprandial TG levels than healthy control subjects [105]. Other studies support a close relationship between dietary habits, postprandial lipemia and CAD [106]. The atherosclerotic risk of postprandial hyperlipidemia is derived from an increase of remnant lipoproteins (RLPs) [107]. In patients with IR, an increase of postprandial RLP values usually occurs and becomes a coronary risk factor. The RLP is easily taken into the macrophage in the arterial wall via the apolipoprotein B48 receptor, promoting foam cell formation of macrophages and performing the atherosclerotic lesion as is oxidized LDL [108]. Stanhope et al showed that consumption of fructose-sweetened but not glucose-sweetened beverages for 10 weeks increases de novo lipid synthesis and the 24-hour postprandial TG including increased levels of apoB, LDL, oxidized LDL, RLP triglyceride, and the apoB / apoA1 ratio ( all biomarkers of increased for CAD) [109].

Dietary habits and genetic determinants, including microsomal transfer protein (MTP) polymorphisms, may promote NASH and atherogenesis via hypoadiponectinaemia [110,111]. Recently, Musso et al reported that the risk of adiponectin single-nucleotide polymorphisms (SNPs) 45TT and 276 GT are significantly more prevalent in NAFLD than in the general population and are associated with the severity of liver disease. In addition, an association with an atherogenic postprandial lipoprotein profile in NASH was detected independently of fasting adipokine and lipid levels [112].

H) Pro-coagulation and hypofibrinolysis

The prothrombotic state in the atherosclerosis process encompasses platelets hyperaggregability, hypercoagulability and hyperfibrinolysis. Markers of fibrinolytic and hemostatic function (e.g. fibrinogen, tissue plasminogen activator, and plasminogen activator inhibitor 1-antigens), are strongly associated with NAFLD. Plasminogen activator inhibitor-1(PAI-1) is expressed in visceral adipose tissue. It is mainly expressed in stromal cells including monocytes, smooth muscle cells and pre-adipocytes [113]. Plasma PAI-1 levels are more closely related to fat accumulation and PAI-1 expression in the liver than in adipose tissue, suggesting that, among insulin-resistant individuals, the fatty liver is an important site of PAI-1 production [114]. We showed also that there is an association between the thrombotic risk factors and the extent of fibrosis in patients with NAFLD [40]. This confirms the central role of the liver in these processes. Fibrinogen, von Willebrand factor (vWF) and PAI-1 are also considered markers of the acute-phase reaction of inflammation and thrombosis, and has been closely linked to CAD and diabetes mellitus [115]. CRP increases PAI-1 expression and activity in human aortic endothelial cells [116].

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6. Clinical implications

It is evident that patients with NASH are more prone to develop CAD (Increase mortality by 86%) than patients with simple steatosis (increase mortality by 55%, 117); however, it has not been clear until now whether the treatment of NAFLD patients will prevent CAD development. We suggest adding a new modality of approaching patients with NAFLD. Once the diagnosis of NAFLD was made, the first step will be a lifestyle intervention using a combination of diet, active walking, and behavior modification [118], with a goal of >10% weight reduction [119]. Mediterranean diet derived mainly from olive oil (rich in omega-9) is recommended [120,121]. We advise to reduce or discontinue the consumption of fast foods and regular soft drinks, which contain fructose [122]. Recently Dunn et al showed that modest wine drinking (20-30 gram/daily) offers protection against suspected NAFLD [123].The second step is to assess the risk of hepatic fibrosis: There are two modalities of assessment of fibrosis in NAFLD: The noninvasive methods of fibrosis include BARD score or Angulo score [124,125]. The invasive methods (liver biopsy) remains the only reliable means to determine prognosis based on the severity of fibrosis.

The third step will include the assessment of cardiovascular risk stratification: We suggest the use of the Framingham score with effort test and/or measurements of the carotids arteries (IMT) as well as biomarkers of inflammation (CRP, fibrinogen), oxidative stress, (MDA, Paraoxonase), Insulin Resistance, (HOMA), lipotoxicity (TG, HDL, LDL, TC), OGTT, and microalbumin/creatinin ratio [126].

The fourth step includes the assessment of malignancy: For patients older than > 45. Colonoscopy, mammography, chest X-ray, gynecology consultation, and tumor markers (CEA, AFP, PSA, and CA19-9, and CA125, stool blood) are recommended since malignancy is the second most common cause of death in patients with NAFLD [127]. The final step is to initiate an appropriate therapy according to the comorbidities, and the clinical status of each patient. A combination therapy is favored.

A) Patients with metabolic syndrome

The most effective antidiabetic agent is metformin especially in obese T2DM or pioglitazone in non-obese patients [128,129]. We advice to delay early insulin therapy because it may increase fibrosis and weight [130]. Whether insulin increases the risk of HCC or not is still under debate. Exenatide induces significant weight loss, which may lead to an insulin-sensitizing effect [131]. Gliptins are a group of drugs, which increase incretin levels by inhibiting the enzyme DPP-4. These agents are relatively new and, as for the GLP-1 analogues, improve insulin resistance in prediabetic individuals and patients with T2DM after weight loss [132]. Lipid-lower agents are mandatory treatment in diabetic patients with NAFLD, statins and fibrates for dyslipidemic and diabetic patients [133-135] are recommended. Renin-angiotensin system (RAS) inhibitors or alpha-blockers for hypertensive patients [136,137]. However, these types of medicines are not approved solely for fatty liver. Low dose aspirin is reasonable for patients with 10 years cardiovascular disease risk >10% and no risk factors for bleeding.

B) Patients without metabolic syndrome

Best evidence for metformin or pioglitazone for 1-2 year in treating NAFLD patients without MetS. However, routine prescription of this drug (pioglitazone) needs further clarification. Vitamin E (400 IU/day) and omega-3 may be recommended [138,139]. However, vitamin E is not approved yet and high dosage may increase all cause mortality (140). Ursodeoxycholic acid has no benefit for NASH patients as compared to placebo (141). Statins for dyslipidemic patients. Aspirin to prevent CAD according to Framingham score (142). Diagnosis of NAFLD may be a clear indication for diabetes screening, and cardiovascular risk screening and should be performed with the use of existing risk calculators and should be guided by established cardiovascular risk factors.

  1. For patients with metabolic syndrome: tailored therapy

  2. Metformin/ Pioglitazon/Insulin for T2DM.

  3. However, routine prescription needs further clarification

  4. Statins /Fibrates for atherogenic dyslipidemia

  5. Renin angiontensin system inhibitors/ α- blockers for hypertension

  6. For patients without metabolic syndrome:

  7. Best evidence for metformin/ pioglitazone or vitamin E.

  8. However, high dose vitamin E (>400 IU/day) may increase mortality

  9. Currently, high dose ursodeoxycholic acid has no benefit for NASH patients

  10. Omega-3 and vitamin D (2000 IU/day) may be beneficial.

  11. For the future:

  12. Promising agents awaiting randomized controlled trials (Fatostatin,

  13. (Aramchol, DPP-4 inhibitors, GLP-1 agonists and combination therapy)

Table 2. Pharmacologic treatment of patients with NAFLD

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7. Conclusion

NAFLD is a growing public health problem worldwide. The clinical impact of NAFLD on CAD risk deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of NAFLD patients. NAFLD is associated with increased biomarkers level of chronic inflammation and atherosclerosis. Pharmacotherapy should be given for patients at high risk for complications (NASH, T2DM, obesity, atherogenic dyslipidemia). However, it is not currently known whether improving NAFLD will prevent the development and progression of CAD. Moreover, the prognostic value of NAFLD in CAD risk stratification has yet to be determined. NAFLD patients should be candidate not only for aggressive treatment of their liver disease, but also for aggressive treatment of underlying CAD risk factors, because many patients with NAFLD will have major CAD events and die prior to the development of advanced liver disease.

References

  1. 1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002 346 1221 1231
  2. 2. Targher G. Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease. Atherosclerosis 2007
  3. 3. Marchesini G. Bugianesi E. Forlani G. Cerrelli F. Lenzi M. Manini R. et al. Nonalcoholic fatty. liver steatohepatitis. the metabolic. syndrome Hepatology 2003 4 917 923
  4. 4. Younossi Z. Diehl A. M. Ong J. P. Nonalcoholic fatty liver disease: an agenda for clinical research. Hepatology 2002 35 746 52
  5. 5. Bruke A. Lucey M. R. Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic liver transplantation. Am J Transplant 2004 5 686 693
  6. 6. Petersen K. F. Dufour S. Hariri A. Nelson-Williams C. Foo J. N. Zhang X. M. et al. Apolipoprotein C. gene variants. in nonalcoholic. fatty liver. disease Nelson-Williams C, Foo JN, Zhang XM, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010 362 1082 1089
  7. 7. Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, et al. 2007Metabolic syndrome and risk of incident cardiovascular events and death: a systemic review and meta-analysis of longitudinal studies. J Am Coll Cardiol
  8. 8. Ford E. S. Schulze M. B. Pischon T. MM Bergmann Joost. H. G. Boeing H. 2008Metabolic syndrome and risk of incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. Cardiovasc Diabetol
  9. 9. Ford E. S. Li C. Sattar N. 2008 Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care ;9 1898 904
  10. 10. Lakka H. M. Laaksonen D. E. Lakka T. A. Niskanen L. K. Kumpusalo E. Tuomilehto J. et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002 21 2709 2716
  11. 11. Isomaa B. Almgren P. Tuomi T. Forsén B. Lahti K. Nissén M. et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001 24 683 689
  12. 12. Malik S. Wong N. D. Franklin S. S. Kamath T. V. L’Italien G. J. Pio J. R. et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004 10 1245 1250
  13. 13. JD Browning Szczepaniak. L. S. Dobbins R. Nuremberg P. JD Horton Cohen. J. C. et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004 40 1387 1395
  14. 14. Sagi R. Reif S. Neuman G. Webb M. Phillip M. Shalitin S. Nonalcoholic fatty liver disease in overweight children and adolescents. Acta Paediatr 2007 96 1209 1213
  15. 15. Hamaguchi M. Kojima T. Takeda N. Nagata C. Takeda J. Sarui H. et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007 13 1579 1584
  16. 16. Abid A. Taha O. Nseir W. Farah R. Grosovski M. Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 2009 51 918 924
  17. 17. Targher G. Bertolini L. Padovani R. Zenari L. Zoppini G. Falezza G. 2004 Relation of nonalcoholic hepatic steatosis to early carotid atherosclerosis in healthy men: role of visceral fat accumulation. Diabetes Care ;10 2498 2500
  18. 18. Brea A. Mosquera D. Martin E. Arizti A. Cordero J. L. Ros E. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: a case-control study. Arterioscler Thromb Vasc Biol 2005 5 1040 1050
  19. 19. Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease.World J Gastroenterol 2005 11 4838 4842
  20. 20. Villanova N. Moscatiello S. Ramilli S. Bugianesi E. Magalotii D. Vanni E. et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005 2 473 480
  21. 21. Schindhelm R. K. Diamant M. Bakker S. J. van Dijk R. A. Scheffer P. G. Teerlink T. et al. Liver alanine. aminotransferase insulin. resistance endothelial dysfunction. in normotriglyceridaemic. subjects with. type . diabetes mellitus. Eur J Clin Invest 2005 6 369 374
  22. 22. Targher G. Bertolini L. Padovani R. Poli F. Scala L. Tessari R. et al. Increased prevalence of cardiovascular disease in Type 2 diabetic patients with non-alcoholic fatty liver disease. Diabet Med 2006 23 403 409
  23. 23. Targher G. Bertolini L. Padovani R. Rodella S. Zoppini G. Zenari L. et al. Relation between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006 29 1325 1330
  24. 24. Akabame S. Hamaguchi M. Tomiyasu K. Tanaka M. Kobayashi-Takenaka Y. Nakano K. et al. Evaluation of vulnerable coronary plaques and non-alcoholic fatty liver disease (NAFLD) by 64-detector multislice computed tomography (MSCT). Circ J 2008 72 618 625
  25. 25. Assy N. Djibre A. Farah R. Grosovski M. Marmor A. Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology 2010 254 393 400
  26. 26. Pacifico L. Cantisani V. Ricci P. Osborn J. F. Schiavo E. Ferrara E. et al. Nonalcoholic fatty liver disease and carotid atherosclerosis in children. Paediatr Res 2008 63 423 427
  27. 27. Adams L. A. Lymp J. F. St Sauver. J. Sanderson S. O. Lindor K. D. Feldstein A. et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005 1 113 121
  28. 28. CA Matteoni Younossi. Z. M. Gramlich T. Boparai N. Liu Y. C. Mc Cullough A. J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999 6 1413 1419
  29. 29. Targher G. Bertolini L. Poli F. Rodella S. Scala L. Tessari R. et al. Nonalcoholic fatty liver disease and risk of future cardiovascular events among type 2 diabetic patients. Diabetes 2005 54 3541 3546
  30. 30. Targher G. Bertolini L. Rodella S. Tessari R. Zenari L. Lippi G. et al. 2007 Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care ; 8 2119 2121
  31. 31. Dunn W. Xu R. Wingard D. L. Rogers C. Angulo P. Younossi Z. M. et al. 2008 Suspected nonalcoholic fatty liver disease and mortality risk in a population-based cohort study. Am J Gastroenterol ;9 2263 2271
  32. 32. Ruttmann E. Brant L. J. Concin H. Diem G. Rapp K. Ulmer H. Gamma-glutamyltransferase as a risk factor for cardiovascular disease mortality: an epidemiological investigation in a cohort of 163,944 Austrian adults. Circulation (2005);14 2130 2137
  33. 33. DS Lee Evans. J. C. Robins S. J. Wilson P. W. Albano I. Fox C. S. et al. Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2007 1 127 133
  34. 34. Ekstedt M. Franzen L. E. Mathiesen U. L. Thorelius L. Holmqvist M. Bodemar G. et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006 40 865 873
  35. 35. Ong J. P. Pitts A. Younossi Z. M. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol 2008 49 608 612
  36. 36. Soderberg C. Stal P. Askling J. Glaumann H. Lindberg G. Marmur J,et. al Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010 2 595 602
  37. 37. Park SH, Kim BI, Yun JW, Kim JW, Park DI, Cho YK, et al.Insulin resistance and C-reactive protein as independent risk factors for non-alcoholic fatty liver disease in non-obese Asian men. J Gastroenterol Hepatol 2004 6 694 698
  38. 38. Lee S. Jin Kim. Y. Yong Jeon. T. Hoi Kim. H. Woo O. H. S. Park Y. et al. Obesity is the only independent factor associated with ultrasound-diagnosed non-alcoholic fatty disease: a cross-sectional case-control study. Scand J Gastroenterol 2006 51 566 572
  39. 39. Hirsch S. Poniachick J. Avendano M. Csendes A. Burdiles P. Smok G. et al. Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition 2005 2 137 141
  40. 40. Assy N. Bekirov I. Mejritsky Y. Solomon L. Szvalb S. Hussein O. Association between thrombotic risk factors and extent of fibrosis in patients with non-alcoholic fatty liver diseases. World J Gastroenterol 2005 37 5834 5839
  41. 41. Sookoian S. Castano G. O. Burgueno A. L. MS Rosselli Gianotti. T. F. Mallardi P. et al. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis 2010 2 585 591
  42. 42. Ruhl CE, Everhart JE.Epidemiology of nonalcoholic fatty liver. Clin Liver Dis 2004 3 501 519
  43. 43. Carulli L. Lonardo A. Lombardini S. Marchesini G. Loria P. Gender fatty. liver G. G. T. Hepatology 2006 44 278 279
  44. 44. Powell KE, Thompson PD, Caspersen CJ, Kendrick JS.Physical activity and the incidence of coronary heart disease. Annu Rev Public Health 1987 8 253 287
  45. 45. Hsieh S. D. Yoshinaga H. Muto T. Sakurai Y. Regular physical activity and coronary risk factors in Japanese men. Circulation 1998 97 661 665
  46. 46. Church T. S. Kuk J. L. Ross R. Priest E. L. Biltoft E. Blair S. N. 2006 Association of cardiorespiratory fitness, body mass index, and waist circumference to nonalcoholic fatty liver disease. Gastroenterology ;7 2023 2030
  47. 47. Zelber-Sagi S. Nitzan-Kaliski D. Goldsmith R. Webb M. Zvibel I. Goldiner I. et al. Role of leisure-time physical activity in alcoholic fatty liver disease: a population-based study. Hepatology 2008 48 1791 1798
  48. 48. Stamler J. Vaccaro O. JD Neaton Wentworth. D. Diabetes other. risk factors. 12-yr cardiovascular. mortality for. men screened. in the. Multiple Risk. Factor Intervention. Trial Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993 16 434 444
  49. 49. Adlerberth A. M. Rosengren A. Wilhelmsen L. Diabetes and long-term risk of mortality from coronary and other causes in middle-aged Swedish men. A general population study. Diabetes Care 1998 21 539 545
  50. 50. De Marco R. Locatelli F. Zoppini G. Verlato G. Bonora E. Muggeo M. Cause-specific mortality in type 2 diabetes. The Verona Diabetes Study. Diabetes Care 1999 22 756 761
  51. 51. Marchesini G. Marzocchi R. Agostini F. Bugianesi E. Nonalcoholic fatty. liver disease. metabolic syndrome. Curr Opin. Lipidol 2005 16 421 427
  52. 52. Hanley A. J. Williams K. Festa A. Wagenknecht L. E. D’Agostino R. B. Jr Kempf J. et al. Insulin resistance atherosclerosis study. Diabetes 2004 53 2623 2632
  53. 53. Stamler J. Wentworth D. JD Neaton Is relationship between serum cholesterol and risk of premature death from coronary heart continues and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986 256 2823 2828
  54. 54. Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. 2000 Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci ; 45:1929-1934
  55. 55. Clark JM, Diehl AM. 2003Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 289 3000 3004
  56. 56. Radu C. Grigoriscu M. Crisan D. Lupsor M. Constantin D. Dina L. Prevalence and associated risk factors of non-alcoholic fatty liver disease in hospitalized patients. J Gastrointestin Liver Dis 2008 17 255 260
  57. 57. Rabkin SW, Mathewson FA, Hsu PH. 1977Relation of body weight to development of ischemic heart disease in a cohort of young North American men after a 26 year of observation period: the Manitoba study. Am J Cardiol 39 452 458
  58. 58. Hubert H. B. Feinleib M. Mc Namara P. M. Castelli W. P. 1983Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67 968 977
  59. 59. Ruhl CE, Everhart JE. 2003 Determination of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 124 71 79
  60. 60. Marcos A, Fisher RA, Ham JM, Olzinski AT, Shiffman ML, Sanyal AJ, Luketic VA, et al. 2000 Selection and outcome of living donors for adult-to-adult right lobe transplantation. Transplantation ; 69:2410-2415
  61. 61. Hilden M. Christoffersen P. Juhl E. Dalgaard J. B. Liver histology in a ‘normal’ population- examination of 503 consecutive fatal traffic casualties. Scand J Gastroenterol 1977 12 593 597
  62. 62. Lee RG.Nonalcoholic steatohepatitis a study of 49 patients. Hum Pathol 1989 594 598
  63. 63. Gholam PM, Kotler DP, Flancbaum LJ.Liver pathology in morbidity obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg 2000 12 49 51
  64. 64. Neal B, MacMahon S, Chapman N.2000 Effects of ACE inhibitors, calcium antagonists, and other blood pressure-lowering drugs. Lancet ; 356:1955-1964 356 1955 1964
  65. 65. Donati G. Stagni B. Piscaglia F. Venturoli N. Morselli-Labate A. M. Rasciti L. et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut 2004 53 1020 1023
  66. 66. Yokohama S. Yoneda M. Haneda M. Okamoto S. Okada M. Aso K. et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004 40 1222 1225
  67. 67. Day CP. 2002 Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut :50:585-588.
  68. 68. Yang S. Zhu H. Gabrielson K. MA Trush Diehl. A. M. Mitochondrial adaptation to obesity-related oxidant stress. Arch Biochem Biophys 2000 378 259 268
  69. 69. Leclercq I. A. Farrel G. C. Field J. Bell D. R. Gonzalez F. J. Robertson G. R. C. Y. P. E. as microsomal C. Y. P. A. catalysts of. lipid peroxides. in murine. nonalcoholic steatohepatitis. J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest 2000 105 1067 1075
  70. 70. Seki S. Kitada T. Yamada T. Sakaguchi H. Nakatani K. Wakasa K. 2002 In situ detection of lipid peroxidation and oxidative DNA damage in non-alcoholic fatty liver disease. J Hepatol 37 56 62
  71. 71. Chalasani N. MA Deeg Crabb. D. W. 2004 Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 99 1497 1502
  72. 72. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, et al. 1995 Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation ;91:2488-2496
  73. 73. Nishio E. Watanabe Y. The involvement of reactive oxygen species and arachidonic acid in alpha 1-adrenoceptor-ibduced smooth muscle cell proliferation and migration. Br J Pharmacol 1997 121 665 70
  74. 74. Schulz E. Anter E. Keaney J. F. Oxidative stress. antioxidants endothelial function. Curr Med Chem 2004 11 1093 1104
  75. 75. Bugianesi E. Mc Cullough A. J. Marchesini G. Insulin resistance. a. metabolic pathway. to chronic. liver disease. Hepatology 2005 42 987 1000
  76. 76. Seppala-Lindroos A. Vehkavaara S. Hakkinen A. M. Goto T. Westerbacka J. Sovijarvi A. et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002 87 3023 3028
  77. 77. Bonora E. Formentini G. Calcaterra F. Lombardi S. Marini F. Zenari L. et al. H. O. M. HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Diabetes Care 2002 25 1135 1141
  78. 78. Pilz S. Scharnagl H. Tiran B. Seelhorst U. Wellnitz B. Boehm B. O. et al. Free fatty acids are independently associated with all-cause and cardiovascular mortality in subjects with coronary artery disease. J Clin Endocrinol Metab 2006 91 2542 2547
  79. 79. Howard G, O’Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, et al. 1996 Insulin sensivity and atherosclerosis: the Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation ; 93:1809-1817
  80. 80. Targher G. Bertolini L. Scala L. Zoppini G. Zenari L. Falezza G. Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue. Diabet Med 2005 22 1354 1358
  81. 81. Wieckowska A. Papouchado B. G. Li Z. Lopez R. Zein N. N. Feldstein A. E. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008 103 1372 1379
  82. 82. Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S, Braunwald E. 2000 Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction. Circulation ; 101:2149-2153
  83. 83. Ridker P. M. Rifai N. MJ Stampfer Hennekens. C. H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000 101 1767 1772
  84. 84. Ridker P. M. Hennekens C. H. Buring J. E. Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Eng J Med 2000 342 836 843
  85. 85. Toss H. Lindahl B. Siegbahn A. Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. Circulation 1997 96 4204 4210
  86. 86. Rebuzzi A. G. Quaranta G. Liuzzo G. Caligiuri G. Lanza G. A. Gallimore J. R. et al. Incremental prognosis value of serum levels of troponin T and C-reactive protein on admission in patients with unstable angina pectoris. Am J Cardiol 1998 82 715 719
  87. 87. Shoelson SE, Lee J, Goldfine AB. 2006 Inflammation and insulin resistance. J Clin Invest ; 116:1793-1801
  88. 88. Van Gaal LF, Mertens IL, De Block CE.Mechanisms linking obesity with cardiovascular disease. Nature 2006 444 875 880
  89. 89. Day CP.From fat to inflammation. Gastroenterology 2006 130 207 210
  90. 90. Marra F. Gastaldelli A. Svegliati Baroni. G. Tell C. Tiribelli C. Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med 2008 14 72 81
  91. 91. Libby P. Inflammation in. atherosclerosis Nature. 2002 420 868 874
  92. 92. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. 2008 JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med ; 359:2195-2207
  93. 93. Hui J. M. Hodge A. Farrell G. C. Kench J. G. Kriketos A. George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 2004 40 46 54
  94. 94. Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, et al. 2004 Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation ; 109:2046-2049
  95. 95. Kobayashi H. Ouchi N. Kihara S. Walsh K. Kumada M. Abe Y. et al. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin. Circ Res 2004e27 31
  96. 96. Schram K. Sweeney G. Implications of myocardial matrix remodeling by adipokines in obesity-related heart failure. Trends Cardiovasc Med. 2008 18 199 205
  97. 97. Lautamäki R. Borra R. Iozzo P. Komu M. Lehtimäki T. Salmi M. Jalkanen S. Airaksinen K. E. Knuuti J. Parkkola R. Nuutila P. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am J Physiol Endocrinol Metab. 2006E282 90
  98. 98. Taskinen MR.Lipoprotein lipase in diabetes. Diabetes Metab Rev 1987 3 551 570
  99. 99. Verges B. New insight into the pathophysiology of lipid abnormalities in type 2 diabetes. Diabetes Metab 2005 31 429 439
  100. 100. Frenais R, Nazih H, Ouguerram K, Maugeais C, Zair Y, Bard JM, et al. 2001 In vivo evidence for the role of lipoprotein lipase activity in the regulation of Apolipoprotein AI metabolism: a kinetic study in control subjects and patients with type II diabetes mellitus. J Clin Endocrinol Metab ; 86:1962-1967
  101. 101. Adiels M. Taskinen M. R. Packard C. MJ Caslake-Paavonen Soro. Westerbacka A. et J. al Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006 49 755 765
  102. 102. Gardner CD, Fortmann SP, Krauss RM.Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. J Am Med Assoc 1996 276 875 881
  103. 103. [103] Kwiterovich. P. O. Clinical relevance of the biochemical, metabolic, and genetic factors that influence low-density lipoprotein heterogeneity. Am J Cardiol 2002i-47i.
  104. 104. Adiels M. Olofsson S. O. Taskinen M. R. Boren J. Diabetic dyslipidemia. Curr Opin Lipidol 2006 17 238 246
  105. 105. Cassader M. Gambino R. Musso G. Depetris N. Mecca F. Cavallo-Perin P. ey al. Postprandial triglyceride-rich lipoprotein metabolism and insulin sensitivity in nonalcoholic steatohepatitis patients. Lipids 2001 1117 1124
  106. 106. Roche HM, Gibney MJ.The impact of postprandial lipemia in accelerating atherothrombosis. J Cardiovasc.Risk 2000 7 317 324
  107. 107. Tanaka A. Postprandial hyperlipidemia and atherosclerosis. J Atheroscler Thromb 2004 11 322 329
  108. 108. Brown M. L. Ramprassad M. P. Umeda P. K. Tanaka A. Kobayashi Y. Watanabe T. et al. A. macrophage receptor. for apolipoprotein. B4 cloning expression. atherosclerosis Proc Natl Acad Sci USA 2000 97 7488 7493
  109. 109. Stanhope KL, SchwarzJM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al. Consuming fructose-sweetened, not glucose- sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensivity in overweight / obese humans. J Clin Invest 2009 119 1322 1334
  110. 110. Musso G. Gambino R. Durazzo M. Biroli G. Carello M. Faga E. et al. Adipokines in. N. A. S. H. postprandial lipid. as metabolism a. link between. adiponectin liver disease. Hepatology 2005 42 1175 1183
  111. 111. Musso G. Gambino R. De Michieli F. Cassader M. Rizzetto M. Durazzo M. et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003 37 909 916
  112. 112. Musso G. Gambino R. De Michieli F. Durazzo M. Pagano G. Cassader M. Adiponectin gene polymorphisms modulate acute adiponectin responses to dietary fat: Possible pathogenetic role in NASH. Hepatology 2008 47 1167 1177
  113. 113. Bastelica D. Morange P. Berthet B. Borghi H. Lacroix O. Grino M. et al. Stromal cells are the main plasminogen activator inhibitor-1-producing cells in human fat: evidence of differences between visceral and subcutaneous deposits. Arterioscler Thromb Vasc Biol 2002 22 173 178
  114. 114. Alessi M. C. Bastelica D. Mavri A. Morange P. Berthet B. Grino M. et al. Plasma P. A. I. levels are. more strongly. related to. liver steatosis. than to. adipose tissue. accumulation Arterioscler Thromb Vasc Biol 2003 23 1262 1268
  115. 115. Esmon CT.The interactions between inflammation and coagulation. Br J Haematol 2005 131 417 430
  116. 116. Devaraj S. Xu D. Y. Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implication for the metabolic syndrome and atherothrombosis. Circulation 2003 107 398 404
  117. 117. Targher G. Non-alcoholic Fatty Liver Disease and Cardiovascular Disease. Curr Cardio Risk Rep 2010 4 32 39
  118. 118. Kantartzis K. Thamer C. Peter A. Machann J. Schick F. Schrami C. et al. High cardiorespiratory fitness is a an independent predictor of the reduction in liver fat during a lifestyle intervention in non-alcoholic fatty liver disease. Gut 2009 58 1281 1288
  119. 119. Promrat K. Kleiner D. E. Niemeier H. M. Jackvony E. Kearns M. Wands J. R. et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010 51 121 129
  120. 120. Assy N, Nassar F, Nasser G, Grosovski M. 2009 Olive oil consumption and non-alcoholic fatty liver disease. World J Gastroenterol ;15:1809-1815
  121. 121. Estruch R, Martinez- Gonzalez MA, Corella D, Salas- Salvado J, Ruiz- Gutierrez V, Covas MI, et al; 2008 PREDIMED study Investigators. Effect of a Mediterranean diet supplemented with nuts on metabolic syndrome status: one-year results of the PREDIMED randomized trial. Arch Intern Med ;22:2449-2458
  122. 122. Nseir W. Nassar F. Assy N. Soft drinks consumption and nonalcoholic fatty liver disease. World J Gastroenterol 2010 16 2579 2588
  123. 123. Dunn W, Xu R, Schwimmer JB. 2008 Modest wine drinking and decreased prevalence of suspected nonalcoholic fatty liver disease. Hepatology ; 47:1947-1954
  124. 124. Harrison S. A. Oliver D. Arnold H. L. Gogia S. BA Neuschwander-Teri Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008 57 1441 1447
  125. 125. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. Hepatology 2007; 45:846-854.
  126. 126. Hwang ST, Cho YK, Yun JW, Park JH, Kim HJ, Park DI, et al. Intern Med J 2009Impact of NAFLD on microalbuminuria in patients with prediabetes and diabetes. May 8. [Epub ahead of print]
  127. 127. Smith RA, Cokkinides V, Brooks D, Saslow D, Brawley OW. 2010 Cancer screening in the United States, 2010: a review of current American Cancer Society guidelines and issues in cancer screening. CA Cancer J Clin ; 60:99-119
  128. 128. Marchesini G. Brizi M. Bianchi G. Tomassetti S. Zoli M. Melchionda N. Metformin in non-alcoholic steatohepatitis. Lancet 2001 9285 893 894
  129. 129. Promrat K. Lutchman G. Uwaifo G. I. Freedman R. J. Soza A. Heller T. et al. A. pilot study. of pioglitazone. treatment for. nonalcoholic steatohepatitis. Hepatology 2004 1 188 196
  130. 130. Paradis V. Perlemuter G. Bonvoust F. Dargere D. Parfait B. Vidaud M. et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001 34 73 44
  131. 131. Klonoff D. C. Buse J. B. Nielsen L. L. Guan X. Bowlus C. L. Holcombe J. H. et al. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin 2008 1 275 286
  132. 132. Balaban Y. H. Korkusuz P. Simsek H. Gokcan H. Gedikoglu G. Pinar A. et al. Dipeptidyl peptidase. I. V. . D. D. P. I. V. in N. A. S. H. patients Ann. Hepatol 2007 4 242 250
  133. 133. Antonopoulos S. Mikros S. Mylonopoulou M. Kokkoris S. Giannoulis G. Rosuvastatin as a novel treatment of non-alcoholic fatty liver disease in hyperlipidemic patients. Atherosclerosis 2006 1 233 234
  134. 134. Gomez-Dominguez E. Gisbert J. P. Moreno-Monteagudo J. A. García-Buey L. Moreno-Otero R. A. pilot study. of atorvastatin. treatment in. dyslipemid non-alcoholic. fatty liver. patients Aliment Pharmacol Ther 2006 11 1643 1647
  135. 135. Browning JD.Stains and hepatic steatosis: perspectives from the Dallas Heart Study. Hepatology 2006 44 466 471
  136. 136. Yoshiji H. Kuriyama S. Yoshii J. Ikenaka Y. Nakatani T. Tsujinoue H. et al. Angiotensin-I I. type . receptor interaction. is a. major regulator. for liver. fibrosis development. in rats. Hepatology 2001 34 745 750
  137. 137. Georgescu E. F. Ionescu R. Niculescu M. Mogoanta L. Vancica L. Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis. World J Gastroenterol 2009 8 942 954
  138. 138. Sanyal A. J. Mofrad P. S. MJ Contos Sargeant. C. Luketic V. A. Sterling R. K. et al. A. pilot study. of vitamin. E. versus vitamin. E. pioglitazone for. the treatment. of nonalcoholic. steatohepatitis Clin Gastroenterol Hepatol 2004 12 1107 1115
  139. 139. Masterton GS, Plevris JN, Hayes PC. Review article: omega-3 fatty acids- a promising novel therapy for non-alcoholic fatty liver disease.Aliment Pharmacol Ther 2010 7 679 692
  140. 140. Miller E. R. 3rd Pastor-Barriuso R. Dalal D. Riemersma R. A. Appel L. J. Guallar E. Meta-analysis high-dosage. vitamin E. supplementation may. increase all-cause. mortality Ann Intern Med. 2005 142 37 46
  141. 141. Leuschner U. F. Lindenthal B. Herrmann G. Arnold J. C. Rössle M. Cordes H. J. Zeuzem S. Hein J. Berg T. Study N. A. S. H. Group High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial. Hepatology. 2010 52 472 9
  142. 142. Targher G. CP Day Bonora. E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med. 2010 363 1341 50

Written By

Nseir W. and Assy N.

Published: 06 September 2011