Diagnosis and Management of Nonalcoholic Fatty Liver Disease and Its Hemostatic/Thrombotic and Vascular Complications

 

 Buy Article Permissions and Reprints

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of progressive liver disease encompassing simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, and, ultimately, cirrhosis. NAFLD is strongly associated with features of the metabolic syndrome including abdominal overweight/obesity, hypertension, atherogenic dyslipidemia, glucose intolerance, or type 2 diabetes. With the advent of increasingly sedentary lifestyles and changing dietary patterns, the prevalence of obesity and insulin resistance has increased and, with this, NAFLD has rapidly become the most common cause of chronic liver disease in many developed countries. Importantly, accumulating evidence indicates that NAFLD is strongly associated with a prothrombotic tendency, which may, at least in part, contribute to the increased risk of atherothrombotic events observed in these patients. NAFLD, especially in its necroinflammatory form (NASH), releases a variety of proinflammatory and prothrombotic mediators that play important roles in the development and progression of acute atherothrombotic complications. NAFLD also exacerbates systemic and hepatic insulin resistance and causes atherogenic dyslipidemia. The purpose of this review is to briefly discuss the epidemiology and diagnosis of NAFLD, to summarize the rapidly expanding body of evidence that supports a strong association between NAFLD and various disorders of coagulation and fibrinolysis and their implications for the development of atherothrombotic complications, and to discuss some of the treatment options that may influence both NAFLD and its related vascular complications.

• References

• 1 Anstee QM, McPherson S, Day CP. How big a problem is non-alcoholic fatty liver disease?. BMJ 2011; 343: d3897
  CrossrefPubMedGoogle Scholar
• 2 Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010; 53 (2) 372-384
  CrossrefPubMedGoogle Scholar
• 3 Chalasani N, Younossi Z, Lavine JE , et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55 (6) 2005-2023
  CrossrefPubMedGoogle Scholar
• 4 Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363 (14) 1341-1350
  CrossrefPubMedGoogle Scholar
• 5 Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor?. Eur Heart J 2012; 33 (10) 1190-1200
  CrossrefPubMedGoogle Scholar
• 6 Targher G, Byrne CD. Non-alcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J Clin Endocrinol Metab 2012; ; In press DOI: 10.1210/jc.2012-3093.
  PubMedGoogle Scholar
• 7 Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link?. J Hepatol 2011; 54 (5) 1020-1029
  CrossrefPubMedGoogle Scholar
• 8 Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology 2010; 51 (5) 1820-1832
  CrossrefPubMedGoogle Scholar
• 9 Tilg H, Diehl AM. NAFLD and extrahepatic cancers: have a look at the colon. Gut 2011; 60 (6) 745-746
  CrossrefPubMedGoogle Scholar
• 10 Argo CK, Caldwell SH. Epidemiology and natural history of non-alcoholic steatohepatitis. Clin Liver Dis 2009; 13 (4) 511-531
  CrossrefPubMedGoogle Scholar
• 11 Mehta SR, Thomas EL, Bell JD, Johnston DG, Taylor-Robinson SD. Non-invasive means of measuring hepatic fat content. World J Gastroenterol 2008; 14 (22) 3476-3483
  CrossrefPubMedGoogle Scholar
• 12 Browning JD, Szczepaniak LS, Dobbins R , et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40 (6) 1387-1395
  CrossrefPubMedGoogle Scholar
• 13 Sirota JC, McFann K, Targher G, Johnson RJ, Chonchol M, Jalal DI. Elevated serum uric acid levels are associated with non-alcoholic fatty liver disease independently of metabolic syndrome features in the United States: Liver ultrasound data from the National Health and Nutrition Examination Survey. Metabolism 2012; ;pii, S0026–0495 (12) 00317-00314
  PubMedGoogle Scholar
• 14 Jimba S, Nakagami T, Takahashi M , et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med 2005; 22 (9) 1141-1145
  CrossrefPubMedGoogle Scholar
• 15 Targher G, Bertolini L, Padovani R , et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30 (5) 1212-1218
  CrossrefPubMedGoogle Scholar
• 16 Williamson RM, Price JF, Glancy S , et al; Edinburgh Type 2 Diabetes Study Investigators. Prevalence of and risk factors for hepatic steatosis and nonalcoholic Fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes Care 2011; 34 (5) 1139-1144
  CrossrefPubMedGoogle Scholar
• 17 Williams CD, Stengel J, Asike MI , et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011; 140 (1) 124-131
  CrossrefPubMedGoogle Scholar
• 18 Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease: the Dionysos nutrition and liver study. Hepatology 2005; 42 (1) 44-52
  CrossrefPubMedGoogle Scholar
• 19 Minervini MI, Ruppert K, Fontes P , et al. Liver biopsy findings from healthy potential living liver donors: reasons for disqualification, silent diseases and correlation with liver injury tests. J Hepatol 2009; 50 (3) 501-510
  CrossrefPubMedGoogle Scholar
• 20 Nadalin S, Malagó M, Valentin-Gamazo C , et al. Preoperative donor liver biopsy for adult living donor liver transplantation: risks and benefits. Liver Transpl 2005; 11 (8) 980-986
  CrossrefPubMedGoogle Scholar
• 21 Mofrad P, Contos MJ, Haque M , et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003; 37 (6) 1286-1292
  CrossrefPubMedGoogle Scholar
• 22 Targher G, Chonchol M, Miele L, Zoppini G, Pichiri I, Muggeo M. Nonalcoholic fatty liver disease as a contributor to hypercoagulation and thrombophilia in the metabolic syndrome. Semin Thromb Hemost 2009; 35 (3) 277-287
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Northup PG, Argo CK, Shah N, Caldwell SH. Hypercoagulation and thrombophilia in nonalcoholic fatty liver disease: mechanisms, human evidence, therapeutic implications, and preventive implications. Semin Liver Dis 2012; 32 (1) 39-48
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Cigolini M, Targher G, Agostino G, Tonoli M, Muggeo M, De Sandre G. Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men—role of the metabolic syndrome. Thromb Haemost 1996; 76 (1) 69-73
  PubMedGoogle Scholar
• 25 Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 2003; 38 (2) 413-419
  PubMedGoogle Scholar
• 26 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 (10) 1354-1358
  CrossrefPubMedGoogle Scholar
• 27 Targher G. Relationship between high-sensitivity C-reactive protein levels and liver histology in subjects with non-alcoholic fatty liver disease. J Hepatol 2006; 45 (6) 879-881 , author reply 881–882
  CrossrefPubMedGoogle Scholar
• 28 Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin?. Hepatology 2004; 40 (1) 46-54
  CrossrefPubMedGoogle Scholar
• 29 Yener S, Akarsu M, Demir T , et al. Plasminogen activator inhibitor-1 and thrombin activatable fibrinolysis inhibitor levels in non-alcoholic steatohepatitis. J Endocrinol Invest 2007; 30 (10) 810-819
  CrossrefPubMedGoogle Scholar
• 30 Jarrar MH, Baranova A, Collantes R , et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008; 27 (5) 412-421
  PubMedGoogle Scholar
• 31 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; 11 (37) 5834-5839
  CrossrefPubMedGoogle Scholar
• 32 Papatheodoridis GV, Chrysanthos N, Cholongitas E , et al. Thrombotic risk factors and liver histologic lesions in non-alcoholic fatty liver disease. J Hepatol 2009; 51 (5) 931-938
  CrossrefPubMedGoogle Scholar
• 33 Targher G, Bertolini L, Rodella S , et al. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men. Obesity (Silver Spring) 2008; 16 (6) 1394-1399
  CrossrefPubMedGoogle Scholar
• 34 Haukeland JW, Damås JK, Konopski Z , et al. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2. J Hepatol 2006; 44 (6) 1167-1174
  CrossrefPubMedGoogle Scholar
• 35 Sookoian S, Castaño GO, Burgueño AL , et al. Circulating levels and hepatic expression of molecular mediators of atherosclerosis in nonalcoholic fatty liver disease. Atherosclerosis 2010; 209 (2) 585-591
  CrossrefPubMedGoogle Scholar
• 36 Alkhouri N, Kistangari G, Campbell C, Lopez R, Zein NN, Feldstein AE. Mean platelet volume as a marker of increased cardiovascular risk in patients with nonalcoholic steatohepatitis. Hepatology 2012; 55 (1) 331
  CrossrefPubMedGoogle Scholar
• 37 Kotronen A, Joutsi-Korhonen L, Sevastianova K , et al. Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease. Liver Int 2011; 31 (2) 176-183
  CrossrefPubMedGoogle Scholar
• 38 Thuy S, Ladurner R, Volynets V , et al. Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 2008; 138 (8) 1452-1455
  PubMedGoogle Scholar
• 39 Yoneda M, Mawatari H, Fujita K , et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH. J Gastroenterol 2007; 42 (7) 573-582
  CrossrefPubMedGoogle Scholar
• 40 Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, Feldstein AE. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am J Gastroenterol 2008; 103 (6) 1372-1379
  CrossrefPubMedGoogle Scholar
• 41 Westerbacka J, Kolak M, Kiviluoto T , et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 2007; 56 (11) 2759-2765
  CrossrefPubMedGoogle Scholar
• 42 Greco D, Kotronen A, Westerbacka J , et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008; 294 (5) G1281-G1287
  CrossrefPubMedGoogle Scholar
• 43 Sookoian S, Gianotti TF, Rosselli MS, Burgueño AL, Castaño GO, Pirola CJ. Liver transcriptional profile of atherosclerosis-related genes in human nonalcoholic fatty liver disease. Atherosclerosis 2011; 218 (2) 378-385
  CrossrefPubMedGoogle Scholar
• 44 Chalasani N, Deeg MA, Crabb DW. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis. Am J Gastroenterol 2004; 99 (8) 1497-1502
  CrossrefPubMedGoogle Scholar
• 45 Yesilova Z, Yaman H, Oktenli C , et al. Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic Fatty liver disease. Am J Gastroenterol 2005; 100 (4) 850-855
  CrossrefPubMedGoogle Scholar
• 46 Konishi M, Iwasa M, Araki J , et al. Increased lipid peroxidation in patients with non-alcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8-isoprostane. J Gastroenterol Hepatol 2006; 21 (12) 1821-1825
  CrossrefPubMedGoogle Scholar
• 47 Musso G, Gambino R, De Michieli F , et al. Nitrosative stress predicts the presence and severity of nonalcoholic fatty liver at different stages of the development of insulin resistance and metabolic syndrome: possible role of vitamin A intake. Am J Clin Nutr 2007; 86 (3) 661-671
  PubMedGoogle Scholar
• 48 Targher G, Zoppini G, Moghetti P, Day CP. Disorders of coagulation and hemostasis in abdominal obesity: emerging role of fatty liver. Semin Thromb Hemost 2010; 36 (1) 41-48
  Article in Thieme ConnectPubMedGoogle Scholar
• 49 Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008; 99 (6) 995-1000
  PubMedGoogle Scholar
• 50 Franchini M, Targher G, Montagnana M, Lippi G. The metabolic syndrome and the risk of arterial and venous thrombosis. Thromb Res 2008; 122 (6) 727-735
  CrossrefPubMedGoogle Scholar
• 51 Bastelica D, Morange P, Berthet B , 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 (1) 173-178
  CrossrefPubMedGoogle Scholar
• 52 Alessi MC, Bastelica D, Mavri A , et al. Plasma PAI-1 levels are more strongly related to liver steatosis than to adipose tissue accumulation. Arterioscler Thromb Vasc Biol 2003; 23 (7) 1262-1268
  CrossrefPubMedGoogle Scholar
• 53 Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006; 116 (7) 1793-1801
  CrossrefPubMedGoogle Scholar
• 54 Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010; 51 (2) 679-689
  CrossrefPubMedGoogle Scholar
• 55 Fabbrini E, Magkos F, Mohammed BS , et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A 2009; 106 (36) 15430-15435
  CrossrefPubMedGoogle Scholar
• 56 Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa?. Dig Liver Dis 2010; 42 (5) 320-330
  CrossrefPubMedGoogle Scholar
• 57 Villanova N, Moscatiello S, Ramilli S , et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005; 42 (2) 473-480
  CrossrefPubMedGoogle Scholar
• 58 Lee YJ, Shim JY, Moon BS , et al. The relationship between arterial stiffness and nonalcoholic fatty liver disease. Dig Dis Sci 2012; 57 (1) 196-203
  CrossrefPubMedGoogle Scholar
• 59 Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 2008; 49 (4) 600-607
  CrossrefPubMedGoogle Scholar
• 60 Targher G, Bertolini L, Padovani R , et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006; 29 (6) 1325-1330
  CrossrefPubMedGoogle Scholar
• 61 Kozakova M, Palombo C, Eng MP , et al; RISC Investigators. Fatty liver index, gamma-glutamyltransferase, and early carotid plaques. Hepatology 2012; 55 (5) 1406-1415
  CrossrefPubMedGoogle Scholar
• 62 Sung KC, Wild SH, Kwag HJ, Byrne CD. Fatty liver, insulin resistance, and features of metabolic syndrome: relationships with coronary artery calcium in 10,153 people. Diabetes Care 2012; 35 (11) 2359-2364
  CrossrefPubMedGoogle Scholar
• 63 Kim D, Choi SY, Park EH , et al. alcoholic fatty liver disease is associated with coronary artery calcification. Hepatology 2012; 56 (2) 605-613
  CrossrefPubMedGoogle Scholar
• 64 Goland S, Shimoni S, Zornitzki T , et al. Cardiac abnormalities as a new manifestation of nonalcoholic fatty liver disease: echocardiographic and tissue Doppler imaging assessment. J Clin Gastroenterol 2006; 40 (10) 949-955
  CrossrefPubMedGoogle Scholar
• 65 Bonapace S, Perseghin G, Molon G , et al. Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 2012; 35 (2) 389-395
  CrossrefPubMedGoogle Scholar
• 66 Perseghin G, Lattuada G, De Cobelli F , et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 2008; 47 (1) 51-58
  PubMedGoogle Scholar
• 67 Rijzewijk LJ, Jonker JT, van der Meer RW , et al. Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am Coll Cardiol 2010; 56 (3) 225-233
  CrossrefPubMedGoogle Scholar
• 68 Lautamäki R, Borra R, Iozzo P , et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am J Physiol Endocrinol Metab 2006; 291 (2) E282-E290
  CrossrefPubMedGoogle Scholar
• 69 Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol 2005; 11 (31) 4838-4842
  CrossrefPubMedGoogle Scholar
• 70 Stepanova M, Younossi ZM. Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population. Clin Gastroenterol Hepatol 2012; 10 (6) 646-650
  CrossrefPubMedGoogle Scholar
• 71 Mirbagheri SA, Rashidi A, Abdi S, Saedi D, Abouzari M. Liver: an alarm for the heart?. Liver Int 2007; 27 (7) 891-894
  CrossrefPubMedGoogle Scholar
• 72 Wong VW, Wong GL, Yip GW , et al. Coronary artery disease and cardiovascular outcomes in patients with non-alcoholic fatty liver disease. Gut 2011; 60 (12) 1721-1727
  CrossrefPubMedGoogle Scholar
• 73 Targher G. Elevated serum γ-glutamyltransferase activity is associated with increased risk of mortality, incident type 2 diabetes, cardiovascular events, chronic kidney disease and cancer - a narrative review. Clin Chem Lab Med 2010; 48 (2) 147-157
  CrossrefPubMedGoogle Scholar
• 74 Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43 (8) 617-649
  CrossrefPubMedGoogle Scholar
• 75 Hamaguchi M, Kojima T, Takeda N , et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol 2007; 13 (10) 1579-1584
  CrossrefPubMedGoogle Scholar
• 76 Haring R, Wallaschofski H, Nauck M, Dörr M, Baumeister SE, Völzke H. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology 2009; 50 (5) 1403-1411
  CrossrefPubMedGoogle Scholar
• 77 Zhou YJ, Li YY, Nie YQ, Huang CM, Cao CY. Natural course of nonalcoholic fatty liver disease in southern China: a prospective cohort study. J Dig Dis 2012; 13 (3) 153-160
  CrossrefPubMedGoogle Scholar
• 78 Lazo M, Hernaez R, Bonekamp S , et al. Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study. BMJ 2011; 343: d6891
  CrossrefPubMedGoogle Scholar
• 79 Targher G, Bertolini L, Rodella S , et al. Nonalcoholic fatty liver disease is independently associated with an increased incidence of cardiovascular events in type 2 diabetic patients. Diabetes Care 2007; 30 (8) 2119-2121
  CrossrefPubMedGoogle Scholar
• 80 Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999; 116 (6) 1413-1419
  CrossrefPubMedGoogle Scholar
• 81 Jepsen P, Vilstrup H, Mellemkjaer L , et al. Prognosis of patients with a diagnosis of fatty liver—a registry-based cohort study. Hepatogastroenterology 2003; 50 (54) 2101-2104
  PubMedGoogle Scholar
• 82 Adams LA, Lymp JF, St Sauver J , et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129 (1) 113-121
  CrossrefPubMedGoogle Scholar
• 83 Ekstedt M, Franzén LE, Mathiesen UL , et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44 (4) 865-873
  CrossrefPubMedGoogle Scholar
• 84 Söderberg C, Stål P, Askling J , et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51 (2) 595-602
  CrossrefPubMedGoogle Scholar
• 85 Angulo P. Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any prognostic significance?. Hepatology 2010; 51 (2) 373-375 Erratum in: Hepatology. 2010; 51: 1868
  CrossrefPubMedGoogle Scholar
• 86 Lippi G, Targher G, Favaloro EJ, Franchini M. Venous thromboembolism in chronic liver disease. Semin Thromb Hemost 2011; 37 (1) 66-76
  Article in Thieme ConnectPubMedGoogle Scholar
• 87 Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC. Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 2011; 9 (9) 1713-1723
  CrossrefPubMedGoogle Scholar
• 88 Søgaard KK, Horváth-Puhó E, Grønbaek H, Jepsen P, Vilstrup H, Sørensen HT. Risk of venous thromboembolism in patients with liver disease: a nationwide population-based case-control study. Am J Gastroenterol 2009; 104 (1) 96-101
  CrossrefPubMedGoogle Scholar
• 89 Wu H, Nguyen GC. Liver cirrhosis is associated with venous thromboembolism among hospitalized patients in a nationwide US study. Clin Gastroenterol Hepatol 2010; 8 (9) 800-805
  CrossrefPubMedGoogle Scholar
• 90 Huerta C, Johansson S, Wallander MA, García Rodríguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 2007; 167 (9) 935-943
  CrossrefPubMedGoogle Scholar
• 91 Di Minno MND, Tufano A, Rusolillo A, Di Minno G, Tarantino G. High prevalence of nonalcoholic fatty liver in patients with idiopathic venous thromboembolism. World J Gastroenterol 2010; 16 (48) 6119-6122
  CrossrefPubMedGoogle Scholar
• 92 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8–9) 526-533
  CrossrefPubMedGoogle Scholar
• 93 Wright M, Goldin R, Hellier S , et al. Factor V Leiden polymorphism and the rate of fibrosis development in chronic hepatitis C virus infection. Gut 2003; 52 (8) 1206-1210
  CrossrefPubMedGoogle Scholar
• 94 Papatheodoridis GV, Papakonstantinou E, Andrioti E , et al. Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis. Gut 2003; 52 (3) 404-409
  CrossrefPubMedGoogle Scholar
• 95 Poujol-Robert A, Boëlle PY, Poupon R, Robert A, Factor V. Factor V Leiden as a risk factor for cirrhosis in chronic hepatitis C. Hepatology 2004; 39 (4) 1174-1175
  CrossrefPubMedGoogle Scholar
• 96 Shi J, Hao JH, Ren WH, Zhu JR. Effects of heparin on liver fibrosis in patients with chronic hepatitis B. World J Gastroenterol 2003; 9 (7) 1611-1614
  CrossrefPubMedGoogle Scholar
• 97 Petrenya N, Dobrodeeva L, Brustad M , et al. Fish consumption and socio-economic factors among residents of Arkhangelsk city and the rural Nenets autonomous area. Int J Circumpolar Health 2011; 70 (1) 46-58
  PubMedGoogle Scholar
• 98 Meyer BJ. Are we consuming enough long chain omega-3 polyunsaturated fatty acids for optimal health?. Prostaglandins Leukot Essent Fatty Acids 2011; 85 (5) 275-280
  CrossrefPubMedGoogle Scholar
• 99 Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PR. Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids. Lipids 2003; 38 (4) 391-398
  CrossrefPubMedGoogle Scholar
• 100 Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, Rawlings RR. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr 2011; 93 (5) 950-962
  CrossrefPubMedGoogle Scholar
• 101 Kris-Etherton PM, Harris WS, Appel LJ. AHA Nutrition Committee. American Heart Association. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003; 23 (2) 151-152
  CrossrefPubMedGoogle Scholar
• 102 Whelan J, Rust C. Innovative dietary sources of n-3 fatty acids. Annu Rev Nutr 2006; 26: 75-103
  CrossrefPubMedGoogle Scholar
• 103 Capanni M, Calella F, Biagini MR , et al. Prolonged n-3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non-alcoholic fatty liver disease: a pilot study. Aliment Pharmacol Ther 2006; 23 (8) 1143-1151
  CrossrefPubMedGoogle Scholar
• 104 Spadaro L, Magliocco O, Spampinato D , et al. Effects of n-3 polyunsaturated fatty acids in subjects with nonalcoholic fatty liver disease. Dig Liver Dis 2008; 40 (3) 194-199
  CrossrefPubMedGoogle Scholar
• 105 Zhu FS, Liu S, Chen XM, Huang ZG, Zhang DW. Effects of n-3 polyunsaturated fatty acids from seal oils on nonalcoholic fatty liver disease associated with hyperlipidemia. World J Gastroenterol 2008; 14 (41) 6395-6400
  CrossrefPubMedGoogle Scholar
• 106 Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eicosapentaenoic acid treatment improves nonalcoholic steatohepatitis. J Clin Gastroenterol 2008; 42 (4) 413-418
  CrossrefPubMedGoogle Scholar
• 107 Parker HM, Johnson NA, Burdon CA, Cohn JS, O'Connor HT, George J. Omega-3 supplementation and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol 2012; 56 (4) 944-951
  CrossrefPubMedGoogle Scholar
• 108 Calder PC. The role of marine omega-3 (n-3) fatty acids in inflammatory processes, atherosclerosis and plaque stability. Mol Nutr Food Res 2012; 56 (7) 1073-1080
  CrossrefPubMedGoogle Scholar
• 109 Cohen MG, Rossi JS, Garbarino J , et al. Insights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: beyond aspirin and clopidogrel. Thromb Res 2011; 128 (4) 335-340
  CrossrefPubMedGoogle Scholar
• 110 Di Minno MN, Russolillo A, Lupoli R, Ambrosino P, Di Minno A, Tarantino G. Omega-3 fatty acids for the treatment of non-alcoholic fatty liver disease. World J Gastroenterol 2012; 18 (41) 5839-5847
  CrossrefPubMedGoogle Scholar
• 111 Smith WL. Cyclooxygenases, peroxide tone and the allure of fish oil. Curr Opin Cell Biol 2005; 17 (2) 174-182
  CrossrefPubMedGoogle Scholar
• 112 Araya J, Rodrigo R, Pettinelli P, Araya AV, Poniachik J, Videla LA. Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients. Obesity (Silver Spring) 2010; 18 (7) 1460-1463
  CrossrefPubMedGoogle Scholar
• 113 Patterson E, Wall R, Fitzgerald GF, Ross RP, Stanton C. Health implications of high dietary omega-6 polyunsaturated Fatty acids. J Nutr Metab 2012; 2012: 539426
  PubMedGoogle Scholar
• 114 Le HD, Meisel JA, de Meijer VE, Gura KM, Puder M. The essentiality of arachidonic acid and docosahexaenoic acid. Prostaglandins Leukot Essent Fatty Acids 2009; 81 (2-3) 165-170
  CrossrefPubMedGoogle Scholar
• 115 Calder PC. Omega-3 fatty acids and inflammatory processes. Nutrients 2010; 2 (3) 355-374
  CrossrefPubMedGoogle Scholar
• 116 Schmitz G, Ecker J. The opposing effects of n-3 and n-6 fatty acids. Prog Lipid Res 2008; 47 (2) 147-155
  CrossrefPubMedGoogle Scholar
• 117 Levy BD. Resolvins and protectins: natural pharmacophores for resolution biology. Prostaglandins Leukot Essent Fatty Acids 2010; 82 (4-6) 327-332
  CrossrefPubMedGoogle Scholar
• 118 Takeuchi Y, Yahagi N, Izumida Y , et al. Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit. J Biol Chem 2010; 285 (15) 11681-11691
  CrossrefPubMedGoogle Scholar
• 119 Neschen S, Morino K, Dong J , et al. n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner. Diabetes 2007; 56 (4) 1034-1041
  CrossrefPubMedGoogle Scholar
• 120 Shearer GC, Savinova OV, Harris WS. Fish oil — how does it reduce plasma triglycerides?. Biochim Biophys Acta 2012; 1821 (5) 843-851
  CrossrefPubMedGoogle Scholar
• 121 Novak EM, Keller BO, Innis SM. Metabolic development in the liver and the implications of the n-3 fatty acid supply. Am J Physiol Gastrointest Liver Physiol 2012; 302 (2) G250-G259
  CrossrefPubMedGoogle Scholar
• 122 Botolin D, Wang Y, Christian B, Jump DB. Docosahexaneoic acid (22:6,n-3) regulates rat hepatocyte SREBP-1 nuclear abundance by Erk- and 26S proteasome-dependent pathways. J Lipid Res 2006; 47 (1) 181-192
  PubMedGoogle Scholar
• 123 Jump DB, Botolin D, Wang Y, Xu J, Demeure O, Christian B. Docosahexaenoic acid (DHA) and hepatic gene transcription. Chem Phys Lipids 2008; 153 (1) 3-13
  CrossrefPubMedGoogle Scholar
• 124 Lorente-Cebrián S, Bustos M, Marti A, Martinez JA, Moreno-Aliaga MJ. Eicosapentaenoic acid stimulates AMP-activated protein kinase and increases visfatin secretion in cultured murine adipocytes. Clin Sci (Lond) 2009; 117 (6) 243-249
  CrossrefPubMedGoogle Scholar
• 125 Harrison SA, Day CP. Benefits of lifestyle modification in NAFLD. Gut 2007; 56 (12) 1760-1769
  CrossrefPubMedGoogle Scholar
• 126 Rodriguez B, Torres DM, Harrison SA. Physical activity: an essential component of lifestyle modification in NAFLD. Nat Rev Gastroenterol Hepatol 2012; 9 (12) 726-731
  CrossrefPubMedGoogle Scholar
• 127 Westerterp-Plantenga MS, Nieuwenhuizen A, Tomé D, Soenen S, Westerterp KR. Dietary protein, weight loss, and weight maintenance. Annu Rev Nutr 2009; 29: 21-41
  CrossrefPubMedGoogle Scholar
• 128 Keller U. Dietary proteins in obesity and in diabetes. Int J Vitam Nutr Res 2011; 81 (2-3) 125-133
  CrossrefPubMedGoogle Scholar
• 129 Wang TJ, Larson MG, Vasan RS , et al. Metabolite profiles and the risk of developing diabetes. Nat Med 2011; 17 (4) 448-453
  CrossrefPubMedGoogle Scholar
• 130 Würtz P, Mäkinen VP, Soininen P , et al. Metabolic signatures of insulin resistance in 7,098 young adults. Diabetes 2012; 61 (6) 1372-1380
  CrossrefPubMedGoogle Scholar
• 131 Scorletti E, Calder PC, Byrne CD. Non-alcoholic fatty liver disease and cardiovascular risk: metabolic aspects and novel treatments. Endocrine 2011; 40 (3) 332-343
  CrossrefPubMedGoogle Scholar
• 132 Chitapanarux T, Tienboon P, Pojchamarnwiputh S, Leelarungrayub D. Open-labeled pilot study of cysteine-rich whey protein isolate supplementation for nonalcoholic steatohepatitis patients. J Gastroenterol Hepatol 2009; 24 (6) 1045-1050
  CrossrefPubMedGoogle Scholar
• 133 Bortolotti M, Maiolo E, Corazza M , et al. Effects of a whey protein supplementation on intrahepatocellular lipids in obese female patients. Clin Nutr 2011; 30 (4) 494-498
  CrossrefPubMedGoogle Scholar
• 134 Kistler KD, Brunt EM, Clark JM, Diehl AM, Sallis JF, Schwimmer JB. NASH CRN Research Group. Physical activity recommendations, exercise intensity, and histological severity of nonalcoholic fatty liver disease. Am J Gastroenterol 2011; 106 (3) 460-468 , quiz 469
  CrossrefPubMedGoogle Scholar
• 135 Hallsworth K, Fattakhova G, Hollingsworth KG , et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut 2011; 60 (9) 1278-1283
  CrossrefPubMedGoogle Scholar
• 136 Strasser B, Siebert U, Schobersberger W. Resistance training in the treatment of the metabolic syndrome: a systematic review and meta-analysis of the effect of resistance training on metabolic clustering in patients with abnormal glucose metabolism. Sports Med 2010; 40 (5) 397-415
  CrossrefPubMedGoogle Scholar
• 137 Strasser B, Schobersberger W. Evidence for resistance training as a treatment therapy in obesity. J Obes 2011; 2011: 482564
  PubMedGoogle Scholar