Vascular Disease in Patients with Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is increasingly being diagnosed and is considered to be the most frequent chronic liver disorder in Western countries. It represents a histopathological spectrum ranging from simple hepatic steatosis to steatohepatitis and finally cirrhosis. NAFLD is considered as the hepatic manifestation of the metabolic syndrome and is associated with increased mortality. Increasing evidence now suggests that NAFLD is also associated with higher cardiovascular disease (CVD) morbidity and mortality independent of conventional cardiometabolic risk factors (such as obesity, insulin resistance, and diabetes mellitus). The exact mechanisms linking NAFLD to increased CVD risk are still incompletely understood and likely reflect multiple coexisting pathways. Recent evidence suggests a contributive effect of an altered hemostasis in patients with NAFLD. For example, patients with NAFLD have higher levels of prothrombotic factors (e.g., von Willebrand factor, fibrinogen, factor VII activity, and plasminogen activator inhibitor-1), which correlate with underlying histological severity of the disease. The current review focuses on these hemostatic abnormalities in NAFLD and the link with increased CVD risk.

Keywords

nonalcoholic fatty liver disease - cardiovascular disease - hemostasis - coagulation disorders - thrombosis

• References

• 1 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
• 2 Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 2011; 34 (3) 274-285
• 3 Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980; 55 (7) 434-438
• 4 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
• 5 Bacon BR, Farahvash MJ, Janney CG, Neuschwander-Tetri BA. Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 1994; 107 (4) 1103-1109
• 6 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
• 7 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
• 8 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
• 9 Charlton MR, Burns JM, Pedersen RA, Watt KD, Heimbach JK, Dierkhising RA. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141 (4) 1249-1253
• 10 Alberti KG, Zimmet P, Shaw J ; IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet 2005; 366 (9491) 1059-1062
• 11 Hamaguchi M, Kojima T, Takeda N , et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005; 143 (10) 722-728
• 12 Marchesini G, Bugianesi E, Forlani G , et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003; 37 (4) 917-923
• 13 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
• 14 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
• 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
• 16 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
• 17 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
• 18 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
• 19 Lin YC, Lo HM, Chen JD. Sonographic fatty liver, overweight and ischemic heart disease. World J Gastroenterol 2005; 11 (31) 4838-4842
• 20 Akabame S, Hamaguchi M, Tomiyasu 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 (4) 618-625
• 21 Treeprasertsuk S, Leverage S, Adams LA, Lindor KD, St Sauver J, Angulo P. The Framingham risk score and heart disease in nonalcoholic fatty liver disease. Liver Int 2012; 32 (6) 945-950
• 22 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
• 23 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
• 24 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
• 25 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
• 26 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
• 27 Ozhan H, Aydin M, Yazici M , et al. Mean platelet volume in patients with non-alcoholic fatty liver disease. Platelets 2010; 21 (1) 29-32
• 28 Shin WY, Jung DH, Shim JY, Lee HR. The association between non-alcoholic hepatic steatosis and mean platelet volume in an obese Korean population. Platelets 2011; 22 (6) 442-446
• 29 Celikbilek M, Gürsoy S, Deniz K, Karaman A, Zararsiz G, Yurci A. Mean platelet volume in biopsy-proven non-alcoholic fatty liver disease. Platelets 2013; 24 (3) 194-199
• 30 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
• 31 Verrijken A, Francque S, Mertens I , et al. Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2014; 59 (1) 121-129
• 32 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
• 33 Tripodi A, Fracanzani AL, Primignani M , et al. Procoagulant imbalance in patients with non-alcoholic fatty liver disease. J Hepatol 2014; 61 (1) 148-154
• 34 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
• 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
• 36 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
• 37 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
• 38 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
• 39 de Larrañaga G, Wingeyer SP, Graffigna M , et al. Plasma plasminogen activator inhibitor-1 levels and nonalcoholic fatty liver in individuals with features of metabolic syndrome. Clin Appl Thromb Hemost 2008; 14 (3) 319-324
• 40 Barbato A, Iacone R, Tarantino G , et al; Olivetti Heart Study Research Group. Relationships of PAI-1 levels to central obesity and liver steatosis in a sample of adult male population in southern Italy. Intern Emerg Med 2009; 4 (4) 315-323
• 41 Kargili A, Cipil H, Karakurt F , et al. Hemostatic alterations in fatty liver disease. Blood Coagul Fibrinolysis 2010; 21 (4) 325-327
• 42 Chang ML, Hsu CM, Tseng JH , et al. Plasminogen activator inhibitor-1 is independently associated with non-alcoholic fatty liver disease whereas leptin and adiponectin vary between genders. J Gastroenterol Hepatol 2015; 30 (2) 329-336
• 43 Bilgir O, Bilgir F, Bozkaya G, Calan M. Changes in the levels of endothelium-derived coagulation parameters in nonalcoholic fatty liver disease. Blood Coagul Fibrinolysis 2014; 25 (2) 151-155
• 44 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
• 45 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
• 46 Tavil Y, Sen N, Yazici HU, Hizal F, Abaci A, Cengel A. Mean platelet volume in patients with metabolic syndrome and its relationship with coronary artery disease. Thromb Res 2007; 120 (2) 245-250
• 47 Muscari A, De Pascalis S, Cenni A , et al. Determinants of mean platelet volume (MPV) in an elderly population: relevance of body fat, blood glucose and ischaemic electrocardiographic changes. Thromb Haemost 2008; 99 (6) 1079-1084
• 48 De Pergola G, Pannacciulli N, Coviello M , et al. sP-selectin plasma levels in obesity: association with insulin resistance and related metabolic and prothrombotic factors. Nutr Metab Cardiovasc Dis 2008; 18 (3) 227-232
• 49 Gokulakrishnan K, Deepa R, Mohan V, Gross MD. Soluble P-selectin and CD40L levels in subjects with prediabetes, diabetes mellitus, and metabolic syndrome—the Chennai Urban Rural Epidemiology Study. Metabolism 2006; 55 (2) 237-242
• 50 Lee WL, Lee WJ, Chen YT , et al. The presence of metabolic syndrome is independently associated with elevated serum CD40 ligand and disease severity in patients with symptomatic coronary artery disease. Metabolism 2006; 55 (8) 1029-1034
• 51 Angelico F, Alessandri C, Ferro D , et al. Enhanced soluble CD40L in patients with the metabolic syndrome: Relationship with in vivo thrombin generation. Diabetologia 2006; 49 (6) 1169-1174
• 52 Sobol AB, Watala C. The role of platelets in diabetes-related vascular complications. Diabetes Res Clin Pract 2000; 50 (1) 1-16
• 53 Murakami T, Horigome H, Tanaka K , et al. Impact of weight reduction on production of platelet-derived microparticles and fibrinolytic parameters in obesity. Thromb Res 2007; 119 (1) 45-53
• 54 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
• 55 Cao W, Zhao C, Shen C, Wang Y. Cytokeratin 18, alanine aminotransferase, platelets and triglycerides predict the presence of nonalcoholic steatohepatitis. PLoS ONE 2013; 8 (12) e82092
• 56 Sumida Y, Yoneda M, Hyogo H , et al; Japan Study Group of Nonalcoholic Fatty Liver Disease (JSG-NAFLD). A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. J Gastroenterol 2011; 46 (2) 257-268
• 57 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
• 58 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
• 59 Targher G, Byrne CD. Diagnosis and management of nonalcoholic fatty liver disease and its hemostatic/thrombotic and vascular complications. Semin Thromb Hemost 2013; 39 (2) 214-228
• 60 Targher G, Bertolini L, Scala L , et al. Plasma PAI-1 levels are increased in patients with nonalcoholic steatohepatitis. Diabetes Care 2007; 30 (5) e31-e32
• 61 Meltzer ME, Doggen CJ, de Groot PG, Rosendaal FR, Lisman T. Plasma levels of fibrinolytic proteins and the risk of myocardial infarction in men. Blood 2010; 116 (4) 529-536
• 62 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
• 63 Greco D, Kotronen A, Westerbacka J , et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008; 294 (5) G1281-G1287
• 64 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
• 65 Northup PG, Sundaram V, Fallon MB , et al; Coagulation in Liver Disease Group. Hypercoagulation and thrombophilia in liver disease. J Thromb Haemost 2008; 6 (1) 2-9
• 66 Sanyal AJ, Banas C, Sargeant C , et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology 2006; 43 (4) 682-689
• 67 Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ. Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52 (3) 355-361
• 68 Tripodi A, Primignani M, Chantarangkul V , et al. An imbalance of pro- vs anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009; 137 (6) 2105-2111
• 69 Gatt A, Riddell A, Calvaruso V, Tuddenham EG, Makris M, Burroughs AK. Enhanced thrombin generation in patients with cirrhosis-induced coagulopathy. J Thromb Haemost 2010; 8 (9) 1994-2000
• 70 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
• 71 Northup PG, McMahon MM, Ruhl AP , et al. Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism. Am J Gastroenterol 2006; 101 (7) 1524-1528 , quiz 1680
• 72 Aldawood A, Arabi Y, Aljumah A , et al. The incidence of venous thromboembolism and practice of deep venous thrombosis prophylaxis in hospitalized cirrhotic patients. Thromb J 2011; 9 (1) 1
• 73 García-Fuster MJ, Abdilla N, Fabiá MJ, Fernández C, Oliver V ; Forner M J. Venous thromboembolism and liver cirrhosis [in Spanish]. Rev Esp Enferm Dig 2008; 100 (5) 259-262
• 74 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
• 75 Tripodi A, Anstee QM, Sogaard KK, Primignani M, Valla DC. Hypercoagulability in cirrhosis: causes and consequences. J Thromb Haemost 2011; 9 (9) 1713-1723
• 76 Lisman T, Kamphuisen PW, Northup PG, Porte RJ. Established and new-generation antithrombotic drugs in patients with cirrhosis - possibilities and caveats. J Hepatol 2013; 59 (2) 358-366
• 77 Potze W, Porte RJ, Lisman T. Management of coagulation abnormalities in liver disease. Expert Rev Gastroenterol Hepatol 2015; 9 (1) 103-114
• 78 Abad Rico JI, Llau Pitarch JV, Rocha E. Overview of venous thromboembolism. Drugs 2010; 70 (Suppl. 02) 3-10
• 79 Stein PD, Goldman J. Obesity and thromboembolic disease. Clin Chest Med 2009; 30 (3) 489-493, viii viii
• 80 Borch KH, Braekkan SK, Mathiesen EB , et al. Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: the Tromsø study. J Thromb Haemost 2009; 7 (5) 739-745
• 81 Di Minno MN, 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
• 82 Stine JG, Shah NL, Argo CK, Pelletier S, Caldwell SH, Northup PG. Increased risk of portal vein thrombosis in non-alcoholic steatohepatitis (NASH) and cryptogenic cirrhosis: evidence for a thrombophilic state. Hepatology 2014; 60 (1) 392A-293A
• 83 Anstee QM, Dhar A, Thursz MR. The role of hypercoagulability in liver fibrogenesis. Clin Res Hepatol Gastroenterol 2011; 35 (8-9) 526-533
• 84 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
• 85 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
• 86 Poujol-Robert A, Boëlle PY, Poupon R, Robert A. Factor V Leiden as a risk factor for cirrhosis in chronic hepatitis C. Hepatology 2004; 39 (4) 1174-1175
• 87 Poujol-Robert A, Rosmorduc O, Serfaty L, Coulet F, Poupon R, Robert A. Genetic and acquired thrombotic factors in chronic hepatitis C. Am J Gastroenterol 2004; 99 (3) 527-531
• 88 Anstee QM, Goldin RD, Wright M, Martinelli A, Cox R, Thursz MR. Coagulation status modulates murine hepatic fibrogenesis: implications for the development of novel therapies. J Thromb Haemost 2008; 6 (8) 1336-1343
• 89 Wanless IR, Belgiorno J, Huet PM. Hepatic sinusoidal fibrosis induced by cholesterol and stilbestrol in the rabbit: 1. Morphology and inhibition of fibrogenesis by dipyridamole. Hepatology 1996; 24 (4) 855-864
• 90 Abdel-Salam OM, Baiuomy AR, Ameen A, Hassan NS. A study of unfractionated and low molecular weight heparins in a model of cholestatic liver injury in the rat. Pharmacol Res 2005; 51 (1) 59-67
• 91 Abe W, Ikejima K, Lang T , et al. Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat. J Hepatol 2007; 46 (2) 286-294
• 92 Duplantier JG, Dubuisson L, Senant N , et al. A role for thrombin in liver fibrosis. Gut 2004; 53 (11) 1682-1687
• 93 Fujita K, Nozaki Y, Wada K , et al. Effectiveness of antiplatelet drugs against experimental non-alcoholic fatty liver disease. Gut 2008; 57 (11) 1583-1591
• 94 Kopec AK, Joshi N, Towery KL , et al. Thrombin inhibition with dabigatran protects against high-fat diet-induced fatty liver disease in mice. J Pharmacol Exp Ther 2014; 351 (2) 288-297
• 95 Joshi N, Kopec AK, O'Brien KM , et al. Coagulation-driven platelet activation reduces cholestatic liver injury and fibrosis in mice. J Thromb Haemost 2015; 13 (1) 57-71
• 96 Luyendyk JP, Kassel KM, Allen K , et al. Fibrinogen deficiency increases liver injury and early growth response-1 (Egr-1) expression in a model of chronic xenobiotic-induced cholestasis. Am J Pathol 2011; 178 (3) 1117-1125
• 97 Kodama T, Takehara T, Hikita H , et al. Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice. Gastroenterology 2010; 138 (7) 2487-2498 , 2498.e1–2498.e7
• 98 Lisman T. Platelets and fibrin in progression of liver disease: friends or foes?. J Thromb Haemost 2015; 13 (1) 54-56