Download PDF
Semin Thromb Hemost 2009; 35(3): 277-287
DOI: 10.1055/s-0029-1222606
© Thieme Medical Publishers

Nonalcoholic Fatty Liver Disease as a Contributor to Hypercoagulation and Thrombophilia in the Metabolic Syndrome

Giovanni Targher1 , Michel Chonchol2 , Luca Miele3 , Giacomo Zoppini1 , Isabella Pichiri1 , Michele Muggeo1
  • 1Section of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona, Verona, Italy
  • 2Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, Denver, Colorado
  • 3Institute of Internal Medicine, Catholic University of Rome, Rome, Italy
Further Information

Publication History

Publication Date:
18 May 2009 (online)

    Permissions and Reprints

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD), comprising its whole spectrum of conditions ranging from simple steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH) and cirrhosis, is the most frequent liver disease in developed countries and is now regarded as the liver manifestation of the metabolic syndrome. Several studies indicate that NAFLD, especially in its necro-inflammatory form (NASH), is associated with a systemic proinflammatory/prothrombotic state, independently of shared metabolic risk factors. This suggests that NAFLD/NASH is not simply a marker of the proinflammatory/prothrombotic state in the metabolic syndrome but is actively involved in its pathogenesis, possibly through the systemic release of proinflammatory and procoagulant factors from the steatotic liver (C-reactive protein, plasminogen activator inhibitor-1, interleukin-6, fibrinogen, and other proinflammatory cytokines). The clinical impact of NAFLD on the proinflammatory/prothrombotic risk profile deserves particular attention in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD.

KEYWORDS

Nonalcoholic fatty liver disease - blood coagulation disorders - hemostatic factors - inflammation

REFERENCES

  • 1 Adams L A, Lindor K D. Nonalcoholic fatty liver disease.  Ann Epidemiol. 2007;  17 863-869
    CrossrefPubMedGoogle Scholar
  • 2 de Alwis N M, Day C P. Non-alcoholic fatty liver disease: the mist gradually clears.  J Hepatol. 2008;  48(Suppl 1) S104-S112
    PubMedGoogle Scholar
  • 3 Clark J M. The epidemiology of nonalcoholic fatty liver disease in adults.  J Clin Gastroenterol. 2006;  40(3, Suppl 1) S5-S10
    PubMedGoogle Scholar
  • 4 Kim H J, Kim H J, Lee K E et al.. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults.  Arch Intern Med. 2004;  164 2169-2175
    CrossrefPubMedGoogle Scholar
  • 5 Targher G, Arcaro G. Non-alcoholic fatty liver disease and increased risk of cardiovascular disease.  Atherosclerosis. 2007;  191 235-240
    CrossrefPubMedGoogle Scholar
  • 6 Kotronen A, Yki-Järvinen H. Fatty liver: a novel component of the metabolic syndrome.  Arterioscler Thromb Vasc Biol. 2008;  28 27-38
    CrossrefPubMedGoogle Scholar
  • 7 Tilg H, Diehl A M. Cytokines in alcoholic and nonalcoholic steatohepatitis.  N Engl J Med. 2000;  343 1467-1476
    CrossrefPubMedGoogle Scholar
  • 8 Bellentani S, Saccoccio G, Masutti F et al.. Prevalence of and risk factors for hepatic steatosis in Northern Italy.  Ann Intern Med. 2000;  132 112-117
    PubMedGoogle Scholar
  • 9 Browning J D, Szczepaniak L S, Dobbins R et al.. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.  Hepatology. 2004;  40 1387-1395
    CrossrefPubMedGoogle Scholar
  • 10 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 44-52
    CrossrefPubMedGoogle Scholar
  • 11 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 1212-1218
    CrossrefPubMedGoogle Scholar
  • 12 Marchesini G, Bugianesi E, Forlani G et al.. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome.  Hepatology. 2003;  37 917-923
    CrossrefPubMedGoogle Scholar
  • 13 Eckel R H, Grundy S M, Zimmet P Z. The metabolic syndrome.  Lancet. 2005;  365 1415-1428
    CrossrefPubMedGoogle Scholar
  • 14 Bonora E. The metabolic syndrome and cardiovascular disease.  Ann Med. 2006;  38 64-80
    CrossrefPubMedGoogle Scholar
  • 15 Alessi M C, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis.  Thromb Haemost. 2008;  99 995-1000
    PubMedGoogle Scholar
  • 16 Lyon C J, Law R E, Hsueh W A. Minireview: adiposity, inflammation, and atherogenesis.  Endocrinology. 2003;  144 2195-2200
    CrossrefPubMedGoogle Scholar
  • 17 Nigro J, Osman N, Dart A M, Little P J. Insulin resistance and atherosclerosis.  Endocr Rev. 2006;  27 242-259
    CrossrefPubMedGoogle Scholar
  • 18 Franchini M, Targher G, Montagnana M, Lippi G. The metabolic syndrome and the risk of arterial and venous thrombosis.  Thromb Res. 2008;  122 727-735
    CrossrefPubMedGoogle Scholar
  • 19 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 69-73
    PubMedGoogle Scholar
  • 20 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
    CrossrefPubMedGoogle Scholar
  • 21 Targher G. Relationship between high-sensitivity C-reactive protein levels and liver histology in subjects with non-alcoholic fatty liver disease.  J Hepatol. 2006;  45 879-881, author reply 881–882
    CrossrefPubMedGoogle Scholar
  • 22 Targher G, Bertolini L, Scala L et al.. Plasma PAI-1 levels are increased in patients with nonalcoholic steatohepatitis.  Diabetes Care. 2007;  30 e31-e32
    CrossrefPubMedGoogle Scholar
  • 23 Haukeland J W, Damås J K, Konopski Z et al.. Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2.  J Hepatol. 2006;  44 1167-1174
    CrossrefPubMedGoogle Scholar
  • 24 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
    CrossrefPubMedGoogle Scholar
  • 25 Musso G, Gambino R, Durazzo M et al.. Adipokines in NASH: postprandial lipid metabolism as a link between adiponectin and liver disease.  Hepatology. 2005;  42 1175-1183
    CrossrefPubMedGoogle Scholar
  • 26 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;  42 573-582
    CrossrefPubMedGoogle Scholar
  • 27 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
    CrossrefPubMedGoogle Scholar
  • 28 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;  30 810-819
    CrossrefPubMedGoogle Scholar
  • 29 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 1452-1455
    PubMedGoogle Scholar
  • 30 Jarrar M H, Baranova A, Collantes R et al.. Adipokines and cytokines in non-alcoholic fatty liver disease.  Aliment Pharmacol Ther. 2008;  27 412-421
    PubMedGoogle Scholar
  • 31 de Larrañaga G, Wingeyer S P, 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;  14 319-324
    CrossrefPubMedGoogle Scholar
  • 32 Ito S, Yukawa T, Uetake S, Yamauchi M. Serum intercellular adhesion molecule-1 in patients with nonalcoholic steatohepatitis: comparison with alcoholic hepatitis.  Alcohol Clin Exp Res. 2007;  31(1, Suppl) S83-S87
    CrossrefPubMedGoogle Scholar
  • 33 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 5834-5839
    CrossrefPubMedGoogle Scholar
  • 34 Targher G, Bertolini L, Rodella S et al.. NASH predicts plasma inflammatory biomarkers independently of visceral fat in men.  Obesity (Silver Spring). 2008;  16 1394-1399
    CrossrefPubMedGoogle Scholar
  • 35 Kugelmas M, Hill D B, Vivian B, Marsano L, McClain C J. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E.  Hepatology. 2003;  38 413-419
    PubMedGoogle Scholar
  • 36 Chalasani N, Deeg M A, Crabb D W. Systemic levels of lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis.  Am J Gastroenterol. 2004;  99 1497-1502
    CrossrefPubMedGoogle Scholar
  • 37 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;  100 850-855
    CrossrefPubMedGoogle Scholar
  • 38 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 1821-1825
    CrossrefPubMedGoogle Scholar
  • 39 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;  86 661-671
    PubMedGoogle Scholar
  • 40 Alessi M C, 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 1262-1268
    CrossrefPubMedGoogle Scholar
  • 41 Wallace T M, Matthews D R. The assessment of insulin resistance in man.  Diabet Med. 2002;  19 527-534
    CrossrefPubMedGoogle Scholar
  • 42 Northup P G, Sundaram V, Fallon M B Coagulation in Liver Disease Group et al. Hypercoagulation and thrombophilia in liver disease.  J Thromb Haemost. 2008;  6 2-9
    PubMedGoogle Scholar
  • 43 Sanyal A J, Banas C, Sargeant C et al.. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.  Hepatology. 2006;  43 682-689
    CrossrefPubMedGoogle Scholar
  • 44 Korenblat K M, Fabbrini E, Mohammed B S, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects.  Gastroenterology. 2008;  134 1369-1375
    CrossrefPubMedGoogle Scholar
  • 45 Day C P. From fat to inflammation.  Gastroenterology. 2006;  130 207-210
    CrossrefPubMedGoogle Scholar
  • 46 Shoelson S E, Lee J, Goldfine A B. Inflammation and insulin resistance.  J Clin Invest. 2006;  116 1793-1801
    CrossrefPubMedGoogle Scholar
  • 47 Ekstedt M, Franzén L E, Mathiesen U L et al.. Long-term follow-up of patients with NAFLD and elevated liver enzymes.  Hepatology. 2006;  44 865-873
    CrossrefPubMedGoogle Scholar
  • 48 Targher G, Bertolini L, Padovani R et al.. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C.  J Hepatol. 2007;  46 1126-1132
    CrossrefPubMedGoogle Scholar
  • 49 Lin Z, Kumar A, SenBanerjee S et al.. Kruppel-like factor 2 (KLF2) regulates endothelial thrombotic function.  Circ Res. 2005;  96 e48-e57
    CrossrefPubMedGoogle Scholar
  • 50 Botella L M, Sánchez-Elsner T, Sanz-Rodriguez F et al.. Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury.  Blood. 2002;  100 4001-4010
    CrossrefPubMedGoogle Scholar
  • 51 Miele L, Beale G, Patman G et al.. The Kruppel-like factor 6 genotype is associated with fibrosis in nonalcoholic fatty liver disease.  Gastroenterology. 2008;  135 282-291
    CrossrefPubMedGoogle Scholar
  • 52 Greco D, Kotronen A, Westerbacka J et al.. Gene expression in human NAFLD.  Am J Physiol Gastrointest Liver Physiol. 2008;  294 G1281-G1287
    CrossrefPubMedGoogle Scholar
  • 53 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 2759-2765
    CrossrefPubMedGoogle Scholar

Dr. Giovanni Targher

Section of Endocrinology, Department of Biomedical and Surgical Sciences, University of Verona

Ospedale Civile Maggiore, Piazzale Stefani, 1, 37126 Verona, Italy

Email: giovanni.targher@univr.it