Digestive Diseases and Sciences

, Volume 52, Issue 10, pp 2622–2628 | Cite as

The Serum Endothelın-1 Level in Steatosıs and NASH, and Its Relatıon wıth Severıty of Lıver Fıbrosıs

  • Bulent DegertekinEmail author
  • Seren Ozenirler
  • Sehri Elbeg
  • Gulen Akyol
Original Paper


Endothelin-1 (ET-1) is known to play an important role in hepatic fibrosis. ET-1 is also a mediator that is elevated in conditions such as insulin resistance, hyperglycemia, oxidative stress, and endothelial cell dysfunction. In this study, we investigated whether ET-1 has a role in determining the severity of liver fibrosis in NASH. Also, the relation between ALT levels, obesity, diabetes, and AST/ALT ratio and fibrosis and ET-1 level was sought. A total of 92 patients were enrolled in the study. The patients were categorized into three groups: group 1, patients with elevated transaminase levels who were diagnosed as NASH by liver biopsy (n=40); group II, patients with only hepatosteatosis determined by biopsy but having elevated transaminase levels (n=12); and group III, patients with hepatosteatosis observed by ultrasonography, having normal transaminase levels (n=40). The serum ET-1 level was measured by an appropriate ELISA kit for all patients. Mean serum ET-1 level was statistically significantly higher in the NASH group compared to the other two groups (15.56±4.63 vs 6.75±2.46 and 5.74±2.34 μmol/L; P < 0.01). Mean serum ET-1 levels in NASH patients with grade I, grade II, and grade IV fibrosis were 14.06±0.92, 17.70±2.32, and 20.40±1.40 μmol/L, respectively. None of the patients were identified as grade III fibrosis. It was found that the serum ET-1 level showed a statistically significant increase as fibrosis severity increased in NASH patients (P < 0.05). In conclusion, the serum ET-1 level is higher in NASH patients compared to patients having only steatosis. There appears to be a correlation between severity of fibrosis and serum ET-1 level in NASH patients. It has been found that NASH patients having a twofold increase in their ALT levels had higher ET-1 levels and a more severe grade of fibrosis.


Nonalcoholic steatohepatitis Liver fibrosis Endothelin-1 Endothelial dysfunction Steatosis 


  1. 1.
    Falck-Ytter Y, Younossi ZM, Marchenissi G, Mc Cullough AJ (2001) Clinical features and natural history of non-alcoholic steatohepatitis syndrome. Semin Liver Dis 21(1):17–25PubMedCrossRefGoogle Scholar
  2. 2.
    Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55:434–438PubMedGoogle Scholar
  3. 3.
    Cassiman D, Libbrecht L, Desmet V, Denef C, Roskams T (2002) Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 36:200–209PubMedCrossRefGoogle Scholar
  4. 4.
    Geerts A (2001) History and heterogeneity of stellate cells, and role in normal liver function. Semin Liver Dis 21:311–336PubMedCrossRefGoogle Scholar
  5. 5.
    Yanagisawa M, Inoue A, Ishikawa T, Kasuya Y, Kimura S, Kumagaye S, Nakajima K (1988) Primary structure, synthesis, and biological activity of rat endothelin, an endothelium-derived vasoconstrictor peptide. Proc Natl Acad Sci USA 85:6964–6967PubMedCrossRefGoogle Scholar
  6. 6.
    Gandhi CR, Behal RH, Harvey SA, Nouchi TA, Olson MS (1992) Hepatic effects of endothelin. Receptor characterization and endothelin induced signal transduction in hepatocytes. Biochem J 287:897–904Google Scholar
  7. 7.
    Housset C, Rockey DC, Bissell DM (1993) Endothelin receptors in rat liver: lipocytes as a contractile target for endothelin 1. Proc Natl Acad Sci USA 90:9266–9270PubMedCrossRefGoogle Scholar
  8. 8.
    Sanyal AJ, Campbell SC, Mirshahi F (2001) Non-alcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–1192PubMedCrossRefGoogle Scholar
  9. 9.
    Valdenaire O, Rohrbacher E, Mattei MG (1995) Organization of the gene encoding the human endothelin-converting enzyme (ECE-1). J Biol Chem 270:29794–29798PubMedCrossRefGoogle Scholar
  10. 10.
    Rockey DC, John J, Chung A (1996) Endothelin antagonism in experimental hepatic fibrosis implications for endothelin in the pathogenesis of wound healing. J Clin Invest 98(6):381–1388CrossRefGoogle Scholar
  11. 11.
    Rockey DC, Housset CN, Friedman SL (1993) Activation-dependent contractility of rat hepatic lipocytes in culture and in vivo. J Clin Invest 92:1795–1804PubMedGoogle Scholar
  12. 12.
    Shao R, Yan W, Rockey DC (1999) Regulation of endothelin-1 synthesis by endothelin-converting enzyme-1 during wound healing. J Biol Chem 274:3228–3234PubMedCrossRefGoogle Scholar
  13. 13.
    Cho JJ, Hocher B, Herbst H, Jia J, Ruehl M, Hahn EG, Riecken EO (2000) An oral endothelin A receptor antagonist blocks collagen synthesis and depostion in advanced rat liver fibrosis. Gastroenterology 118:1169–1178PubMedCrossRefGoogle Scholar
  14. 14.
    Rockey DC (2001) Cellular pathophysiology of portal hypertension and prospects for management with gene therapy. Clin Liver Dis 5:851–865PubMedCrossRefGoogle Scholar
  15. 15.
    Sakurai T, Yanagisawa M, Masaki T (1992) Molecular characterization of endothelin receptors. Trends Pharmacol Sci 13:103–108PubMedCrossRefGoogle Scholar
  16. 16.
    Mallat A, Fouassier L, Preaux AM, Gal CS, Raufaste D, Rosenbaum J, Dhumeaux D, Jouneaux C, Mavier P, Lotersztajn S (1995) Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway. J Clin Invest 96:42–49Google Scholar
  17. 17.
    Hu RM, Levin ER, Pedram A (1993) Insulin stimulates production and secretion of endothelin from bovine endothelial cells. Diabetes 42:351–358PubMedCrossRefGoogle Scholar
  18. 18.
    Tard ES, Giles WH, Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA 287:356–359CrossRefGoogle Scholar
  19. 19.
    Gore RM (1994) Diffuse liver disease. In: Gore RM, Levine MS, Laufer I (eds) Textbook of gastrointestinal radiology. Saunders, Philadelphia, pp 1968–2017Google Scholar
  20. 20.
    Brunt EM (2001) Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 21:3–16PubMedCrossRefGoogle Scholar
  21. 21.
    Fong DG, Nehra V, Lindor K (2000) Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology 32:3–10PubMedCrossRefGoogle Scholar
  22. 22.
    Marchesini G, Brizi M, Morselli-Labate AM (1999) Association of nonalcoholic fatty liver disease with insulin resistance. Am J Med 107:450–455PubMedCrossRefGoogle Scholar
  23. 23.
    Angulo P (1999) Independent predictors of liver fibrosis in patients with NASH. Hepatology 30:1356–1362PubMedCrossRefGoogle Scholar
  24. 24.
    Bacon BR, Farahvash MJ, Janney CG, Neuschwander Tetri BA (1994) Nonalcoholic steatohepatitis: an expanded clinical entity. Gastroenterology 107:1103–1109PubMedGoogle Scholar
  25. 25.
    Stephenson K, Harvey SA, Akıncı SB, Olson MS (1995) Endothelin association with the cultured rat Kupffer cell: characterization and regulation. Hepatology 22:896–905PubMedGoogle Scholar
  26. 26.
    Hattori Y, Kasai K, Nakamura T, Emoto T, Shimoda S (1991) Effects of glucose and insulin on immunoreactive endothelin-1 release from cultured porcine aortic endothelial cells. Metabolism 40:165–169PubMedCrossRefGoogle Scholar
  27. 27.
    Yamauchi T, Ohnaka K, Takayanagi R, Umeda F, Nawata H (1990) Enhanced secretion of endothelin-1 by elevated glucose levels from cultured bovine aortic endothelial cells. FEBS Lett 267:16–18PubMedCrossRefGoogle Scholar
  28. 28.
    Donatelli M, Colletti I, Bucalo ML, Russo V, Verga S (1994) Plasma endothelin levels in NIDDM patients with macroangiopathy. Diabetes Res 25:159–164PubMedGoogle Scholar
  29. 29.
    Ferri C, De Mattia G (1995) The effect of insulin on endothelin-1 (ET-1) secretion in human cultured endothelial cell. Metabolism 44:689–690PubMedCrossRefGoogle Scholar
  30. 30.
    Schleiffer T, Nagel D, Franz H, Falk M, Valentiner I, Wildburg G, Stark M, Brass H (1994) Endothelin and atrial natriuretic peptid in non-insulindependent diabetic versus non-diabetic patients on chronic hemodialysis. Renal Fail 16:747–758Google Scholar
  31. 31.
    Dixon JB, Bhathal PS, O'Brien PE (2001) Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121:91–100PubMedCrossRefGoogle Scholar
  32. 32.
    Muzzi A, Leandro G, Rubbia-Brandt L, James R, Keiser O, Malinverni R, Dufour JF, Helbling B, Hadengue A, Gonvers JJ, Mullhaupt B, Cerny A, Mondelli MU, Negro F (2005) Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol 42(1):41–46PubMedCrossRefGoogle Scholar
  33. 33.
    Younossi ZM, Gramlich T, Matteoni CA, Boparai N, McCullough AJ (2004) Nonalcoholic fatty liver disease in patients with type 2 diabetes. Clin Gastroenterol Hepatol 2(3):262–265PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science&#x002B;Business Media, Inc. 2006

Authors and Affiliations

  • Bulent Degertekin
    • 1
    • 3
    Email author
  • Seren Ozenirler
    • 1
  • Sehri Elbeg
    • 2
  • Gulen Akyol
    • 3
  1. 1.Department of Gastroenterology and HepatologyGazi University School of MedicineAnkaraTurkey
  2. 2.Department of BiochemistryGazi University School of MedicineAnkaraTurkey
  3. 3.Gazi Universitesi Tip Fakultesi GastroenterolojiAnkaraTurkey

Personalised recommendations