Skip to main content
  • Original article
  • Open access
  • Published:

Serum angiopoietin-2 as a noninvasive diagnostic marker of stages of liver fibrosis in chronic hepatitis C patients



The process of fibrogenesis is associated with the development of disease-specific markers. The management of chronic hepatitis C (CHC) depends on the staging of liver fibrosis. Use of noninvasive methods is preferable in diagnosis and follow-up.


The aim of this study is to evaluate serum angiopoietin-2 (Ang-2) as a noninvasive marker in the diagnosis of different stages of liver fibrosis in CHC patients.

Materials and methods

A total of 90 individuals were included. They were divided into a patient group (75 patients) and a control group (15 normal individuals). Serum Ang-2 was measured using enzyme-linked immunosorbent assay. Pretreatment liver biopsy was performed for the patients. The METAVIR score was used in the staging of liver fibrosis. A comparison of Ang-2 was performed between patients and controls, and between different stages of liver fibrosis. A receiver operating characteristic curve analysis was carried out to determine the best cutoff values of Ang-2 in the differentiation of different stages of fibrosis.


Ang-2 serum levels were significantly higher in advanced stages of liver fibrosis. The cutoff points 869.3, 2226, and 7205 pg/ml were the best for differentiating fibrosis stages >F1; >F2; and >F3, respectively. Ang-2, international normalized ratio, α-fetoprotein, and albumin were found to be independent predictors of liver fibrosis using univariate analysis.


Ang-2 correlated significantly with liver fibrosis stage. It can aid noninvasive differentiation between different stages of liver fibrosis in patients with CHC.


  1. Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; 36: S35–S46.

    PubMed  Google Scholar 

  2. Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, et al. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011; 31(Suppl 2):61–80.

    Article  Google Scholar 

  3. Doss W, Esmat G, El Serafy M, Sayed MHE, Hassany M, Yousry A, et al. Interim analysis for sofosbuvir national treatment program in Egypt National Liver Institute, Menoufia, Egypt. J Viral Hepat 2015; 22:19–135.

    Google Scholar 

  4. Lee MH, Yang HI, Chen CH. Long-term health outcomes of chronic hepatitis C patients: a review of findings of REVEAL-HCV cohort study. BioMedicine 2012; 2:99–107.

    Article  Google Scholar 

  5. Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 2012; 56:769–775.

    Article  CAS  Google Scholar 

  6. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134:1655–1669.

    Article  CAS  Google Scholar 

  7. Baranova A, Lal P, Birerdinc A, Younossi ZM. Non-invasive markers for hepatic fibrosis. BMC Gastroenterol 2011; 11–91

  8. Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142:1293–1302.

    Article  Google Scholar 

  9. Barton WA, Tzvetkova D, Nikolov DB. Structure of the angiopoietin-2 receptor binding domain and identification of surfaces involved in Tie2 recognition. Structure 2005; 13:825–832.

    Article  CAS  Google Scholar 

  10. Fiedler U, Scharpfenecker M, Koidl S, Hegen A, Grunow V, Schmidt JM, et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 2004; 103:4150–4156.

    Article  CAS  Google Scholar 

  11. Hashizume H, Falcon BL, Kuroda T, Baluk P, Coxon A, Yu D, et al. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res, 2010; 70: 2213–2223.

    Article  CAS  Google Scholar 

  12. Tugues S, Fernandez-Varo G, Muñoz-Luque J, Ros J, Arroyo V, Rodés J, et al. Antiangiogenic treatment with sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats. Hepatology 2007; 46:1919–1926.

    Article  CAS  Google Scholar 

  13. Bedossa P, Poynard T An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 1996; 24:289–293.

    Article  CAS  Google Scholar 

  14. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003; 38:518–526.

    Article  Google Scholar 

  15. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. APRICOT Clinical Investigators: development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006; 43:1317–1325.

    Article  CAS  Google Scholar 

  16. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1998; 95:734–739.

    Article  Google Scholar 

  17. Kanwal F, Hoang T, Kramer JR, Asch SM, Goetz MB, Zeringue A et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology 2011; 140:1182–1188.

    Article  Google Scholar 

  18. Mahmoud YA, Mumtaz DR, Riome S, Miller D, Abu-Raddad L The epidemiology of hepatitis C virus in Egypt: a systematic review and data synthesis. BMC Infect Dis 2013; 13–288

  19. Abdel-Aziz F, Habib M, Mohamed MK, Abdel-Hamid M, Gamil F, Madkour S, et al. Hepatitis C virus (HCV) infection in a community in the Nile Delta: population description and HCV prevalence. Hepatology 2000; 32:111–115.

    Article  CAS  Google Scholar 

  20. Lee YS, Yoon SK, Chung ES, Bae SH, Choi JY, Han JY, et al. The relationship of histologic activity to serum ALT, HCV genotype and HCV RNA titers in chronic hepatitis C. J Korean Med Sci 2001; 16:585–591.

    Article  CAS  Google Scholar 

  21. Kim YW, Kwon JH, Jang JH, Kim MJ, OH BS, Chung KW, et al. Diagnostic usefulness of real-time elastography for liver fibrosis in chronic viral hepatitis B and C. Gastroenterol Res Pract 2014; 2014:210407.

    PubMed  PubMed Central  Google Scholar 

  22. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 2004; 99:1160–1174.

    Article  Google Scholar 

  23. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT et al. Sampling error and intra-observer variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002; 97: 2614–2618.

    Article  Google Scholar 

  24. Rockey DC, Bissell DM. Noninvasive measures of liver fibrosis. Hepatology 2006; 43:S113–S120.

  25. Hernández-Bartolomé A,López-Rodríguez R, Rodríguez-Muñoz Y, Martín-Vílchez S, Borque MJ, García-Buey L, et al. Angiopoietin-2 serum levels improve noninvasive fibrosis staging in chronic hepatitis C. PLoS One 2013; 8:e66143.

  26. Sebastiani G, Alberti A. How far is noninvasive assessment of liver fibrosis from replacing liver biopsy in hepatitis C? J Viral Hepat 2012; 1:18–32.

    Article  Google Scholar 

  27. Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht J. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C. J Hepatol 2001; 34:730–739.

    Article  CAS  Google Scholar 

  28. Wong V, Caronia S, Wight D, Palmer CR, Petrik J, Britton P, Alexander GJ. Importance of age in hepatitis C virus infection. J Viral Hepat 1997; 4:255–264.

    Article  CAS  Google Scholar 

  29. Costa LB, Ferraz ML, Perez RM, Ferreira AS, Matos CA, Lanzoni VP, Silva AE. Effect of host-related factors on the intensity of liver fibrosis in patients with chronic hepatitis C virus infection. Braz J Infect Dis 2002; 6:219–224.

    PubMed  Google Scholar 

  30. Adinolfi LE, Giordano MG, Andreana A, Tripodi MF, Utili R, Cesaro G, et al. Hepatic fibrosis plays a central role in the pathogenesis of thrombocytopenia in patients with chronic viral hepatitis. Br J Haematol 2001; 113:590–595.

    Article  CAS  Google Scholar 

  31. Zechini B, Pasquazzi C, Aceti A. Correlation of serum aminotransferases with HCV RNA levels and histological findings in patients with chronic hepatitis C: the role of serum aspartate transaminase in the evaluation of disease progression. Eur J Gastroenterol Hepatol 2004; 16:891–896.

    Article  CAS  Google Scholar 

  32. Giannini E, Risso D, Botta F, Chiarbonello B, Fasoli A, Malfatti F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 2003; 163:218–224.

    Article  Google Scholar 

  33. Liu Pei, Li Ying, Sun Cui-Ming. Correlations of serum hepatitis C.Liver Dis 2000; 20:0047–0056.

  34. Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology 2011; 53:726–736.

    Article  Google Scholar 

  35. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 2009; 10:165–177.

    Article  CAS  Google Scholar 

  36. Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol 2206 27:552–558.

  37. Salcedo X, Medina J, Sanz-Cameno P, Garcia-Buey L, Martin-Vilchez S, Borque MJ, et al. The potential of angiogenesis soluble markers in chronic hepatitis C. Hepatology 2005; 42:696–701.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Shereen A. B. Saleh MD.

Additional information

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work noncommercially, as long as the author is credited and the new creations are licensed under the identical terms

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Makhlouf, M.M., Osman, M.A., Saleh, S.A.B. et al. Serum angiopoietin-2 as a noninvasive diagnostic marker of stages of liver fibrosis in chronic hepatitis C patients. Egypt J Intern Med 28, 140–148 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: