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The Egyptian Journal of Internal Medicine
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Significance of hepatocyte growth factor concentrations in serum of patients with liver cirrhosis and patients with hepatocellular carcinoma

The Egyptian Journal of Internal Medicine volume 27, pages 92–101 (2015)Cite this article

Abstract

Objective

Egypt has the highest prevalence of chronic hepatitis C virus (HCV) infection worldwide with the development of cirrhosis and hepatocellular carcinoma (HCC). The hepatocyte growth factor (HGF)–cMET axis promotes cell survival, proliferation, migration, and invasion. This study aimed to evaluate the role of serum HGF as a noninvasive biomarker in the diagnosis of liver cirrhosis and HCC.

Patients and methods

This study included 80 individuals. They were divided into three groups: group 1 included 20 healthy volunteers as a control group, group 2 included 30 patients with liver cirrhosis, and group 3 included 30 patients with HCC.

Results

HGF was highly significantly elevated in the HCC group (median 3709 pg/ml) and the cirrhotic group (median 2843.5 pg/ml) compared with the control group (median 913 pg/ml). α-Fetoprotein (AFP) was highly significantly elevated in the HCC group (median 128.5 ng/ml) than both the cirrhotic (median 4.9 ng/ml) and the control (median 3.15 ng/ml) group. Results of aspartate aminotransferase/alanine aminotransferase, APRI, fibroindex, and model 3 in the cirrhotic group were highly significantly different from those in the control group. We found a positive significant correlation between HGF and AFP for all the participants studied. There were direct correlations between HGF and aspartate aminotransferase/platelet ratio index (APRI), fibroindex, and model 3. The sensitivity and specificity of HGF for selective detection of the HCC group over the non-HCC group (HCV group and healthy control group) were 93.3 and 46%, respectively, at a cut-off value of 1415 pg/ml, whereas that of AFP were 100 and 92%, respectively, at a cut-off value of 10 ng/ml, and area under the curve of HGF and AFP were 0.787 and 0.999, respectively. The sensitivity and specificity of both AFP and HGF together were 100 and 66%, respectively, at the same cut-off values. The odds ratio of occurrence of HCC in patients with elevated HGF levels was 11.926 and 95% confidence interval 2.56–55.55.

Conclusion

We conclude from this study that both HGF and AFP can be used as noninvasive biomarkers for early detection of HCC in HCV cirrhotic patients, especially if their values match the cut-off levels detected in our study.

References

  1. Brandao DF, Ramalho LNZ, Ramalho FS, Zucoloto S, Martinelli A, Castro E, et al. Liver cirrhosis and hepatic stellate cells. Acta Cir Bras 2006; 21: 54–57.

    PubMed  Google Scholar 

  2. Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 1978; 31: 395–414.

    CAS  Google Scholar 

  3. Groszmann RJ, Atterbury CE. The pathophysiology of portal hypertension: a basis for classification. Semin Liver Dis 1982; 2: 177–186.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Sattler M, Salgia R. The MET axis as a therapeutic target. Update Cancer Ther 2009; 3: 109–118.

    PubMed  PubMed Central  Google Scholar 

  6. Zekri AR, Alam El-Din HM, Bahnassy AA, Zayed NA, Mohamed WS, El-Masry SH, et al. Serum levels of soluble Fas, soluble tumor necrosis factor-receptorll, interleukin 2 receptor and interleukin 8 as early predictors of hepatocellular carcinoma in Egyptian patients with hepatitis C genotype 4. Comp Hepatol 2010; 9: 1.

    PubMed  PubMed Central  Google Scholar 

  7. Marrero CR, Marrero JA. Viral hepatitis and hepatocellular carcinoma. Arch Med Res. 2007; 38: 612–620.

    CAS  PubMed  Google Scholar 

  8. Liovet J, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1907–1917.

    Google Scholar 

  9. Hussein MM, Ibrahim AA, Abdella HM, Montasser IF, Hassan MI. Evaluation of serum squamous cell carcinoma antigen as a novel biomarker for diagnosis of hepatocellular carcinoma in Egyptian patients. Indian J Cancer 2008; 45: 167–172.

    CAS  PubMed  Google Scholar 

  10. Schwartz M, Roayaie S, Konstadoulakis M. Strategies for the management of hepatocellular carcinoma. Nat Clin Pract Oncol 2007; 4: 424–432.

    CAS  PubMed  Google Scholar 

  11. Di Bisceglie AM, Sterling RK, Chung RT, Everhart JE, Dienstag JL, Bonkovsky HL, et al. HALT-C Trial Group Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial. J Hepatol 2005; 43: 434–441.

    PubMed  Google Scholar 

  12. Gomaa AI, Khan SA, Leen ELS, Waked I, Taylor-Robinson. Diagnosis of hepatocellular carcinoma. World J Gastroenterol 2009; 15: 1301–1314.

    PubMed  PubMed Central  Google Scholar 

  13. Nakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad Ser B Phys Biol Sci 2010; 86: 588–610.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Venepalli NK, Goff L. Targeting the HGF–cMET axis in hepatocellular carcinoma. Int J Hepatol 2013; 2013: 341636.

    PubMed  PubMed Central  Google Scholar 

  15. Atta H, El-Rehany M, Hammam O, Abdel-Ghany H, Ramzy M, Roderfeld M, et al. Mutant MMP-9 and HGF gene transfer enhance resolution of CCl4-induced liver fibrosis in rats: role of ASH1 and EZH2 methyltransferases repression. PLoS One 2014; 9: e112384.

    PubMed  PubMed Central  Google Scholar 

  16. Nagai T, Arao T, Furuta K, Sakai K, Kudo K, Kaneda H, et al. Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. Mol Cancer Ther 2011; 10: 169–177.

    CAS  PubMed  Google Scholar 

  17. 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.

    PubMed  Google Scholar 

  18. Koda M, Matunaga Y, Kawakami M, Kishimoto Y, Suou T, Murawaki Y. FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C. Hepatology 2007; 45: 297–306.

    PubMed  Google Scholar 

  19. Lok AS, Ghany MG, Goodman ZD, Wright EC, Everson GT, Sterling RK, et al. Predicting cirrhosis in patients with hepatitis C based on standard laboratory tests: results of the HALT-C cohort. Hepatology 2005; 42: 282–292.

    PubMed  Google Scholar 

  20. Bi S, Yan Y, Yang X, Zhang S. Gold nanolabels for new enhanced chemiluminescence immunoassay of alpha-fetoprotein based on magnetic beads. Chemistry 2009; 15: 4704–4709.

    CAS  PubMed  Google Scholar 

  21. Chau GY, Lui WY, Chi CW, Chau YP, Li AF, Kao HL, Wu CW. Significance of serum hepatocyte growth factor levels in patients with hepatocellular carcinoma undergoing hepatic resection. Eur J Surg Oncol 2008; 34: 333–338.

    PubMed  Google Scholar 

  22. Lehman EM, Wilson ML. Epidemiology of hepatitis viruses among hepatocellular carcinoma cases and healthy people in Egypt: a systematic review and meta-analysis. Int J Cancer 2009; 124: 690–697.

    CAS  PubMed  Google Scholar 

  23. Strickland GT. Liver disease in Egypt: hepatitis C superseded schistosomiasis as a result of iatrogenic and biological factors. Hepatology 2006; 43: 915–922.

    PubMed  Google Scholar 

  24. Gogel BM, Goldstein RM, Kuhn JA, McCarty TM, Donahoe A, Glastad K. Diagnostic evaluation of hepatocellular carcinoma in a cirrhotic liver. Oncology (Williston Park) 2000; 14 (Suppl 3): 15–20.

    CAS  Google Scholar 

  25. Mungunsukh O, McCart EA, Day RM. Hepatocyte growth factor isoforms in tissue repair, cancer, and fibrotic remodeling. Biomedicines 2014; 2: 301–326.

    PubMed  PubMed Central  Google Scholar 

  26. Shiota G, Umeki K, Okano J, Kawasaki H. Hepatocyte growth factor and acute phase proteins in patients with chronic liver diseases. J Med 1995; 26: 295–308.

    CAS  PubMed  Google Scholar 

  27. Vejchapipat P, Tangkijvanich P, Theamboonlers A, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. Association between serum hepatocyte growth factor and survival in untreated hepatocellular carcinoma. J Gastroenterol 2004; 39: 1182–1188.

    CAS  PubMed  Google Scholar 

  28. Yamagamim H, Moriyama M, Matsumura H, Aoki H, Shimizu T, Saito T, et al. Serum concentrations of human hepatocyte growth factor is a useful indicator for predicting the occurrence of hepatocellular carcinomas in C-viral chronic liver diseases. Cancer 2002; 95: 824–834.

    CAS  PubMed  Google Scholar 

  29. Karabulut S, Tas F, Akyüz F, Ormeci AC, Serilmez M, Soydinç HO, et al. Clinical significance of serum hepatocyte growth factor (HGF) levels in hepatocellular carcinoma. Tumour Biol 2014; 35: 2327–2333.

    CAS  PubMed  Google Scholar 

  30. Jia HL, Xing XJ, Ye QH, Qin LX. Application of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2008; 30: 440–443.

    CAS  PubMed  Google Scholar 

  31. Cheng KS, Tang HL, Chou FT, Chou JW, Hsu CH, Yu CJ, et al. Cytokine evaluation in liver cirrhosis and hepatocellular carcinoma. Hepatogastroenterology 2009; 56: 1105–1110.

    CAS  PubMed  Google Scholar 

  32. Gadelhak NA, Gadelhak SA, El-Morsi DA, Abdelaziz MM, Abbas AT, El-Emshaty HM. Prognostic significance of three hepatitis markers (P53 antibodies, vascular endothelial growth factors and alpha fetoprotein) in patients with hepatocellular carcinoma. Hepatogastroentrology 2009; 56: 1417–1424.

    CAS  Google Scholar 

  33. El Badrawy N, Hammam OA, El Ghanam M, Al Ansary M, Hassan M, Ai Saleem AA. OV6, a-fetoprotein, hepatocyte growth factor and transforming growth factor beta 1 in patients with chronic hepatitis, cirrhosis and hepato cellular carcinoma. J Am Sci 2013; 9: 647–657.

    Google Scholar 

  34. Lackner C, Struber G, Liegl B, Leibl S, Ofner P, Bankuti C et al. Comparison and validation of simple noninvasive tests for prediction of fibrosis in chronic hepatitis C. Hepatology 2005; 41: 1376–1382.

    PubMed  Google Scholar 

  35. Andersen ES, Ruhwald M, Moessner B, Christensen PB, Andersen O, Eugen-Olsen J, Weis N. Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1. Eur J Clin Microbiol Infect Dis 2011; 30: 761–766.

    CAS  PubMed  Google Scholar 

  36. Taketa K, Okada S, Win N, Hlaing NK, Wind KM. Evaluation of tumor markers for the detection of hepatocellular carcinoma in Yangon General Hospital, Myanmar. Acta Med Okayama 2002; 56: 317–320.

    PubMed  Google Scholar 

  37. Gad A, Tanaka E, Matsumoto A, Serwah AEH, Attia F, Hassan A, et al. Ethnicity affects the diagnostic validity of alpha-fetoprotein in hepatocellular carcinoma. Asia Pac J Clin Oncol 2005; 1: 64–70.

    Google Scholar 

  38. Stefaniuk P, Cianciara J, Wiercinska-Drapalo A. Present and future possibilities for early diagnosis of hepatocellular carcinoma. World J Gastroenterol 2010; 16: 418–424.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen L, Ho DW, Lee NP, Sun S, Lam B, Wong KF, et al. Enhanced detection of early hepatocellular carcinoma by serum SELDI-TOF proteomic signature combined with alpha-fetoprotein marker. Ann Surg Oncol 2010; 17: 2518–2525.

    PubMed  PubMed Central  Google Scholar 

  40. Lok AS, Sterling RK, Everhart JE, Wright EC, Hoefs JC, Di Bisceglie AM, et al. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma. Gastroenterology 2010; 138: 493–502.

    CAS  PubMed  Google Scholar 

  41. Sheng SL, Wang Q, Huang G, Yu B, Qin WX. Simultaneous determination of alpha-fetoprotein immune complexes and alpha-fetoprotein concentration in hepatocellular carcinoma using dual-label time-resolved immunofluorometric assays. J Clin Lab Anal 2009; 23: 179–185.

    PubMed  PubMed Central  Google Scholar 

  42. Marrero JA, Feng Z, Wang Y, Nguyen MH, Befeler AS, Roberts LR, et al. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma. Gastroenterology 2009; 137: 110–118.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Yamamoto K, Imamura H, Matsuyama Y, Hasegawa K, Beck Y, Sugawara Y, et al. Significance of alpha-fetoprotein and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy. Ann Surg Oncol 2009; 16: 2795–2804.

    PubMed  Google Scholar 

  44. Zhou L, Rui JA, Wang SB, Chen SG, Qu Q. The significance of serum AFP cut-off values, 20 and 400 ng/ml in curatively resected patients with hepatocellular carcinoma and cirrhosis might be of difference. Hepatogastroenterology 2012; 59: 840–843.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Departments of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt

    Heba S. El Deen

  2. Departments of I nternal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt

    Hemmat E. El Haddad

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  1. Heba S. El Deen
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Correspondence to Hemmat E. El Haddad.

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El Deen, H.S., El Haddad, H.E. Significance of hepatocyte growth factor concentrations in serum of patients with liver cirrhosis and patients with hepatocellular carcinoma. Egypt J Intern Med 27, 92–101 (2015). https://doi.org/10.4103/1110-7782.165437

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