Journal of Gastroenterology

, Volume 46, Issue 1, pp 92–100 | Cite as

Alpha-fetoprotein above normal levels as a risk factor for the development of hepatocellular carcinoma in patients infected with hepatitis C virus

  • Masakuni Tateyama
  • Hiroshi YatsuhashiEmail author
  • Naota Taura
  • Yasuhide Motoyoshi
  • Shinya Nagaoka
  • Kenji Yanagi
  • Seigo Abiru
  • Koji Yano
  • Atsumasa Komori
  • Kiyoshi Migita
  • Minoru Nakamura
  • Hiroyasu Nagahama
  • Yutaka Sasaki
  • Yuzo Miyakawa
  • Hiromi Ishibashi
Original Article—Liver, Pancreas, and Biliary Tract



Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV).


A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received.


The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6–20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6–20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively.


Not only high (>20 ng/mL), but also even slightly elevated (6–20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.


Alpha-fetoprotein Hepatitis C virus Hepatocellular carcinoma 



This work was sponsored in part by grants from the Ministry of Health, Labour and Welfare of Japan.


  1. 1.
    Afdhal NH. The natural history of hepatitis C. Semin Liver Dis. 2004;24(Suppl 2):3–8.CrossRefPubMedGoogle Scholar
  2. 2.
    Cohen J. Virology. Culture systems for hepatitis C virus in sight at last. Science. 2005;308:1539–41.CrossRefPubMedGoogle Scholar
  3. 3.
    Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis. 2005;25:143–54.CrossRefPubMedGoogle Scholar
  4. 4.
    Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007;13:2436–41.PubMedGoogle Scholar
  5. 5.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.CrossRefPubMedGoogle Scholar
  6. 6.
    Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of Hepatocarcinogenesis by Interferon Therapy. Ann Intern Med. 1999;131:174–81.PubMedGoogle Scholar
  7. 7.
    Liang TJ, Heller T. Pathogenesis of hepatitis C-associated hepatocellular carcinoma. Gastroenterology. 2004;127:S62–71.CrossRefPubMedGoogle Scholar
  8. 8.
    Saadeh S, Cammell G, Carey WD, Younossi Z, Barnes D, Easley K. The role of liver biopsy in chronic hepatitis C. Hepatology. 2001;33:196–200.CrossRefPubMedGoogle Scholar
  9. 9.
    Gebo KA, Herlong HF, Torbenson MS, Jenckes MW, Chander G, Ghanem KG, et al. Role of liver biopsy in management of chronic hepatitis C: a systematic review. Hepatology. 2002;36:S161–72.CrossRefPubMedGoogle Scholar
  10. 10.
    Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Yu ML, Lin SM, Lee CM, Dai CY, Chang WY, Chen SC, et al. A simple noninvasive index for predicting long-term outcome of chronic hepatitis C after interferon-based therapy. Hepatology. 2006;44:1086–97.CrossRefPubMedGoogle Scholar
  12. 12.
    Ono E, Shiratori Y, Okudaira T, Imamura M, Teratani T, Kanai F, et al. Platelet count reflects stage of chronic hepatitis C. Hepatol Res. 1999;15:192–200.CrossRefGoogle Scholar
  13. 13.
    Matsumura H, Moriyama M, Goto I, Tanaka N, Okubo H, Arakawa Y. Natural course of progression of liver fibrosis in Japanese patients with chronic liver disease type C—a study of 527 patients at one establishment. J Viral Hepat. 2000;7:268–75.CrossRefPubMedGoogle Scholar
  14. 14.
    Pohl A, Behling C, Oliver D, Kilani M, Monson P, Hassanein T. Serum aminotransferase levels and platelet counts as predictors of degree of fibrosis in chronic hepatitis C virus infection. Am J Gastroenterol. 2001;96:3142–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Degos F, Christidis C, Ganne-Carrie N, Farmachidi JP, Degott C, Guettier C, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut. 2000;47:131–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Rodriguez-Diaz JL, Rosas-Camargo V, Vega-Vega O, Morales-Espinosa D, Mendez-Reguera A, Martinez-Tlahuel JL, et al. Clinical and pathological factors associated with the development of hepatocellular carcinoma in patients with hepatitis virus-related cirrhosis: a long-term follow-up study. Clin Oncol (R Coll Radiol). 2007;19:197–203.Google Scholar
  17. 17.
    Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Aoyagi K, Ohue C, Iida K, Kimura T, Tanaka E, Kiyosawa K, et al. Development of a simple and highly sensitive enzyme immunoassay for hepatitis C virus core antigen. J Clin Microbiol. 1999;37:1802–8.PubMedGoogle Scholar
  19. 19.
    Tanaka E, Ohue C, Aoyagi K, Yamaguchi K, Yagi S, Kiyosawa K, et al. Evaluation of a new enzyme immunoassay for hepatitis C virus (HCV) core antigen with clinical sensitivity approximating that of genomic amplification of HCV RNA. Hepatology. 2000;32:388–93.CrossRefPubMedGoogle Scholar
  20. 20.
    Simmonds P, Holmes EC, Cha TA, Chan SW, McOmish F, Irvine B, et al. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol. 1993;74(Pt 11):2391–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Ohno O, Mizokami M, Wu RR, Saleh MG, Ohba K, Orito E, et al. New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a. J Clin Microbiol. 1997;35:201–7.PubMedGoogle Scholar
  22. 22.
    Aizawa Y, Shibamoto Y, Takagi I, Zeniya M, Toda G. Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C. A long term follow-up study after histologic diagnosis. Cancer. 2000;89:53–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.CrossRefPubMedGoogle Scholar
  24. 24.
    Kiyosawa K, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K, Gad A, et al. Hepatocellular carcinoma: recent trends in Japan. Gastroenterology. 2004;127:S17–26.CrossRefPubMedGoogle Scholar
  25. 25.
    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.CrossRefPubMedGoogle Scholar
  26. 26.
    Colombo M, de Franchis R, Del Ninno E, Sangiovanni A, De Fazio C, Tommasini M, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl J Med. 1991;325:675–80.CrossRefPubMedGoogle Scholar
  27. 27.
    Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, et al. Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med. 1993;328:1797–801.CrossRefPubMedGoogle Scholar
  28. 28.
    Oka H, Tamori A, Kuroki T, Kobayashi K, Yamamoto S. Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology. 1994;19:61–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Ganne-Carrie N, Chastang C, Chapel F, Munz C, Pateron D, Sibony M, et al. Predictive score for the development of hepatocellular carcinoma and additional value of liver large cell dysplasia in Western patients with cirrhosis. Hepatology. 1996;23:1112–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Sangiovanni A, Colombo E, Radaelli F, Bortoli A, Bovo G, Casiraghi MA, et al. Hepatocyte proliferation and risk of hepatocellular carcinoma in cirrhotic patients. Am J Gastroenterol. 2001;96:1575–80.CrossRefPubMedGoogle Scholar
  31. 31.
    Ikeda K, Arase Y, Saitoh S, Kobayashi M, Someya T, Hosaka T, et al. Prediction model of hepatocarcinogenesis for patients with hepatitis C virus-related cirrhosis. Validation with internal and external cohorts. J Hepatol. 2006;44:1089–97.CrossRefPubMedGoogle Scholar
  32. 32.
    Bruce MG, Bruden D, McMahon BJ, Christensen C, Homan C, Sullivan D, et al. Clinical significance of elevated alpha-fetoprotein in Alaskan Native patients with chronic hepatitis C. J Viral Hepat. 2008;15:179–87.CrossRefPubMedGoogle Scholar
  33. 33.
    Taketa K. Alpha-fetoprotein: reevaluation in hepatology. Hepatology. 1990;12:1420–32.CrossRefPubMedGoogle Scholar
  34. 34.
    Chu CW, Hwang SJ, Luo JC, Lai CR, Tsay SH, Li CP, et al. Clinical, virologic, and pathologic significance of elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C. J Clin Gastroenterol. 2001;32:240–4.CrossRefPubMedGoogle Scholar
  35. 35.
    Lu LG, Zeng MD, Wan MB, Li CZ, Mao YM, Li JQ, et al. Grading and staging of hepatic fibrosis, and its relationship with noninvasive diagnostic parameters. World J Gastroenterol. 2003;9:2574–8.PubMedGoogle Scholar
  36. 36.
    Hu KQ, Kyulo NL, Lim N, Elhazin B, Hillebrand DJ, Bock T. Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol. 2004;99:860–5.CrossRefPubMedGoogle Scholar
  37. 37.
    Wilfredo Canchis P, Gonzalez SA, Isabel Fiel M, Chiriboga L, Yee H, Edlin BR, et al. Hepatocyte proliferation in chronic hepatitis C: correlation with degree of liver disease and serum alpha-fetoprotein. Liver Int. 2004;24:198–203.CrossRefPubMedGoogle Scholar
  38. 38.
    Di Bisceglie AM, Sterling RK, Chung RT, Everhart JE, Dienstag JL, Bonkovsky HL, et al. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C trial. J Hepatol. 2005;43:434–41.CrossRefPubMedGoogle Scholar
  39. 39.
    Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995;346:1051–5.CrossRefPubMedGoogle Scholar
  40. 40.
    Yu ML, Huang CF, Dai CY, Huang JF, Chuang WL. Long-term effects of interferon-based therapy for chronic hepatitis C. Oncology. 2007;72(Suppl 1):16–23.CrossRefPubMedGoogle Scholar
  41. 41.
    Imai Y, Kawata S, Tamura S, Yabuuchi I, Noda S, Inada M, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Osaka Hepatocellular Carcinoma Prevention Study Group. Ann Intern Med. 1998;129:94–9.PubMedGoogle Scholar
  42. 42.
    Kasahara A, Hayashi N, Mochizuki K, Takayanagi M, Yoshioka K, Kakumu S, et al. Risk factors for hepatocellular carcinoma and its incidence after interferon treatment in patients with chronic hepatitis C. Osaka Liver Disease Study Group. Hepatology. 1998;27:1394–402.CrossRefPubMedGoogle Scholar
  43. 43.
    Ikeda K, Saitoh S, Arase Y, Chayama K, Suzuki Y, Kobayashi M, et al. Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis type C: a long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis. Hepatology. 1999;29:1124–30.CrossRefPubMedGoogle Scholar
  44. 44.
    Okanoue T, Itoh Y, Kirishima T, Daimon Y, Toyama T, Morita A, et al. Transient biochemical response in interferon therapy decreases the development of hepatocellular carcinoma for five years and improves the long-term survival of chronic hepatitis C patients. Hepatol Res. 2002;23:62–77.CrossRefPubMedGoogle Scholar
  45. 45.
    Hino K, Okita K. Interferon therapy as chemoprevention of hepatocarcinogenesis in patients with chronic hepatitis C. J Antimicrob Chemother. 2004;53:19–22.CrossRefPubMedGoogle Scholar
  46. 46.
    Valla DC, Chevallier M, Marcellin P, Payen JL, Trepo C, Fonck M, et al. Treatment of hepatitis C virus-related cirrhosis: a randomized, controlled trial of interferon alfa-2b versus no treatment. Hepatology. 1999;29:1870–5.CrossRefPubMedGoogle Scholar
  47. 47.
    Camma C, Di Bona D, Craxi A. The impact of antiviral treatments on the course of chronic hepatitis C: an evidence-based approach. Curr Pharm Des. 2004;10:2123–30.CrossRefPubMedGoogle Scholar
  48. 48.
    Shiffman ML, Hofmann CM, Contos MJ, Luketic VA, Sanyal AJ, Sterling RK, et al. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology. 1999;117:1164–72.CrossRefPubMedGoogle Scholar
  49. 49.
    Stein DF, Myaing M. Normalization of markedly elevated alpha-fetoprotein in a virologic nonresponder with HCV-related cirrhosis. Dig Dis Sci. 2002;47:2686–90.CrossRefPubMedGoogle Scholar
  50. 50.
    Murashima S, Tanaka M, Haramaki M, Yutani S, Nakashima Y, Harada K, et al. A decrease in AFP level related to administration of interferon in patients with chronic hepatitis C and a high level of AFP. Dig Dis Sci. 2006;51:808–12.CrossRefPubMedGoogle Scholar
  51. 51.
    Yano H, Iemura A, Haramaki M, Ogasawara S, Takayama A, Akiba J, et al. Interferon alfa receptor expression and growth inhibition by interferon alfa in human liver cancer cell lines. Hepatology. 1999;29:1708–17.CrossRefPubMedGoogle Scholar
  52. 52.
    Tarao K, Rino Y, Ohkawa S, Shimizu A, Tamai S, Miyakawa K, et al. Association between high serum alanine aminotransferase levels and more rapid development and higher rate of incidence of hepatocellular carcinoma in patients with hepatitis C virus-associated cirrhosis. Cancer. 1999;86:589–95.CrossRefPubMedGoogle Scholar
  53. 53.
    Tarao K, Rino Y, Ohkawa S, Tamai S, Miyakawa K, Takakura H, et al. Close association between high serum alanine aminotransferase levels and multicentric hepatocarcinogenesis in patients with hepatitis C virus-associated cirrhosis. Cancer. 2002;94:1787–95.CrossRefPubMedGoogle Scholar
  54. 54.
    Moriyama M, Matsumura H, Aoki H, Shimizu T, Nakai K, Saito T, et al. Long-term outcome, with monitoring of platelet counts, in patients with chronic hepatitis C and liver cirrhosis after interferon therapy. Intervirology. 2003;46:296–307.CrossRefPubMedGoogle Scholar
  55. 55.
    Velazquez RF, Rodriguez M, Navascues CA, Linares A, Perez R, Sotorrios NG, et al. Prospective analysis of risk factors for hepatocellular carcinoma in patients with liver cirrhosis. Hepatology. 2003;37:520–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Masakuni Tateyama
    • 1
    • 2
  • Hiroshi Yatsuhashi
    • 1
    Email author
  • Naota Taura
    • 1
  • Yasuhide Motoyoshi
    • 1
  • Shinya Nagaoka
    • 1
  • Kenji Yanagi
    • 1
  • Seigo Abiru
    • 1
  • Koji Yano
    • 1
  • Atsumasa Komori
    • 1
  • Kiyoshi Migita
    • 1
  • Minoru Nakamura
    • 1
  • Hiroyasu Nagahama
    • 2
  • Yutaka Sasaki
    • 2
  • Yuzo Miyakawa
    • 3
  • Hiromi Ishibashi
    • 1
  1. 1.Clinical Research CenterNational Nagasaki Medical CenterNagasakiJapan
  2. 2.Department of Gastroenterology and Hepatology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
  3. 3.Miyakawa Memorial Research FoundationTokyoJapan

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