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

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

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).

Methods

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.

Results

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.

Conclusions

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.

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References

  1. Afdhal NH. The natural history of hepatitis C. Semin Liver Dis. 2004;24(Suppl 2):3–8.

    Article  PubMed  Google Scholar 

  2. Cohen J. Virology. Culture systems for hepatitis C virus in sight at last. Science. 2005;308:1539–41.

    Article  CAS  PubMed  Google Scholar 

  3. Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis. 2005;25:143–54.

    Article  PubMed  Google Scholar 

  4. Alter MJ. Epidemiology of hepatitis C virus infection. World J Gastroenterol. 2007;13:2436–41.

    PubMed  Google Scholar 

  5. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  7. Liang TJ, Heller T. Pathogenesis of hepatitis C-associated hepatocellular carcinoma. Gastroenterology. 2004;127:S62–71.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  17. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513–20.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  23. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127:S35–50.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  25. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208–36.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  33. Taketa K. Alpha-fetoprotein: reevaluation in hepatology. Hepatology. 1990;12:1420–32.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  45. Hino K, Okita K. Interferon therapy as chemoprevention of hepatocarcinogenesis in patients with chronic hepatitis C. J Antimicrob Chemother. 2004;53:19–22.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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Acknowledgments

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

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Authors and Affiliations

  1. Clinical Research Center, National Nagasaki Medical Center, Nagasaki, 856-8562, Japan

    Masakuni Tateyama, Hiroshi Yatsuhashi, Naota Taura, Yasuhide Motoyoshi, Shinya Nagaoka, Kenji Yanagi, Seigo Abiru, Koji Yano, Atsumasa Komori, Kiyoshi Migita, Minoru Nakamura & Hiromi Ishibashi

  2. Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Masakuni Tateyama, Hiroyasu Nagahama & Yutaka Sasaki

  3. Miyakawa Memorial Research Foundation, Tokyo, 107-0062, Japan

    Yuzo Miyakawa

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  1. Masakuni Tateyama
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  2. Hiroshi Yatsuhashi
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  3. Naota Taura
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  4. Yasuhide Motoyoshi
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Correspondence to Hiroshi Yatsuhashi.

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Tateyama, M., Yatsuhashi, H., Taura, N. et al. Alpha-fetoprotein above normal levels as a risk factor for the development of hepatocellular carcinoma in patients infected with hepatitis C virus. J Gastroenterol 46, 92–100 (2011). https://doi.org/10.1007/s00535-010-0293-6

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  • DOI: https://doi.org/10.1007/s00535-010-0293-6

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