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Hepatocyte regeneration in chronic hepatitis C and interferon treatment: Analysis of immunohistological identification of proliferating cell nuclear antigen (PCNA)

  • Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

To evaluate the usefulness of proliferating cell nuclear antigen (PCNA) immunostaining in the assessment of the efficacy of interferon (IFN) therapy in chronic hepatitis C, we investigated the proliferative activity of hepatocytes in 67 patients with chronic hepatitis C, using this immunostaining method. The percentage of PCNA-positive hepatocytes was 2.4% in patients with chronic persistent hepatitis, 2.5% in those with chronic aggressive hepatitis 2A, and 3.9% in those with chronic aggressive hepatitis 2B. The PCNA count increased with the progression of the liver disease. Patients were classified as complete, partial, and non-responders to IFN; the percentage of PCNA-positive hepatocytes before IFN therapy was 1.6% in the complete responders, 3.9% in the partial responders, and 4.9% in the non-responders. There was a significant negative correlation between the percentage of PCNA-positive hepatocytes and the response to IFN treatment. Thirty-two of 53 cases (60.4%) in which the PCNA labeling index (LI) was less than 5.0 were complete responders compared with 13 of 14 cases (92.9%) in which the PCNA LI was higher than 5.0, representing partial responders or non-responders (P<0.001). Most complete responders had a low PCNA LI, irrespective of HCV genotype. Our findings indicate that PCNA immunostaining is a simple and reliable index of cell proliferation in liver regeneration, and may be a useful predictor of the response to IFN treatment in chronic hepatitis C.

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References

  1. Bravo R, Frank R, Blundell PA, et al. Cyclin/PCNA is the auxiliary protein of DNA polymerase-δ. Nature 1987;326:515–517.

    Article  CAS  PubMed  Google Scholar 

  2. Jaskulski D, DeRiel JK, Mercer WE, et al. Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science 1988;240:1544–1546.

    CAS  PubMed  Google Scholar 

  3. Waseem NH, Lane DP. Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA): Structural conservation and the detection of a nucleolar form. J Cell Science 1990;96:121–129.

    CAS  PubMed  Google Scholar 

  4. Hall PA, Levison DA, Woods AL, et al. Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: An index of cell proliferation with evidence of deregulated expression in some neoplasmas. J Pathol 1990;162:285–294.

    Article  CAS  PubMed  Google Scholar 

  5. Robbins BA, Vega D, Ogata K, et al. Immunohistochemical detection of proliferating cell nuclear antigen in solid human malignancies. Arch Pathol Lab Med 1987;111:841–845.

    CAS  PubMed  Google Scholar 

  6. Jain S, Filipe MI, Hall PA, et al. Prognostic value of proliferating cell nuclear antigen in gastric carcinoma. J Clin Pathol 1991;44:655–659.

    CAS  PubMed  Google Scholar 

  7. Nakajima T, Kagawa K, Ueda K, et al. Evaluation of hepatic proliferative activity in chronic liver diseases and hepatocellular carcinomas by proliferating cell nuclear antigen (PCNA) immunohistochemical staining of methanol-fixed tissues. Gastroenterol 1994;29:450–454.

    CAS  Google Scholar 

  8. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: A preliminary report. N Engl J Med 1986;315:1575–1578.

    CAS  PubMed  Google Scholar 

  9. Thomson BJ, Doran M, Lever AML, et al. Alpha-interferon therapy for non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy. Lancet 1987;I:539–541.

    Google Scholar 

  10. Jacyna MR, Brooks MG, Loke RHT, et al. Randomised controlled trial of interferon alpha (lymphoblastoid interferon) in chronic non-A non-B hepatitis. Br Med J 1989;298:80–82.

    CAS  Google Scholar 

  11. Omata M, Ito Y, Yokosuka O, et al. Histological changes of the liver by treatment of chronic non-A, non-B hepatitis with recombinant leukocyte interferon alpha. Dig Dis Sci 1989;34: 330–337.

    Article  CAS  PubMed  Google Scholar 

  12. Okamoto H, Sugiyama Y, Okada S, et al. Typing hepatitis C virus by polymerase chain reaction with type-specific primers: Application to clinical surveys and tracing infectious sources. J Gen Virol 1992;73:673–679.

    CAS  PubMed  Google Scholar 

  13. Machida A, Ohnuma H, Tsuda F, et al. Two distinct subtypes of hepatitis C virus defined by antibodies directed to the putative core protein. Hepatology 1992;16:886–891.

    CAS  PubMed  Google Scholar 

  14. Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–435.

    CAS  PubMed  Google Scholar 

  15. Kamel OW, LeBrun DP, Davis RE, et al. Growth fraction estimation of malignant lymphomas in formalin-fixed paraffinembedded tissue using anti-PCNA/cyclin 19A2. Am J Pathol 1991;138:1471–1477.

    CAS  PubMed  Google Scholar 

  16. MacDonald RA. “Lifespan” of liver cells. Arch Intern Med 1961;107:335–343.

    CAS  PubMed  Google Scholar 

  17. Wolf HK, Michalopoulos GK, Hepatocyte regeneration in acute fulminant and nonfulminant hepatitis: A study of proliferating cell nuclear antigen expression. Hepatology 1992;15:707–713.

    CAS  PubMed  Google Scholar 

  18. Tanaka K, Yamashita A, Okita K. Immunohistological detection of PCNA/cyclin in paraffin-embedded liver tissue. Int Hepatol Commun 1993;1:97–103.

    Article  Google Scholar 

  19. Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alpha: A multicenter randomized, controlled trial. N Engl J Med 1989;321:1501–1506.

    CAS  PubMed  Google Scholar 

  20. DiBisceglie AM, Martin P, Kassianides C, et al. Recombinant interferon alpha therapy for chronic hepatitis C; a randomized, double-blind, placebo-controlled trial. N Engl J Med 1989;321: 1506–1510.

    CAS  Google Scholar 

  21. Matsumoto A, Tanaka E, Suzuki T, et al. Viral and host factors that contribute to efficacy of interferon-α2a therapy in patients with chronic hepatitis C. Dig Dis Sci 1994;39:1273–1280.

    CAS  PubMed  Google Scholar 

  22. Tsubota A, Chayama K, Ikeda K, et al. Factors predictive of response to interferon-α therapy in hepatitis C virus infection. Hepatology 1994;19:1088–1094.

    Article  CAS  PubMed  Google Scholar 

  23. Yoshioka K, Kakumu S, Wakita T, et al. Detection of hepatitis C virus by polymerase chain reaction and response to interferon-α therapy: Relationship to genotypes of hepatitis C virus. Hepatology 1992;16:293–299.

    CAS  PubMed  Google Scholar 

  24. Yuki N, Hayashi N, Hagiwara H, et al. Quantitative analysis of antibodies to hepatitis C virus during interferon-α therapy. Hepatology 1993;17:960–965.

    Article  CAS  PubMed  Google Scholar 

  25. Kobayashi Y, Watanabe S, Konishi M, et al. Detection of hepatitis C virus RNA by nested polymerase chain reaction in sera of patients with chronic non-A, non-B hepatitis treated with interferon. J Hepatol 1992;16:138–144.

    Article  CAS  PubMed  Google Scholar 

  26. Diodati G, Bonetti P, Noventa F, et al. Treatment of chronic hepatitis C with recombinant human interferon-α2a: Resuls of a randomized controlled clinical trial. Hepatology 1994;19:1–5.

    Article  CAS  PubMed  Google Scholar 

  27. Cristiano K, DiBisceglie AM, Hoofnagle JH et al. Hepatitis C viral RNA in serum of patients with chronic non-A, non-B hepatitis: Detection by the polymerase chain reaction using multiple primer sets. Hepatology 1991;14:51–55.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The First Department of Internal Medicine, Mie University, School of Medicine, 2-174 Edobashi, 514, Tsu, Mie, Japan

    Minoru Hamada, Takayuki Kihira, Koujirou Takase & Takeshi Nakano

  2. The Department of Laboratory Medicine, Mie University, School of Medicine, 2-174 Edobashi, 514, Tsu, Mie, Japan

    Yukihiko Tameda & Yoshitane Kosaka

Authors
  1. Minoru Hamada
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  2. Takayuki Kihira
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  3. Koujirou Takase
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  4. Takeshi Nakano
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  5. Yukihiko Tameda
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  6. Yoshitane Kosaka
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Hamada, M., Kihira, T., Takase, K. et al. Hepatocyte regeneration in chronic hepatitis C and interferon treatment: Analysis of immunohistological identification of proliferating cell nuclear antigen (PCNA). J Gastroenterol 30, 372–378 (1995). https://doi.org/10.1007/BF02347514

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  • DOI: https://doi.org/10.1007/BF02347514

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