Biological Trace Element Research

, Volume 64, Issue 1–3, pp 185–196 | Cite as

Failure to respond to interferon-α 2a therapy is associated with increased hepatic iron levels in patients with chronic hepatitis C

  • Fujito Kageyama
  • Yoshimasa Kobayashi
  • Gou Murohisa
  • Erina Shimizu
  • Fumitaka Suzuki
  • Masataka Kikuyama
  • Kenichi Souda
  • Tsunehisa Kawasaki
  • Hirotoshi Nakamura
Original Articles


Recent reports suggest the hepatic iron concentration (HIC) may influence the activity of hepatitis and the response to interferon (IFN) therapy in patients with chronic hepatitis C (CH-C). We have evaluated iron status in 28 patients with CH-C and determined if pretreatment iron status can predict the response to IFN-α therapy in these patients. Increased serum iron, transferrin saturation, and ferritin levels were observed in 3 (11%), 11 (39%), and 5 (18%) patients, respectively. Hepatic iron deposits were histologically detected in 17 (61%) patients, and 14 of them had stainable hepatocytic iron. However, all HIC values were within the normal range (203–1279 μg/g). Seven of 17 patients treated with IFN-α for 6 mo had normalization of serum transaminases and disappearance of serum HCV-RNA (responders). Nonresponders had a significantly higher median HIC compared with responders (710 vs 343 μg/g, respectively;p < 0.05). There was no significant difference in other pretreatment iron parameters, serum HCV-RNA level, or HCV-genotype between responders and nonresponders. In conclusion, mild hepatic iron accumulation occurs in patients with CH-C. Increased hepatic iron stores are associated with poor response to IFN therapy. Pretreatment HIC may be an additional host-specific parameter with a predictive value for responsiveness to IFN therapy, in addition to well-known predictive viral factors.

Index entries

Iron chronic hepatitis C liver interferon-α therapy 


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  1. 1.
    H. L. Bonkovsky, B. F. Banner, R. W. Lambrecht, and R. B. Rubin, Iron in liver diseases other than hemochromatosis,Semin Liv Dis 16, 65–82 (1996).CrossRefGoogle Scholar
  2. 2.
    A. Piperno, R. D’Alba, S. Fargion, L. Roffi, M. Sanpietro, S. Parma, et al., Liver iron concentration in chronic viral hepatitis: a study of 98 patients,Eur. J. Gastroenterol. Hepatol. 7, 1203–1208 (1995).PubMedCrossRefGoogle Scholar
  3. 3.
    B. R. Bacon, M. W. Fried, and A. M. Di Bisceglie, A 39-year-old man with chronic viral hepatitis, elevated serum ferritin values, and a family history of hemochromatosis,Semin. Liv. Dis. 13, 101–105 (1993).Google Scholar
  4. 4.
    C. Q. Edwards, L. M. Griffen, D. Goldgar, C. Drummond, M. H. Skolnick, and J. P. Kushner, Prevalence of hemochromatosis among 11,065 presumably healthy blood donors,N. Engl. J. Med. 318, 1355–1362 (1988).PubMedCrossRefGoogle Scholar
  5. 5.
    C. Q. Edward, L. M. Griffen, and J. P. Kushner, Disorders of excess iron,Hosp. Pract. 26 (Suppl 3), 30–36 (1991).Google Scholar
  6. 6.
    M. Shindo, A. M. Di Bisceglie, and J. H. Hoofnagle, Long-term follow-up of patients with chronic hepatitis C treated with alpha-interferon,Hepatology 15, 1013–1016 (1992).PubMedCrossRefGoogle Scholar
  7. 7.
    L. Chemello, P. Bonetti, L. Cavalletto, F. Talato, V. Donadon, P. Casarin, et al., Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C,Hepatology 22, 700–706 (1995).PubMedGoogle Scholar
  8. 8.
    M. Martinot-Peignoux, P. Marcellin, M. Pouteau, C. Casternau, N. Boyer, M. Poliquin, et al., Pretreatment serum HCV RNA levels and HCV genotype are the main and independent prognostic factors of sustained response to alpha interferon therapy in chronic hepatitis C,Hepatology 22, 1050–1056 (1995).PubMedCrossRefGoogle Scholar
  9. 9.
    D. H. Van Thiel, L. Friedlander, S. Fagiuoli, H. I. Wright, W. Irish, J. S. Gavaler, et al., Response to α-interferon therapy is influenced by the iron content of the liver,J. Hepatol 20, 410–115 (1994).PubMedCrossRefGoogle Scholar
  10. 10.
    J. K. Olynyk, K. R. Reddy, A. M. Di Bisceglie, L. J. Feffers, T. I. Parker, J. L. Radick, et al., Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C,Gastroenterology 108, 1104–1109 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    N. Izumi, N. Enomoto, M. Uchihara, T. Murakami, K. Ono, O. Noguchi, et al., Hepatic iron contents and response to interferon-alpha in patients with chronic hepatitis C. Relationship to genotypes of hepatitis C virus,Dig. Dis. Sci. 41, 989–94 (1996).PubMedCrossRefGoogle Scholar
  12. 12.
    B. F. Banner, A. L. Barton, E. E Cable, L. Smith, and H. L. Bonkovsky, A detailed analysis of the Knodell score and other histologic parameters as predictors of response to interferon therapy in chronic hepatitis C,Modern Pathol. 8, 232–238 (1995).Google Scholar
  13. 13.
    A. L. Barton, E Barbara, B. E Banner, E. E Cable, and H. L. Bonkovsky, Distribution of iron in the liver predicts the response of chronic hepatitis C infection to interferon therapy,Am. J. Clin. Pathol. 103, 419–424 (1995).PubMedGoogle Scholar
  14. 14.
    Y. Ikura, H. Morimoto, H. Johmura, M. Fukui, and M. Sakurai, Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C,Am. J. Gastroenterol. 91, 1367–1373 (1996).PubMedGoogle Scholar
  15. 15.
    J. Torrance and T. H. Bothwell, A simple technique for measuring storage iron concentrations in formalinized liver samples,S. Afr. J. Med. Sci. 33, 9–11 (1968).PubMedGoogle Scholar
  16. 16.
    K. M. Summers, J. W. Halliday, and L. W. Powell, Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index,Hepatology 12, 20–5 (1990).PubMedCrossRefGoogle Scholar
  17. 17.
    V. J. Desmet, M. Gerber, J. H. Hoofnagle, M. Manns, and P. J. Sheuer, Classification of chronic hepatitis C: diagnosis, grading and staging,Hepatology 19, 1513–1520 (1994).PubMedGoogle Scholar
  18. 18.
    H. Okamoto, S. Okada, Y. Sugiyama, T. Tanaka, Y. Sugai, Y. Akahane, et al., Detection of hepatitis C virus RNA by a two-stage polymerase chain reaction with two pairs of primers deduced from the 5′-noncoding region,Jpn. J. Exp. Med. 60, 215–222 (1990).PubMedGoogle Scholar
  19. 19.
    H. Okamoto, Y. Sugiyama, S. Okada, K. Kurai, Y. Akahane, Y. Sugai, et al, Typing hepatitis C virus by polymerase chain reaction with type-specific primers: application to clinical surveys and tracing infection source,J. Gen. Virol. 73, 673–679 (1992).PubMedGoogle Scholar
  20. 20.
    A. M. Di Bisceglie, C. A. Axiotis, J. H. Hoofnagle, and B. R. Bacon, Measurement of iron status in patients with chronic hepatitis,Gastroenterology 102, 2108–2113 (1992).PubMedGoogle Scholar
  21. 21.
    T. Isomura, M. Yano, H. Hayashi, and N. Sakamoto, Excess iron in the liver of patients with chronic hepatitis C,J. Clin. Electron. Microsc. 25, 231–237 (1992).Google Scholar
  22. 22.
    M. Kobune, Y. Kohga, J. Kato, E. Miyazaki, and Y. Niitsu, Interleukin-6 enhances hepatic transferrin uptake and ferritin expression in rats,Hepatology 19, 1468–1475 (1994).PubMedGoogle Scholar
  23. 23.
    J. N. Feder, A. Gnirke, W. Thomas, J. N. Feder, A. Gnirke, W. Thomas, et al., A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis,Nature Genetics 13, 399–408 (1996).PubMedCrossRefGoogle Scholar
  24. 24.
    R. S. Britton, Metal-induced hepatotoxicity,Semin. Liv. Dis. 16, 3–11 (1996).Google Scholar
  25. 25.
    H. Hayashi, T. Takukawa, N. Nishimura, M. Yano, T. Isomura, and N. Sakamoto, Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron,Am. J. Gastroenterol. 89, 986–988 (1994).PubMedGoogle Scholar
  26. 26.
    F. Farinati, R. Cardin, N. De Maria, G. D. Libera, C. Martin, E. Lecis, et al., Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis,J. Hepatol. 22, 449–456 (1995).PubMedCrossRefGoogle Scholar
  27. 27.
    N. Enomoto, I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, et al., Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus lb infection,N. Engl. J. Med. 11, 77–81 (1996).CrossRefGoogle Scholar
  28. 28.
    N. Enomoto, I. Sakuma, Y Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, et al., Comparison of full-length sequences of interferon-sensitive and resistant hepatitis C virus lb,J. Clin. Invest. 96, 224–230 (1995).PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1998

Authors and Affiliations

  • Fujito Kageyama
    • 1
  • Yoshimasa Kobayashi
    • 1
  • Gou Murohisa
    • 1
  • Erina Shimizu
    • 1
  • Fumitaka Suzuki
    • 1
  • Masataka Kikuyama
    • 1
  • Kenichi Souda
    • 1
  • Tsunehisa Kawasaki
    • 1
  • Hirotoshi Nakamura
    • 1
  1. 1.Second Division, Department of Internal MedicineHamamatsu University School of MedicineShizuokaJapan

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