Skip to main content
SpringerLink
Log in

Iron and Hepatitis C

  • Published:
Current Hepatitis Reports Aims and scope Submit manuscript

Abstract

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide. Iron may play a comorbid role in HCV disease and other liver diseases. Although adjunctive treatment of HCV disease with iron reduction is popular in east Asia, especially Japan, it is less popular in the United States. However, iron reduction may be of importance, especially for certain HCV patient subgroups that have not responded to or cannot tolerate standard therapy. This review focuses on recent advances in understanding how iron may influence HCV infection and vice versa. A key is effects on levels of expression of the hepcidin gene in hepatocytes, because hepcidin has emerged as the key regulator of iron homeostasis. This review also summarizes prior clinical studies involving iron reduction therapy and clinical implications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Alla V, Bonkovsky HL: Iron in nonhemochromatotic liver disorders. Semin Liver Dis 2005, 25:461–472.

    Article  CAS  PubMed  Google Scholar 

  2. • Bonkovsky HL, Banner BF, Rothman AL: Iron and chronic viral hepatitis. Hepatology 1997, 25:759–768. This article provides an important authoritative review, summarizing comprehensively earlier literature.

    Article  CAS  PubMed  Google Scholar 

  3. • Scobey M, Bonkovsky H: Iron: a putative reason for gender-based differences in chronic liver disease. In Female Hepatology: Impact of Female Sex Against Progression of Liver Disease. Edited by Shimizu I. Kerala, India: Research Signpost; 2009:97–128. This reference is a recent overview and synthesis of how iron may be a key factor that accounts for gender-based differences in severity of liver disease.

    Google Scholar 

  4. Isom HC, McDevitt EI, Moon MS: Elevated hepatic iron: a confounding factor in chronic hepatitis C. Biochim Biophys Acta 2009, 1790:650–662.

    CAS  PubMed  Google Scholar 

  5. Philippe MA, Ruddell RG, Ramm GA: Role of iron in hepatic fibrosis: one piece in the puzzle. World J Gastroenterol 2007, 13:4746–4754.

    CAS  PubMed  Google Scholar 

  6. •• Bonkovsky HL, Naishadham D, Lambrecht RW, et al.: Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 2006, 131:1440–1451. This article is a report of the larger HALT-C cohort, showing associations of iron with severity of CHC and yet showing that the H63D genetic variation of HFE improved the chances of response to IFN/ribavirin.

    Article  CAS  PubMed  Google Scholar 

  7. Afridi HI, Kazi TG, Kazi NG, et al.: Determination of copper and iron in biological samples of viral hepatitis (A–E) female patients. Biol Trace Elem Res 2009, 129:78–87.

    Article  CAS  PubMed  Google Scholar 

  8. Shan Y, Lambrecht RW, Bonkovsky HL: Association of hepatitis C virus infection with serum iron status: analysis of data from the third National Health and Nutrition Examination Survey. Clin Infect Dis 2005, 40:834–841.

    Article  CAS  PubMed  Google Scholar 

  9. Guyader D, Thirouard AS, Erdtmann L, et al.: Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol 2007, 46:587–595.

    Article  CAS  PubMed  Google Scholar 

  10. Won JE, Jeong SH, Chung JI, et al.: Hepatic iron, serum ferritin, HFE mutation, and hepatic fibrosis in chronic hepatitis C. Intervirology 2009, 52:239–246.

    Article  CAS  PubMed  Google Scholar 

  11. Fujita N, Sugimoto R, Urawa N, et al.: Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol 2007, 22:1886–1893.

    Article  CAS  PubMed  Google Scholar 

  12. Kohgo Y, Ikuta K, Ohtake T, et al.: Iron overload and cofactors with special reference to alcohol, hepatitis C virus infection and steatosis/insulin resistance. World J Gastroenterol 2007, 13:4699–4706.

    CAS  PubMed  Google Scholar 

  13. Cho H, Lee HC, Jang SK, Kim YK: Iron increases translation initiation directed by internal ribosome entry site of hepatitis C virus. Virus Genes 2008, 37:154–160.

    Article  CAS  PubMed  Google Scholar 

  14. Hou WH, Rossi L, Shan Y, et al.: Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells. World J Gastroenterol 2009, 15:4499–4510.

    Article  CAS  PubMed  Google Scholar 

  15. Lehmann E, El-Tantawy WH, Ocker M, et al.: The heme oxygenase 1 product biliverdin interferes with hepatitis C virus replication by increasing antiviral interferon response. Hepatology 2010, 51:398–404.

    CAS  PubMed  Google Scholar 

  16. •• Furutani T, Hino K, Okuda M, et al.: Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein. Gastroenterology 2006, 130:2087–2098. This article is a clear demonstration of the importance of iron in development of HCC in HCV-expressing hepatocytes.

    Article  CAS  PubMed  Google Scholar 

  17. Fillebeen C, Muckenthaler M, Andriopoulos B, et al.: Expression of the subgenomic hepatitis C virus replicon alters iron homeostasis in Huh7 cells. J Hepatol 2007, 47:12–22.

    Article  CAS  PubMed  Google Scholar 

  18. Price L, Kowdley KV: The role of iron in the pathophysiology and treatment of chronic hepatitis C. Can J Gastroenterol 2009, 23:822–828.

    PubMed  Google Scholar 

  19. Drakesmith H, Prentice A: Viral infection and iron metabolism. Nat Rev Microbiol 2008, 6:541–552.

    Article  CAS  PubMed  Google Scholar 

  20. Peslova G, Petrak J, Kuzelova K, et al.: Hepcidin, the hormone of iron metabolism, is bound specifically to alpha-2-macroglobulin in blood. Blood 2009, 113:6225–6236.

    Article  CAS  PubMed  Google Scholar 

  21. • Nemeth E, Ganz T: The role of hepcidin in iron metabolism. Acta Haematol 2009, 122:78–86. This article is a contemporary review by leaders in the study of hepcidin.

    Article  CAS  PubMed  Google Scholar 

  22. • Fujita N, Sugimoto R, Takeo M, et al.: Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007, 13:97–104. This article provides a demonstration of low hepcidin in CHC.

    Article  CAS  PubMed  Google Scholar 

  23. Girelli D, Pasino M, Goodnough JB, et al.: Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol 2009, 51:845–852.

    Article  CAS  PubMed  Google Scholar 

  24. Fujita N, Sugimoto R, Motonishi S, et al.: Patients with chronic hepatitis C achieving a sustained virological response to peginterferon and ribavirin therapy recover from impaired hepcidin secretion. J Hepatol 2008, 49:702–710.

    Article  CAS  PubMed  Google Scholar 

  25. Nishina S, Hino K, Korenaga M, et al.: Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 2008, 134:226–238.

    Article  CAS  PubMed  Google Scholar 

  26. • Miura K, Taura K, Kodama Y, et al.: Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 2008, 48:1420–1429. This article describes one mechanism whereby HCV suppresses hepatic hepcidin expression.

    Article  CAS  PubMed  Google Scholar 

  27. Verga Falzacappa MV, Vujic Spasic M, Kessler R, et al.: STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood 2007, 109:353–358.

    Article  PubMed  Google Scholar 

  28. Wrighting DM, Andrews NC: Interleukin-6 induces hepcidin expression through STAT3. Blood 2006, 108:3204–3209.

    Article  CAS  PubMed  Google Scholar 

  29. Mleczko-Sanecka K, Casanovas G, Ragab A, et al.: SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood 2010, 115:2657–2665.

    Article  CAS  PubMed  Google Scholar 

  30. Kautz L, Meynard D, Monnier A, et al.: Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood 2008, 112:1503–1509.

    Article  CAS  PubMed  Google Scholar 

  31. Valenti L, Guido M, Dongiovanni P, et al.: Ferroportin-1 in the recurrence of hepatic iron overload after liver transplantation. Dig Liver Dis 2009, 41:e17–e20.

    Article  CAS  PubMed  Google Scholar 

  32. Lin TJ, Liao LY, Lin CL, et al.: Hepatic iron influences responses to combination therapy with peginterferon alfa and ribavirin in chronic hepatitis C. Hepatogastroenterology 2008, 55:1412–1415.

    CAS  PubMed  Google Scholar 

  33. Lambrecht R, Naishadham D, Sterling R, et al.: Relationship of iron [Fe] and HFE genetic variations to progression and outcomes of advanced chronic hepatitis C in the HALT-C Trial. Hepatology 2009, 50:1050A.

    Google Scholar 

  34. Ladero JM, Lopez-Alonso G, Devesa MJ, et al.: Oscillations in serum ferritin associated with antiviral therapy in chronic hepatitis C. Rev Esp Enferm Dig 2009, 101:31–40.

    Article  CAS  PubMed  Google Scholar 

  35. Ferrara F, Ventura P, Vegetti A, et al.: Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C. Am J Gastroenterol 2009, 104:605–616.

    Article  CAS  PubMed  Google Scholar 

  36. • Desai TK, Jamil LH, Balasubramaniam M, et al.: Phlebotomy improves therapeutic response to interferon in patients with chronic hepatitis C: a meta-analysis of six prospective randomized controlled trials. Dig Dis Sci 2008, 53:815–822. This article provides the definitive meta-analysis establishing that iron reduction significantly improves SVR achieved by IFN alone.

    Article  CAS  PubMed  Google Scholar 

  37. Gentile I, Viola C, Paesano L, et al.: Iron depletion before HCV antiviral therapy: a pilot, randomized, controlled trial. J Clin Apher 2009, 24:190–196.

    Article  PubMed  Google Scholar 

  38. Rossini A, Contessi G, Liali C, et al.: Efficacy of iron depletion and antiviral therapy in patients with porphyria cutanea tarda and hepatitis C. Hepatology 2004, 40:320A.

    Google Scholar 

  39. • Tanaka N, Horiuchi A, Yamaura T, et al.: Efficacy and safety of 6-month iron reduction therapy in patients with hepatitis C virus-related cirrhosis: a pilot study. J Gastroenterol 2007, 42:49–55. This article is a demonstration of tolerability of iron reduction by therapeutic phlebotomy even in patients with cirrhosis.

    Article  CAS  PubMed  Google Scholar 

  40. Sumida Y, Kanemasa K, Fukumoto K, et al.: Effects of dietary iron reduction versus phlebotomy in patients with chronic hepatitis C: results from a randomized, controlled trial on 40 Japanese patients. Intern Med 2007, 46:637–642.

    Article  PubMed  Google Scholar 

  41. Sartori M, Andorno S, Rossini A, et al.: Phlebotomy improves histology in chronic hepatitis C males with mild iron overload. World J Gastroenterol 2010, 16:596–602.

    Article  CAS  PubMed  Google Scholar 

  42. Taher AT, Musallam KM, Khalife M, Barada K: Hepatitis C antiviral response in thalassemia: what is the role of liver iron concentration? Ann Hematol 2009, 88:1033–1034.

    Article  PubMed  Google Scholar 

  43. Di Marco V, Capra M, Gagliardotto F, et al.: Liver disease in chelated transfusion-dependent thalassemics: the role of iron overload and chronic hepatitis C. Haematologica 2008, 93:1243–1246.

    Article  PubMed  Google Scholar 

  44. Nahon P, Sutton A, Rufat P, et al.: Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008, 134:102–110.

    Article  CAS  PubMed  Google Scholar 

  45. •• Kato J, Miyanishi K, Kobune M, et al.: Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 2007, 42:830–836. This article describes an important long-term study suggesting benefits of sustained iron reduction, albeit not a prospective, randomized, controlled trial.

    Article  CAS  PubMed  Google Scholar 

  46. Van Thiel DH, Friedlander L, Molloy PJ, et al.: Retreatment of hepatitis C interferon nonresponders with larger doses of interferon with and without phlebotomy. Hepatogastroenterology 1996, 43:1557–1561.

    PubMed  Google Scholar 

  47. Fong TL, Han SH, Tsai NC, et al.: A pilot randomized, controlled trial of the effect of iron depletion on long-term response to alpha-interferon in patients with chronic hepatitis C. J Hepatol 1998, 28:369–374.

    Article  CAS  PubMed  Google Scholar 

  48. Di Bisceglie AM, Bonkovsky HL, Chopra S, et al.: Iron reduction as an adjuvant to interferon therapy in patients with chronic hepatitis C who have previously not responded to interferon: a multicenter, prospective, randomized, controlled trial. Hepatology 2000, 32:135–138.

    Article  PubMed  Google Scholar 

  49. Fontana RJ, Israel J, Leclair P et al.: Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology 2000, 31:730–736.

    Article  Google Scholar 

  50. Fargion S, Fracanzani AL, Rossini A, et al.: Iron reduction and sustained response to interferon a therapy in patients with chronic hepatitis C: results of an Italian multicenter randomized study. Am J Gastroenterol 2002, 97:1204–1210.

    CAS  PubMed  Google Scholar 

  51. Carlo C, Daniela P, Giancarlo C: Iron depletion and response to interferon in chronic hepatitis C. Hepatogastroenterology 2003, 50(53):1467–1471.

    Google Scholar 

Download references

Disclosure

In the preceding 12 months, Dr. Bonkovsky served as a paid advisor to Clinuvel, Inc., Novartis Pharmaceutical, and Lundbeck SA. He is on the speaker’s bureau of Lundbeck. He receives support for research studies from the National Institutes of Health, the American Porphyria Foundation, Clinuvel, Novartis, and Vertex. During the past 12 months, Dr. Bonkovsky has served as an expert witness for plaintiffs in litigation regarding suspected drug-induced liver injury. No other potential conflict of interest relevant to this article was reported.

Author information

Authors and Affiliations

  1. Departments of Medicine and Research and The Liver-Biliary-Pancreatic Center, Carolinas Medical Center, Suite 201, Cannon Research Center, 1542 Garden Terrace, Charlotte, NC, 28203, USA

    Herbert L. Bonkovsky

  2. Department of Medicine, Advanced/Transplant Hepatology, Carolinas Medical Center, Charlotte, NC, USA

    Tarun K. Narang

  3. Cannon Research Center, Carolinas Medical Center, Charlotte, NC, USA

    Hossein Sendi

  4. Department of Medicine, Division of Gastroenterology, Carolinas Medical Center, Charlotte, NC, USA

    Martin W. Scobey

Authors
  1. Tarun K. Narang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hossein Sendi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Martin W. Scobey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Herbert L. Bonkovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Herbert L. Bonkovsky.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Narang, T.K., Sendi, H., Scobey, M.W. et al. Iron and Hepatitis C. Curr Hepatitis Rep 9, 169–177 (2010). https://doi.org/10.1007/s11901-010-0049-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11901-010-0049-z

Keywords

Search

Navigation