Digestive Diseases and Sciences

, Volume 53, Issue 3, pp 815–822 | Cite as

Phlebotomy Improves Therapeutic Response to Interferon in Patients with Chronic Hepatitis C: A Meta-Analysis of Six Prospective Randomized Controlled Trials

  • Tusar K. Desai
  • Laith H. Jamil
  • Mamtha Balasubramaniam
  • Raymond Koff
  • Herbert L. Bonkovsky
Original Paper


Prospective randomized controlled trials (RCTs) comparing phlebotomy and interferon (IFN) treatment to IFN alone in patients with chronic hepatitis C (CHC) have suggested a benefit for the phlebotomy group. However, statistical significance was achieved in only one of these trials. We performed a meta-analysis of RCTs comparing phlebotomy and IFN to IFN alone for the treatment of CHC. The MEDLINE database and Cochrane registry of controlled trials were searched using the key words “phlebotomy” and “treatment of hepatitis C.” Reference lists of review articles discussing the interaction between iron and CHC, and prospective RCTs comparing phlebotomy plus IFN therapy to IFN alone were searched to identify additional RCTs that compared phlebotomy plus IFN to IFN alone. Peto odds ratios with their 95% confidence intervals and Forrest plots were generated for each variable to assess the relationships among the studies that had provided that information. Statistical analysis was performed using Comprehensive META-Analysis version 2.0. Six prospective RCTs were identified: all used sustained viral response (SVR) as an endpoint. The three largest RCTs excluded patients with cirrhosis. Two RCTs specifically included only patients with either high ferritin or high hepatic iron content. IFN treatment regimes varied. Length of treatment varied between 6 and 12 months. The phlebotomy plus IFN group and the IFN group did not differ with respect to the percentage of patients with cirrhosis or genotype 1. SVR was attained in 50/182 (27%) patients in the phlebotomy plus IFN group, compared to 22/185 (12%) patients in the IFN group. Peto odds ratio for SVR in phlebotomy plus IFN group was 2.7; 95% CI 1.6–4.5, < 0.0001. All five RCTs published in manuscript form showed a trend towards a benefit from the phlebotomy plus IFN in attaining SVR, and the results of the meta-analysis were not dependent on any single RCT, since excluding any single RCT did not change the results. Phlebotomy improves the SVR in response to IFN treatment in patients with CHC. Confirmation of this will require RCT with detailed pre-treatment iron studies and appropriately powered to demonstrate a statistically significant benefit.


Phlebotomy Chronic hepatitis C Interferon Meta-analysis 



Grant support: Supported by NIH contracts NO1 DK29236 and UO1 DK065193 and NIH grant RO1 DK38825 (to HLB).


  1. 1.
    Bonkovsky HL, Banner BF, Rothman AL (1997) Iron and chronic viral hepatitis. Hepatology 25(3):759–768PubMedCrossRefGoogle Scholar
  2. 2.
    Di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR (1992) Measurements of iron status in patients with chronic hepatitis. Gastroenterology 102(6):2108–2113PubMedGoogle Scholar
  3. 3.
    Piperno A, D’Alba R, Fargion S et al (1995) Liver iron concentration in viral hepatitis: a study of 98 patients. Eur J Gastroenterol Hepatol 7(12):1203–1208PubMedCrossRefGoogle Scholar
  4. 4.
    Hayashi H, Takikawa T, Nishimura N et al (1994) Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol 89(7):986–988PubMedGoogle Scholar
  5. 5.
    Muretto P, Angelucci E, Lucarelli G (2002) Reversibility of cirrhosis in patients cured of thalassemia by bone marrow transplantation. Ann Intern Med 136(9):667–672PubMedGoogle Scholar
  6. 6.
    Yano M, Hayashi H, Wakusawa S et al (2002) Long term effects of phlebotomy on biochemical and histological parameters of chronic hepatitis C. Am J Gastroenterol 97(1):133–137PubMedCrossRefGoogle Scholar
  7. 7.
    Van Thiel DH, Friedlander L, Fagiuoli S et al (1994) Response to interferon therapy is influenced by the iron content of the liver. J Hepatol 20(3):410–415PubMedCrossRefGoogle Scholar
  8. 8.
    Olynyk JK, Reddy KR, Di Bisceglie AM et al (1995) Hepatic iron concentration as a predictor of response to interferon alpha therapy in chronic hepatitis C. Gastroenterology 108(4):1104–1109PubMedCrossRefGoogle Scholar
  9. 9.
    Fargion S, Fracanzani AL, Sampietro M et al (1997) Liver iron influences the response to interferon alpha therapy in chronic hepatitis C. Eur J Gastroenterol Hepatol 9(5):497–503PubMedGoogle Scholar
  10. 10.
    Piperno A, Sampietro M, D’Alba R et al (1996) Iron stores response to interferon therapy and affects of iron depletion in chronic hepatitis C. Liver 16(4):248–254PubMedGoogle Scholar
  11. 11.
    Ikura Y, Morimoto H, Johmura H et al (1996) Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C. Am J Gastroenterol 91(7):1367–1373PubMedGoogle Scholar
  12. 12.
    Arber N, Moshkowitz M, Konikoff F et al (1995) Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection. Dig Dis Sci 40(11):2431–2433PubMedCrossRefGoogle Scholar
  13. 13.
    Barton AL, Banner BF, Cable EE et al (1995) Distribution of iron in the liver predicted the response of chronic hepatitis C infection to interferon therapy. Am J Clin Pathol 103(4):419–424PubMedGoogle Scholar
  14. 14.
    Rulyak SJ, Eng SC, Patel K et al (2005) Relationships between hepatic iron content and virologic response in chronic hepatitis C patients treated with interferon and ribavirin. Am J Gastroenterol 100(2):332–337PubMedCrossRefGoogle Scholar
  15. 15.
    Pianko S, McHutchison JG, Gordon SC et al (2002) Hepatic iron concentration does not influence response to therapy with interferon plus ribavirin in chronic HCV infection. J Interferon Cytokine Res 22(4):483–489PubMedCrossRefGoogle Scholar
  16. 16.
    Fontana RJ, Israel J, LeClair P et al (2000) Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology 31(3):730–736PubMedCrossRefGoogle Scholar
  17. 17.
    Fargion S, Francanzani AL, Rossini A et al (2002) Iron reduction and sustained response to interferon-alpha therapy in patients with chronic hepatitis C: results of an Italian multicenter randomized study. Am J Gastroenterol 97(5):1204–1210PubMedGoogle Scholar
  18. 18.
    Carlo C, Daniela P, Giancarlo C (2003) Iron depletion and response to interferon in chronic hepatitis C. Hepatogastroenterology 50(53):1467–1471PubMedGoogle Scholar
  19. 19.
    Fong TL, Han SH, Tsai NC et al (1998) 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 28(3):369–374PubMedCrossRefGoogle Scholar
  20. 20.
    Van Thiel DH, Friedlander L, Molloy PJ et al (1996) Retreatment of hepatitis C interferon non-responders with larger doses of interferon with and without phlebotomy. Hepatogastroenterology 43(12):1557–1561PubMedGoogle Scholar
  21. 21.
    Rossini A, Contessi GB, Liali C et al (2004) Efficacy of iron depletion and antiviral therapy in patients with porphyria cutanea tarda and hepatitis C. Hepatology 40:320A. http://www.hcvadvocate.org/news/reports/AASLD_2004/Posters_AASLD_2004.htm. 10 Aug 2007
  22. 22.
    Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12PubMedCrossRefGoogle Scholar
  23. 23.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560PubMedCrossRefGoogle Scholar
  24. 24.
    Cockayne S, Adamson J, Lanham-New S et al (2006) Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 166(12):1256–1261PubMedCrossRefGoogle Scholar
  25. 25.
    Fernandez I, Castellano G, de Salamanca RE et al (2003) Porphyria cutanea tarda as a predictor of poor response to interferon alfa therapy in chronic hepatitis C. Scand J Gastroenterol 38(3):314–319PubMedCrossRefGoogle Scholar
  26. 26.
    Distante S, Bjoro K, Hellum KB et al (2002) Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Liver 22(3):269–275PubMedCrossRefGoogle Scholar
  27. 27.
    Bonkovsky HL, Naishadham D, Lambrecht RW et al (2006) Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 131(5):1440–1451PubMedCrossRefGoogle Scholar
  28. 28.
    Di Bisceglie AM, Bonkovsky HL, Chopra S et al (2000) 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 32(1):135–138PubMedCrossRefGoogle Scholar
  29. 29.
    Chapoutot C, Esslimani M, Joomaye Z et al (2000) Liver iron excess in patients with hepatocellular carcinoma developed on viral C cirrhosis. Gut 46(5):711–714PubMedCrossRefGoogle Scholar
  30. 30.
    Deugnier Y, Turlin B, Loreal O (1998) Iron and neoplasia. J Hepatol 28(Suppl 1):21–25PubMedCrossRefGoogle Scholar
  31. 31.
    Newman BH (2004) Blood donor complications after whole-blood donation. Curr Opin Hematol 11(5):339–345PubMedCrossRefGoogle Scholar
  32. 32.
    Hayden M, Pignone M, Phillips C, Mulrow C (2002) Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 136(2):161–172PubMedGoogle Scholar
  33. 33.
    Bayraktar Y, Koseoglu T, Somner C et al (1996) The use of deferoxamine infusions to enhance the response rate to interferon-alpha treatment of chronic viral hepatitis B. J Viral Hepat 3(3):129–135PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Tusar K. Desai
    • 1
    • 2
  • Laith H. Jamil
    • 1
  • Mamtha Balasubramaniam
    • 3
  • Raymond Koff
    • 4
  • Herbert L. Bonkovsky
    • 4
  1. 1.William Beaumont HospitalRoyal OakUSA
  2. 2.SouthfieldUSA
  3. 3.Research InstituteWilliam Beaumont HospitalRoyal OakUSA
  4. 4.University of Connecticut Health CenterFarmingtonUSA

Personalised recommendations