Journal of Molecular Medicine

, Volume 81, Issue 12, pp 780–787 | Cite as

Hemochromatosis and transferrin receptor gene polymorphisms in chronic hepatitis C: impact on iron status, liver injury and HCV genotype

  • Sven G. Gehrke
  • Wolfgang Stremmel
  • Inge Mathes
  • Hans-Dieter Riedel
  • Karin Bents
  • Birgit Kallinowski
Original Article


Mild iron overload in chronic hepatitis C is associated with liver fibrosis, hepatitis C virus (HCV) genotype 1b infection, and an impaired response to interferon therapy. In this study we evaluated whether polymorphisms in the hemochromatosis gene HFE and the transferrin receptor gene TFR1 are associated with these typical findings. The study considered 246 HCV-infected patients and 200 blood donors as controls, in which C282Y, H63D, and S65C mutations (HFE) and the S142G polymorphism (TFR1) were detected. HCV genotype, serum ferritin levels, stainable intrahepatic iron, and grade of fibrosis according to the METAVIR score (F0–F4) were determined. In HCV-infected patients, heterozygosity for the C282Y mutation in HFE was significantly associated with elevated serum ferritin levels, stainable liver iron, and advanced fibrosis or cirrhosis (F2–F4). By multivariate logistic regression analysis the odds ratio for the development of advanced fibrosis or cirrhosis (F2–F4) was 2.5 for HCV-infected patients carrying a heterozygous C282Y mutation and 4.8 for HCV-infected patients with C282Y/H63D and C282Y/S65C compound heterozygosity. Heterozygosity for the C282Y mutation in HFE contributes to iron accumulation and fibrosis progression in chronic hepatitis C.


Hepatitis C Fibrosis Siderosis Hemochromatosis Genetic polymorphisms 



Hepatitis C virus


  1. 1.
    Di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR (1992) Measurements of iron status in patients with chronic hepatitis. Gastroenterology 102:2108–2113PubMedGoogle Scholar
  2. 2.
    Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, Burra P, Floreani A, Cecchetto A, Naccarato R (1995) Iron storage, lipid peroxidation and gluthathione turnover in chronic anti-HCV positive patients. J Hepatol 22:449–456CrossRefPubMedGoogle Scholar
  3. 3.
    Boucher E, Bourienne A, Adams P, Turlin B, Brissot P, Deugnier Y (1997) Liver iron concentration and distribution in chronic hepatitis C before and after interferon treatment. Gut 41:115–120PubMedGoogle Scholar
  4. 4.
    Barbaro G, Di Lorenzo G, Ribersani M, Soldini M, Giancaspro G, Bellomo G, Belloni G, Grisorio B, Barbarini G (1999) Serum ferritin and hepatic glutathione concentrations in chronic hepatitis C patients related to the hepatitis C virus genotype. J Hepatol 30:774–782CrossRefPubMedGoogle Scholar
  5. 5.
    Beinker NK, Voigt MD, Arendse M, Smit J, Stander IA, Kirsch RE (1996) Threshold effect of liver iron content on hepatic inflammation and fibrosis in hepatitis B and C. J Hepatol 25:633–638CrossRefPubMedGoogle Scholar
  6. 6.
    Hézode C, Cazeneuve C, Coué O, Roudot-Thoraval F, Lonjon I, Bastie A, Duvoux C, Pawlotsky JM, Zafrani ES, Amselem S, Dhumeaux D (1999) Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions. J Hepatol 31:979–984CrossRefPubMedGoogle Scholar
  7. 7.
    Fargion S, Fracanzani AL, Sampietro M, Molteni V, Boldorini R, Mattioli M, Cesana B, Lunghi G, Piperno A, Valsecchi C, Fiorelli G (1997) Liver iron influences the response to interferon alpha therapy in chronic hepatitis C. Eur J Gastroenterol Hepatol 9:497–503PubMedGoogle Scholar
  8. 8.
    Olynyk JK, Reddy KR, Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, Schiff ER, Bacon BR (1995) Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 108:1104–1109PubMedGoogle Scholar
  9. 9.
    Van Thiel DH, Friedlander L, Fagiuoli S, Wright HI, Irish W, Gavaler JS (1994) Response to interferon α therapy is influenced by the iron content of the liver. J Hepatol 20:410–415PubMedGoogle Scholar
  10. 10.
    Fontana RJ, Israel J, LeClair P, Banner BF, Tortorelli K, Grace N, Levine RA, Fiarman G, Thiim M, Tavill AS, Bonkovsky HL (2000) Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology 31:730–736PubMedGoogle Scholar
  11. 11.
    Piperno A, D’Alba R, Fargion S, Roffi L, Sampietro M, Parma S, Arosio V, Faré M, Fiorelli G (1995) Liver iron concentration in chronic viral hepatitis: a study of 98 patients. Eur J Gastroenterol Hepatol 7:1203–1208PubMedGoogle Scholar
  12. 12.
    Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A et al (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408PubMedGoogle Scholar
  13. 13.
    Pietrangelo A (2003) Haemochromatosis. Gut 52 [Suppl 2]:II23–II30Google Scholar
  14. 14.
    George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW (1998) Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 114:311–318PubMedGoogle Scholar
  15. 15.
    Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH (1997) Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet 349:321–323PubMedGoogle Scholar
  16. 16.
    Bulaj ZJ, Phillips JD, Ajioka RS, Franklin MR, Griffen LM, Guinee DJ, Edwards CQ, Kushner JP (2000) Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 95:1565–1571PubMedGoogle Scholar
  17. 17.
    Smith BC, Grove J, Guzail MA, Day CP, Daly AK, Burt AD, Bassendine MF (1998) Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology 27:1695–1699Google Scholar
  18. 18.
    Bonkovsky HL, Troy N, McNeal K, Banner BF, Sharma A, Obando J, Mehta S, Koff RS, Liu Q, Hsieh CC (2002) Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C. J Hepatol 37:848–854CrossRefPubMedGoogle Scholar
  19. 19.
    Tung BY, Emond MJ, Bronner MP, Raaka SD, Cotler SJ, Kowdley KV (2003) Hepatitis C, iron status, and disease severity: relationship with HFE mutations. Gastroenterology 124:318–326CrossRefPubMedGoogle Scholar
  20. 20.
    Erhardt A, Maschner-Olberg A, Mellenthin C, Kappert G, Adams O, Donner A, Willers R, Niederau C, Häussinger D (2003) HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis. J Hepatol 38:335–342CrossRefPubMedGoogle Scholar
  21. 21.
    Kazemi-Shirazi L, Datz C, Maier-Dobersberger T, Kaserer K, Hackl F, Polli C, Steindl PE, Penner E, Ferenci P (1999) The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C. Gastroenterology 116:127–134PubMedGoogle Scholar
  22. 22.
    Martinelli ALC, Franco RF, Villanova MG, Figueiredo JFC, Secaf M, Tavella MH, Ramalho LNZ, Zucoloto S, Zago MA (1999) Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection? Acta Haematol 102:152–156CrossRefGoogle Scholar
  23. 23.
    Negro F, Samii K, Rubbia-Brandt L, Quadri R, Male PJ, Zarski JP, Baud M, Giostra E, Beris P, Hadengue A (2000) Hemochromatosis gene mutations in chronic hepatitis C patients with and without liver siderosis. J Med Virol 60:21–27CrossRefPubMedGoogle Scholar
  24. 24.
    Thorburn D, Curry G, Spooner R, Spence E, Oien K, Halls D, Fox R, McCruden EA, MacSween RN, Mills PR (2002) The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C. Gut 50:248–252CrossRefPubMedGoogle Scholar
  25. 25.
    Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC (1998) The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 95:1472–1477CrossRefPubMedGoogle Scholar
  26. 26.
    Riedel HD, Muckenthaler MU, Gehrke SG, Mohr I, Brennan K, Herrmann T, Fitscher BA, Hentze MW, Stremmel W (1999) HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Blood 94:3915–3921PubMedGoogle Scholar
  27. 27.
    Van Landeghem GF, Beckman LE, Wahlin A, Markevärn B, Beckman L (1998) Interaction between hemochromatosis and transferrin receptor genes in multiple myeloma. Lancet 352:1285–1286Google Scholar
  28. 28.
    Beckman LE, Van Landeghem GF, Sikström C, Wahlin A, Markevärn B, Hallmans G, Lenner P, Athlin L, Stenling R, Beckman L (1999) Interaction between haemochromatosis and transferrin receptor genes in different neoplastic disorders. Carcinogenesis 20:1231–1233CrossRefPubMedGoogle Scholar
  29. 29.
    Beckman LE, Hägerstrand I, Stenling R, Van Landeghem GF, Beckman L (2000) Interaction between haemochromatosis and transferrn receptor genes in hepatocellular carcinoma. Oncology 59:317–322CrossRefPubMedGoogle Scholar
  30. 30.
    Bedossa P, Poynard T (1996) An algorithm for the grading of activity in chronic hepatitis C. Hepatology 24:289–293PubMedGoogle Scholar
  31. 31.
    Von Ahsen N, Schutz E, Armstrong VW, Oellerich M (1999) Rapid detection of prothrombotic mutations of prothrombin (G20210A), factor V (G1691A), and methylenetetrahydrofolate reductase (C677T) by real-time fluorescence PCR with the LightCycler. Clin Chem 45:694–696PubMedGoogle Scholar
  32. 32.
    Bataller R, North KE, Brenner DA (2003) Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 37:493–503CrossRefPubMedGoogle Scholar
  33. 33.
    Izumi N, Enomoto N, Uchihara M, Murakami T, Ono K, Noguchi O, Miyake S, Nouchi T, Fujisawa K, Marumo F, Sato C (1996) Hepatic iron contents and response to interferon-α in patients with chronic hepatitis C-relationship to genotypes of hepatitis C virus. Dig Dis Sci 41:989–994PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Sven G. Gehrke
    • 1
  • Wolfgang Stremmel
    • 1
  • Inge Mathes
    • 1
  • Hans-Dieter Riedel
    • 1
  • Karin Bents
    • 1
  • Birgit Kallinowski
    • 1
  1. 1.Department of Internal Medicine IVUniversity Hospital of HeidelbergHeidelbergGermany

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