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“Double Punch”: Hepatitis C in Patients with Genetic Defects of Iron Metabolism

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Abstract

The review is focused on the development of chronic viral hepatitis C in patients with a genetic defect in the hereditary hemochromatosis (HFE) gene that controls iron metabolism. The effect of HFE gene mutations on the patient’s susceptibility to viral attack, the development of pathological processes in the liver, including the most severe complications, such as liver cirrhosis and hepatocellular carcinoma in chronic viral hepatitis C, and responsiveness of patients carrying the mutations to the treatment of viral hepatitis C are discussed.

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REFERENCES

  1. Price, L. and Kowdley, K.V., The role of iron in the pathophysiology and treatment of chronic hepatitis C, Can. J. Gastroenterol., 2009, vol. 23, no. 12, pp. 822–828.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Tai, A.W., Benita, Y., Peng, L.F., Kim, S.-S., Sakamoto, N., Xavier, R.J., and Chung, R.T., A functional genomic screen identifies cellular cofactors of hepatitis C virus replication, Cell Host. Microbe, 2009, vol. 5, no. 3, pp. 298–307. https://doi.org/10.1016/j.chom.2009.02.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Petruzziello, A., Marigliano, S., Loquercio, G., and Cacciapuoti, C., Global epidemiology of hepatitis C virus infection: an up-date of the distribution and circulation of hepatitis C virus genotypes, World J. Gastroenterol., 2016, vol. 22, no. 34, pp. 7824–7840. https://doi.org/10.3748/wjg.v22.i34.7824

    Article  PubMed  PubMed Central  Google Scholar 

  4. Eisenbach, C., Gehrke, S.G., and Stremmel, W., Iron, the HFE gene, and hepatitis C, Clin. Liver. Dis., 2004, vol. 8, no. 4, pp. 775–785. https://doi.org/10.1016/jcld.2004.06.006

    Article  PubMed  Google Scholar 

  5. Wallace, D.F. and Subramaniam, V.N., Co-factors in liver disease: the role of HFE-related hereditary hemochromatosis and iron. Biochim. Biophys. Acta, 2009, vol. 1790, no. 7, pp. 663–70. https://doi.org/10.1016/j.bbagen.2008.09.002

    Article  CAS  PubMed  Google Scholar 

  6. Houghton, M., The long and winding road leading to the identification of the hepatitis C virus, J. Hepatol., 2009, vol. 51, no. 5, pp. 939–948. https://doi.org/10.1016/jhep.2009.08.004

    Article  CAS  PubMed  Google Scholar 

  7. McGivern, D.R. and Lemon, S.M., Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer, Oncogene, 2011, vol. 30, no. 17, pp. 1969–1983. https://doi.org/10.1038/onc2010.594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Feder, J.N., Gnirke, A., Thomas, W., Tsuchihashi, Z., Ruddy, D.A., Basava, A., Dormishian, F., Domingo, R., Jr., Ellis, M.C., Fullan, A., Hinton, L.M., Jones, N.L., Kimmel, B.E., Kronmal, G.S., Lauer, P., Lee, V.K., Loeb, D.B., Mapa, F.A., McClelland, E., Meyer, N.C., Mintier, G.A., Moeller, N., Moore, T., Morikang, E., Prass, C.E., Quintana, L., Starnes, S.M., Schatzman, R.C., Brunke, K.J., Drayna, D.T., Risch, N.J., Bacon, B.R., and Wolff, R.K., A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis, Nat. Genet., 1996, vol. 13, no. 4, pp. 399–408. https://doi.org/10.1038/ng0896-399

    Article  CAS  PubMed  Google Scholar 

  9. Waheed, A., Parkkila, S., Saarnio, J., Fleming, R.E., Zhou, X.Y., Tomatsu, S., Britton, R.S., Bacon, B.R., and Sly, W.S., Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum, Proc. Natl. Acad. Sci. U. S. A., 1999, vol. 96, no. 4, pp. 1579–1584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Trinder, D., Olynyk, J.K., Sly, W.S., and Morgan, E.H., Iron uptake from plasma transferrin by the duodenum is impaired in the HFE knockout mouse, Proc. Natl. Acad. Sci. U. S. A., 2002, vol. 99, no. 8, pp. 5622–5626. https://doi.org/10.1073/pnas.082112299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Umbreit, J., Iron deficiency: a concise review, Am. J. Hematol., 2005, vol. 78, no. 3, pp. 225–231. https://doi.org/10.1002/ajh.20249

    Article  CAS  PubMed  Google Scholar 

  12. Drakesmith, H. and Prentice, A., Viral infection and iron metabolism, Nat. Rev. Microbiol., 2008, vol. 6, no. 7, pp. 541–552. https://doi.org/10.1038/nrmicro1930

    Article  CAS  PubMed  Google Scholar 

  13. Martinelli, A.L., Ramalho, L.N., and Zucoloto, S., Hepatic stellate cells in hepatitis C patients: relationship with liver iron deposits and severity of liver disease, J. Gastroenterol Hepatol., 2004, vol. 19, no. 1, pp. 91–98. https://doi.org/10.1111/j.1440-1746.2004.03255.x

    Article  PubMed  Google Scholar 

  14. Merryweather-Clarke, A.T., Pointon, J.J., Jouanolle, A.M., Rochette, J., and Robson, K.J., Geography of HFE C282Y and H63D mutations, Genet. Test., 2000, vol. 4, no. 2, pp. 183–198. https://doi.org/10.1089/10906570050114902

    Article  CAS  PubMed  Google Scholar 

  15. Vujic, M., Molecular basis of HFE-hemochromatosis, Front. Pharmacol., 2014, vol. 5, no. 42, pp. 1–6. https://doi.org/10.3389/fphar.2014.00042

    Article  CAS  Google Scholar 

  16. Andrews, N.C., Hereditary hemochromatosis protein, HFE, interaction with transferring receptor, p. 2. Hereditary hemochromatosis protein, HFE, interaction with transferring receptor 2 suggests a molecular mechanism for mammalian iron sensing, J. Biol. Chem., 2006, vol. 281, no. 39, pp. 28494–28498. https://doi.org/10.1074/jbc.C600197200

    Article  PubMed  Google Scholar 

  17. Kiss, J., Herrmann, T., Galy, B., Martinache, S., Stolte, J., Grone, H.J., Stremmel, W., Hentze, M.W., and Muckenthaler, M.U., HFE acts in hepatocytes to prevent hemochromatosis, Cell Metab., 2008, vol. 7, no. 2, pp. 173–178.

    Article  PubMed  Google Scholar 

  18. Babitt, J.L. and Herbert, Y.L., The molecular pathogenesis of hereditary hemochromatosis seminars in liver disease, Semin. Liver. Dis., vol. 31, no. 3, pp. 280–292. https://doi.org/10.1055/s-0031-1286059

    Article  CAS  PubMed  Google Scholar 

  19. Valore, E.V. and Ganz, T., Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin, Blood Cells Mol. Dis., 2008, vol. 40, no. 1, pp. 132–138. https://doi.org/10.1016/j.bcmd.2007.07.009

    Article  CAS  PubMed  Google Scholar 

  20. Park, C.H., Valore, E.V., Waring, A.J., and Ganz, T., Hepcidin, a urinary antimicrobial peptide synthesized in the liver, J. Biol. Chem., 2001, vol. 276, no. 11, pp. 7806–7810. https://doi.org/10.1074/jbc.M008922200

    Article  CAS  PubMed  Google Scholar 

  21. Ganz, T., Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation, Blood, 2003, vol. 102, no. 3, pp. 783–788. https://doi.org/10.1182/blood-2003-03-0672

    Article  CAS  PubMed  Google Scholar 

  22. Nemeth, E., Tuttle, M.S., Powelson, J., Vaughn, M.B., Donovan, A., Ward, D.M., Ganz, T., and Kaplan, J., Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization, Science, 2004, vol. 306, no. 5704, pp. 2090–2093. https://doi.org/10.1126/science.1104742

    Article  CAS  PubMed  Google Scholar 

  23. Hentze, M.W., Muckenthaler, M.U., Galy, B., and Camaschella, C., Two to tango: Regulation of mammalian iron metabolism, Cell, 2010, vol. 142, no. 1, pp. 24–38. https://doi.org/10.1016/j.cell.2010.06.028

    Article  CAS  PubMed  Google Scholar 

  24. Silva, B. and Faustino, P., An overview of molecular basis of iron metabolism regulation and the associated pathologies, Biochim. Biophys. Acta, 2015, vol. 1852, no. 7, pp. 1347–1359. https://doi.org/10.1016/j.bbadis.2015.03.011

    Article  CAS  PubMed  Google Scholar 

  25. Sivitskaya, L.N. and Kushniarevich, A.I., Hereditary haemochromatosis: C282Y and H63D mutations frequencies of HFE gene in Belarus population, Proc. Natl. Acad. Sci. Belarus, 2007, vol. 6, no. 1, pp. 414–418.

    Google Scholar 

  26. Di Bisceglie, A.M., Axiotis, C.A., Hoofnagle, J.H., and Bacon, B.R., Measurements of iron status in patients with chronic hepatitis, Gastroenterology, 1992, vol. 102, no. 6, pp. 2108–2113.

    Article  CAS  PubMed  Google Scholar 

  27. Piperno, A., D’Alba R., Fargion S., Sampietro M., Parma S., Arosio V., Fare M., and Fiorelli, G., Liver iron concentration in chronic viral hepatitis: a study of 98 patients, Eur. J. Gastroenterol. Hepatol., 1995, vol. 7, no. 12, pp. 1203–1208.

    Article  CAS  PubMed  Google Scholar 

  28. Tung, B.Y., Emond, M.J., Bronner, M.P., Raaka, S.D., Cotler, S.J., and Kowdley, K.V., Hepatitis C, iron status, and disease severity: relationship with HFE mutations, Gastroenterology, 2003, vol. 124, no. 2, pp. 318–326. https://doi.org/10.1053/gast.2003.50046

    Article  CAS  PubMed  Google Scholar 

  29. Souza, R.F., Feakins, R., and Mears, L., Relationship between serum ferritin, hepatic iron staining, diabetes mellitus and fibrosis progression in patients with chronic hepatitis C, Aliment. Pharmacol. Ther., 2005, vol. 21, no. 5, pp. 519–524. https://doi.org/10.1111/j.1365-2036.2005.02382.x

    Article  CAS  PubMed  Google Scholar 

  30. Silva, I.S., Perez, R.M., Oliveira, P.V., Cantagalo, M.I., Dantas, E., Sisti, C., Figueiredo-Mendes, C., Lanzoni, V.P., Silva, A., and Ferraz, M.L., Iron overload in patients with chronic hepatitis C virus infection: clinical and histological study, J. Gastroenterol. Hepatol., 2005, vol. 20, no. 2, pp. 243–248. https://doi.org/10.1111/j.1440-1746.2004.03549.x

    Article  CAS  PubMed  Google Scholar 

  31. Isomura, T., Yano, M., Hayashi, H., and Sakamoto, N., Excess iron in the liver of patients with chronic hepatitis C, J. Clin. Electron. Microsc., 1992, vol. 25, pp. 231–237.

    Google Scholar 

  32. Fujita, N. and Takei, Y., Iron, hepatitis C virus, and hepatocellular carcinoma: iron reduction preaches the gospel for chronic hepatitis C, J. Gastroenterol., 2007, vol. 42, no. 10, pp. 923–926. https://doi.org/10.1007/s00535-007-2110-4

    Article  PubMed  Google Scholar 

  33. Bassett, S.E., Di Bisceglie, A.M., Bacon, B.R., Sharp, R.M., Govindarajan, S., Hubbard, G.B., Brasky, K.M., and Lanford, R.E., Effects of iron loading on pathogenicity in hepatitis C virus-infected chimpanzees, Hepatology, 1999, vol. 29, no. 6, pp. 1884–1892. https://doi.org/10.1002/hep.510290623

    Article  CAS  PubMed  Google Scholar 

  34. Bonkovsky, H.L., Naishadham, D., Lambrecht, R.W., Chung, R.T., Hoefs, J.C., Nash, S.R., Rogers, T.E., Banner, B.F., Sterling, R.K., Donovan, J.A., Fontana, R.J., Di Bisceglie, A.M., Ghany, M.G., and Morishima, C., HALT-C Trial Group. Roles of Iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C, Gastroenterology, 2006, vol. 131, no. 5, pp. 1440–1451. https://doi.org/10.1053/j.gastro.2006.08.036

    Article  CAS  PubMed  Google Scholar 

  35. Pietrangelo, A., Hemochromatosis gene modifies course of hepatitis C viral infection, Gastroenterology, 2003, vol. 124, no. 5, pp. 1509–1523.

    Article  CAS  PubMed  Google Scholar 

  36. Pietrangelo, A., Dierssen, U., Valli, L., Garuti, C., Rump, A., Corradini, E., Ernst, M., Klein, C., and Trautwein, C., STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo, Gastroenterology, 2007, vol. 132, no. 1, pp. 294–300. https://doi.org/10.1053/j.gastro.2006.10.018

    Article  CAS  PubMed  Google Scholar 

  37. Foka, P., Dimitriadis, A., Karamichalia, D.A., Kyratzopoulou, E., Giannimaras, D., Koskinas, J., Varaklioti, A., Mamalaki, A., and Georgopoulou, U., Alterations in the iron homeostasis network: a driving force for macrophage mediated hepatitis C virus persistency, Virulence, 2016, vol. 7, no. 6, pp. 679–690. https://doi.org/10.1080/21505594.2016.1175700

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kohjima, M., Yoshimoto, T., Enjoji, M., Fukushima, N., Fukuizumi, K., Nakamura, T., Kurokawa, M., Fujimori, N., Sasaki, Y., Shimonaka, Y., Murata, Y., Koyama, S., Kawabe, K., Haraguchi, K., Sumida, Y., Harada, N., Kato, M., Kotoh, K., and Nakamuta, M., Hepcidin/ferroportin expression levels involve efficacy of pegylated-interferon plus ribavirin in hepatitis C virus-infected liver, World. J. Gastroenterol., 2015, vol. 21, no. 11, pp. 3291–3299. https://doi.org/10.3748/wjg.v21.i11.3291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Liu, H., Trinh, T.L., Dong, H., Keith, R., Nelson, D., and Liu, C., Iron regulator hepcidin exhibits antiviral activity against hepatitis C virus, PLoS One, 2012, vol. 7, no. 10. e46631.https://doi.org/10.1371/journal.pone.0046631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Miura, K., Taura, K., Kodama, Y., Schnabl, B., and Brenner, D.A., Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity, Hepatology, 2008, vol. 48, no. 5, pp. 1420–1429. https://doi.org/10.1002/hep.22486

    Article  CAS  PubMed  Google Scholar 

  41. Pirisi, M., Scott, C.A., Avellini, C., Toniutto, P., Fabris, C., Soardo, G., Beltrami, C.A., and Bartoli, E., Iron deposition and progression of disease in chronic hepatitis C. Role of interface hepatitis, portal inflammation, and HFE missense mutations, Am. J. Clin. Pathol., 2000, vol. 113, no. 4, pp. 546–554. https://doi.org/10.1309/TRB1-JXUJ-L9R6-9NHX

    Article  CAS  PubMed  Google Scholar 

  42. Geier, A., Reugels, M., Weiskirchen, R., Wasmuth, H.E., Dietrich, C.G., Siewert, E., Gartung, C., Lorenzen, J., Bosserhoff, A.K., Brugmann, M., Gressner, A.M., Matern, S., and Lammert, F., Common heterozygous hemochromatosis gene mutations are risk factors for inflammation and fibrosis in chronic hepatitis C, Liver Int., 2004, vol. 24, no. 4, pp. 285–294. https://doi.org/10.1111/j.1478-3231.2004.0928.x

    Article  CAS  PubMed  Google Scholar 

  43. Erhardt, A., Maschner-Olberg, A., Mellenthin, C., Kappert, G., Adams, O., Donner, A., Willers, R., Niederau, C., and Haussinger, D., HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis, J. Hepatol., 2003, vol. 38, no. 3, pp. 335–342.

    Article  CAS  PubMed  Google Scholar 

  44. Mills, P.R., The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C, Gut, 2002, vol. 50, no. 2, pp. 248–252.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lebray, P., Zylberberg, H., Hue, S., Poulet, B., Carnot, F., Martin, S., Chretien, Y., Pol., S., Caillat-Zuckman, S., Brechot, C., and Nalpas, B., Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C, J. Viral. Hepatitis, 2004, vol. 11, no. 2, pp. 175–182.

    Article  CAS  Google Scholar 

  46. Gattoni, A., Parlato, A., Vangieri, B., Bresciani, M., Derna, R., and Baldassarre, R., Role of hemochromatosis genes in chronic hepatitis C, Clinica Terapeutica, 2006, vol. 157, no. 1, pp. 61–68.

    CAS  Google Scholar 

  47. Piperno, A., Vergani, A., Malosio, I., Parma, L., Fossati, L., Ricci, A., Bovo, G., Boari, G., and Mancia, G., Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations, Hepatology, 1998, vol. 28, no. 4, pp. 1105–1109. https://doi.org/10.1002/hep.510280427

    Article  CAS  PubMed  Google Scholar 

  48. Smith, B.C., Gorve, J., Guzail, M.A., Day, C.P., Daly, A.K., Burt, A.D., and Bassendine, M.F., Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C, Hepatology, 1998, vol. 27, no. 6, pp. 1695–1699. https://doi.org/10.1002/hep.510270631

    Article  CAS  PubMed  Google Scholar 

  49. Martinelli, A.L., Franco, R.F., Villanova, M.G., Figueiredo, J.F., Secaf, M., Tavella, M.H., Ramalho, L.N., Zucoloto, S., and Zago, M.A., Are haemochromatosis mutations related to the severity of liver disease in hepatitis C virus infection?, Acta Haematol., 2000, vol. 102, no. 3, pp. 152–156. https://doi.org/10.1159/000040991

    Article  CAS  PubMed  Google Scholar 

  50. Bonkovsky, H.L., Troy, N., McNeal, K., Banner, B.F., Sharma, A., Obando, J., Mehta, S., Koff, R.S., Liu, Q., and Hsieh, C.C., Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C, J. Hepatol., 2002, vol. 37, no. 6, pp. 848–854.

    Article  CAS  PubMed  Google Scholar 

  51. Hezode, C., Cazeneuve, C., Coue, O., Roudot-Thoraval, F., Lonjon, I., Bastie, A., Duvoux, C., Pawlotsky, J.M., Zafrani, E.S., Amselem, S., and Dhumeaux, D., 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., 1999, vol. 31, no. 6, pp. 979–84.

    Article  CAS  PubMed  Google Scholar 

  52. Negro, F., Samii, K., Rubbia-Brandt, L., Quadri, R., Male, P.J., Zarski, J.P., Baud, M., Giostra, E., Beris, P., and Hadengue, A., Hemochromatosis gene mutations in chronic hepatitis C patients with and without liver siderosis, J. Med. Virol., 2000, vol. 60, no. 1, pp. 21–27.

    Article  CAS  PubMed  Google Scholar 

  53. Bataller, R., North, K.E., and Brenner, D.A., Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal, Hepatology, 2003, vol. 37, no. 3, pp. 493–503. https://doi.org/10.1053/jhep.2003.50127

    Article  CAS  PubMed  Google Scholar 

  54. Richardson, M.M., Powell, E.E., Barrie, H.D., Clouston, A.D., Purdie, D.M., and Jonsson, J.R., A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C, J. Med. Genet., 2005, vol. 42. e45. https://doi.org/10.1136/jmg.2005.032557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lozano, R., Naghavi, M., Foreman, K., Lim, S., Shibuya, K., Aboyans, V., Abraham, J., Adair, T., Aggarwal, R., Ahn, S.Y., Alvarado, M., Anderson, H.R., Anderson, L.M., Andrews, K.G., Atkinson, C., Baddo, L.M., Barker-Collo, S., Bartels, D.H., Bell, M.L., Benjamin, E.J., Bennett, D., Bhalla, K., Bikbov, B., Bin Abdulhak, A., Birbeck, G., Blyth, F., Bolliger, I., Boufous, S., Bucello, C., Burch, M., Burney, P., Carapetis, J., Chen, H., Chou, D., Chugh, S.S., Coffeng, L.E., Colan, S.D., Colquhoun, S., Colson, K.E., Condon, J., Connor, M.D., Cooper, L.T., Corriere, M., Cortinovis, M., de Vaccaro, K.C., Couser, W., Cowie, B.C., Criqui, M.H., Cross, M., Dabhadkar, K.C., Dahodwala, N., De Leo, D., Degenhardt, L., Delossantos, A., Denenberg, J., Des Jarlais, D.C., Dharmaratne, S.D., Dorsey, E.R., Driscoll, T., Duber, H., Ebel, B., Erwin, P.J., Espindola, P., Ezzati, M., Feigin, V., Flaxman, A.D., Forouzanfar, M.H., Fowkes, F.G., Franklin, R., Fransen, M., Freeman, M.K., Gabriel, S.E., Gakidou, E., Gaspari, F., Gillum, R.F., Gonzalez-Medina, D., Halasa, Y.A., Haring, D., Harrison, J.E., Havmoeller, R., Hay, R.J., Hoen, B., Hotez, P.J., Hoy, D., Jacobsen, K.H., James, S.L., Jasrasaria, R., Jayaraman, S., Johns, N., Karthikeyan, G., Kassebaum, N., Keren, A., Khoo, J.P., Knowlton, L.M., Kobusingye, O., Koranteng, A., Krishnamurthi, R., Lipnick, M., Lipshultz, S.E., Ohno, S.L., Mabweijano, J., MacIntyre, M.F., Mallinger, L., March, L., Marks, G.B., Marks, R., Matsumori, A., Matzopoulos, R., Mayosi, B.M., McAnulty, J.H., McDermott, M.M., McGrath, J., Mensah, G.A., Merriman, T.R., Michaud, C., Miller, M., Miller, T.R., Mock, C., Mocumbi, A.O., Mokdad, A.A., Moran, A., Mulholland, K., Nair, M.N., Naldi, L., Narayan, K.M., Nasseri, K., Norman, P., O’Donnell, M., Omer, S.B., Ortblad, K., Osborne, R., Ozgediz, D., Pahari, B., Pandian, J.D., Rivero, A.P., Padilla, R.P., Perez-Ruiz, F., Perico, N., Phillips, D., Pierce, K., Pope, C.A., Porrini, E., Pourmalek, F., Raju, M., Ranganathan, D., Rehm, J.T., Rein, D.B., Remuzzi, G., Rivara, F.P., Roberts, T., De Leon, F.R., Rosenfeld, L.C., Rushton, L., Sacco, R.L., Salomon, J.A., Sampson, U., Sanman, E., Schwebel, D.C., Segui-Gomez, M., Shepard, D.S., Singh, D., Singleton, J., Sliwa, K., Smith, E., Steer, A., Taylor, J.A., Thomas, B., Tleyjeh, I.M., Towbin, J.A., Truelsen, T., Undurraga, E.A., Venketasubramanian, N., Vijayakumar, L., Vos, T., Wagner, G.R., Wang, M., Wang, W., Watt, K., Weinstock, M.A., Weintraub, R., Wilkinson, J.D., Woolf, A.D., Wulf, S., Yeh, P.H., Yip, P., Zabetian, A., Zheng, Z.J., Lopez, A.D., Murray, C.J., AlMazroa, M.A., and Memish, Z.A. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010, Lancet, 2012, vol. 380, no. 9859, pp. 2095–2128. https://doi.org/10.1016/S0140-6736(12)61728-0

    Article  PubMed  Google Scholar 

  56. Bruix, J. and Sherman, M., Management of hepatocellular carcinoma: an update, Hepatology, 2011, vol. 53, no. 3, pp. 1020–1022. https://doi.org/10.1002/hep.24199

    Article  PubMed  Google Scholar 

  57. King, L.Y., Canasto Chibuque, C., Johnson, K.B., Yip, S., Chen, X., Kojima, K., Deshmukh, M., Venkatesh, A., Tan, P.S., Sun, X., Villanueva, A., Sangiovanni, A., Nair, V., Mahajan, M., Kobayashi, M., Kumada, H., Iavarone, M., Colombo, M., Fiel, M.I., Friedman, S.L., Llovet, J.M., Chung, R.T., and Hoshida, Y.A., Genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration, Gut, 2015, vol. 64, no. 8, pp. 1296–1302. https://doi.org/10.1136/gutjnl-2014-307862

    Article  CAS  PubMed  Google Scholar 

  58. Bonkovsky, H.L., Jawaid, Q., Tortorelli, K., LeClair, P., Cobb, J., Lambrecht, R.W., and Banner, B.F., Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in nonalcoholic steatohepatitis, J. Hepatol., 1999, vol. 31, no. 3, pp. 421–429.

    Article  CAS  PubMed  Google Scholar 

  59. Moczulski, D.K., Grzeszczak, W., and Gawlik, B., Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy, Diabetes Care, 2001, vol. 24, no. 7, pp. 1187–1191.

    Article  CAS  PubMed  Google Scholar 

  60. Melis, M.A., Cau, M., Deidda, F., Barella, S., Cao, A., and Galanello, R., H63D mutation in the HFE gene increases iron overload in beta-thalassemia carriers, Haematologica, 2002, vol. 87, no. 3, pp. 242–245.

    CAS  PubMed  Google Scholar 

  61. Tannapfel, A., Stolzel, U., Kostler, E., Melz, S., Richter, M., Keim, V., Schuppan, D., and Wittekind, C., C282Y and H63D mutation of the hemochromatosis gene in German porphyria cutanea tarda patients, Virchows Arch., 2001, vol. 439, no. 1, pp. 1–5.

    Article  CAS  PubMed  Google Scholar 

  62. Lee, D.W., Andersen, J.K., and Kaur, D., Iron dysregulation and neurodegeneration: the molecular connection, Mol. Interv., 2006, vol. 6, no. 2, pp. 89–97.https://doi.org/10.1124/mi.6.2.6

    Article  CAS  PubMed  Google Scholar 

  63. Xia, J., Xu, H., Jiang, H., and Xie, J., The association between the C282Y and H63D polymorphisms of HFE gene and the risk of Parkinson’s disease: a meta-analysis, Neurosci. Lett., 2015, vol. 595, pp. 99–103. https://doi.org/10.1016/j.neulet.2015.04.010

    Article  CAS  PubMed  Google Scholar 

  64. Lian, J., Xu, L., and Huang, Y., Le Y., Jiang D., Yang X., Xu W., Huang X., Dong C., Ye M., Zhou J., Duan S., Meta-analyses of HFE variants in coronary heart disease, Gene, 2013, vol. 527, no. 1, pp. 167–173. https://doi.org/10.1016/j.gene.2013.06.034

    Article  CAS  PubMed  Google Scholar 

  65. Ellervik, C., Tybjaerg-Hansen, A., and Appleyard, M., Hereditary hemochromatosis genotypes and risk of ischemic stroke, Neurology, 2007, vol. 68, no. 13, pp. 1025–1031. https://doi.org/10.1212/01.wnl.0000257814.77115.d6

    Article  CAS  PubMed  Google Scholar 

  66. Sini, M., Sorbello, O., Civolani, A., and Demelia, L., Hemochromatosis gene mutations: prevalence and effects on pegylated-interferon and ribavirin therapy response in chronic hepatitis C in Sardinia, J. Clin. Exp. Hepatol., 2012, vol. 2, no. 3, pp. 211–217. https://doi.org/10.1016/j.jceh.2012.06.004

    Article  PubMed  PubMed Central  Google Scholar 

  67. Mazzanti, R., Arena, U., and Tassi, R., Hepatocellular carcinoma: where are we?, World J. Exp. Med., 2016, vol. 6, no. 1, pp. 21–36. https://doi.org/10.5493/wjem.v6.i1.21

    Article  PubMed  PubMed Central  Google Scholar 

  68. Della, CorteC., Aghemo, A., and Colombo, M., Individualized hepatocellular carcinoma risk: the challenges for designing successful chemoprevention strategies, World J. Gastroenterol., 2013, vol. 19, no. 9, pp. 1359–1371. https://doi.org/10.3748/wjg.v19.i9.1359

    Article  Google Scholar 

  69. World Health Organization. Mortality database. http://www.who.int/whosis/en.

  70. Bruno, S., Crosignani, A., Maisonneuve, P., Rossi, S., Silini, E., and Mondelli, M.U., Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: a seventeen-year prospective cohort study, Hepatology, 2007, vol. 46, no. 5, pp. 1350–6. https://doi.org/10.1002/hep.21826

    Article  CAS  PubMed  Google Scholar 

  71. Lauret, E., Rodriguez, M., Gonzalez, S., Lina-res, A., Lopez-Vazquez, A., Martinez-Borra, J., Rodrigo, L., and Lopez-Larrea, C., HFE gene mutations in alcoholic and virus related cirrhotic patients with hepatocellular carcinoma, Am. J. Gastroenterol., 2002, vol. 97, no. 4, pp. 1016–10121. https://doi.org/10.1111/j.1572-0241.2002.05553.x

    Article  CAS  PubMed  Google Scholar 

  72. Jin, F., Qu Li-Shuai, Shen X.Z., Association between C282Y and H63Dmutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis, J. Exp. Clin. Cancer Res., 2010, vol. 29, no. 1, p. 18. https://doi.org/10.1186/1756-9966-29-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nahon, P., Sutton, A., Rufat, P., Simon, C., Trinchet, J.C., Gattegno, L., Beaugrand, M., and Charnaux, N., Chemokine system polymorphisms, survival and hepatocellular carcinoma occurrence in patients with hepatitis C virus-related cirrhosis, World J. Gastroenterol., 2008, vol. 14, no. 5, pp. 713–719. https://doi.org/10.3748/wjg.14.713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kew, M.C., Hepatic iron overload and hepatocellular carcinoma, Cancer Lett., 2009, vol. 286, no. 1, pp. 38–43. https://doi.org/10.1016/j.canlet.2008.11.001

    Article  CAS  PubMed  Google Scholar 

  75. Marshall, A., Lukk, M., Kutter, C., Davies, S., Alexander, G., and Odom, D.T., Global gene expression profiling reveals Spink1 as a potential hepatocellular carcinoma marker, PLoS One, 2013, vol. 8, no. 3, e59459. https://doi.org/10.1371/journal.pone.0059459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jiang, S., Yang, Z., Li, W., Li, X., Wang, Y., Zhang, J., Xu, C., Chen, P.J., Hou, J., McCrae, M.A., Chen, X., Zhuang, H., and Lu, F., Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis, PLoS One, 2012, vol. 7, no. 9, e40363. https://doi.org/10.1371/journal.pone.0040363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Cevik, O., Li, D., Baljinnyam, E., Manvar, D., Pimenta, E.M., Waris, G., Barnes, B.J., and Kaushik-Basu, N., Interferon regulatory factor 5 (IRF5) suppresses hepatitis C virus (HCV) replication and HCV-associated hepatocellular carcinoma, J. Biol. Chem., 2017, vol. 292, no. 52, pp. 21676–21689. https://doi.org/10.1074/jbc.M117.792721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Furutani, T., Hino, K., Okuda, M., Gondo, T., Nishina, S., Kitase, A., Korenaga, M., Xiao, S.Y., Weinman, S.A., Lemon, S.M., Sakaida, I., and Okita, K., Hepatic iron overload induces hepatocellular carcinoma in transgenic mice expressing the hepatitis C virus polyprotein, Gastroenterology, 2006, vol. 130, no. 7, pp. 2087–2098. https://doi.org/10.1053/j.gastro.2006.02.060

    Article  CAS  PubMed  Google Scholar 

  79. Hoshida, Y., Fuchs, B.C., Bardeesy, N., Baumert, T.F., and Chung, R.T., Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma, J. Hepatol., 2014, vol. 61, no. 10, pp. S79–S90. https://doi.org/10.1016/j.jhep.2014.07

  80. Singal, A.G., Manjunath, H., Yopp, A.C., Beg, M.S., Marrero, J.A., Gopal, P., and Waljee, A.K., The effect of PNPLA3 on fibrosis progression and development of hepatocellular carcinoma: a meta-analysis, Am. J. Gastroenterol., 2014, vol. 109, no. 3, pp. 325–334. https://doi.org/10.1038/ajg.2013.476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. El-Serag, H.B., Kanwal, F., Davila, J.A., Kramer, J., and Richardson, P., A new laboratory-based algorithm to predict development of hepatocellular carcinoma in patients with hepatitis C and cirrhosis, Gastroenterology, 2014, vol. 46, no. 5, pp. 1249–1255.

    Article  Google Scholar 

  82. McHutchison, J.G., Gordon, S.C., Schiff, E.R., Shiffman, M.L., Lee, W.M., Rustgi, V.K., Goodman, Z.D., Ling, M.H., Cort, S., and Albrecht, J.K., Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C, N. Engl. J. Med., 1998, vol. 339, no. 21, pp. 1485–1492.

    Article  CAS  PubMed  Google Scholar 

  83. Glue, P., Rouzier-Panis, R., Raffanel, C., Sabo, R., Gupta, S.K., Salfi, M., Jacobs, S., and Clement, R.P., A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C, Hepatology, 2000, vol. 32, no. 3, pp. 647–653.

    Article  CAS  PubMed  Google Scholar 

  84. Manns, M.P., John, G., McHutchison, RustgiV.K., Shiffman, M., Reindollar, R., Goodman, Z.D., Koury, K., Ling, M., and Albrecht, J.K., Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial, Lancet, 2001, vol. 358, no. 9286, pp. 958–965.

    Article  CAS  PubMed  Google Scholar 

  85. Katano, Y., Honda, T., Hayashi, K., Ishigami, M., Itoh, A., Hirooka, Y., Nakano, I., and Goto, H., Clinical impact of HFE mutations in Japanese patients with chronic hepatitis C, J. Gastroenterol. Hepatol., 2012, vol. 27, no. 6, pp. 1112–1116. https://doi.org/10.1111/j.1440-1746.2011.06976.x

    Article  PubMed  Google Scholar 

  86. Carvalho, I., Cardoso, C., Cordeiro, J.V., Azevedo, J.E., Neefjes, J., and de Sousa, M., HFE cross-talks with the MHC class I antigen presentation pathway, Blood, 2005, vol. 106, pp. 971–977. https://doi.org/10.1182/blood-2004-12-4640

    Article  CAS  PubMed  Google Scholar 

  87. Lawless, M., White, M., Mankan, A., O’Dwyer, M.J., and Norris, S., Elevated MCP-1 serum levels are associated with the H63D mutation and not the C282Y mutation in hereditary hemochromatosis, Tissue Antigens, 2007, vol. 70, no. 4, pp. 294–300. https://doi.org/10.1111/j.1399-0039.2007.00895.x

    Article  CAS  PubMed  Google Scholar 

  88. Li, S.H., Zhao, H., Ren, Y.Y., Liu, Y.Z., Song, G., Ding, P., Ding, Y.P., and Wang, G.Q., The H63D mutation of the hemochromatosis gene is associated with sustained virological response in chronic hepatitis C patients treated with interferon-based therapy: a meta-analysis, Tohoku J. Exp. Med., 2012, vol. 226, no. 4, pp. 293–299. https://doi.org/10.1620/tjem.226.293

    Article  CAS  PubMed  Google Scholar 

  89. Kato, J., Miyanishi, K., Kobune, M., Nakamura, T., Takada, K., Takimoto, R., Kawano, Y., Takahashi, S., Takahashi, M., Sato, Y., Takayama, T., and Niitsu, Y., Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C, J. Gastroenterol., 2007, vol. 42, no. 10, pp. 830–836. https://doi.org/10.1007/s00535-007-2095-z

    Article  CAS  PubMed  Google Scholar 

  90. Desai, T.K., Jamil, L.H., Balasubramaniam, M., Koff, R., and Bonkovsky, H.L., 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, vol. 53, no. 3, pp. 815–822. https://doi.org/10.1007/s10620-007-9945-7

    Article  CAS  PubMed  Google Scholar 

  91. Nirei, K., Matsuoka, S., Nakamura, H., Matsumura, H., and Moriyama, M., Incidence of hepatocellular carcinoma reduced by phlebotomy treatment in patients with chronic hepatitis C, Intern. Med., 2015, vol. 54, no. 2, pp. 107–117.https://doi.org/10.2169/internalmedicine.54.2715

    Article  PubMed  Google Scholar 

  92. Kazemi-Shirazi, L., Datz, C., Maier-Dobersberger, T., Kaserer, K., Hackl, F., Polli, C., Steindl, P.E., Penner, E., and Ferenci, P., The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C, Gastroenterology, 1999, vol. 116, no. 1, pp. 127–134.

    Article  CAS  PubMed  Google Scholar 

  93. Sampietro, M., Piperno, A., Lupica, L., Arosio, C., Vergani, A., Corbetta, N., Malosio, I., Mattioli, M., Fracanzani, A.L., Cappellini, M.D., Fiorelli, G., and Fargion, S., High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda, Hepatology, 1998, vol. 27, no. 1, pp. 181–184.

    Article  CAS  PubMed  Google Scholar 

  94. Dostalikova-Cimburova, M., Kratka, K., and Stransky, J., Iron overload and HFE gene mutations in Czech patients with chronic liver diseases, Dis. Markers, 2012, vol. 32, no. 1, pp. 65–72. https://doi.org/10.3233/DMA-2012-0861

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was performed within the “Genomic and Post-Genomic Technologies” section (Task 14) of the “Innovative Biotechnology–2020” research program of the “Advanced Technologies and Equipment” State Program.

This study was not supported by any specific grant from any state, commercial, or noncommercial funding organization.

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Authors and Affiliations

  1. Institute of Genetics and Cytology, National Academy of Sciences of Belarus, 220072, Minsk, Belarus

    N. G. Danilenko, M. G. Siniauskaya & O. G. Davydenko

  2. Belarusian State Medical University, 220116, Minsk, Belarus

    S. P. Lukashyk & I. A. Karpov

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  1. N. G. Danilenko
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  2. M. G. Siniauskaya
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  3. S. P. Lukashyk
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  4. I. A. Karpov
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  5. O. G. Davydenko
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Correspondence to N. G. Danilenko or S. P. Lukashyk.

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Danilenko, N.G., Siniauskaya, M.G., Lukashyk, S.P. et al. “Double Punch”: Hepatitis C in Patients with Genetic Defects of Iron Metabolism. Cytol. Genet. 53, 407–417 (2019). https://doi.org/10.3103/S0095452719050062

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