Biological Trace Element Research

, Volume 155, Issue 1, pp 5–10 | Cite as

Iron and Proinflammatory Cytokines in Chronic Hepatitis C Virus Infection

  • Javier López-Prieto
  • Emilio González-ReimersEmail author
  • M. Remedios Alemán-Valls
  • María José de la Vega-Prieto
  • Pedro Abreu-González
  • Ricardo Pelazas-González
  • Rubén Hernández-Luis
  • Carlos Jorge-Ripper
  • Francisco Santolaria-Fernández


Steatohepatitis is a common finding in chronic hepatitis C virus (HCV) infection. As in other forms of steatohepatitis, oxidative damage may play an outstanding role. However, there are conflicting results relative to the role of iron on hepatic lipogenesis. Proinflammatory cytokines up-regulate ferritin expression, probably reflecting a defensive mechanism against increased oxidative stress, capable to open haem ring and release reactive iron. On the contrary, some adipokines, such as adiponectin, are associated with low ferritin levels. The aim of this study is to analyse the relationships of the amount of liver steatosis with serum iron, transferrin and ferritin as well as with proinflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, and adiponectin levels. We included 82 HCV infected patients and assessed the amount of liver fat by histomorphometry and its relationships with serum iron, ferritin and transferrin, adiponectin and TNF-α and IL-6. Liver steatosis was observed in 67 patients out of 82; in the remaining 15 patients, no steatosis at all was found. Patients with steatosis showed significantly higher serum ferritin levels than patients without steatosis (Z = 2.14; p = 0.032). When patients were classified in quartiles according to the intensity of steatosis, we observed that both TNF-α (KW = 10.6; p = 0.014) and IL-6 (KW = 15.2; p = 0.002) were significantly different among the four groups. Patients with more intense steatosis (highest quartile) showed the highest TNF-α and IL-6 values. Patients with severe hepatitis had higher levels of serum iron than patients with mild to moderate hepatitis. Serum iron also showed a correlation with the proportion of fibrosis (ρ = 0.30; p = 0.007). Serum iron levels are related with biochemical and histological parameters derived from liver inflammation in HCV-associated liver disease. Serum ferritin is higher among those with intense steatosis and also shows a (non-significant) trend to be associated with the more severe forms of hepatitis.


Adiponectin Proinflammatory cytokines Hepatitis C virus Liver steatosis Serum iron Serum ferritin 



Authors are indebted to the nurses and staff of the internal medicine unit and section for infectious diseases of the Hospital Universitario de Canarias.

Conflict of Interest

The authors declare that there is no conflict of interest regarding this manuscript.


  1. 1.
    Woreta TA, Sutcliffe CG, Mehta SH, Brown TT, Higgins Y, Thomas DL, Torbenson MS, Moore RD, Sulkowski MS (2011) Incidence and risk factors for steatosis in adults coinfected with HIV and hepatitis C virus. Gastroenterol 140:809–817CrossRefGoogle Scholar
  2. 2.
    James OF, Day CP (1998) Non-alcoholic steatohepatitis (NASH): a disease of emerging identity and importance. J Hepatol 29:495–501PubMedCrossRefGoogle Scholar
  3. 3.
    García-Heredia A, Kensicki E, Mohney RP, Rull A, Triguero I, Marsillach J, Tormos C, Mackness B, Mackness M, Shih DM, Pedro-Botet J, Joven J, Saez G, Camps J (2013) Paraoxonase-1 deficiency is associated with severe liver steatosis in mice fed a high-fat high- cholesterol diet: a metabolomic approach. J Proteome Res (in press)Google Scholar
  4. 4.
    Ahmed U, Latham S, Oates PS (2012) Interactions between hepatic iron and lipid metabolism with possible relevance to steatohepatitis. World J Gastroenterol 18:4651–4658PubMedCrossRefGoogle Scholar
  5. 5.
    Balla J, Vercellotti GM, Jeney V, Yachie A, Varga Z, Jacob HS, Eaton JW, Balla G (2007) Heme, heme-oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment. Antioxid Redox Signal 9:2119–2137PubMedCrossRefGoogle Scholar
  6. 6.
    Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM (1992) Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem 5:18148–18153Google Scholar
  7. 7.
    Gabrielsen JS, Gao Y, Simcox JA, Huang J, Thorup D, Jones D, Cooksey RC, Gabrielsen D, Adams TD, Hunt SC, Hopkins PN, Cefalu WT, McClain DA (2012) Adipocyte iron regulates adiponectin and insulin sensitivity. J Clin Invest 122:3529–3540PubMedCrossRefGoogle Scholar
  8. 8.
    Torti FM, Torti SV (2002) Regulation of ferritin genes and protein. Blood 99:3505–3516PubMedCrossRefGoogle Scholar
  9. 9.
    Kikugawa K, Kojima T, Yamaki S, Kosugi H (1992) Interpretation of the thiobarbituric acid reactivity of rat liver and brain homogenates in the presence of ferric ion and ethylenediaminetetraacetic acid. Anal Biochem 202:249–255PubMedCrossRefGoogle Scholar
  10. 10.
    Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J (1981) Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1:431–435PubMedCrossRefGoogle Scholar
  11. 11.
    Bedossa P, Poynard T (1996) An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology 24:289–293PubMedCrossRefGoogle Scholar
  12. 12.
    Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP (2004) Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterol 126:586–597CrossRefGoogle Scholar
  13. 13.
    Basaranoglu M, Basaranoglu G, Sentürk H (2013) From fatty liver to fibrosis: a tale of “second hit”. World J Gastroenterol 19:1158–1165PubMedCrossRefGoogle Scholar
  14. 14.
    Sheikh MY, Choi J, Qadri I, Friedman JE, Sanyal AJ (2008) Hepatitis C virus infection: molecular pathways to metabolic syndrome. Hepatology 47:2127–2133PubMedCrossRefGoogle Scholar
  15. 15.
    Chandok N, Minuk G, Wengiel M, Uhanova J (2012) Serum ferritin levels do not predict the stage of underlying non-alcoholic fatty liver disease. J Gastrointestin Liver Dis 21:53–58PubMedGoogle Scholar
  16. 16.
    Rojkind M, Dunn MA (1979) Hepatic fibrosis. Gastroenterol 76:849–863Google Scholar
  17. 17.
    George DK, Goldwurm SW, Mc Donald GA, CowleyLL WNI, Ward PJ, Jazwinska EC, Powell LW (1998) Increased hepatic iron concentration in non-alcoholic steatohepatitis is associated with increased fibrosis. Gastroenterol 114:311–318CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Javier López-Prieto
    • 1
  • Emilio González-Reimers
    • 1
    Email author
  • M. Remedios Alemán-Valls
    • 1
  • María José de la Vega-Prieto
    • 2
  • Pedro Abreu-González
    • 3
  • Ricardo Pelazas-González
    • 1
  • Rubén Hernández-Luis
    • 1
  • Carlos Jorge-Ripper
    • 1
  • Francisco Santolaria-Fernández
    • 1
  1. 1.Servicio de Medicina Interna, Hospital Universitario de CanariasUniversidad de La LagunaTenerifeSpain
  2. 2.Servicio de Laboratorio, Hospital Universitario de CanariasUniversidad de La LagunaTenerifeSpain
  3. 3.Departamento de FisiologíaUniversidad de La LagunaTenerifeSpain

Personalised recommendations