Aim. Chronic hepatitis C (CHepC) is frequently associated with hepatic iron overload, yet mechanisms underlying iron-induced liver injury have not been elucidated. We examined the significance of iron deposition in hepatocytes (HC) and reticuloendothelial cells (REC) in CHepC. Methods. Stainable hepatic iron was scored according to the iron deposition pattern in 373 patients. The levels of serum soluble TNF-α receptor (sTNFR2) and hepatic hepcidin mRNA and the efficacy of phlebotomy were compared among patients with different iron deposition patterns. Results. Serum transaminase levels and hepatic scores of stage, grade, and steatosis were higher in patients with REC iron staining than in those without. REC iron scores were independently associated with advanced stage. Serum sTNFR2 levels were significantly higher in patients with REC iron than in those without. REC iron scores were independently correlated with sTNFR2 levels. Compared with patients without stainable iron, those with iron overload had decreased ratios of hepcidin mRNA to serum ferritin. The efficacy of phlebotomy was greater in patients with REC iron than in those without REC iron. Conclusions. The present results show the importance of REC iron for the development of CHepC and the therapeutic effect of phlebotomy in CHepC. 1. Introduction Chronic hepatitis C (CHepC) is frequently associated with hepatic iron overload [1–3]. Elevation of serum iron indices or stainable hepatic iron has been shown in 40 to 70% of patients with CHepC [1–3]. From these observations, iron-induced oxidative stress has been considered to be an underlying mechanism of liver injury and of development of hepatocellular carcinoma [4–6]. The mechanisms of hepatic iron overload in CHepC have not yet been elucidated. However, hepcidin has attracted much attention as an important factor in the disease process. Hepcidin is exclusively produced in the liver and regulates body iron stores [7, 8]. Hepcidin causes internalization and degradation of iron-transporter ferroportin on duodenal enterocytes and macrophages, thereby blocking iron absorption and iron recycling, respectively [9]. In hereditary hemochromatosis (HH), defective hepcidin synthesis results in a subsequent increase in body iron stores [10]. In CHepC, hepatic iron overload has been attributed to the mutation of the hemochromatosis protein (HFE) gene [11], since several reports have found an association between HFE genotypes and iron overload in patients with CHepC [12–14]. Another possible mechanism is the direct effect of the hepatitis C virus (HCV) on
References
[1]
Y. Ikura, H. Morimoto, H. Johmura, M. Fukui, and M. Sakurai, “Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C,” American Journal of Gastroenterology, vol. 91, no. 7, pp. 1367–1373, 1996.
[2]
C. Hézode, C. Cazeneuve, O. Coué, et al., “Liver iron accumulation in patients with chronic active hepatitis C: prevalence and role of hemochromatosis gene mutations and relationship with hepatic histological lesions,” Journal of Hepatology, vol. 3, pp. 979–984, 1999.
[3]
M. Pirisi, C. A. Scott, C. Avellini et al., “Iron deposition and progression of disease in chronic hepatitis C: role of interface hepatitis, portal inflammation, and HFE missense mutations,” American Journal of Clinical Pathology, vol. 113, no. 4, pp. 546–554, 2000.
[4]
J. Choi and J. H. J. Ou, “Mechanisms of liver injury. III. Oxidative stress in the pathogenesis of hepatitis C virus,” American Journal of Physiology, vol. 290, no. 5, pp. G847–G851, 2006.
[5]
S. Mueller, N. H. Afdhal, and D. Schuppan, “Iron, HCV, and liver cancer: hard metal setting the pace?” Gastroenterology, vol. 130, no. 7, pp. 2229–2234, 2006.
[6]
J. Kato, K. Miyanishi, M. Kobune et al., “Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C,” Journal of Gastroenterology, vol. 42, no. 10, pp. 830–836, 2007.
[7]
C. H. Park, E. V. Valore, A. J. Waring, and T. Ganz, “Hepcidin, a urinary antimicrobial peptide synthesized in the liver,” Journal of Biological Chemistry, vol. 276, no. 11, pp. 7806–7810, 2001.
[8]
M. W. Hentze, M. U. Muckenthaler, and N. C. Andrews, “Balancing acts: molecular control of mammalian iron metabolism,” Cell, vol. 117, no. 3, pp. 285–297, 2004.
[9]
E. Nemeth, G. C. Preza, C. L. Jung, J. Kaplan, A. J. Waring, and T. Ganz, “The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study,” Blood, vol. 107, no. 1, pp. 328–333, 2006.
[10]
T. Ganz, “Iron homeostasis: fitting the puzzle pieces together,” Cell Metabolism, vol. 7, no. 4, pp. 288–290, 2008.
[11]
A. Pietrangelo, “Hemochromatosis gene modifies course of hepatitis C viral infection,” Gastroenterology, vol. 124, no. 5, pp. 1509–1523, 2003.
[12]
L. Kazemi-Shirazi, C. Datz, T. Maier-Dobersberger et al., “The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C,” Gastroenterology, vol. 116, no. 1, pp. 127–134, 1999.
[13]
B. Y. Tung, M. J. Emond, M. P. Bronner, S. D. Raaka, S. J. Cotler, and K. V. Kowdley, “Hepatitis C, iron status, and disease severity: relationship with HFE mutations,” Gastroenterology, vol. 124, no. 2, pp. 318–326, 2003.
[14]
H. L. Bonkovsky, N. Troy, K. McNeal et al., “Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C,” Journal of Hepatology, vol. 37, no. 6, pp. 848–854, 2002.
[15]
S. Nishina, K. Hino, M. Korenaga et al., “Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription,” Gastroenterology, vol. 134, no. 1, pp. 226–238, 2008.
[16]
E. M. Brunt, “Pathology of hepatic iron overload,” Seminars in Liver Disease, vol. 25, no. 4, pp. 392–401, 2005.
[17]
Y. Kohgo, T. Ohtake, K. Ikuta et al., “Iron accumulation in alcoholic liver diseases,” Alcoholism, vol. 29, no. 11, pp. 189S–193S, 2005.
[18]
J. E. Nelson, L. Wilson, E. M. Brunt et al., “Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease,” Hepatology, vol. 53, no. 2, pp. 448–457, 2011.
[19]
A. M. Di Bisceglie, C. A. Axiotis, J. H. Hoofnagle, and B. R. Bacon, “Measurements of iron status in patients with chronic hepatitis,” Gastroenterology, vol. 102, no. 6, pp. 2108–2113, 1992.
[20]
T. Ohno, M. Mizokami, R. R. Wu et al., “New hepatitis C virus (HCV) genotyping system that allows for identification of HCV genotypes 1a, 1b, 2a, 2b, 3a, 3b, 4, 5a, and 6a,” Journal of Clinical Microbiology, vol. 35, no. 1, pp. 201–207, 1997.
[21]
K. Tsukiyama-Kohara, K. Yamaguchi, N. Maki et al., “Antigenicities of group I and II hepatitis C virus polypeptides-molecular basis of diagnosis,” Virology, vol. 192, no. 2, pp. 430–437, 1993.
[22]
G. A. Spinas, U. Keller, and M. Brockhaus, “Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia,” Journal of Clinical Investigation, vol. 90, no. 2, pp. 533–536, 1992.
[23]
F. Ichida, T. Tsuji, M. Omata, et al., “New lnuyama Classification, new criteria for histological assessment of chronic hepatitis,” International Hepatology Communications, vol. 6, no. 2, pp. 112–119, 1996.
[24]
B. Turlin and Y. Deugnier, “Evaluation and interpretation of iron in the liver,” Seminars in Diagnostic Pathology, vol. 15, no. 4, pp. 237–245, 1998.
[25]
T. Sohda, J. Yanai, H. Soejima, and K. Tamura, “Frequencies in the Japanese population of HFE gene mutations,” Biochemical Genetics, vol. 37, no. 1-2, pp. 63–68, 1999.
[26]
C. A. Bradham, J. Plümpe, M. P. Manns, D. A. Brenner, and C. Trautwein, “Mechanisms of hepatic toxicity: I. TNF-induced liver injury,” American Journal of Physiology, vol. 275, no. 3, pp. G387–G392, 1998.
[27]
Y. Itoh and T. Okanoue, “Serum levels of soluble tumor necrosis factor receptors and effects of interferon therapy in patients with chronic hepatitis C virus infection,” American Journal of Gastroenterology, vol. 94, no. 5, pp. 1332–1340, 1999.
[28]
N. Nieto, S. L. Friedman, P. Greenwel, and A. I. Cederbaum, “CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells,” Hepatology, vol. 30, no. 4, pp. 987–996, 1999.
[29]
A. Pietrangelo, R. Gualdi, G. Casalgrandi, G. Montosi, and E. Ventura, “Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents,” Journal of Clinical Investigation, vol. 95, no. 4, pp. 1824–1831, 1995.
[30]
S. Recalcati, M. Locati, E. Gammella, P. Invernizzi, and G. Cairo, “Iron levels in polarized macrophages: regulation of immunity and autoimmunity,” Autoimmunity Reviews, vol. 11, no. 12, pp. 883–889, 2012.
[31]
N. Fujita, R. Sugimoto, M. Takeo et al., “Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C,” Molecular Medicine, vol. 13, no. 1-2, pp. 97–104, 2007.
