Chronic liver diseases and iron: a concise review with emphasis on hypotransferrinemia and hypohepcidinemia

Chronic liver diseases and iron: a concise review with emphasis on hypotransferrinemia and hypohepcidinemia

Abstract: Iron studies in chronic liver diseases (CLDs) have a long history. Currently we can mention certainties, uncertainties, and hopes related to this topic. It is certain that iron metabolism problems and hepatic siderosis are frequent in CLDs and they get more frequent as CLD progresses, but true iron overload is rare. There are conflicting literature data on the mechanism of siderosis, the role of iron in CLD pathogenesis, and the potential benefits of iron removal. We may hope that pharmacological approaches targeting iron metabolism disorders of CLD will be actively evaluated in the future. In this review, we aimed to present a general outlook of this extensively studied topic.

___

  • 1. Beaumont C, Vaulont S. Iron homeostasis. In: Beaumont C, Beris P, Beuzard Y, Brugnara C, editors. Disorders of Iron Homeostasis, Erythrocytes, Erythropoiesis. Paris, France: European School of Haematology; 2006. pp. 392-406.
  • 2. Fleming RE, Sly WS. Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. P Natl Acad Sci USA 2001; 98: 8160- 8162.
  • 3. Batts KP. Iron overload syndromes and the liver. Mod Pathol 2007; 20 (Suppl.): S31-39.
  • 4. Riva A, Trombini P, Mariani R, Salvioni A, Coletti S, Bonfadini S, Paolini V, Pozzi M, Facchetti R, Bovo G et al. Revaluation of clinical and histological criteria for diagnosis of dysmetabolic iron overload syndrome. World J Gastroenterol 2008; 14: 4745- 4752.
  • 5. Turlin B, Mendler MH, Moirand R, Guyader D, Guillygomarch A, Deugnier Y. Histologic features of the liver in insulin resistance-associated iron overload. A study of 139 patients. Am J Clin Pathol 2001;116: 263-270.
  • 6. Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, Le Gall JY, Brissot P, David V, Deugnier Y. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117: 1155-1163.
  • 7. Herbut PA, Tamaki HT. Cirrhosis of the liver and diabetes as related to hemochromatosis. Am J Clin Pathol 1946; 16: 640- 650.
  • 8. MacDonald RA. Idiopathic hemochromatosis. A variant of portal cirrhosis and idiopathic hemosiderosis. Arch Intern Med 1961; 107: 606-616.
  • 9. Zimmerman HJ, Chomet B, Kulesh MH, McWhorter CA. Hepatic hemosiderin deposits. Incidence in 558 biopsies from patients with and without intrinsic hepatic disease. Arch Intern Med 1961; 107: 494-503.
  • 10. Ludwig J, Hashimoto E, Porayko MK, Moyer TP, Baldus WP. Hemosiderosis in cirrhosis: a study of 447 native livers. Gastroenterology 1997; 112: 882-888.
  • 11. Barry M, Cartei G, Sherlock S. Measurement of iron stores in cirrhosis using diethylenetriamine penta-acetic acid. Gut 1970; 11: 899-904.
  • 12. Callender ST, Malpas JS. Absorption of iron in cirrhosis of liver. Br Med J 1963; 2: 1516-1518.
  • 13. Friedman BI, Schaefer JW, Schiff L. Increased iron-59 absorption in patients with hepatic cirrhosis. J Nucl Med 1966; 7: 594-602.
  • 14. Golberg L, Smith JP. Iron overloading and hepatic vulnerability. Am J Pathol 1960; 36: 125-149.
  • 15. Schwartz SO. Exogenous hemochromatosis; concept and general description. Am J Clin Pathol 1956; 26: 744-749.
  • 16. Krause A, Neitz S, Mägert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000; 480: 147-150.
  • 17. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001; 276: 7806-7810.
  • 18. Batts KP. Iron overload syndromes and the liver. Mod Pathol 2007; 20 (Suppl. 1): S31-39.
  • 19. Détivaud L, Nemeth E, Boudjema K, Turlin B, Troadec MB, Leroyer P, Ropert M, Jacquelinet S, Courselaud B, Ganz T et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function. Blood 2005; 106: 746-748.
  • 20. Girelli D, Pasino M, Goodnough JB, Nemeth E, Guido M, Castagna A, Busti F, Campostrini N, Martinelli N, Vantini I et al. Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol 2009; 51: 845-852.
  • 21. Fargion S, Valenti L, Fracanzani AL. Beyond hereditary hemochromatosis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis 2011; 43: 89-95.
  • 22. Hino K, Nishina S, Hara Y. Iron metabolic disorder in chronic hepatitis C: mechanisms and relevance to hepatocarcinogenesis. J Gastroenterol Hepatol 2013; 28 (Suppl. 4): 93-98.
  • 23. Lee SH, Jeong SH, Park YS, Hwang JH, Kim JW, Kim N, Lee DH. Serum prohepcidin levels in chronic hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease. Korean J Hepatol 2010; 16: 288-294.
  • 24. Olmez OF, Gurel S, Yilmaz Y. Plasma prohepcidin levels in patients with chronic viral hepatitis: relationship with liver fibrosis. Eur J Gastroenterol Hepatol 2010; 22: 461-465.
  • 25. Jaroszewicz J, Rogalska M, Flisiak I, Flisiak R. Successful antiviral therapy is associated with a decrease of serum prohepcidin in chronic hepatitis C. World J Gastroenterol 2010; 16: 1747-1752.
  • 26. Lin TJ, Liao LY, Chou JM, Liu SO, Wang CK. Serum prohepcidin levels correlate with hepatic iron stores in chronic hepatitis C patients. Hepatogastroenterology 2009; 56: 1146-1151.
  • 27. Wang XH, Cheng PP, Jiang F, Jiao XY. The effect of hepatitis B virus infection on hepcidin expression in hepatitis B patients. Ann Clin Lab Sci 2013; 43: 126-134.
  • 28. Tsochatzis E, Papatheodoridis GV, Koliaraki V, Hadziyannis E, Kafiri G, Manesis EK, Mamalaki A, Archimandritis AJ. Serum hepcidin levels are related to the severity of liver histological lesions in chronic hepatitis C. J Viral Hepat 2010; 17: 800-806.
  • 29. Jaroszewicz J, Rogalska M, Flisiak R. Serum prohepcidin reflects the degree of liver function impairment in liver cirrhosis. Biomarkers 2008; 13: 478-485.
  • 30. Miura K, Taura K, Kodama Y, Schnabl B, Brenner DA. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 2008; 48: 1420-1429.
  • 31. Fujita N, Sugimoto R, Motonishi S, Tomosugi N, Tanaka H, Takeo M, Iwasa M, Kobayashi Y, Hayashi H, Kaito M et al. Patients with chronic hepatitis C achieving a sustained virological response to peginterferon and ribavirin therapy recover from impaired hepcidin secretion. J Hepatol 2008; 49: 702-710.
  • 32. Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidaka I et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 2008; 134: 226-238.
  • 33. Fujita N, Sugimoto R, Takeo M, Urawa N, Mifuji R, Tanaka H, Kobayashi Y, Iwasa M, Watanabe S, Adachi Y et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007; 13: 97-104.
  • 34. Sikorska K, Romanowski T, Stalke P, Izycka Swieszewska E, Bielawski KP. Association of hepcidin mRNA expression with hepatocyte iron accumulation and effects of antiviral therapy in chronic hepatitis C infection. Hepat Mon 2014; 14: e21184.
  • 35. Caliskan Y, Yelken B, Ozkok A, Gorgulu N, Yazici H, Telci A, Yildiz A. Lower serum prohepcidin levels associated with lower iron and erythropoietin requirements in hemodialysis patients with chronic hepatitis C. BMC Nephrol 2012; 13: 56.
  • 36. Tan TC, Crawford DH, Franklin ME, Jaskowski LA, Macdonald GA, Jonsson JR, Watson MJ, Taylor PJ, Fletcher LM. The serum hepcidin:ferritin ratio is a potential biomarker for cirrhosis. Liver Int 2012; 32: 1391-1399.
  • 37. Abd Elmonem E, Tharwa ES, Farag MA, Fawzy A, El Shinnawy SF, Suliman S. Hepcidin mRNA level as a parameter of disease progression in chronic hepatitis C and hepatocellular carcinoma. J Egypt Natl Canc Inst 2009; 21: 333-342.
  • 38. Sugimoto R, Fujita N, Tomosugi N, Hara N, Miyachi H, Tanaka H, Takeo M, Nakagawa N, Iwasa M, Kobayashi Y et al. Impaired regulation of serum hepcidin during phlebotomy in patients with chronic hepatitis C. Hepatol Res 2009; 39: 619-624.
  • 39. Nagashima M, Kudo M, Chung H, Ishikawa E, Hagiwara S, Nakatani T, Dote K. Regulatory failure of serum prohepcidin levels in patients with hepatitis C. Hepatol Res 2006; 36: 288- 293.
  • 40. Harrison-Findik DD, Klein E, Crist C, Evans J, Timchenko N, Gollan J. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 2007; 46: 1979-1985.
  • 41. Ohtake T, Saito H, Hosoki Y, Inoue M, Miyoshi S, Suzuki Y, Fujimoto Y, Kohgo Y. Hepcidin is down-regulated in alcohol loading. Alcohol Clin Exp Res 2007; 31 (Suppl. 1): S2-8.
  • 42. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, Fein E, Andriopoulos B, Pantopoulos K, Gollan J. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem 2006; 281: 22974-22982.
  • 43. Bridle K, Cheung TK, Murphy T, Walters M, Anderson G, Crawford DG, Fletcher LM. Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res 2006; 30: 106-112.
  • 44. Costa-Matos L, Batista P, Monteiro N, Simões M, Egas C, Pereira J, Pinho H, Santos N, Ribeiro J, Cipriano MA et al. Liver hepcidin mRNA expression is inappropriately low in alcoholic patients compared with healthy controls. Eur J Gastroenterol Hepatol 2012; 24: 1158-1165.
  • 45. Yonal O, Akyuz F, Demir K, Ciftci S, Keskin F, Pinarbasi B, Uyanikoglu A, Issever H, Ozdil S, Boztas G et al. Decreased prohepcidin levels in patients with HBV-related liver disease: relation with ferritin levels. Dig Dis Sci 2010; 55: 3548-3551.
  • 46. Aoki CA, Rossaro L, Ramsamooj R, Brandhagen D, Burritt MF, Bowlus CL. Liver hepcidin mRNA correlates with iron stores, but not inflammation, in patients with chronic hepatitis C. J Clin Gastroenterol 2005; 39: 71-74.
  • 47. Flanagan JM, Peng H, Beutler E. Effects of alcohol consumption on iron metabolism in mice with hemochromatosis mutations. Alcohol Clin Exp Res 2007; 31: 138-143.
  • 48. Gan EK, Powell LW, Olynyk JK. Natural history and management of HFE-hemochromatosis. Semin Liver Dis 2011; 31: 293-301.
  • 49. Deugnier Y, Turlin B. Pathology of hepatic iron overload. World J Gastroenterol 2007; 13: 4755-4760.
  • 50. Piperno A. Classification and diagnosis of iron overload. Haematologica 1998; 83: 447-455.
  • 51. Corengia C, Galimberti S, Bovo G, Vergani A, Arosio C, Mariani R, Redaelli A, Riva A, Cestari C, Pozzi M et al. Iron accumulation in chronic hepatitis C: relation of hepatic iron distribution, HFE genotype, and disease course. Am J Clin Pathol 2005; 124: 846-853.
  • 52. Hunt AH, Parr RM, Taylor DM, Trott NG. Relation between cirrhosis and trace metal content of liver wıth special reference to primary biliary cirrhosis and copper. Br Med J 1963; 2: 1498- 1501.
  • 53. Hayashi H, Piperno A, Tomosugi N, Hayashi K, Kimura F, Wakusawa S, Yano M, Tatsumi Y, Hattori A, Pelucchi S et al. Patients with chronic hepatitis C may be more sensitive to iron hepatotoxicity than patients with HFE-hemochromatosis. Intern Med 2010; 49: 2371-2377.
  • 54. Silva IS, Perez RM, Oliveira PV, Cantagalo MI, Dantas E, Sisti C, Figueiredo-Mendes C, Lanzoni VP, Silva A, Ferraz ML. Iron overload in patients with chronic hepatitis C virus infection: clinical and histological study. J Gastroenterol Hepatol 2005; 20: 243-248.
  • 55. Shiono Y, Hayashi H, Wakusawa S, Sanae F, Takikawa T, Yano M, Yoshioka K, Saito H. Body iron stores and iron restoration rate in Japanese patients with chronic hepatitis C as measured during therapeutic iron removal revealed neither increased body iron stores nor effects of C282Y and H63D mutations on iron indices. Nagoya J Med Sci 2001; 64: 51-57. 56. Barry M. Iron and the liver. Gut 1974; 15: 324-334.
  • 57. Kent G, Volini FI, Minick OT, Orfei E, Delahuerga J. Effect of iron loading upon the formation of collagen ın the hepatic injury induced by carbon tetrachlorıde. Am J Pathol 1964; 45: 129-155.
  • 58. Lisboa PE. Experimental hepatic cirrhosis in dogs caused by chronic massive iron overload. Gut 1971; 12: 363-368.
  • 59. Deugnier YM, Loréal O, Turlin B, Guyader D, Jouanolle H, Moirand R, Jacquelinet C, Brissot P. Liver pathology in genetic hemochromatosis: a review of 135 homozygous cases and their bioclinical correlations. Gastroenterology 1992; 102: 2050- 2059.
  • 60. Deugnier Y, Turlin B. Pathology of hepatic iron overload. Semin Liver Dis 2011; 31: 260-271.
  • 61. Mackinnon M, Clayton C, Plummer J, Ahern M, Cmielewski P, Ilsley A, Hall P. Iron overload facilitates hepatic fibrosis in the rat alcohol/low-dose carbon tetrachloride model. Hepatology 1995; 21: 1083-1088.
  • 62. Barry M, Flynn DM, Letsky EA, Risdon RA. Long-term chelation therapy in thalassaemia major: effect on liver iron concentration, liver histology, and clinical progress. Br Med J 1974; 2: 16-20.
  • 63. Powell LW, Dixon JL, Ramm GA, Purdie DM, Lincoln DJ, Anderson GJ, Subramaniam VN, Hewett DG, Searle JW, Fletcher LM et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med 2006; 166: 294-301.
  • 64. Falize L, Guillygomarch A, Perrin M, Lainé F, Guyader D, Brissot P, Turlin B, Deugnier Y. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 2006; 44: 472-477.
  • 65. Deugnier Y, Turlin B, Ropert M, Cappellini MD, Porter JB, Giannone V, Zhang Y, Griffel L, Brissot P. Improvement in liver pathology of patients with β-thalassemia treated with deferasirox for at least 3 years. Gastroenterology 2011; 141: 1202-1211.
  • 66. Mendes LS, Nita ME, Ono-Nita SK, Mello ES, da Silva LC, Alves VA, Carrilho FJ. Prognostic factors for progression of liver structural lesions in chronic hepatitis C patients. World J Gastroenterol 2008; 14: 2522-2528.
  • 67. Beinker NK, Voigt MD, Arendse M, Smit J, Stander IA, Kirsch RE. Threshold effect of liver iron content on hepatic inflammation and fibrosis in hepatitis B and C. J Hepatol 1996; 25: 633-638.
  • 68. Chapoutot C, Esslimani M, Joomaye Z, Ramos J, Perney P, Laurent C, Fabbro-Peray P, Larrey D, Domergue J, Blanc F. Liver iron excess in patients with hepatocellular carcinoma developed on viral C cirrhosis. Gut 2000; 46: 711-714.
  • 69. Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis. Semin Liver Dis 1996; 16: 13-30.
  • 70. Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G et al. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood 2002; 100: 17- 21.
  • 71. Farinati F, Cardin R, De Maria N, Della Libera G, Marafin C, Lecis E, Burra P, Floreani A, Cecchetto A, Naccarato R. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol 1995; 22: 449-456.
  • 72. Miyanishi K, Hoki T, Tanaka S, Kato J. Prevention of hepatocellular carcinoma: Focusing on antioxidant therapy. World J Hepatol 2015; 7: 593-599.
  • 73. George DK, Goldwurm S, MacDonald GA, Cowley LL, Walker NI, Ward PJ, Jazwinska EC, Powell LW. Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis. Gastroenterology 1998; 114: 311-318.
  • 74. Fujita N, Sugimoto R, Urawa N, Araki J, Mifuji R, Yamamoto M, Horiike S, Tanaka H, Iwasa M, Kobayashi Y et al. Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol 2007; 22: 1886- 1893.
  • 75. Ryder SD, Irving WL, Jones DA, Neal KR, Underwood JC; Trent Hepatitis C Study Group. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study. Gut 2004; 53: 451-455.
  • 76. Bonkovsky HL, Troy N, McNeal K, Banner BF, Sharma A, Obando J, Mehta S, Koff RS, Liu Q, Hsieh CC. Iron and HFE or TfR1 mutations as comorbid factors for development and progression of chronic hepatitis C. J Hepatol 2002; 37: 848-854.
  • 77. Chino S, Moriyama M, Matsumura H, Ono Y, Arakawa Y. Clinical pathological significance of iron metabolism with chronic hepatitis C patients. Hepatol Res 2002; 24: 245.
  • 78. Diwakaran HH, Befeler AS, Britton RS, Brunt EM, Bacon BR. Accelerated hepatic fibrosis in patients with combined hereditary hemochromatosis and chronic hepatitis C infection. J Hepatol 2002; 36: 687-691.
  • 79. Rigamonti C, Andorno S, Maduli E, Morelli S, Pittau S, Nicosia G, Boldorini R, Sartori M. Iron, hepatic stellate cells and fibrosis in chronic hepatitis C. Eur J Clin Invest 2002; 32 (Suppl. 1): 28-35.
  • 80. Casaril M, Stanzial AM, Tognella P, Pantalena M, Capra F, Colombari R, Corrocher R. Role of iron load on fibrogenesis in chronic hepatitis C. Hepatogastroenterology 2000; 47: 220- 225.
  • 81. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, Schiff ER, Bacon BR. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 1995; 108: 1104-1109.
  • 82. Lebray P, Zylberberg H, Hue S, Poulet B, Carnot F, Martin S, Chretien Y, Pol S, Caillat-Zuckman S, Bréchot C et al. Influence of HFE gene polymorphism on the progression and treatment of chronic hepatitis C. J Viral Hepat 2004; 11: 175-182.
  • 83. Piperno A, Sampietro M, D’Alba R, Roffi L, Fargion S, Parma S, Nicoli C, Corbetta N, Pozzi M, Arosio V et al. Iron stores, response to alpha-interferon therapy, and effects of iron depletion in chronic hepatitis C. Liver 1996; 16: 248-254.
  • 84. Fargion S, Fracanzani AL, Rossini A, Borzio M, Riggio O, Belloni G, Bissoli F, Ceriani R, Ballarè M, Massari M et al. 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 2002; 97: 1204-1210.
  • 85. Clemente MG, Congia M, Lai ME, Lilliu F, Lampis R, Frau F, Frau MR, Faa G, Diana G, Dessì C et al. Effect of iron overload on the response to recombinant interferon-alfa treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 1994; 125: 123-128.
  • 86. Barton AL, Banner BF, Cable EE, Bonkovsky HL. Distribution of iron in the liver predicts the response of chronic hepatitis C infection to interferon therapy. Am J Clin Pathol 1995; 103: 419-424.
  • 87. Banner BF, Barton AL, Cable EE, Smith L, Bonkovsky HL. A detailed analysis of the Knodell score and other histologic parameters as predictors of response to interferon therapy in chronic hepatitis C. Mod Pathol 1995; 8: 232-238.
  • 88. Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, Schiff ER, Bacon BR. Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 1995; 108: 1104-1109.
  • 89. Arber N, Moshkowitz M, Konikoff F, Halpern Z, Hallak A, Santo M, Tiomny E, Baratz M, Gilat T. Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection. Dig Dis Sci 1995; 40: 2431-2433.
  • 90. Izumi N, Enomoto N, Uchihara M, Murakami T, Ono K, Noguchi O, Miyake S, Nouchi T, Fujisawa K, Marumo F et al. Hepatic iron contents and response to interferon-alpha in patients with chronic hepatitis C. Relationship to genotypes of hepatitis C virus. Dig Dis Sci 1996; 41: 989-994.
  • 91. Ikura Y, Morimoto H, Johmura H, Fukui M, Sakurai M. Relationship between hepatic iron deposits and response to interferon in chronic hepatitis C. Am J Gastroenterol 1996; 91: 1367-1373.
  • 92. Fargion S, Fracanzani AL, Sampietro M, Molteni V, Boldorini R, Mattioli M, Cesana B, Lunghi G, Piperno A, Valsecchi C et al. Liver iron influences the response to interferon alpha therapy in chronic hepatitis C. Eur J Gastroenterol Hepatol 1997; 9: 497-503.
  • 93. Kaji K, Nakanuma Y, Harada K, Sakai A, Kaneko S, Kobayashi K. Hemosiderin deposition in portal endothelial cells is a histologic marker predicting poor response to interferon-alpha therapy in chronic hepatitis C. Pathol Int 1997; 47: 347-352.
  • 94. Kaserer K, Fiedler R, Steindl P, Müller CH, Wrba F, Ferenci P. Liver biopsy is a useful predictor of response to interferon therapy in chronic hepatitis C. Histopathology 1998; 32: 454- 461.
  • 95. Ferrara F, Ventura P, Vegetti A, Guido M, Abbati G, Corradini E, Fattovich G, Ferrari C, Tagliazucchi M, Carbonieri A et al. Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C. Am J Gastroenterol 2009; 104: 605- 616.
  • 96. Lin TJ, Liao LY, Lin CL, Chang TA, Liu SO. Hepatic iron influences responses to combination therapy with peginterferon alfa and ribavirin in chronic hepatitis C. Hepatogastroenterology 2008; 55: 1412-1415.
  • 97. Bonkovsky HL, Naishadham D, Lambrecht RW, Chung RT, Hoefs JC, Nash SR, Rogers TE, Banner BF, Sterling RK, Donovan JA, et al. Roles of iron and HFE mutations on severity and response to therapy during retreatment of advanced chronic hepatitis C. Gastroenterology 2006; 131: 1440-1451.
  • 98. Distante S, Bjøro K, Hellum KB, Myrvang B, Berg JP, Skaug K, Raknerud N, Bell H. Raised serum ferritin predicts nonresponse to interferon and ribavirin treatment in patients with chronic hepatitis C infection. Liver 2002; 22: 269-275.
  • 99. Kageyama F, Kobayashi Y, Murohisa G, Shimizu E, Suzuki F, Kikuyama M, Souda K, Kawasaki T, Nakamura H. Failure to respond to interferon-alpha 2a therapy is associated with increased hepatic iron levels in patients with chronic hepatitis C. Biol Trace Elem Res 1998; 64: 185-196.
  • 100. Di Bisceglie AM, Bonkovsky HL, Chopra S, Flamm S, Reddy RK, Grace N, Killenberg P, Hunt C, Tamburro C, Tavill AS et al. 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 2000; 32: 135-138.
  • 101. Kawamura Y, Akuta N, Sezaki H, Hosaka T, Someya T, Kobayashi M, Suzuki F, Suzuki Y, Saitoh S, Arase Y et al. Determinants of serum ALT normalization after phlebotomy in patients with chronic hepatitis C infection. J Gastroenterol 2005; 40: 901-906.
  • 102. Hayashi H, Takikawa T, Nishimura N, Yano M, Isomura T, Sakamoto N. Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol 1994; 89: 986-988.
  • 103. Guyader D, Boucher E, André P, Even C, Cottereau J, Bianchi A, Gasser P, Mendler MH, Deugnier Y, Brissot P. A pilot study of iron depletion as adjuvant therapy in chronic hepatitis C patients not responding to interferon. Am J Gastroenterol 1999; 94: 1696-1698.
  • 104. Hayashi H, Takikawa T, Nishimura N, Yano M, Isomura T, Sakamoto N. Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron. Am J Gastroenterol 1994; 89: 986-988.
  • 105. Girelli CM, Mirata C, Casiraghi A. Effect of blood letting on serum aminotransferase levels of patients with chronic hepatitis C and iron overload. Recenti Prog Med 1998; 89: 241- 244.
  • 106. Fong TL, Han SH, Tsai NC, Morgan TR, Mizokami M, Qian D, Phan C, Goad K, Redeker AG. 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 1998; 28: 369-374.
  • 107. Herrera JL. Iron depletion is not effective in inducing a virologic response in patients with chronic hepatitis C who failed to respond to interferon therapy. Am J Gastroenterol 1999; 94: 3571-3575.
  • 108. Jurczyk K, Karpińska E, Wawrzynowicz-Syczewska M, Morańska I, Noceń I, Chlubek D, Boroń-Kaczmarska A. State of the iron metabolism in patients with chronic hepatitis C type C does not influence antiviral treatment with interferon and ribavirin. Hepatogastroenterology 2008; 55: 557-561.
  • 109. Sumida Y, Kanemasa K, Fukumoto K, Yoshida N, Sakai K. Effects of dietary iron reduction versus phlebotomy in patients with chronic hepatitis C: results from a randomized, controlled trial on 40 Japanese patients. Intern Med 2007; 46: 637-642.
  • 110. Tanaka N, Horiuchi A, Yamaura T, Komatsu M, Tanaka E, Kiyosawa K. Efficacy and safety of 6-month iron reduction therapy in patients with hepatitis C virus-related cirrhosis: a pilot study. J Gastroenterol 2007; 42: 49-55.
  • 111. Alexander J, Tung BY, Croghan A, Kowdley KV. Effect of iron depletion on serum markers of fibrogenesis, oxidative stress and serum liver enzymes in chronic hepatitis C: results of a pilot study. Liver Int 2007; 27: 268-273.
  • 112. Yano M, Hayashi H, Yoshioka K, Kohgo Y, Saito H, Niitsu Y, Kato J, Iino S, Yotsuyanagi H, Kobayashi Y et al. A significant reduction in serum alanine aminotransferase levels after 3-month iron reduction therapy for chronic hepatitis C: a multicenter, prospective, randomized, controlled trial in Japan. J Gastroenterol 2004; 39: 570-574.
  • 113. Iwasa M, Iwata K, Kaito M, Ikoma J, Yamamoto M, Takeo M, Kuroda M, Fujita N, Kobayashi Y, Adachi Y. Efficacy of longterm dietary restriction of total calories, fat, iron, and protein in patients with chronic hepatitis C virus. Nutrition 2004; 20: 368-371.
  • 114. Carlo C, Daniela P, Giancarlo C. Iron depletion and response to interferon in chronic hepatitis C. Hepatogastroenterology 2003; 50: 1467-1471.
  • 115. Iwasa M, Kaito M, Ikoma J, Kobayashi Y, Tanaka Y, Higuchi K, Takeuchi K, Iwata K, Watanabe S, Adachi Y. Dietary iron restriction improves aminotransferase levels in chronic hepatitis C patients. Hepatogastroenterology 2002; 49: 529- 531.
  • 116. Tanaka N, Horiuchi A, Yamaura T, Komatsu M, Yokoyama T, Okaniwa S, Nagaya T, Yoshizawa K, Kiyosawa K, Aoyama T et al. Efficacy and safety of addition of minor bloodletting (petit phlebotomy) in hepatitis C virus-infected patients receiving regular glycyrrhizin injections. J Gastroenterol 2009; 44: 577- 582.
  • 117. Sartori M, Andorno S, Rigamonti C, Boldorini R. Chronic hepatitis C treated with phlebotomy alone: biochemical and histological outcome. Dig Liver Dis 2001; 33: 157-162.
  • 118. Fontana RJ, Israel J, LeClair P, Banner BF, Tortorelli K, Grace N, Levine RA, Fiarman G, Thiim M, Tavill AS et al. Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology 2000; 31: 730-736.
  • 119. Kato J, Kobune M, Nakamura T, Kuroiwa G, Takada K, Takimoto R, Sato Y, Fujikawa K, Takahashi M, Takayama T et al. Normalization of elevated hepatic 8-hydroxy-2’- deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. Cancer Res 2001; 61: 8697-8702.
  • 120. Van Thiel DH, Friedlander L, Fagiuoli S, Wright HI, Irish W, Gavaler JS. Response to interferon alpha therapy is influenced by the iron content of the liver. J Hepatol 1994; 20: 410-415.
  • 121. Sartori M, Andorno S, Rossini A, Boldorini R, Bozzola C, Carmagnola S, Del Piano M, Albano E. Phlebotomy improves histology in chronic hepatitis C males with mild iron overload. World J Gastroenterol 2010; 16: 596-602.
  • 122. Sartori M, Andorno S, Rossini A, Boldorini R, Bozzola C, Carmagnola S, Del Piano M, Albano E. A case-control histological study on the effects of phlebotomy in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2011; 23: 1178-1184.
  • 123. Kageyama F, Kobayashi Y, Kawasaki T, Toyokuni S, Uchida K, Nakamura H. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C. Am J Gastroenterol 2000; 95: 1041-1050.
  • 124. Desai TK, Jamil LH, Balasubramaniam M, Koff R, Bonkovsky HL. 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; 53: 815-822.
  • 125. Van Thiel DH, Friedlander L, Molloy PJ, Kania RJ, Fagiuoli S, Wright HI,Gasbarrini A, Caraceni P. Retreatment of hepatitis C interferon non-responders with larger doses of interferon with and without phlebotomy. Hepatogastroenterology 1996; 43: 1557-1561.
  • 126. Nirei K, Matsuoka S, Nakamura H, Matsumura H, Moriyama M. Incidence of hepatocellular carcinoma reduced by phlebotomy treatment in patients with chronic hepatitis C. Intern Med 2015; 54: 107-117.
  • 127. Kato J, Miyanishi K, Kobune M, Nakamura T, Takada K, Takimoto R, Kawano Y, Takahashi S, Takahashi M, Sato Y et al. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 2007; 42: 830-836.
  • 128. Ganne-Carrié N, Christidis C, Chastang C, Ziol M, Chapel F, Imbert-Bismut F, Trinchet JC, Guettier C, Beaugrand M. Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow up study. Gut 2000; 46: 277-282.
  • 129. Purohit V, Russo D, Salin M. Role of iron in alcoholic liver disease: introduction and summary of the symposium. Alcohol 2003; 30: 93-97.
  • 130. Halliwell B, Clement MV, Long LH. Hydrogen peroxide in the human body. FEBS Lett 2000; 486: 10-13.
  • 131. Martinelli AL, Filho AB, Franco RF, Tavella MH, Ramalho LN, Zucoloto S, Rodrigues SS, Zago MA. Liver iron deposits in hepatitis B patients: association with severity of liver disease but not with hemochromatosis gene mutations. J Gastroenterol Hepatol 2004; 19: 1036-1041.
  • 132. Sebastiani G, Tempesta D, Alberti A. Hepatic iron overload is common in chronic hepatitis B and is more severe in patients coinfected with hepatitis D virus. J Viral Hepat 2012; 19: e170- 176.
  • 133. Nelson JE, Wilson L, Brunt EM, Yeh MM, Kleiner DE, UnalpArida A, Kowdley KV; Nonalcoholic Steatohepatitis Clinical Research Network. Relationship between the pattern of hepatic iron deposition and histological severity in nonalcoholic fatty liver disease. Hepatology 2011; 53: 448-457.
  • 134. Kushner JP, Steinmuller DP, Lee GR. The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase. J Clin Invest 1975; 56: 661- 667.
  • 135. Nahon P, Ganne-Carrié N, Trinchet JC, Beaugrand M. Hepatic iron overload and risk of hepatocellular carcinoma in cirrhosis. Gastroenterol Clin Biol 2010; 34: 1-7.
  • 136. Sorrentino P, D’Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 2009; 50: 351-357.
  • 137. Ko C, Siddaiah N, Berger J, Gish R, Brandhagen D, Sterling RK, Cotler SJ, Fontana RJ, McCashland TM, Han SH et al. Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 2007; 27: 1394-1401.
  • 138. Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359: 211-218.
  • 139. Waalen J, Felitti VJ, Gelbart T, Beutler E. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood 2008; 111: 3373-3376.
  • 140. Guyader D, Thirouard AS, Erdtmann L, Rakba N, Jacquelinet S, Danielou H, Perrin M, Jouanolle AM, Brissot P, Deugnier Y. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol 2007; 46: 587-595.
  • 141. Nahon P, Sutton A, Rufat P, Ziol M, Thabut G, Schischmanoff PO, Vidaud D, Charnaux N, Couvert P, Ganne-Carrie N et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008; 134: 102-110.
  • 142. D’Souza RF, Feakins R, Mears L, Sabin CA, Foster GR. Relationship between serum ferritin, hepatic iron staining, diabetes mellitus and fibrosis progression in patients with chronic hepatitis C. Aliment Pharmacol Ther 2005; 21: 519- 524.
  • 143. Thorburn D, Curry G, Spooner R, Spence E, Oien K, Halls D, Fox R, McCruden EA, MacSween RN, Mills PR. The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C. Gut 2002; 50: 248-252.
  • 144. Pirisi M, Scott CA, Avellini C, Toniutto P, Fabris C, Soardo G, Beltrami CA, 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; 113: 546-554.
  • 145. Haque S, Chandra B, Gerber MA, Lok AS. Iron overload in patients with chronic hepatitis C: a clinicopathologic study. Hum Pathol 1996; 27: 1277-1281.
  • 146. Jaskiewicz K, Banach L, Lancaster E. Hepatic siderosis, fibrosis and cirrhosis: the association with hepatocellular carcinoma in high-risk population. Anticancer Res 1997; 17: 3897-3899.
  • 147. Younossi ZM, Gramlich T, Bacon BR, Matteoni CA, Boparai N, O’Neill R, McCullough AJ. Hepatic iron and nonalcoholic fatty liver disease. Hepatology 1999; 30: 847-850.
  • 148. Won JE, Jeong SH, Chung JI, Lee JH, Hwang SH, Kim JW, Lee SH, Kim N, Park YS, Lee DH et al. Hepatic iron, serum ferritin, HFE mutation, and hepatic fibrosis in chronic hepatitis C. Intervirology 2009; 52: 239-246.
  • 149. Guyader D, Thirouard AS, Erdtmann L, Rakba N, Jacquelinet S, Danielou H, Perrin M, Jouanolle AM, Brissot P, Deugnier Y. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol 2007; 46: 587-595.
  • 150. Lin TJ, Liao LY, Lin SY, Lin CL, Chang TA. Influence of iron on the severity of hepatic fibrosis in patients with chronic hepatitis C. World J Gastroenterol 2006; 12: 4897-4901.
  • 151. Fernández-Rodriguez CM, Gutiérrez ML, Serrano PL, Lledó JL, Santander C, Fernández TP, Tomás E, Cacho G, Nevado M, Casas ML. Factors influencing the rate of fibrosis progression in chronic hepatitis C. Dig Dis Sci 2004; 49: 1971-1976.
  • 152. Bugianesi E, Manzini P, D’Antico S, Vanni E, Longo F, Leone N, Massarenti P, Piga A, Marchesini G, Rizzetto M. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004; 39: 179-187.
  • 153. Ebara M, Fukuda H, Hatano R, Yoshikawa M, Sugiura N, Saisho H, Kondo F, Yukawa M. Metal contents in the liver of patients with chronic liver disease caused by hepatitis C virus. Reference to hepatocellular carcinoma. Oncology 2003; 65: 323-330.
  • 154. Larson AM, Taylor SL, Bauermeister D, Rosoff L Jr, Kowdley KV. Pilot study of the relationship between histologic progression and hepatic iron concentration in chronic hepatitis C. J Clin Gastroenterol 2003; 37: 406-411.
  • 155. Hourigan LF, Macdonald GA, Purdie D, Whitehall VH, Shorthouse C, Clouston A, Powell EE. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology 1999; 29: 1215-1219.
  • 156. Sajjad S, Garcia M, Malik A, Van Thiel DH. Hepatic iron quantitation and its relationship with disease measures and histologically assessed iron content. Dig Dis Sci 2008; 53: 1390- 1394.
  • 157. Tsai NC, Zuckerman E, Han SH, Goad K, Redeker AG, Fong TL. Effect of iron depletion on long-term response to interferonalpha in patients with chronic hepatitis C who previously did not respond to interferon therapy. Am J Gastroenterol 1997; 92: 1831-1834.
  • 158. Pereira PS, Silva IS, Uehara SN, Emori CT, Lanzoni VP, Silva AE, Ferraz ML. Chronic hepatitis C: hepatic iron content does not correlate with response to antiviral therapy. Rev Inst Med Trop Sao Paulo 2009; 51: 331-336.
  • 159. Gentile I, Viola C, Paesano L, D’Onofrio M, D’Agostino E, Cerini R, Borrelli F, Piazza M, Borgia G. Iron depletion before HCV antiviral therapy: a pilot, randomized, controlled trial. J Clin Apher 2009; 24: 190-196.
  • 160. Souza RM, Freitas LA, Lyra AC, Moraes CF, Braga EL, Lyra LG. Effect of iron overload on the severity of liver histologic alterations and on the response to interferon and ribavirin therapy of patients with hepatitis C infection. Braz J Med Biol Res 2006; 39: 79-83.
  • 161. Hofer H, Osterreicher C, Jessner W, Penz M, Steindl-Munda P, Wrba F, Ferenci P. Hepatic iron concentration does not predict response to standard and pegylated-IFN/ribavirin therapy in patients with chronic hepatitis C. J Hepatol 2004; 40: 1018- 1022.
  • 162. Sievert W, Pianko S, Warner S, Bowden S, Simpson I, Bowden D, Locarnini S. Hepatic iron overload does not prevent a sustained virological response to interferon-alpha therapy: a long term follow-up study in hepatitis C-infected patients with beta thalassemia major. Am J Gastroenterol 2002; 97: 982-987.
  • 163. Guyader D, Boucher E, André P, Even C, Cottereau J, Bianchi A, Gasser P, Mendler MH, Deugnier Y, Brissot P. A pilot study of iron depletion as adjuvant therapy in chronic hepatitis C patients not responding to interferon. Am J Gastroenterol 1999; 94: 1696-1698.
  • 164. Bayraktar Y, Koseoglu T, Somner C, Kayhan B, Temizer A, Uzunalimoglu B, De Maria N, Van Thiel DH. The use of deferoxamine infusions to enhance the response rate to interferon-alpha treatment of chronic viral hepatitis B. J Viral Hepat 1996; 3: 129-135.
  • 165. Deugnier Y, Turlin B, le Quilleuc D, Moirand R, Loréal O, Messner M, Meunier B, Brissot P, Launois B. A reappraisal of hepatic siderosis in patients with end-stage cirrhosis: practical implications for the diagnosis of hemochromatosis. Am J Surg Pathol 1997; 21: 669-675.
  • 166. Büyükaşik NS, Nadir I, Akın FE, Çakal B, Kav T, Ersoy O, Büyükaşik Y. Serum iron parameters in cirrhosis and chronic hepatitis: detailed description. Turk J Gastroenterol 2011; 22: 606-611.
  • 167. Kayali Z, Ranguelov R, Mitros F, Shufelt C, Elmi F, Rayhill SC, Schmidt WN, Brown KE. Hemosiderosis is associated with accelerated decompensation and decreased survival in patients with cirrhosis. Liver Int 2005; 25: 41-48.
  • 168. Arain SA, Kazi TG, Afridi HI, Talpur FN, Mughal MA, Shah F, Arain SS, Panhwar AH. Estimation of copper and iron burden in biological samples of various stages of hepatitis C and liver cirrhosis patients. Biol Trace Elem Res 2014; 160: 197-205.
  • 169. Hattori H. High prevalence of haemosiderin accumulation in the cytoplasm of gastric glands in patients with liver cirrhosis. J Clin Pathol 2004; 57: 621-624.
  • 170. Abu Rajab M, Guerin L, Lee P, Brown KE. Iron overload secondary to cirrhosis: a mimic of hereditary haemochromatosis? Histopathology 2014; 65: 561-569.
  • 171. Vagu C, Sultana C, Ruta S. Serum iron markers in patients with chronic hepatitis C infection. Hepat Mon 2013; 13: e13136.
  • 172. Cho HJ, Kim SS, Ahn SJ, Park JH, Kim DJ, Kim YB, Cho SW, Cheong JY. Serum transferrin as a liver fibrosis biomarker in patients with chronic hepatitis B. Clin Mol Hepatol 2014; 20: 347-354.
  • 173. Potter BJ, Chapman RW, Nunes RM, Sorrentino D, Sherlock S. Transferrin metabolism in alcoholic liver disease. Hepatology 1985; 5: 714-721.
  • 174. Mao W, Hu Y, Lou Y, Chen Y, Zhang J. Abnormal serum iron markers in chronic hepatitis B virus infection may be because of liver injury. Eur J Gastroenterol Hepatol 2015; 27: 130-136.
  • 175. Lambrecht RW, Sterling RK, Naishadham D, Stoddard AM, Rogers T, Morishima C, Morgan TR, Bonkovsky HL; HALT-C Trial Group. Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C. Gastroenterology 2011; 140: 1490-1500.
  • 176. Fabris C, Toniutto P, Scott CA, Falleti E, Avellini C, Del Forno M, Mattiuzzo M, Branca B, Pirisi M. Serum iron indices as a measure of iron deposits in chronic hepatitis C. Clin Chim Acta 2001; 304: 49-55.
  • 177. Metwally MA, Zein CO, Zein NN. Clinical significance of hepatic iron deposition and serum iron values in patients with chronic hepatitis C infection. Am J Gastroenterol 2004; 99: 286-291.
  • 178. Rigamonti C, Andorno S, Maduli E, Capelli F, Boldorini R, Sartori M. Gender and liver fibrosis in chronic hepatitis: the role of iron status. Aliment Pharmacol Ther 2005; 21: 1445- 1451.
  • 179. Giannini E, Mastracci L, Botta F, Romagnoli P, Fasoli A, Risso D, Faravelli F, Ceppa P, Lantieri PB, Icardi GC et al. Liver iron accumulation in chronic hepatitis C patients without HFE mutations: relationships with histological damage, viral load and genotype and alpha-glutathione S-transferase levels. Eur J Gastroenterol Hepatol 2001; 13: 1355-1361.
  • 180. Sartori M, Andorno S, La Terra G, Boldorini R, Leone F, Pittau S, Zecchina G, Aglietta M, Saglio G. Evaluation of iron status in patients with chronic hepatitis C. Ital J Gastroenterol Hepatol 1998; 30: 396-401.
  • 181. Vergani A, Bovo G, Trombini P, Caronni N, Arosio C, Malosio I, Fossati L, Roffi L, Piperno A. Semiquantitative and qualitative assessment of hepatic iron in patients with chronic viral hepatitis: relation with grading, staging and haemochromatosis mutations. Ital J Gastroenterol Hepatol 1999; 31: 395-400.
  • 182. Piperno A, Vergani A, Malosio I, Parma L, Fossati L, Ricci A, Bovo G, Boari G, Mancia G. Hepatic iron overload in patients with chronic viral hepatitis: role of HFE gene mutations. Hepatology 1998; 28: 1105-1109.
  • 183. Hézode C, Cazeneuve C, Coué O, Roudot-Thoraval F, Lonjon I, Bastie A, Duvoux C, Pawlotsky JM, Zafrani ES, Amselem S 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. J Hepatol 1999; 31: 979-984.
  • 184. Vidali M, Occhino G, Ivaldi A, Rigamonti C, Sartori M, Albano E. Combination of oxidative stress and steatosis is a risk factor for fibrosis in alcohol-drinking patients with chronic hepatitis C. Am J Gastroenterol 2008; 103: 147-153.
  • 185. Hayashi A, Wada Y, Suzuki T, Shimizu A. Studies on familial hypotransferrinemia: unique clinical course and molecular pathology. Am J Hum Genet 1993; 53: 201-213.
  • 186. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood 2000; 96: 4071-4074.
  • 187. Aslan D, Crain K, Beutler E. A new case of human atransferrinemia with a previously undescribed mutation in the transferrin gene. Acta Haematol 2007; 118: 244-247.
  • 188. Heilmeyer l, Keller W, Vivell O, Keiderling W, Betke K, Woehler F, Schultze HE. Congenital atransferrinemia in a 7-year-old girl. Dtsch Med Wochenschr 1961; 86: 1745-1751 (in German).
  • 189. Brissot P, Ropert M, Le Lan C, Loréal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity. Biochim Biophys Acta 2012; 1820: 403-410.
  • 190. Craven CM, Alexander J, Eldridge M, Kushner JP, Bernstein S, Kaplan J. Tissue distribution and clearance kinetics of nontransferrin-bound iron in the hypotransferrinemic mouse: a rodent model for hemochromatosis. P Natl Acad Sci USA 1987; 84: 3457-3461.
  • 191. Harford JB, Rouault TA, Huebers HA, Klausner RD. Molecular mechanisms of iron metabolism. In: Stamatoyannopoulos G, Nienhuis AW, Majerus PW, Varmus H, editors. The Molecular Basis of Blood Diseases. Philadelphia, PA, USA: W.B. Saunders; 1994. pp. 351-378.
  • 192. Preza GC, Ruchala P, Pinon R, Ramos E, Qiao B, Peralta MA, Sharma S, Waring A, Ganz T, Nemeth E. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest 2011; 121: 4880-4888.
  • 193. Ramos E, Ruchala P, Goodnough JB, Kautz L, Preza GC, Nemeth E, Ganz T. Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood 2012; 120: 3829-3836.
Turkish Journal of Medical Sciences-Cover
  • ISSN: 1300-0144
  • Yayın Aralığı: Yılda 6 Sayı
  • Yayıncı: TÜBİTAK
Sayıdaki Diğer Makaleler

Interlukine-17 and TGF-ß levels in patients with acute brucellosisbefore and after treatment

Shima CHEREI, Masoomeh SOFIAN, Alia MOUSAVI, Mohammad BANIFAZL, Ali CHEREI, Arezoo AGHAKHANI, Amitis RAMEZANI

Effects of crocin on experimental obesity and type-2 diabetes

Laçine AKSOY, Ömer HAZMAN, Ahmet BÜYÜKBEN

Study of mouse induced pluripotent stem cell transplantation intoWistar albino rat cochleae after hair cell damage

Mustafa Kürşat GÖKCAN, Emre OCAK, Selçuk MÜLAZİMOĞLU, Ömer BEŞALTI, Murat ÇALIŞKAN, Pınar CAN, Serpil DİZBAY SAK, Gülşah KAYGUSUZ

Effect of methylprednisolone injection on interleukin-4 and interferon-gamma expression following hepatitis B vaccination in mice

Peter UGHACHUKWU, Paul OKONKWO, John OGAMA, Prince UNEKWE

Evaluation of cutaneous anthrax cases during an outbreak in the east region of Turkey

Nazlı DİZEN NAMDAR, Deniz Bahar AKGÜN KARAPINAR, Esra KURAL ÜNÜVAR

Lung transplantation in Turkey: lessons from surgeons and pulmonologists

Stephen CLARK, Levent DALAR, Erdal TAŞÇI, Gül DABAK

Mohammad KHALAJ-KONDORI, Farzaneh SADEGHI, Mohammad Ali HOSSEINPOURFEIZI, Farzam SHAIKHZADEH-HESARI, Aylar NAKHLBAND, Mohammad RAHMATI-YAMCHI

Efficacy of mitomycin-C and infliximab in reducing adhesionand fibrosis following strabismus surgery

Tuba ÖZCAN METİN, Ayşe Ayça SARI, Bahar TAŞDELEN, Erdem DİNÇ, Banu ÇOŞKUN YILMAZ, Emin Serbülent GÜÇLÜ

Kürşat DİKMEN, Asiye Uğraş DİKMEN, Hasan BOSTANCI, Ahmet KARAMERCAN, Abdullah Münci YAĞCI, Murat AKIN, Bülent AYTAÇ

Ferit Kerim KÜÇÜKLER, Yasin ŞİMŞEK, Ümit GÖRKEM, Berçem Ayçiçek DOĞAN, Serdar GÜLER