Beyond hereditary hemochromatosis: New insights into the relationship between iron overload and chronic liver diseases

Digestive and Liver Disease

Volumn 43, Issue 2, 2011, Pages 89-95

  Fargion, Silvia ^a   Valenti, Luca ^a   Fracanzani, Anna Ludovica ^a  

^a FONDAZIONE IRCCS CA GRANDA OSPEDALE MAGGIORE POLICLINICO   (Italy)

Author keywords

Chronic hepatitis C; Hepatocarcinoma; Hepcidin; Nonalcoholic steatohepatitis

Indexed keywords

FERRITIN; HEPCIDIN; PEGINTERFERON ALPHA; RIBAVIRIN;

ALCOHOL LIVER DISEASE; CANCER SUSCEPTIBILITY; CHRONIC LIVER DISEASE; DISEASE COURSE; DRUG DOSE REDUCTION; END STAGE LIVER DISEASE; FERRITIN BLOOD LEVEL; FIBROGENESIS; GENETIC TRANSCRIPTION; HEMOCHROMATOSIS; HEPATITIS C; HUMAN; INSULIN RESISTANCE; IRON DEPLETION; IRON METABOLISM; IRON OVERLOAD; IRON STORAGE; LIVER CELL CARCINOMA; METABOLIC REGULATION; MORTALITY; MUTAGENESIS; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOGENESIS; PORPHYRIA CUTANEA TARDA; PRIORITY JOURNAL; REVIEW; RISK FACTOR;

ANTI-BACTERIAL AGENTS; ANTIMICROBIAL CATIONIC PEPTIDES; BIOLOGICAL MARKERS; CARCINOMA, HEPATOCELLULAR; CHRONIC DISEASE; DISEASE PROGRESSION; FERRITINS; HEMOCHROMATOSIS; HEPATOCYTES; HUMANS; INSULIN RESISTANCE; IRON; IRON OVERLOAD; LIVER DISEASES; RISK FACTORS;

EID: 78651455570     PISSN: 15908658     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.dld.2010.07.006     Document Type: Review

References (101)

1. Fracanzani A.L., Piperno A., Valenti L., et al. Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors. Hepatology 2010, 51:501-510.
2. Fargion S., Fracanzani A.L., Piperno A., et al. Prognostic factors for hepatocellular carcinoma in genetic hemochromatosis. Hepatology 1994, 20:1426-1431.
3. Pietrangelo A. Hemochromatosis: an endocrine liver disease. Hepatology 2007, 46:1291-1301.
4. Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 2005, 106:3710-3717.
5. Jehn M., Clark J.M., Guallar E. Serum ferritin and risk of the metabolic syndrome in U.S. adults. Diabetes Care 2004, 27:2422-2428.
6. Bozzini C., Girelli D., Olivieri O., et al. Prevalence of body iron excess in the metabolic syndrome. Diabetes Care 2005, 28:2061-2063.
7. Wrede C.E., Buettner R., Bollheimer L.C., et al. Association between serum ferritin and the insulin resistance syndrome in a representative population. Eur J Endocrinol 2006, 154:333-340.
8. Edgren G., Nyren O., Melbye M. Cancer as a ferrotoxic disease: are we getting hard stainless evidence?. J Natl Cancer Inst 2008, 100:976-977.
9. Pietrangelo A. Hereditary hemochromatosis - a new look at an old disease. N Engl J Med 2004, 350:2383-2397.
10. Olynyk J.K., St Pierre T.G., Britton R.S., et al. Duration of hepatic iron exposure increases the risk of significant fibrosis in hereditary hemochromatosis: a new role for magnetic resonance imaging. Am J Gastroenterol 2005, 100:837-841.
11. Recalcati S., Invernizzi P., Arosio P., et al. New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J Autoimmun 2008, 30:84-89.
12. Ruddell R.G., Hoang-Le D., Barwood J.M., et al. Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology 2009, 49:887-900.
13. Valenti L., Pulixi E.A., Arosio P., et al. Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis. Haematologica 2007, 92:1037-1042.
14. Corengia C., Galimberti S., Bovo G., 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.
15. Shan Y., Lambrecht R.W., Bonkovsky H.L. Association of hepatitis C virus infection with serum iron status: analysis of data from the third National Health and Nutrition Examination Survey. Clin Infect Dis 2005, 40:834-841.
16. Nishina S., Hino K., Korenaga M., et al. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 2008, 134:226-238.
17. Miura K., Taura K., Kodama Y., et al. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology 2008, 48:1420-1429.
18. Muckenthaler M.U. Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab 2008, 8:1-3.
19. Trinder D., Ayonrinde O.T., Olynyk J.K. HCV, iron, and oxidative stress: the new choreography of hepcidin. Gastroenterology 2008, 134:348-351.
20. Fujita N., Sugimoto R., Takeo M., et al. Hepcidin expression in the liver: relatively low level in patients with chronic hepatitis C. Mol Med 2007, 13:97-104.
21. Girelli D., Pasino M., Goodnough J.B., et al. Reduced serum hepcidin levels in patients with chronic hepatitis C. J Hepatol 2009, 51:845-852.
22. Fujita N., Sugimoto R., Motonishi S., 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.
23. Ben-Arieh S.V., Zimerman B., Smorodinsky N.I., et al. Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J Virol 2001, 75:10557-10562.
24. Tung B.Y., Emond M.J., Bronner M.P., et al. Hepatitis C, iron status, and disease severity: relationship with HFE mutations. Gastroenterology 2003, 124:318-326.
25. Smith B.C., Gorve J., Guzail M.A., et al. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology 1998, 27:1695-1699.
26. Thorburn D., Curry G., Spooner R., et al. The role of iron and haemochromatosis gene mutations in the progression of liver disease in chronic hepatitis C. Gut 2002, 50:248-252.
27. Gattoni A., Parlato A., Vangieri B., et al. Role of hemochromatosis genes in chronic hepatitis C. Clin Ter 2006, 157:61-68.
28. Erhardt A., Maschner-Olberg A., Mellenthin C., et al. HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis. J Hepatol 2003, 38:335-342.
29. Di Iorio B.R., Aucella F., Stallone C., et al. Thalassaemia minor: national survey of uraemic patients under substitutive treatment. G Ital Nefrol 2002, 19:286-293.
30. Sartori M., Andorno S., Pagliarulo M., et al. Heterozygous {beta}-globin gene mutations as a risk factor for iron accumulation and liver fibrosis in chronic hepatitis c. Gut 2006, 56:693-698.
31. Guyader D., Thirouard A.S., Erdtmann L., et al. Liver iron is a surrogate marker of severe fibrosis in chronic hepatitis C. J Hepatol 2007, 46:587-595.
32. Angelucci E., Muretto P., Nicolucci A., 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.
33. Fargion S., Fracanzani A.L., Rossini A., 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.
34. Bonkovsky H.L., Naishadham D., Lambrecht R.W., 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.
35. Ferrara F., Ventura P., Vegetti A., et al. Serum ferritin as a predictor of treatment outcome in patients with chronic hepatitis C. Am J Gastroenterol 2009, 104:605-616.
36. Browning J.D., Szczepaniak L.S., Dobbins R., et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004, 40:1387-1395.
37. Marchesini G., Brizi M., Bianchi G., et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001, 50:1844-1850.
38. Targher G., Bertolini L., Padovani R., et al. Relations between carotid artery wall thickness and liver histology in subjects with nonalcoholic fatty liver disease. Diabetes Care 2006, 29:1325-1330.
39. Ekstedt M., Franzen L.E., Mathiesen U.L., et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006, 44:865-873.
40. Bugianesi E., Leone N., Vanni E., et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002, 123:134-140.
41. Villanova N., Moscatiello S., Ramilli S., et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology 2005, 42:473-480.
42. Marchesini G., Bugianesi E., Forlani G., et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003, 37:917-923.
43. Day C.P. From fat to inflammation. Gastroenterology 2006, 130:207-210.
44. Mendler M.H., Turlin B., Moirand R., et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999, 117:1155-1163.
45. Moirand R., Mendler M.H., Guillygomarc'h A., et al. Non-alcoholic steatohepatitis with iron: part of insulin resistance-associated hepatic iron overload?. J Hepatol 2000, 33:1024-1026.
46. Kim CH, Kim HK, Bae SJ, et al. Association of elevated serum ferritin concentration with insulin resistance and impaired glucose metabolism in Korean men and women. Metabolism 2010; in press, PMID: 20423745.
47. Fernandez-Real J.M., Lopez-Bermejo A., Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes 2002, 51:2348-2354.
48. Houstis N., Rosen E.D., Lander E.S. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006, 440:944-948.
49. Aigner E., Theurl I., Haufe H., et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology 2008, 135:680-688.
50. Aigner E., Theurl I., Theurl M., et al. Pathways underlying iron accumulation in human nonalcoholic fatty liver disease. Am J Clin Nutr 2008, 87:1374-1383.
51. Barisani D., Pelucchi S., Mariani R., et al. Hepcidin and iron-related gene expression in subjects with Dysmetabolic Hepatic Iron Overload. J Hepatol 2008, 49:123-133.
52. Chitturi S., Weltman M., Farrell G.C., et al. HFE mutations, hepatic iron, and fibrosis: ethnic-specific association of NASH with C282Y but not with fibrotic severity. Hepatology 2002, 36:142-149.
53. Bugianesi E., Manzini P., D'Antico S., et al. Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology 2004, 39:179-187.
54. Valenti L., Dongiovanni P., Fracanzani A.L., et al. HFE mutations in nonalcoholic fatty liver disease. Hepatology 2008, 47:1794-1795. [author reply 5-6].
55. Neri S., Pulvirenti D., Signorelli S., et al. The HFE gene heterozygosis H63D: a cofactor for liver damage in patients with steatohepatitis? Epidemiological and clinical considerations. Intern Med J 2008, 38:254-258.
56. Valenti L., Fracanzani A., Bugianesi E., et al. HFE genotype, parenchymal iron accumulation, and liver fibrosis in patients with nonalcoholic fatty liver disease. Gastroenterology 2010, 138:905-912.
57. Valenti L, Canavesi E, Galmozzi E, et al. Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with nonalcoholic fatty liver disease. J Hepatol 2010; in press. doi:10.1016/j.jhep.2010.05.023.
58. Facchini F.S., Hua N.W., Stoohs R.A. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 2002, 122:931-939.
59. Facchini F.S. Effect of phlebotomy on plasma glucose and insulin concentrations. Diabetes Care 1998, 21:2190.
60. Facchini F.S., Saylor K.L. Effect of iron depletion on cardiovascular risk factors: studies in carbohydrate-intolerant patients. Ann NY Acad Sci 2002, 967:342-351.
61. Valenti L., Fracanzani A.L., Dongiovanni P., et al. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol 2007, 102:1251-1258.
62. Dongiovanni P., Valenti L., Ludovica Fracanzani A., et al. Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. Am J Pathol 2008, 172:738-747.
63. Valenti L, Swinkels DW, Burdick L, et al. Serum ferritin levels are associated with vascular damage in patients with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc 2010; in press, doi:10.1016/j.numecd.2010.01.003.
64. Harrison-Findik D.D., Klein E., Crist C., et al. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 2007, 46:1979-1985.
65. Grove J., Daly A.K., Burt A.D., et al. Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease. Gut 1998, 43:262-266.
66. Gleeson D., Evans S., Bradley M., et al. HFE genotypes in decompensated alcoholic liver disease: phenotypic expression and comparison with heavy drinking and with normal controls. Am J Gastroenterol 2006, 101:304-310.
67. Fargion S., Mandelli C., Piperno A., et al. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology 1992, 15:655-659.
68. Wood M.J., Powell L.W., Ramm G.A. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008, 111:4456-4462.
69. Powell E.E., Ali A., Clouston A.D., et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005, 129:1937-1943.
70. Swinkels D.W., Drenth J.P. Hepcidin in the management of patients with mild non-hemochromatotic iron overload: Fact or fiction?. J Hepatol 2008, 49:680-685.
71. Sampietro M., Fracanzani A.L., Corbetta N., et al. High prevalence of hepatitis C virus type 1b in Italian patients with Porphyria cutanea tarda. Ital J Gastroenterol Hepatol 1997, 29:543-547.
72. Sampietro M., Piperno A., Lupica L., et al. High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda. Hepatology 1998, 27:181-184.
73. Ajioka R.S., Phillips J.D., Weiss R.B., et al. Down-regulation of hepcidin in porphyria cutanea tarda. Blood 2008, 112:4723-4728.
74. Dongiovanni P., Valenti L., Fracanzani A.L., et al. TNFalpha promoter polymorphisms in Italian patients with porphyria cutanea tarda. Dig Liver Dis 2003, 35:596-597.
75. Valenti L., Fracanzani A.L., Dongiovanni P., et al. Can nonalcoholic steatohepatitis trigger porphyria cutanea tarda clinical manifestations?. Intern Emerg Med 2009, 4:91-92.
76. Fracanzani A.L., Fargion S., Stazi M.A., et al. Association between heterozygosity for HFE gene mutations and hepatitis viruses in hepatocellular carcinoma. Blood Cells Mol Dis 2005, 35:27-32.
77. Farazi P.A., DePinho R.A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006, 6:674-687.
78. Fracanzani A.L., Taioli E., Sampietro M., et al. Liver cancer risk is increased in patients with porphyria cutanea tarda in comparison to matched control patients with chronic liver disease. J Hepatol 2001, 35:498-503.
79. Nahon P., Sutton A., Rufat P., et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008, 134:102-110.
80. Hellerbrand C., Poppl A., Hartmann A., et al. HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence. Clin Gastroenterol Hepatol 2003, 1:279-284.
81. Boige V., Castera L., de Roux N., et al. Lack of association between HFE gene mutations and hepatocellular carcinoma in patients with cirrhosis. Gut 2003, 52:1178-1181.
82. Fracanzani A.L., Conte D., Fraquelli M., et al. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology 2001, 33:647-651.
83. Zacharski L.R., Chow B.K., Howes P.S., et al. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 2008.
84. Turlin B., Juguet F., Moirand R., et al. Increased liver iron stores in patients with hepatocellular carcinoma developed on a noncirrhotic liver. Hepatology 1995, 22:446-450.
85. Wu K.J., Polack A., Dalla-Favera R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science 1999, 283:676-679.
86. Boult J., Roberts K., Brookes M.J., et al. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin Cancer Res 2008, 14:379-387.
87. Brookes M.J., Hughes S., Turner F.E., et al. Modulation of iron transport proteins in human colorectal carcinogenesis. Gut 2006, 55:1449-1460.
88. Whitnall M., Howard J., Ponka P., et al. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc Natl Acad Sci U S A 2006, 103:14901-14906.
89. Asare G.A., Paterson A.C., Kew M.C., et al. Iron-free neoplastic nodules and hepatocellular carcinoma without cirrhosis in Wistar rats fed a diet high in iron. J Pathol 2006, 208:82-90.
90. Lauret E., Rodriguez M., Gonzalez S., et al. HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma. Am J Gastroenterol 2002, 97:1016-1021.
91. Lehmann U., Wingen L.U., Brakensiek K., et al. Epigenetic defects of hepatocellular carcinoma are already found in non-neoplastic liver cells from patients with hereditary haemochromatosis. Hum Mol Genet 2007, 16:1335-1342.
92. Jin F., Qu L.S., Shen X.Z. Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. J Exp Clin Cancer Res 2010, 29:18.
93. Sutton A., Nahon P., Pessayre D., et al. Genetic polymorphisms in antioxidant enzymes modulate hepatic iron accumulation and hepatocellular carcinoma development in patients with alcohol-induced cirrhosis. Cancer Res 2006, 66:2844-2852.
94. Dongiovanni P., Fracanzani A., Cairo G., et al. Iron dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. Am J Pathol 2010, 176:1006-1017.
95. Sorrentino P., D'Angelo S., Ferbo U., et al. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol 2009, 50:351-357.
96. Fujita N., Miyachi H., Tanaka H., et al. Iron overload is associated with hepatic oxidative damage to DNA in nonalcoholic steatohepatitis. Cancer Epidemiol Biomarkers Prev 2009, 18:424-432.
97. Zhang K.H., Tian H.Y., Gao X., et al. Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. Cancer Res 2009, 69:5340-5348.
98. Licata A., Nebbia M.E., Cabibbo G., et al. Hyperferritinemia is a risk factor for steatosis in chronic liver disease. World J Gastroenterol 2009, 15:2132-2138.
99. Fargion S., Valenti L., Fracanzani A.L. Hemochromatosis gene (HFE) mutations and cancer risk: expanding the clinical manifestations of hereditary iron overload. Hepatology 2010, 51:1119-1121.
100. Walker N.M., Stuart K.A., Ryan R.J., et al. Serum ferritin concentration predicts mortality in patients awaiting liver transplantation. Hepatology 2010.
101. Fenton H., Torbenson M., Vivekanandan P., et al. Marked iron in liver explants in the absence of major hereditary hemochromatosis gene defects: a risk factor for cardiac failure. Transplantation 2009, 87:1256-1260.