The global burden of iron overload

Hepatology International

Volumn 3, Issue 3, 2009, Pages 434-444

  Wood, Marnie J ^a,b   Skoien, Richard ^a,c   Powell, Lawrie W ^a,b,c  

^a UNIVERSITY OF QUEENSLAND   (Australia)

^b QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

^c UNIVERSITY OF QUEENSLAND   (Australia)

Author keywords

Haemochromatosis; HFE haemochromatosis; Iron metabolism; Secondary iron overload

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; BONE MORPHOGENETIC PROTEIN; CD71 ANTIGEN; DEFERASIROX; FERROPORTIN; HEMOJUVELIN; HEPCIDIN; HFE PROTEIN; IRON CHELATING AGENT; SMAD PROTEIN; TRANSFERRIN RECEPTOR 2;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALCOHOL ABSTINENCE; AMINO ACID SUBSTITUTION; ARTHROPATHY; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CARDIOMYOPATHY; CLINICAL TRIAL; COMORBIDITY; DIABETES MELLITUS; DIET THERAPY; DISEASE ASSOCIATION; DRUG EFFICACY; ELASTOGRAPHY; ENVIRONMENTAL FACTOR; FATTY LIVER; GENE MUTATION; GENETIC SCREENING; HEART ARRHYTHMIA; HEMOCHROMATOSIS; HEREDITY; HOMEOSTASIS; HOMOZYGOTE; HUMAN; IRON ABSORPTION; IRON METABOLISM; IRON OVERLOAD; IRON TRANSPORT; LIVER BIOPSY; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER FIBROSIS; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOGENESIS; PENETRANCE; PHENOTYPE; PHLEBOTOMY; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; REVIEW; SEA FOOD; SYMPTOMATOLOGY; THALASSEMIA;

EID: 68949163771     PISSN: 19360533     EISSN: 19360541     Source Type: Journal    
DOI: 10.1007/s12072-009-9144-z     Document Type: Review

References (100)

1. von Reckinghausen F. Uber Haemochromatose. Tageblatt Versammlung Dtsche Naturforscher 1889;62:324-325
2. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 1996;13:399-408
3. Khusainova R, Khusnutdinova N, Khusnutdinova E. Analysis of the hemochromatosis gene (HFE) mutations, C282Y and H63D, in the populations of Central Asia. Russian J Genet 2006;42:333-338
4. Hayashi H, Wakusawa S, Motonishi S, Miyamoto K-I, Okada H, Inagaki Y, et al. Genetic background of primary iron overload syndromes in Japan. Intern Med 2006;45:1107-1111
5. Lee JY, Yoo KH, Hahn SH. HFE gene mutation, C282Y causing hereditary hemochromatosis in Caucasian is extremely rare in Korean population. J Korean Med Sci 2000;15:179-182
6. Steiner M, Ocran K, Genschel J, Meier P, Gerl H, Ventz M, et al. A homozygous HFE gene splice site mutation (IVS5 + 1 G/A) in a hereditary hemochromatosis patient of Vietnamese origin. Gastroenterology 2002;122:789-795
7. Ganz T. Iron homeostasis: Fitting the puzzle pieces together. Cell Metab 2008;7:288-290
8. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-2093
9. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037-1044
10. Harrison-Findik DD, Schafer D, Klein E, Timchenko NA, Kulaksiz H, Clemens D, et al. Alcohol metabolism-mediated oxidative stress down-regulates hepcidin transcription and leads to increased duodenal iron transporter expression. J Biol Chem 2006;281:22974-22982
11. Bridle KR, Cheung T-K, Murphy TL, Walters MM, Anderson GJ, Crawford DHG, et al. Hepcidin is down-regulated in alcoholic liver injury: implications for the pathogenesis of alcoholic liver disease. Alcohol Clin Exp Res 2006;30:106-112
12. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003;101:2461-2463
13. Bridle KR, Frazer DM, Wilkins SJ, Dixon JL, Purdie DM, Crawford DHG, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003;361:669-673
14. Zhang A-S, Xiong S, Tsukamoto H, Enns CA. Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes. Blood 2004;103:1509-1514
15. Parkkila S, Waheed A, Britton RS, Feder JN, Tsuchihashi Z, Schatzman RC, et al. Immunohistochemistry of HLA-H, the protein defective in patients with hereditary hemochromatosis, reveals unique pattern of expression in gastrointestinal tract. Proc Natl Acad Sci USA 1997;94:2534-2539
16. Vujic Spasic M, Kiss J, Herrmann T, Kessler R, Stolte J, Galy B, et al. Physiologic systemic iron metabolism in mice deficient for duodenal HFE. Blood 2007;109:4511-4517
17. Vujic Spasic M, Kiss J, Herrmann T, Galy B, Martinache S, Stolte J, et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab 2008;7:173-178
18. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 2006;281:28494-28498
19. Waheed A, Parkkila S, Saarnio J, Fleming RE, Zhou XY, Tomatsu S, et al. Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc Natl Acad Sci USA 1999;96:1579-1584
20. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab 2008;7:205-214
21. Chen J, Chloupkova M, Gao J, Chapman-Arvedson TL, Enns CA. HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1/HFE interactions. J Biol Chem 2007;282(51):36862-36870
22. Babitt JL, Huang FW, Wrighting DM, Xia Y, Sidis Y, Samad TA, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006;38:531-539
23. Lin L, Valore EV, Nemeth E, Goodnough JB, Gabayan V, Ganz T. Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4. Blood 2007;110:2182-2189
24. Pantopoulos K. Function of the hemochromatosis protein HFE: Lessons from animal models. World J Gastroenterol 2008;45:6893-6901
25. Milet J, Dhais V, Bourgain C, Jouanolle AM, Mosser A, Perrin M, et al. Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance. Am J Hum Genet 2007;81:799-807
26. Drakesmith H, Schimanski LM, Ormerod E, Merryweather-Clarke AT, Viprakasit V, Edwards JP, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood 2005;106:1092-1097
27. Girelli D, De Domenico I, Bozzini C, Campostrini N, Busti F, Castagna A, et al. Clinical, pathological, and molecular correlates in ferroportin disease: A study of two novel mutations. J Hepatol 2008;49:664-671
28. Njajou OT, Vaessen N, Joosse M, Berghuis B, van Dongen JWF, Breuning MH, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 2001;28:213-214
29. Arden KE, Wallace DF, Dixon JL, Summerville L, Searle JW, Anderson GJ, et al. A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient. Gut 2003;52:1215-1217
30. Mougiou A, Pietrangelo A, Caleffi A, Kourakli A, Karakantza M, Zoumbos N. G80S-linked ferroportin disease: The first clinical description in a Greek family. Blood Cells Mol Dis 2008;41:138-139
31. Wallace DF, Pedersen P, Dixon JL, Stephenson P, Searle JW, Powell LW, et al. Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 2002;100:692-694
32. Tanno T, Bhanu NV, Oneal PA, Goh S-H, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007;13:1096-1101
33. Adams PC, Deugnier Y, Moirand R, Brissot P. The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis. Hepatology 1997;25:162-166
34. Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-1119
35. Crooks CJ, West J, Solaymani-Dodaran M, Card TR. The epidemiology of haemochromatosis: A population-based study. Aliment Pharmacol Ther 2009;29:183-192
36. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 2005;352:1769-1778
37. Allen KJ, Gurrin LC, Constantine CC, Osborne NJ, Delatycki MB, Nicoll AJ, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008;358:221-230
38. Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK. HFE genotype in patients with hemochromatosis and other liver diseases. Ann Intern Med 1999;130:953-962
39. Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet 1997;34:275-278
40. 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
41. Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718-724
42. Pedersen P, Melsen GV, Milman N, Pedersen P, Melsen GV, Milman N. Frequencies of the haemochromatosis gene (HFE) variants C282Y, H63D and S65C in 6, 020 ethnic Danish men. Ann Hematol 2008;87:735-740
43. Phatak PD, Ryan DH, Cappuccio J, Oakes D, Braggins C, Provenzano K, et al. Prevalence and penetrance of HFE mutations in 4865 unselected primary care patients. Blood Cells Mol Dis 2002;29:41-47
44. Harris EL, McLaren CE, Reboussin DM, Gordeuk VR, Barton JC, Acton RT, et al. Serum ferritin and transferrin saturation in Asians and Pacific Islanders. Arch Intern Med 2007;167:722-726
45. Powell LW, Dixon JL, Ramm GA, Purdie DM, Lincoln DJ, Anderson GJ, et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Intern Med 2006;166:294-301
46. Asberg A, Hveem K, Thorstensen K, Ellekjter E, Kannelonning K, Fjosne U, et al. Screening for hemochromatosis: High prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastroenterol 2001;36:1108-1115
47. Fletcher LM, Dixon JL, Purdie DM, Powell LW, Crawford DHG. Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology 2002;122:281-289
48. Adams PC, Agnew S. Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings. Hepatology 1996;23:724-727
49. Tsukamoto H, Horne W, Kamimura S, Niemela O, Parkkila S, Yla-Herttuala S, et al. Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 1995;96:620-630
50. Cade JE, Moreton JA, O'Hara B, Greenwood DC, Moor J, Burley VJ, et al. Diet and genetic factors associated with iron status in middle-aged women. Am J Clin Nutr 2005;82:813-820
51. Kaltwasser JP, Werner E, Schalk K, Hansen C, Gottschalk R, Seidl C. Clinical trial on the effect of regular tea drinking on iron accumulation in genetic haemochromatosis. Gut 1998;43:699-704
52. Hutchinson C, Geissler C, Powell J, Bomford A. Proton pump inhibitors suppress absorption of dietary non-haem iron in hereditary haemochromatosis. Gut 2007;6(9):1291-1295
53. 2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nat Med 2007;13:448-454
54. Milward EA, Baines SK, Knuiman MW, Bartholomew HC, Divitini ML, Ravine DG, et al. Noncitrus fruits as novel dietary environmental modifiers of iron stores in people with or without HFE gene mutations. Mayo Clin Proc 2008;83:543-549
55. Jacobs EM, Hendriks JC, van Deursen CT, Kreeftenberg HG, de Vries RA, Marx JJ, et al. Severity of iron overload of proband determines serum ferritin levels in families with HFE-related hemochromatosis: The HEmochromatosis FAmily Study. J Hepatol 2009;50:174-183
56. Whiting PW, Fletcher LM, Dixon JK, Gochee P, Powell LW, Crawford DHG. Concordance of iron indices in homozygote and heterozygote sibling pairs in hemochromatosis families: Implications for family screening. J Hepatol 2002;37:309-314
57. Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 2004;103:2835-2840
58. Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, et al. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet 2003;12:2241-2247
59. Le Gac G, Scotet V, Ka C, Gourlaouen I, Bryckaert L, Jacolot S, et al. The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 2004;13:1913-1918
60. Gouya L, Muzeau F, Robreau A-M, Letteron P, Couchi E, Lyoumi S, et al. Genetic study of variation in normal mouse iron homeostasis reveals ceruloplasmin as an HFE-hemochromatosis modifier gene. Gastroenterology 2007;132:679-686
61. Levy JE, Montross LK, Andrews NC. Genes that modify the hemochromatosis phenotype in mice. J Clin Invest 2000;105:1209-1216
62. Altes A, Bach V, Ruiz A, Esteve A, Remacha AF, Sarda MP, et al. Does the SLC40A1 gene modify HFE-related haemochromatosis phenotypes? Ann Hematol 2009;88:341-345
63. Leandro G, Mangia A, Hui J, Fabris P, Rubbia-Brandt L, Colloredo G, et al. Group HCVM-AIPDS. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: A meta-analysis of individual patient data. Gastroenterology 2006;130:1636-1642
64. Powell EE, Ali A, Clouston AD, Dixon JL, Lincoln DJ, Purdie DM, et al. Steatosis is a cofactor in liver injury in hemochromatosis. Gastroenterology 2005;129:1937-1943
65. Facchini FS, Hua NW, Stoohs RA. Effect of iron depletion in carbohydrate-intolerant patients with clinical evidence of nonalcoholic fatty liver disease. Gastroenterology 2002;122:931-939
66. Valenti L, Fracanzani AL, Dongiovanni P, Bugianesi E, Marchesini G, Manzini 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
67. 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
68. Nahon P, Sutton A, Rufat P, Ziol M, Thabut G, Schischmanoff P-O, et al. Liver iron, HFE gene mutations, and hepatocellular carcinoma occurrence in patients with cirrhosis. Gastroenterology 2008;134:102-110
69. Mummadi R, Kasturi K, Sood G. Iron depletion and response to interferon in chronic hepatitis C: A meta-analysis. Hepatology 2007;46:365A
70. Andersen RV, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard BG. Hemochromatosis mutations in the general population: Iron overload progression rate. Blood 2004;103:2914-2919
71. Olynyk JK, Hagan SE, Cullen DJ, Beilby J, Whittall DE. Evolution of untreated hereditary hemochromatosis in the Busselton population: A 17-year study. Mayo Clin Proc 2004;79:309-313
72. Gurrin LC, Osborne NJ, Constantine CC, McLaren CE, English DR, Gertig DM, et al. The Natural history of serum iron indices for HFE C282Y Homozygosity associated with hereditary hemochromatosis. Gastroenterology 2008;135:1945-1952
73. De Gobbi M, Roetto A, Piperno A, Mariani R, Alberti F, Papanikolaou G, et al. Natural history of juvenile haemochromatosis. Br J Haematol 2002;117(4):973-979
74. Gualdi R, Casalgrandi G, Montosi G, Ventura E, Pietrangelo A. Excess iron into hepatocytes is required for activation of collagen type I gene during experimental siderosis. Gastroenterology 1994;107:1118-1124
75. Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR. Screening for hereditary hemochromatosis: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006;145:209-223
76. Qaseem A, Aronson M, Fitterman N, Snow V, Weiss KB, Owens DK, et al. Screening for Hereditary Hemochromatosis: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2005;143:517-521
77. Tavill AS. Diagnosis and management of hemochromatosis. Hepatology 2001;33:1321-1328
78. Picot J, Bryant J, Cooper K, Clegg A, Roderick P, Rosenberg W, et al. Psychosocial aspects of DNA testing for hereditary hemochromatosis in at-risk individuals: A systematic review. Genet Test Biol Markers 2009;13(1):7-14
79. Anderson RT, Press N, Tucker DC, Snively BM, Wenzel L, Ellis SD, et al. Patient acceptability of genotypic testing for hemochromatosis in primary care. Genet Med 2005;7:557-563
80. Patch C, Roderick PM, Rosenberg W. Comparison of genotypic and phenotypic strategies for population screening in hemochromatosis: assessment of anxiety, depression, and perception of health. Genet Med 2005;7:550-556
81. Allen KJ, Nisselle AE, Collins VR, Williamson R, Delatycki MB. Asymptomatic individuals at genetic risk of haemochromatosis take appropriate steps to prevent disease related to iron overload. Liver Int 2008;28:363-369
82. Hall MAJD, Barton JC, Adams PC, McLaren CE, Reiss JA, Castro O, et al. Genetic screening for iron overload: No evidence of discrimination at 1 year: Few patients had insurance or employment problems after being screened for hemochromatosis and iron overload. J Fam Pract 2007;56:829833-829835
83. Beaton M, Guyader D, Deugnier Y, Moirand R, Chakrabarti S, Adams P. Noninvasive prediction of cirrhosis in C282Y-linked hemochromatosis. Hepatology 2002;36:673-678
84. George DK, Ramm GA, Walker NI, Powell LW, Crawford DH. Elevated serum type IV collagen: A sensitive indicator of the presence of cirrhosis in haemochromatosis. J Hepatol 1999;31:47-52
85. Colombo M, Annoni G, Donato MF, Conte D, Martines D, Zaramella MG, et al. Serum type III procollagen peptide in alcoholic liver disease and idiopathic hemochromatosis: Its relationship to hepatic fibrosis, activity of the disease and iron overload. Hepatology 1985;5:475-479
86. Crawford DHG, Murphy TL, Ramm LE, Fletcher LM, Clouston AD, Anderson GJ, et al. Serum hyaluronic acid with serum ferritin accurately predicts cirrhosis and reduces the need for liver biopsy in C282Y hemochromatosis. Hepatology 2009;49:418-425
87. Mirault T, Lucidarme D, Turlin B, Vandevenne P, Gosset P, Ernst O, et al. Non-invasive assessment of liver fibrosis by transient elastography in post transfusional iron overload. Eur J Haematol 2008;80:337-340
88. Gandon PY, Olivié D, Guyader PD, Aubé C, Oberti F, Sebille V, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004;363:357-362
89. St. Pierre TG, Clark PR, Chua-Anusorn W, Fleming AJ, Jeffrey GP, Olynyk JK, et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005;105:855-861
90. Alustiza JM, Artetxe J, Castiella A, Agirre C, Emparanza JI, Otazua P, et al. MR quantification of hepatic iron concentration. Radiology 2004;230:479-484
91. Wood JC. Magnetic resonance imaging measurement of iron overload. Curr Opin Hematol 2007;14:183-190
92. Olynyk JK, St. Pierre TG, Britton RS, Brunt EM, Bacon BR. 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
93. Barton JC, McDonnell SM, Adams PC, Brissot P, Powell LW, Edwards CQ, et al. Management of hemochromatosis. Ann Intern Med 1998;129:932-939
94. Falize L, Guillygomarc'h A, Perrin M, Lainé F, Guyader D, Brissot P, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: A study of 36 cases. Hepatology 2006;44:472-477
95. Fracanzani AL, Fargion S, Romano R, Conte D, Piperno A, D'Alba R, et al. Portal hypertension and iron depletion in patients with genetic hemochromatosis. Hepatology 1995;22:1127-1131
96. Piperno A, Girelli D, Nemeth E, Trombini P, Bozzini C, Poggiali E, et al. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 2007;110:4096-4100
97. Lim FL, Dooley JS, Roques AW, Grellier L, Dhillon AP, Walker AP. Hepatic iron concentration, fibrosis and response to venesection associated with the A77D and V162del "loss of function" mutations in ferroportin disease. Blood Cells Mol Dis 2008;40:328-333
98. Nielsen P, Fischer R, Buggisch P, Janka-Schaub G. Effective treatment of hereditary haemochromatosis with desferrioxamine in selected cases. Br J Haematol 2003;123:952-953
99. Cappellini MD. Long-term efficacy and safety of deferasirox. Blood Rev 2008;22:S35-S41
100. Pietrangelo A. Hereditary hemochromatosis - a new look at an old disease. N Engl J Med 2004;350:2383-2397