Iron metabolism and diagnosis of iron overload disorders

Expert Opinion on Medical Diagnostics

Volumn 4, Issue 1, 2010, Pages 67-77

  Dever, John ^a   Kowdley, Kris V ^a  

^a VIRGINIA MASON MEDICAL CENTER   (United States)

Author keywords

Hemochromatosis; Hepcidin; HFE; Iron; Iron balance; Iron diagnosis; Iron homeostasis; Iron metabolism; Iron overload; Liver biopsy

Indexed keywords

FERRITIN; HEPCIDIN; IRON; TRANSFERRIN;

HEMOCHROMATOSIS; HUMAN; INTESTINE ABSORPTION; IRON ABSORPTION; IRON BALANCE; IRON BINDING CAPACITY; IRON METABOLISM; IRON OVERLOAD; IRON TRANSPORT; LIVER BIOPSY; NUCLEAR MAGNETIC RESONANCE IMAGING; PHLEBOTOMY; REVIEW;

EID: 77953370832     PISSN: 17530059     EISSN: 17530067     Source Type: Journal    
DOI: 10.1517/17530050903440138     Document Type: Review

References (110)

1. Lubec G. The hydroxyl radical: from chemistry to human disease. J Invest Med 1996;44:324-346
2. Graham RM, Chua AC, Herbison CE, et al. Liver iron transport. World J Gastroenterol 2007;13:4725-4736
3. Hallberg L, Brune M, Rossander L, et al. Effect of ascorbic acid on iron absorption from different types of meals. Studies with ascorbic-acid-rich foods and synthetic ascorbic acid given in different amounts with different meals. Hum Nutr Appl Nutr 1986;40:97
4. McKie AT, Latunde-Dada GO, Miret S, et al. Molecular evidence for the role of a ferric reductase in iron transport. Biochem Soc Trans 2002;30:722-724
5. Conrad ME, Umbreit JN. Pathways or iron absorption. Blood Cells Mol Dis 2002;29:336
6. Gunshin H, MacKenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 1997;388:482-488
7. Barisani D, Berg CL, Wessling-Resnick M, et al. Evidence for a low Km transporter for non-transferrin-bound iron in isolated rat hepatocytes. Am J Physiol 1995;269:570-576
8. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc is essential for iron homeostasis. Cell Metab 2005;1:191-200
9. Mckie AT, Marciani P, Rolfs A, et al. A novel duodenal iron regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000;5:299-309
10. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin 1 identifies a conserved vertebrate iron exporter. Nature 2000;403:776
11. Cabantchik ZI, Breuer W, Zanninelli G, et al. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol 2005;18:277-287
12. De Domenico I, Nemeth E, Nelson JM, et al. The hepcidin-binding site on ferroportin is evolutionarily conserved. Cell Metab 2008;8:146-156
13. Krause A, Neitz S, Magert H, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000;480:147-150
14. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001;276:7806-7810
15. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem 2001;276:7811
16. Nicolas G, Benoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci USA 2001;98:8780-8785
17. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci USA 2002;99:4596-4601
18. Roy CN, Mak HH, Akpan I, et al. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood 2007;109:4038
19. Weinstein DA, Roy CN, Fleming MD, et al. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 2002;100:3776-3781
20. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004;306:2090-2093
21. De Domenico I, Ward DM, Langelier C, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 2007;18:2569-2578
22. Rivera S, Nemeth E, Gabayan V, et al. Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. Blood 2005;104:2388-2392
23. Rivera S, Nemeth E, Gabayan V, et al. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood 2005;106:2196-2199
24. Laftah AH, Ramesh B, Simpson RJ, et al. Effect of hepcidin on intestinal iron absorption in mice. Blood 2004;103;3940
25. Nicolas G, Chauvet C, Viatte L. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002;110:1037-1044
26. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007;13:1096-1101
27. Finkerstedt A, Bianchi P, Theuri I, et al. Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency. Br J Haematol 2009;144:789-793
28. Harrison-Findik DD, Klein E, et al. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology 2007;46:1979-1985
29. Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homeostasis. Lancet 2003;361:669-673
30. Ahmad KA, Ahmann JR, Migas MC, et al. Decreased liver hepcidin expression in the Hfe knockout mouse. Blood Cells Mol Dis 2002;29:361-366
31. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 2003;33:21-22
32. Truksa J, Peng H, Lee P, et al. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci USA 2006;103:10289-10293
33. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006;38:531-539
34. Gao J, Chen J, Kramer M, et al. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab 2009:9:217-227
35. Roy CN, Custodio , De Graaf J, et al. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysacchardie-indcued inflammation in mice. Nat Genet 2004;36:481-485
36. Kemna E, Pickkers P, Nemeth E, et al. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005;106:1864-1866
37. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004;113:1271-1276
38. Nemeth E, Valore EV, Territo M, et al. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 2003;101:2461-2463
39. Chung A, Leo K, Wong G, et al. Giant hepatocellular adenoma presenting with chronic iron deficiency anemia. Am J Gastroenterol 2006;101:2160-2162
40. Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008;40:569-571
41. Finch C. Regulators of iron balance in humans. Blood 1994;84:1697-1702
42. Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:1986-1995
43. Finch CA, Huebers H. Perspectives in iron metabolism.N Engl J Med 1982;306:1520
44. Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003;101:3359-3364
45. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 2000;275:19906-19912
46. Trinder D, Fox C, Vautier G, et al. Molecular pathogenesis of iron overload. Gut 2002;51:290-295
47. Laufberger V. Sur la cristallisation de la ferritine. Soc Chim Biol 1937;19:1575-1582
48. Jacobs A, Beamish MR, Allison M. The measurement of circulating ferritin. J Clin Pathol 1972;25:1003
49. Koorts AM, Viljoen M. Ferritin and ferritin isoforms I: structure-function relationships, synthesis, degradation and secretion. Arch Physiol Biochem 2007;113:30-54
50. Pan Y, Jackson RT. Insights into the ethnic differences in serum ferritin between black and white US adult men. Am J Hum Biol 2008;20:406-416
51. Dawkins FW, Gordeuk VR, Snively BM, et al. African Americans at risk for increased iron stores or liver disease. Am J Med 2007;120:734
52. Piperno A. Classification and diagnosis or iron overload. Haematologica 1998;83:447-455
53. Licata A, Nebbia ME, Cabibbo G, et al. Hyperferritinemia is a risk factor for steatosis in chronic liver disease. World J Gastroenterol 2009;15:2132-2138
54. Wong K, Adams PC. The diversity of liver diseases among outpatient referrals for an elevated serum ferritin. Can J Gastroenterol 2006;20:467-470
55. Ferreira C, Santambrogio P, Martin ME, et al. H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload. Blood 2001;98:525
56. Bell H, Skinningsrud A, Raknerud N, et al. Serum ferritin and transferrin saturation in patients with chronic alcoholic and non-alcoholic liver diseases. J Intern Med 1994;236:315-322
57. Giler S, Moroz C. The significance of ferritin in malignant diseases. Biomedicine 1978;28:203-206
58. Esumi N, Ikushima S, Hibi S, et al. High serum ferritin level as a marker of malignant histiocytosis and virus-associated hemophagocytic syndrome. Cancer 1988;61:2071-2076
59. Wixom RL, Prutkin L, Munro HN. Hemosiderin: nature, formation and significance. Int Rev Exp Pathol 1980;22:193
60. Schade AL, Caroline L. An iron-binding component in human plasma. Science 1946;104:340-341
61. Phatak PD, Bonkovsky HL, Kowdley KV. Hereditary hemochromatosis: time for targeted screening. Ann Intern Med 2008;149:270-272
62. Kasvosve I, Delanghe J. Total iron binding capacity and transferrin concentration in the assessment of iron status. Clin Chem Lab Med 2002;40:1014-1018
63. Grant A, Neuberger J. Guidelines on the use of liver biopsy in clinical practice British society of gastroenterology. Gut 1999; 45 (Suppl 4):IV1-11
64. Brissot P, Bourel M, Herry D, et al. Assessment of liver iron content in 271 patients: a reevaluation of direct and indirect methods. Gastroenterology 1981;80:557-565
65. Imbert-Bismut F, Charlotte F, Turlin B, et al. Low hepatic iron concentration: evaluation of two complementary methods, colorimetric assay and iron histological scoring J Clin Pathol 1999;52:430-434
66. Kowdley KV, Trainer TD, Saltzman JR, et al. Utility of hepatic iron index in American patients with hereditary hemochromatosis. Gastroenterology 1997;113:1270
67. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495
68. Powell LW, George DK, McDonnell SM, et al. Diagnosis of hemochromatosis. Ann Intern Med 1998;129:925-931
69. McLaren CE, Barton JC, Adams PC, et al. Hemochromatosis and Iron Overload Screening (HEIRS) study design for an evaluation of 100,000 primary care-based adults. Am J Med Sci 2003;325:53-62
70. Gandon Y, Olivie D, Guyader D, et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004;363:357-362
71. Alústiza JM, Artetxe J, Castiella A, et al. MR quantification of hepatic iron concentration. Radiology 2004;230:479-484
72. Nielsen P, Engelhardt R, Düllman J, et al. Non-invasive liver iron quantification by SQUID-biosusceptometry and serum ferritin iron as new diagnostic parameters in hereditary hemochromatosis. Blood Cells Mol Dis 2002;29:451-458
73. Sheth S. SQUID biosusceptometry in the measurement of hepatic iron. Pediatr Radiol 2003;33:373-377
74. Feder JN, Grinke A, Thomas W, et al. A novel MHC class 1-like gene is mutated in patients with hereditary haemochomatosis. Nat Genet 1996;13:399-408
75. Gochee PA, Powell LW, Cullen DJ, et al. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002;122:646-651
76. Deugnier Y, Brissot P, Loreal O. Iron and the liver: Update 2008. J Hepatol 2008;48:S113-23
77. Edwards CQ, Kushner JP. Screening for hemochromatosis. N Engl J Med 1993;328:1616-1620
78. Gurrin LC, Osborne NJ, Constantine CC, et al. The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis. Gastroenterology 2008;135:1945-1952
79. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008;358:221-230
80. Beutler E, Gelbart T, West C, et al. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 1996;22:187-194
81. Niederau C, Fischer R, Purschel A, et al. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996;110:1107-1119
82. Laine F, Jouannolle AM, Morcet J, et al. Phenotypic expression in detected C282Y homozygous women depends on body mass index. J Hepatol 2005;43:1055-1059
83. Distante S, Berg JP, Lande K, et al. HFE gene mutation (C282Y) and phenotypic expression among a hospitalized population in a high prevalence area of haemochromatosis. Gut 2000;47:575-579
84. Lamon JM, Marynick SR, Roseblatt R, et al. Idiopathic hemochromatosis in a young female. A case study and review of the syndrome in young people. Gastroenterology 1979;76:178-183
85. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004;36:77-82
86. Pietrangelo A. Non-HFE hemochromatosis. Hepatology 2004;39:21-29
87. Lanzara C, Roetto A, Daraio F, et al. The spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 2004;103:4317-4321
88. Vaiopoulos G, Papanikolaou G, Politou M, et al. Arthropathy in juvenile hemochromatosis. Arthritis Rheum 2003;48:227-230
89. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 2000;25:14-15
90. Kawabata H, Yang R, Hirama T, et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 1999;274:20826-20832
91. Fleming RE, Migas MC, Holden CC, et al. Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci USA 2000;97:2214-2219
92. West AP Jr, Bennett MJ, Sellers VM, et al. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. J Biol Chem 2000;275:38135-38138
93. Njajou OT, Vaessen N, Joosse M, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 2001;28:213-214
94. Batts KP. Iron overload syndromes and the liver. Mod Pathol 2007;20:S31-9
95. Wallace DF, Browett P, Wong P, et al. Identification of ferroportin disease in the Indian subcontinent. Gut 2005;54:567-568
96. Pietrangelo A, Montosi G, Totaro A, et al. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 1999;341:725-732
97. Pietrangelo A. The ferroportin disease. Blood Cells Mol Dis 2004;32:131-138
98. De Domenico I, Ward DM, Musci G, et al. Iron overload due to mutations in ferroportin. Haematologica 2006;91:92-95
99. Shneider BL. Genetic counseling in neonatal hemochromatosis. J Pediatr Gastroenterol Nutr 2002;34:328
100. Kelly AL, Lunt PW, Rodrigues F, et al. Classification and genetic features of neonatal heamochromatosis: a study of 27 affected pedigrees and molecular analysis of genes implicated in iron metabolism. J Med Genet 1996;33:444-449
101. Whitington PF, Malladi P. Neonatal hemochromatosis: is it an alloimmune disease? J Pediatr Gastroenterol Nutr 2005;40:544-549
102. Murray KF, Kowdley KV. Neonatal hemochromatosis. Pediatrics 2001;108:960-964
103. Knisley AS, O'shea PA, Stocks JF, et al. Oropharyngeal and upper respiratory tract mucosal-gland siderosis in neonatal hemochromatosis: an approach to biopsy diagnosis. J Pediatr 1988;113:871-874
104. Ekong UD, Melin-Aldana H, Whitington PF. Regression of severe fibrotic liver disease in 2 children with neonatal hemochromatosis. J Pediatr Gastroenterol Nutr 2008;46:329-333
105. Alexander J, Kowdley KV. HFE-associated hereditary hemochromatosis. Genet Med 2009;11:307-313
106. Adams PC, Reboussin DM, Press BD, et al. Biological variability of transferrin saturation and unsaturated iron binding capacity. Am J Med 2007;120:999
107. Whitlock EP, Garlitz BA, Harris EL, et al. Screening for hereditary hemochromatosis: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006;145:209-223
108. Kowdley KV. Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 2004;127:79-86
109. Waalen J, Felitti VJ, Gelbart T, et al. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood 2008;111:3373-3376
110. Yen AW, Fancher TL, Bowlus CL. Revisiting hemochromatosis: current concepts and progress. Am J Med 2006;119:391-399