University of Wisconsin Hematology

Iron deficiency, metabolism, overload

Iron metabolism

  1. Wang and Babitt. Liver iron sensing and body iron homeostasis. Blood 2019;133:18
  2. Camaschella C. Iron-deficiency anemia. NEJM 2015;372:1832
  3. Ganz and Nemeth. The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders. Hematology 2011: 538
  4. Andrews NC. Closing the iron gate. NEJM 2012;366:376
  5. Finberg KE. Unraveling mechanisms regulating systemic iron homeostasis. Hematology 2011:532
  6. Meynard et al. The liver: conductor of systemic iron balance. Blood 2014;123:168
  7. Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117:4425
  8. Girelli et al Hepcidin in the diagnosis of iron disorders. Blood 2016;127;2809
  9. Ganz et al. Immunoassay for serum hepcidin. Blood 2008;112:4292
  10. Kautz and Nemeth. Molecular liasons between erythropoiesis and iron metabolism. Blood 2014;124:479
  11. Kautz et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014;46:678(May mediate the suppression of hepcidin production in patients with erythroid hyperplasia)
  12. Tanaka et al. A genome-wide association analysis of serum iron concentrations. Blood 2010;115:94(Polymorphisms of TMPRSS6 – see above reference – correlated strongly with serum iron, hemoglobin, MCV)
  13. De Domenico et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Nat Acad Sci USA 2005;102:8955
  14. Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood 2005;106:3710
  15. Mastrogiannaki et al. The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. Blood 2013;122:885
  16. Barber and Elde. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 2014;346:1362(Transferrin variants have evolved to better compete with bacterial iron-binding proteins; with editorial)

Iron deficiency

  1. Pasricha et al.  Iron deficiency.  Lancet 2021;397:233
  2. Camaschella C. Iron deficiency. Blood 2019;133:30
  3. Hod et al. A randomized trial of blood donor iron repletion on red cell quality for transfusion and donor cognition and well-being. Blood 2022;140:2730 (Iron repletion in non-anemic donors with low ferritin did not improve quality of life or cognition)
  4. Goodnough et al. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010;116:4754
  5. Xavier-Ferrucio et al. Low iron promotes megakaryocytic commitment of megakaryocytic-erythroid progenitors in humans and mice. Blood 2019;134:1547(Why iron deficiency causes thrombocytosis)
  6. Hershko and Camaschella. How I treat unexplained refractory iron deficiency anemia. Blood 2014;123:326(Ddx includes H pylori, celiac dz, autoimmune gastritis, genetic disorders)
  7. Rogozińska et al. Iron preparations for women of reproductive age with iron deficiency anaemia in pregnancy (FRIDA): a systematic review and network meta-analysis. Lancet Haematol 2021;8:e503
  8. Auerbach et al. Intravenous iron: a framework for changing the management of iron deficiency. Lancet Haematol 2020;7:e342
  9. Avni et al. The safety of intravenous iron preparations. Systematic review and meta-analysis. Mayo Clin Proc 2015;90:12
  10. Krayenbuehl et al. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Blood 2011;118:3222(Most benefit in women with ferritin levels <15; see also this editorial)
  11. Rampton et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica 2014;99:16771
  12. Wang et al. Comparative Risk of Anaphylactic Reactions Associated With Intravenous Iron Products. JAMA 2015;314:2062(Anaphylaxis least common with iron sucrose, most common with iron dextran; see also a critique of this study)
  13. Dave et al. Risks for Anaphylaxis With Intravenous Iron Formulations. A Retrospective Cohort Study. Ann Intern Med 2022;175:656 (Generally low rates, but higher for iron dextran and ferric carboxymaltose than iron sucrose)
  14. Halfdanarson et al. Hematologic manifestations of celiac disease. Blood 2007;109:412
  15. Anker et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. NEJM 2009;361:2436(with editorial)
  16. Kalra et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet 2022;400:2199 (Iron treatment associated with fewer hospitalizations for heart failure and lower rate of cardiovascular death)
  17. Mentz et al. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. NEJM 2023;379:975 (Less evidence of benefit in a lower-risk population; with editorial)
  18. Khalafallah et al. Intravenous ferric carboxymaltose versus standard care in the management of postoperative anaemia: a prospective, open-label, randomised controlled trial. Lancet Haematol 2016;3: e415(Preemptive single dose of IV iron after surgery hastened recovery of Hb, decreased transfusion requirements, shortened hospital stay, lowered infection rate)
  19. Stoffel et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol 2017;4:e524 (Twice daily dosing increased hepcidin levels and reduced iron absorption; single daily dose or alternate day dosing may be preferable)
  20. Moretti et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood 2015;126:1981
  21. von Siebenthal et al. Effect of dietary factors and time of day on iron absorption from oral iron supplements in iron deficient women. Am J Hematol 2023;98:1356 (4-fold increase in absorption if oral iron taken with OJ vs coffee; AM administration better)
  22. Macdougall et al. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis. NEJM 2019;380:447(More aggressive iron replacement diminished ESA requirements)
  23. Hain et al. Iron-Deficiency Anemia in CKD: A Narrative Review for the Kidney Care Team. Kidney Med 2023 5:100677
  24. Spahn et al. Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial. Lancet 2019;393:2201(IV iron + EPO + folate + B12 prior to surgery reduced subsequent transfusion requirements)

Hereditary hemochromatosis

  1. Adams et al. Haemochromatosis. Lancet 2023;401:1811
  2. Olynyk and Ramm. Hemochromatosis.  NEJM 2022;387:2159
  3. Sandhu et al. Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease. Blood 2018;132:101(Non-HFE HH has earlier onset and more severe course, but less joint disease)
  4. Girelli et al. Hemochromatosis classification: update and recommendations by the BIOIRON Society. Blood 2022;139:3018
  5. Pilling et al. Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank. BMJ 2019;364:k5222(Morbidity mainly associated with C282Y homozygosity; compound heterozygotes and heterozygotes had minimal risk)
  6. Zumerle et al. Targeted disruption of hepcidin in the liver recapitulates the hemochromatotic phenotype. Blood 2014;123:3646
  7. Wood et al. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008;111:4456
  8. Beutler et al. The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Intern Med 2000;133:329
  9. Allen et al. Iron-Overload–Related Disease in HFE Hereditary Hemochromatosis. NEJM 2008;358:221(28% of male C282Y homozygotes, but only 1% of females, developed clinical iron overload)
  10. McLaren and Gordeuk. Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Hematology 2009;195
  11. U.S. Preventive Services Task Force. Screening for hemochromatosis: Recommendation statement. Ann Intern Med 2006;145:204(Screening asymptomatic patients for hemochromatosis not recommended)
  12. Qaseem et al. Screening for Hereditary Hemochromatosis: A Clinical Practice Guideline from the American College of Physicians. Ann Intern Med 2005;143:517
  13. Schmitt et al. Screening Primary Care Patients for Hereditary Hemochromatosis with Transferrin Saturation and Serum Ferritin Level: Systematic Review for the American College of Physicians. Ann Intern Med 2005;143:522
  14. Morrison et al.  Serum Ferritin Level Predicts Advanced Hepatic Fibrosis among U.S. Patients with Phenotypic Hemochromatosis.  Ann Intern Med 2003;138:627
  15. Atkins et al. Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy. JAMA 2020;324:2048(>10-fold higher risk for liver cancer in men homozygous for C282Y; no increased risk for women)
  16. Waalen et al. Screening for hemochromatosis by measuring ferritin levels: a more effective approach. Blood 2008;111:3373(40% of people with ferritin > 1000 had inherited hemochromatosis)
  17. Fischer and Harmatz. Non-invasive assessment of tissue iron overload. Hematology 2009;215
  18. Brissot and de Bels. Current Approaches to the Management of Hemochromatosis. Hematology 2006;36-41
  19. Ong et al. Reduction of body iron in HFE-related haemochromatosis and moderate iron overload (Mi-Iron): a multicentre, participant-blinded, randomised controlled trial. Lancet Haematol 2017;4:e607(Patients homozygous for C282Y and ferritin levels of 300-1000 may benefit from lower ferritin to 300 or less)
  20. Mottelson et al. Iron, hemochromatosis genotypes, and risk of infections: a cohort study of 142 188 general population individuals. Blood 2024;144:693 (> 2-fold risk of death from infection in C282Y homozygotes, including those with normal ferritin)

Other causes of iron overload; drug therapy of iron overload

  1. Coates T. Management of iron overload: lessons from transfusion-dependent hemoglobinopathies. Blood 2025;145:359
  2. Angelucci E. How I manage iron overload in the hematopoietic cell transplantation setting. Blood 2025;145:372
  3. Leitch and Buckstein. How I treat iron overload in adult MDS. Blood 2025;145:383
  4. Harris et al. Serum Ferritin and Transferrin Saturation in Asians and Pacific Islanders. Arch Intern Med 2007;167:722
  5. Camaschella C. Treating iron overload. NEJM 2013;368:2325
  6. Casu et al. Hepcidin agonists as theraeputic tools. Blood 2018;131:1790
  7. Lok et al. Iron overload in the Asian community. Blood 2009;114:20
  8. Adams et al. Hemochromatosis and iron-overload screening in a racially diverse population. NEJM 2005;352:1769(Iron overload in non-whites is usually not caused by HFE mutations)
  9. Wood JC. Impact of iron assessment by MRI. Hematology 2011:443
  10. Fischer and Harmatz. Non-invasive assessment of tissue iron overload. Hematology 2009;215
  11. Adamkiewicz et al. Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury. Blood 2009; 114:4632(Ferritin < 1500 typically not associated with clinical sequelae; ferritin > 3000 associated with liver injury)
  12. Schafer et al. Clinical consequences of acquired transfusional iron overload in adults. NEJM 1981; 304:319
  13. Hoffbrand et al. How I treat transfusional iron overload. Blood 2012;120:3657
  14. Brittenham GM. Iron-chelating therapy for transfusional iron overload. NEJM 2011;364:146
  15. Taher et al. Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia. Br J Haematol 2015;168:284(Suggests treatment when ferritin > 800, stopping when ferritin < 300, dose escalation when ferritin > 2000)
  16. Pullarkat V. Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the eye? Blood 2009;114:5251(Suggests that chelation may decrease infection risk, delay leukemic transformation and improve stem cell transplant outcomes)
  17. Kwiatkowski JL. Real-world use of iron chelators. Hematology 2011:451
  18. Jensen et al. Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: a study in adult patients with acquired anemias. Blood 2003;101:91
  19. Franchini et al. Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood 2000;95:2776
  20. Hider et al. The role of deferiprone in iron chelation. NEJM 2018;379:2140
  21. Cohen et al. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone.  Blood 2003;102:1583
  22. Chan et al. Use of the oral chelator deferiprone in the treatment of iron overload in patients with Hb H disease. Br J Haematol 2006;133:198
  23. Borgna-Pignatti et al. Cardiac morbidity and mortality in deferoxamine- or deferiprone-treated patients with thalassemia major. Blood 2006;107:3733
  24. Pennell et al. Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major patients with asymptomatic myocardial siderosis. Blood 2006;107:3738
  25. Cappellini et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with -thalassemia. Blood 2006;107:3455
  26. Chirnomas et al. Deferasirox pharmacokinetics in patients with adequate versus inadequate response. Blood 2009;114:4009(Poor responders had lower drug bioavailability)
  27. Pennell et al. Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia. Blood 2010;115:2364
  28. Wood et al. The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores. Blood 2010;116:537(Chelation effective in patients wth mild to moderate, but not severe, iron overload)
  29. Cappellini et al. Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. Blood 2011;118:884
  30. Pennell et al. A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA). Blood 2014;123:1447(Both drugs similarly effective)
  31. Lee et al. Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial. Blood 2010;116:2448
  32. Angelucci et al. Iron Chelation in Transfusion-Dependent Patients With Low- to Intermediate-1–Risk Myelodysplastic Syndromes. A Randomized Trial. Ann Intern Med 2021;172:513
  33. List et al. Deferasirox Reduces Serum Ferritin and Labile Plasma Iron in RBC Transfusion–Dependent Patients With Myelodysplastic Syndrome. J Clin Oncol 2012;30:2134
  34. Aydinok et al. Effects of deferasirox-deferoxamine on myocardial and liver iron in patients with severe transfusional iron overload. Blood 2015;125:3868
  35. Neufeld et al. A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload. Blood 2012;119:3263(Well-tolerated and effective oral chelator)
  36. Fernandes et al. A randomized trial of amlodipine in addition to standard chelation therapy in patients with thalassemia major. Blood 2016;128:1555
  37. Cohen et al. Effect of transfusional iron intake on response to chelation therapy in β-thalassemia major. Blood 2008;111:583
  38. Leitch and Vickars. Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron? Hematology 2009;664
  39. Kremastinos and Farmakis. Iron overload cardiomyopathy in clinical practice. Circulation 2011;124:2253