Iron overload syndromes other than hereditary hemochromatosis
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders
- Section Editor — Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Bruce R Bacon, MD
Bruce R Bacon, MD
- Professor of Internal Medicine
- Saint Louis University School of Medicine
In normal subjects there is no mechanism to regulate iron loss from the body, which averages about 1 mg/day in adult men from sweat, shed skin cells, and gastrointestinal losses. Premenopausal adult women lose an additional 0.5 to 1.0 mg/day because of menses. Therefore, to insure normal stores of iron within the body, iron absorption must be tightly regulated. A simple calculation will make this clear. If iron absorption is increased in an individual by as little as 1.5 mg/day above the amount needed to achieve homeostasis, this will result in the accumulation of 5.5 grams of iron every decade, 16 grams in 30 years and 33 grams in 60 years. This latter figure corresponds to the amount of iron (30 to 40 g) usually found in patients with clinically detected hereditary hemochromatosis (HH) and explains both the delayed time for the clinical appearance of this disease in men and its rarity in premenopausal women. (See "Regulation of iron balance".)
As a result of the inability to increase iron loss, iron overload is an inevitable response to increased iron entry into the body. This can occur by one of three mechanisms (table 1):
●A massive increase in iron intake
●An increase in iron absorption when iron intake is normal
●The parenteral administration of iron, as with transfusional overload
- Pootrakul P, Kitcharoen K, Yansukon P, et al. The effect of erythroid hyperplasia on iron balance. Blood 1988; 71:1124.
- Ginzburg Y, Rivella S. β-thalassemia: a model for elucidating the dynamic regulation of ineffective erythropoiesis and iron metabolism. Blood 2011; 118:4321.
- Barron R, Grace ND, Sherwood G, Powell LW. Iron overload complicating sideroblastic anemia--is the gene for hemochromatosis responsible? Gastroenterology 1989; 96:1204.
- Gardenghi S, Marongiu MF, Ramos P, et al. Ineffective erythropoiesis in beta-thalassemia is characterized by increased iron absorption mediated by down-regulation of hepcidin and up-regulation of ferroportin. Blood 2007; 109:5027.
- 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.
- Pasricha SR, Frazer DM, Bowden DK, Anderson GJ. Transfusion suppresses erythropoiesis and increases hepcidin in adult patients with beta thalassemia major: a longitudinal study. Blood 2013.
- Kautz L, Nemeth E. Molecular liaisons between erythropoiesis and iron metabolism. Blood 2014; 124:479.
- Fertrin KY, Lanaro C, Franco-Penteado CF, et al. Erythropoiesis-driven regulation of hepcidin in human red cell disorders is better reflected through concentrations of soluble transferrin receptor rather than growth differentiation factor 15. Am J Hematol 2014; 89:385.
- Kautz L, Jung G, Valore EV, et al. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014; 46:678.
- Finch CA, Huebers H. Perspectives in iron metabolism. N Engl J Med 1982; 306:1520.
- Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, et al. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology 1998; 27:1661.
- 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.
- Ajioka RS, Phillips JD, Weiss RB, et al. Down-regulation of hepcidin in porphyria cutanea tarda. Blood 2008; 112:4723.
- Roberts AG, Whatley SD, Morgan RR, et al. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet 1997; 349:321.
- 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.
- Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood 2000; 95:1565.
- Chapman RW, Morgan MY, Laulicht M, et al. Hepatic iron stores and markers of iron overload in alcoholics and patients with idiopathic hemochromatosis. Dig Dis Sci 1982; 27:909.
- Gordeuk V, Mukiibi J, Hasstedt SJ, et al. Iron overload in Africa. Interaction between a gene and dietary iron content. N Engl J Med 1992; 326:95.
- Moyo VM, Mandishona E, Hasstedt SJ, et al. Evidence of genetic transmission in African iron overload. Blood 1998; 91:1076.
- McNamara L, MacPhail AP, Gordeuk VR, et al. Is there a link between African iron overload and the described mutations of the hereditary haemochromatosis gene? Br J Haematol 1998; 102:1176.
- Gordeuk VR, Caleffi A, Corradini E, et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis 2003; 31:299.
- Gordeuk VR, McLaren CE, MacPhail AP, et al. Associations of iron overload in Africa with hepatocellular carcinoma and tuberculosis: Strachan's 1929 thesis revisited. Blood 1996; 87:3470.
- Moyo VM, Makunike R, Gangaidzo IT, et al. African iron overload and hepatocellular carcinoma (HA-7-0-080). Eur J Haematol 1998; 60:28.
- Walker AR, Segal I. Iron overload in Sub-Saharan Africa: to what extent is it a public health problem? Br J Nutr 1999; 81:427.
- Ware HM, Kwiatkowski JL. Evaluation and treatment of transfusional iron overload in children. Pediatr Clin North Am 2013; 60:1393.
- Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassemia. Blood 1997; 89:739.
- Forget BG, Pearson HA. Hemoglobin synthesis and the thalassemias. In: Basic Principles and Practice, 3rd ed, Hoffma R, Benz EJ Jr, Shattil SJ, et al. (Eds), Churchill Livingstone, New York 2000. p.1525.
- Schwartz E, Benz EJ Jr. Thalassemia syndromes. In: Smith's Blood Diseases of Infancy and Childhood, 6th ed, Miller DR, Baehner RL (Eds), CV Mosby, St. Louis 1989. p.428.
- Beris P. Introduction: management of thalassemia. Semin Hematol 1995; 32:243.
- Cao A, Galanello R, Rosatelli MC, et al. Clinical experience of management of thalassemia: the Sardinian experience. Semin Hematol 1996; 33:66.
- Roberts DJ, Rees D, Howard J, et al. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalassaemia. Cochrane Database Syst Rev 2005; :CD004450.
- Parkkila S, Niemelä O, Savolainen ER, Koistinen P. HFE mutations do not account for transfusional iron overload in patients with acute myeloid leukemia. Transfusion 2001; 41:828.
- Vichinsky E, Butensky E, Fung E, et al. Comparison of organ dysfunction in transfused patients with SCD or beta thalassemia. Am J Hematol 2005; 80:70.
- Fung EB, Harmatz PR, Lee PD, et al. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Br J Haematol 2006; 135:574.
- Berdoukas V, Nord A, Carson S, et al. Tissue iron evaluation in chronically transfused children shows significant levels of iron loading at a very young age. Am J Hematol 2013; 88:E283.
- Franchini M, Gandini G, Veneri D, et al. Efficacy and safety of phlebotomy to reduce transfusional iron overload in adult, long-term survivors of acute leukemia. Transfusion 2004; 44:833.
- Ghoti H, Rachmilewitz EA, Simon-Lopez R, et al. Evidence for tissue iron overload in long-term hemodialysis patients and the impact of withdrawing parenteral iron. Eur J Haematol 2012; 89:87.
- Silver MM, Beverley DW, Valberg LS, et al. Perinatal hemochromatosis. Clinical, morphologic, and quantitative iron studies. Am J Pathol 1987; 128:538.
- Flynn DM, Mohan N, McKiernan P, et al. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed 2003; 88:F124.
- Pan X, Kelly S, Melin-Aldana H, et al. Novel mechanism of fetal hepatocyte injury in congenital alloimmune hepatitis involves the terminal complement cascade. Hepatology 2010; 51:2061.
- Moirand R, Mortaji AM, Loréal O, et al. A new syndrome of liver iron overload with normal transferrin saturation. Lancet 1997; 349:95.
- Tuomainen TP, Nyyssönen K, Salonen R, et al. Body iron stores are associated with serum insulin and blood glucose concentrations. Population study in 1,013 eastern Finnish men. Diabetes Care 1997; 20:426.
- Mendler MH, Turlin B, Moirand R, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology 1999; 117:1155.
- Davis RJ, Corvera S, Czech MP. Insulin stimulates cellular iron uptake and causes the redistribution of intracellular transferrin receptors to the plasma membrane. J Biol Chem 1986; 261:8708.
- Tanner LI, Lienhard GE. Insulin elicits a redistribution of transferrin receptors in 3T3-L1 adipocytes through an increase in the rate constant for receptor externalization. J Biol Chem 1987; 262:8975.
- Macdonald GA, Powell LW. More clues to the relationship between hepatic iron and steatosis: An association with insulin resistance? Gastroenterology 1999; 117:1241.
- Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 1960-1994. Int J Obes Relat Metab Disord 1998; 22:39.
- Kral JG, Schaffner F, Pierson RN Jr, Wang J. Body fat topography as an independent predictor of fatty liver. Metabolism 1993; 42:548.
- ANEMIA DUE TO INEFFECTIVE ERYTHROPOIESIS
- Mechanism for increased iron absorption
- PORPHYRIA CUTANEA TARDA
- Liver disease
- HFE gene mutations
- HCV infection
- LIVER IRON OVERLOAD WITH NORMAL TRANSFERRIN SATURATION
- AFRICAN IRON OVERLOAD
- TRANSFUSIONAL IRON OVERLOAD
- REPEATED PARENTERAL IRON INFUSION
- Intravenous iron preparations
- Intravenous hematin/hemin
- NEONATAL OR PERINATAL IRON OVERLOAD
- INSULIN RESISTANCE
- EXTREMELY HIGH FERRITIN LEVELS
- CHELATION THERAPY