Abstract
The mystery surrounding the apparent lack of iron within the macrophages of individuals with hereditary hemochromatosis, a condition of excessive uptake of dietary iron, has yet to be fully explained. We have suggested that iron deficiency of macrophages in people with hereditary hemochromatosis mutations is associated with increased resistance to infection by Yersinia and other intracellular pathogens, a selection pressure resulting in unusually high current population frequencies of hereditary hemochromatosis mutations. Such selection pressure has been called Epidemic Pathogenic Selection (EPS). In support of the theory of EPS, a considerable number of virulent species of bacteria multiply mainly in iron-rich macrophages of their mammalian hosts. Among these fastidious pathogens are strains of Chlamydia, Coxiella, Francisella, Legionella, Mycobacterium, Salmonella and Yersinia. Iron deficiency of macrophages of persons with hereditary hemochromatosis gene mutations may result in increased resistance to members of these bacterial pathogens. People with genes that result in hereditary hemochromatosis may be protected against coronary artery disease associated with Chlamydia and Coxiella infection in the absence of iron overload. In the clinical setting, when a patient appears to be iron deficient, the reason for this should be carefully evaluated. Iron supplementation may adversely affect the health of individuals who have mounted an acute phase response to infection, injury or stress, or who carry genes predisposing them to iron overload disorders.
Similar content being viewed by others
References
Andrews NC, Fleming MD, Levy JE. 1999 Molecular insights into mechanisms of iron transport. Curr Opin Hematol 6, 61-64.
Cairo G, Recalcati S, Montosi G, et al. 1997 Inappropriately high iron regulatory protein activity in monocytes of patients with genetic hemochromatosis. Blood 89, 2546-2553.
Crawford DH, Jazwinska EC, Cullen LM et al. 1998 Expression of HLA-linked hemochromatosis in subjects homozygous or heterozygous for the C282Y mutation. Gastro 114, 1003-1008.
Feder JN, Gnirke A, Thomas W et al. 1996 A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13, 399-408.
Fox CJ, Cullen DJ, Knuiman MW et al. 2002 Effects of body iron stores and haemochromatosis genotypes on coronary heart disease outcomes in the Busselton health study. J Cardiovasc Risk 9, 287-293.
Gangaidzo IT, Moyo VM, Saungweme T et al. 1999 Iron overload in urban Africans in the 1990s. Gut 45, 278-283.
Gangaidzo IT, Moyo VM, Mvundura E et al. 2001 Association of pulmonary tuberculosis with increased dietary iron. J Infect Dis 184, 936-939.
Gerhard GS, Levin KA, Price-Goldstein J et al. 2001 Vibrio vulnificus septicemia in a patient with the hemochromatosis HFE C282Y mutation. Arch Pathol Lab Med 125: 1107-1109.
Gordeuk V, Mukiibi J, Hasstedt SJ et al. 1992 Iron overload in Africa. Interaction between a gene and dietary iron content. N Engl J Med 326, 95-100.
Howe D, Mallavia LP. 1999 Coxiella burnetii infection increases transferrin receptors on J774A. 1 cells. Infect Immun 67, 3236-3241.
Iancu TC, Lichterman L, Neustein HB. 1978 Hepatic sinusoidal cells in iron overload. Ultrastructural observations. Isr J Med Sci 14, 1191-1201.
Jazwinska EC. 1998 Hemochromatosis: a genetic defect in iron metabolism. Bioessays 20, 562-568.
Legssyer R, Geisser P, McArdle H et al. 2003 Comparison of injectable iron complexes in their ability to iron load tissues and to induce oxidative stress. Biometals 16, 425-433.
Moalem S, Percy ME, Andrews DF et al. 2000 Are hereditary hemochromatosis mutations involved in Alzheimer disease? Am J Med Genet 93, 58-66.
Moalem S, Percy ME, Kruck TP et al. 2002 Epidemic pathogenic selection: an explanation for hereditary hemochromatosis? Med Hypotheses 59, 325-329.
Moalem S, Somerville MJ, O'Brien L et al. 2002 Parkinson disease and hereditary hemochromatosis mutations in a Swedish sample. Conference Proceedings of the 7th International Symposium on Metal Ions in Biology and Medicine, Saint Petersburg, Russia 7, 399-401.
Moczulski DK, Grzeszczak W, Gawlik B. 2001 Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy. Diab Care 24, 1187-1191.
Montosi G, Paglia P, Garuti C et al. 2000 Wild-type HFE protein normalizes transferrin iron accumulation in macrophages from subjects with hereditary hemochromatosis. Blood 96, 1125-1129.
Moyo VM, Mandishona E, Hasstedt SJ et al. 1998 Evidence of genetic transmission in African iron overload. Blood 91, 1076-1086.
Olakanmi O, Schlesinger LS, Ahmed A et al. 2002 Intraphagosomal Mycobacterium tuberculosis acquires iron from both extracellular transferrin and intracellular iron pools. Impact of interferon-gamma and hemochromatosis. J Biol Chem 277, 49727-49734.
Oppenheimer SJ. 1998 Iron and infection in the tropics: paediatric clinical correlates. Ann Trop Paediatr 18, S81-87.
Ritchie RF, Palomaki GE, Neveux LM et al. 2002. Reference distributions for serum iron and transferrin saturation: a practical, simple, and clinically relevant approach in a large cohort. J Clin Lab Anal 16, 237-245.
Recalcati S, Pometta R, Levi S et al. 1998 Response of monocyte iron regulatory protein activity to inflammation: abnormal behavior in genetic hemochromatosis. Blood 91, 2565-2572.
Simon M, Alexandre JL, Fauchet R et al. 1980 The genetics of hemochromatosis. Prog Med Genet 4, 135-168.
Sullivan JL, Weinberg ED. 1999 Iron and the role of Chlamydia pneumoniae in heart disease. Emerg Infect Dis 5, 724-726.
Vikram HR, Bia FJ. 2002 Severe Legionella pneumophila pneumonia in a patient with iron overload. Scand J Infect Dis 34, 772-774.
Waalen J, Felitti V, Gelbart T et al. 2002 Prevalence of coronary heart disease associated with HFE mutations in adults attending a health appraisal center. Am J Med 113, 472-479.
Walker AR, Segal I. 1999 Iron overload in Sub-Saharan Africa: to what extent is it a public health problem? Br J Nutr 81, 427-434.
Weinberg ED. 2000 Microbial pathogens with impaired ability to acquire host iron. Biometals 13, 85-89.
Weiss G. 2002. Iron and immunity: A double-edged sword. Eur J Clin Invest 32, 70-78.
Witte DL, Crosby WH, Edwards CQ et al. 1996. Hereditary hemochromatosis. Clin Chim Acta 245, 139-200.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Moalem, S., Weinberg, E.D. & Percy, M.E. Hemochromatosis and the enigma of misplaced iron: Implications for infectious disease and survival. Biometals 17, 135–139 (2004). https://doi.org/10.1023/B:BIOM.0000018375.20026.b3
Issue Date:
DOI: https://doi.org/10.1023/B:BIOM.0000018375.20026.b3