Hemochromatosis and the enigma of misplaced iron: Implications for infectious disease and survival

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.

Time-course analysis of serum hepcidin, iron and cytokines in a C282Y homozygous patient with Schnitzler's syndrome treated with IL-1 receptor antagonist

“…These findings on the cross-talk between pathways regulating hepcidin provides indirect information on the iron availability to certain pathogens relevant in critical host defense strategies. 2,[22][23][24] It furthermore suggests that chronic inflammation may reduce iron stores in C282Y homozygotes, contributing to the variable penetrance of the C282Y mutation.…”

The molecular genetics of haemochromatosis

“…It could be related either to the use of the HFE protein as a cell surface receptor by some infectious agent 34 or to the relative iron deficiency that occurs with the C282Y mutation, and posits a possible protection against a number of virulent species of bacteria that multiply mainly in rich-iron macrophages. 37 By contrast, the H63D variant is older than C282Y and is carried on a greater diversity of haplotypes. Its allele frequency is more than 5% in the Celtic population as well as in other Caucasian, Asian, Indian and African populations, and is particularly high in Southern-European regions like Spain (up to 32.3%).…”

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

“…Still, high iron is positively associated with viral load and mortality in HIV (24 -26), suggesting that an optimal balance of iron is necessary. In general terms, low iron status is protective, whereas elevated iron levels promote infection (27,28). The complexity of host-pathogen interactions therefore presents a clinical conundrum; although iron supplements protect against iron deficiency, such measures could negatively impact infectious diseases (29,30).…”