Evolutionary Approach to Medicine

Marcelo Turkienicz Berlim, MD, Alberto Mantovani Abeche, MD, Department of Gynecology and Obstetrics, Federal University of Rio Grande do Sul, School of Medicine, Porto Alegre, RS, Brazil

South Med J. 2001;94(1) 

In This Article

Iron "Withholding" System

Our organism has another defense mechanism, known as iron "withholding," which physicians often unintentionally try to frustrate.[1,2] Iron is essential for all pathogens, and to obtain it from low concentrations present in host plasma, microorganisms have developed sophisticated mechanisms[18] such as (1) erythrocyte lysis, hemoglobin digestion, and heme assimilation; (2) binding siderophilins with iron extraction at the cell plasma membrane; (3) obtainment of host intracellular iron; and (4) use of siderophores that remove iron from transferrin.[19]

Conversely, the human organism has conceived primitive defense systems to both avoid tissue damages due to iron exposure and prevent the access of pathogens to this essential ion.[20] Among these host defense mechanisms are (1) constitutive mechanisms such as iron-binding proteins (transferrin in blood, lymph, and cerebrospinal fluid; ferritin in host cells; and lactoferrin in secretions of lachrymal glands, and of the respiratory, gastrointestinal, and genital tracts); and (2) processes induced at the time of infection, such as suppression of the assimilation of about 80% of dietary iron (activated by IL-1, IL-6, and tumor necrosis factor), neutrophil release of apolactoferrin to bind iron at septic sites, synthesis of nitric oxide by macrophages to disrupt the iron metabolism of pathogens, hepatic release of hemopexin and haptoglobin (to bind hemin and hemoglobin, respectively), and many others.[19] All systems mentioned play a central role in the maintenance of host iron concentrations at relatively low levels, which is essential for bacteriostatic and bactericidal systems.[18,21] However, these antibacterial systems are abolished when iron becomes freely available,[21] as for instance when an infected patient (who presents low protective serum iron levels) receives parenteral or oral iron supplementation.[1,2,22] This results in faster bacterial growth and increased virulence.[19,21,22] An analog effect was reported in patients with end-stage renal disease: overtreatment with iron increases the preexisting risk for episodes of infection caused by dialysis, malnutrition, and other factors.[22]

Moreover, iron loading is thought to increase the risk for neoplasia, infection, cardiomyopathy, arthropathy, and several endocrine and perhaps neurodegenerative disorders. Thus, certain populations (such as patients with hemochromatosis, alcoholism, and asplenia) may benefit from screening tests for iron loading, and this can provide important information concerning therapeutics, prophylaxis, and diagnosis of iron-related illnesses.[19]

In an explanatory controlled study done by Murray et al,[23] the incidence of infection was compared among 137 Somali nomads who showed constitutive low serum iron levels. One group received placebo, and the other received a food supplement with iron. After 1 month, 50.7% of the individuals who had received the iron supplement had episodes of infection, as against 10.6% of those who had received placebo (P < .001). Moreover, experiments with Escherichia coli showed that the lethal dose for guinea pigs on intraperitoneal injection was 108 bacteria. Titration of the effect of iron compounds showed that bacterial virulence increased 100,000-fold with Fe3+, and 10,000-fold with hemoglobin,[24] and this implies that resistance of these animals to E coli had been virtually eliminated.[21]

Thus, the evolved mechanism that regulates iron plasma and tissue concentrations is another specific illustration of the principle that physicians should be careful when distinguishing defenses from other manifestations of infection and before concluding that a defensive response from the body is an undesirable adaptation problem.[1,2] This attempt to strengthen natural resistance can help, for example, in the treatment of septic peritonitis (where donated plasma could provide unsaturated transferrin, which binds free iron, and haptoglobin, which binds free hemoglobin)[25] and in the development of new antibacterial drugs based on interference with iron metabolism of microorganisms.[21]


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