Opportunistic Infections with Iron Overload

Withholding iron from potential pathogens is a host defense strategy. Transferrin's extremely high affinity for iron, coupled with the fact that two-thirds of the iron binding sites of the protein normally are unoccupied, essentially eliminates free iron from plasma and extracellular tissues. Both transferrin and the structurally related protein, lactoferrin, are bacteriostatic in vitro for a number of bacteria. Lactoferrin is a prominent component of the granules of polymorphonuclear leukocytes. The protein is released at high concentrations by the cells in areas of infection. There is also evidence that iron overload per se compromises the ability of phagocytes to kill microorganisms. A combination of problems likely contribute to the increase in susceptibility to infection in these patients.

The very high transferrin saturations attained in patients with iron overload compromise the bacteriostatic properties of the protein. Iron sequestration is not a frontline defense against microbes. Therefore, iron overload does not produce the susceptibility to infection seen with defects in more central systems (e.g., chronic granulomatous disease). Nonetheless, a number of infections, often with unusual organisms, have been reported in patients with iron overload (Bullen, Spaulding et al. 1991); (Abbott, Galloway et al. 1986); (Christopher 1985). Patients with sideroblastic anemia are often neutropenic or have neutrophil dysfunction. Iron overload in these patients adds to an already compromised defensive network. Some of the infections that have been reported are listed in Table 1. Although aggressive antimicrobial therapy is occasionally successful, some infections, such as the mucormycosis produced by Rhizopus oryazae, are almost uniformally fatal (Daly, Velazquez et al. 1989).
Table 1- Infections Associated with Iron Overload (partial listing)
  • Mucormycosis (Rhizopus oryazae
  • Listeria monocytogenes 
  • Yersenia enterocolitica 
  • Aeromonus hydrophilia 
  • Eschericia coli 
  • Cunninghamella bertholletiae 
  • Vibrio vulnificus 

The iron chelator, desferrioxamine, has also been implicated in the development of opportunistic infections in some patients with iron overload (Robins-Browne and Prpic 1985); (Boelaert, van Roost et al. 1988); (Windus, Stokes et al. 1987). Streptomyces pilosis synthesizes the siderophore when grown in an iron-deficient environment. Desferrioxamine is released in the vicinity of the microbes, binds iron, and returns the element to the microorganisms where it is used for growth and replication. Some pathogenic bacteria and fungi can utilize the iron bound by desferrioxamine to promote their growth, thereby enhancing the risk of severe infection.

The question of when to begin chelation therapy in a patient with transfusional hemochromatosis lacks a simple answer. The decision must be carefully individualized. Serious infection in patients treated with desferrioxamine is uncommon, and the benefits of therapy to prevent iron-induced organ damage generally outweigh the risk of infectious complications.