title: Iron overload before cecal ligation and puncture increases mortality.
abstract: Iron metabolism is dysregulated in critically ill patients. A mouse model of dysregulated iron metabolism was used to examine the consequence of iron loading upon sepsis. Mice deleted in the hfe gene (hfe-/-) abnormally accumulate iron in tissue; defects in the human hfe gene are clinically expressed as hemochromatosis. Hfe-/- mice and wild-type counterparts were randomized to receive either high- or low-iron diets for 2 weeks. After iron loading, mice were subjected to cecal ligation and puncture (CLP), a clinically relevant animal model of intra-abdominal sepsis. A preliminary (but underpowered) study suggested that iron-loaded hfe-/- mice had increased mortality as compared with hfe-/- mice fed a low-iron diet. There was no difference between wild-type and hfe-/- mice fed a low-iron diet or between wild-type mice fed hihg- and low-iron diets. A subsequent, appropriately powered study showed that iron-loaded hfe-/- mice had significantly higher mortality from intra-abdominal sepsis than hfe-/- mice fed a low-iron diet. Iron loading was confirmed through chemical assay of iron concentration in hepatic tissue. Animals with dysregulated iron handling, loaded with iron and subjected to CLP, had double the mortality of animals with normal iron levels. Critical care patients often have altered iron metabolism. In clinical practice, critically ill patients may receive iron through direct administration and the transfusion of blood products. Iron therapy may adversely affect the clinical outcome from sepsis.
authors.affiliation: Department of Surgery, Washington University School of Medicine, 660 South Euclid Street, St. Louis, MO 63110, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Wizorek
authors.forename: Isaiah R
authors.initials: IR
authors.lastname: Turnbull
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Buchman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002432:Cecum; D016638:Critical Illness; D004195:Disease Models, Animal; D005260:Female; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D011677:Punctures; D018805:Sepsis / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron