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.

Change of Transferrin Sialylation Differs between Mild Sepsis and Severe Sepsis and Septic Shock

“…Transferrin concentrations decrease rapidly in inflammation, apparently to deprive bacteria of iron needed for growth (30,31). Sialylation of transferrin influences its half-life and its function: desialylated transferrin is responsible for faster delivery of iron to hepatic storage (32) and also has a shorter half-life than normally sialylated transferrin (30); transferrin with a low sialic acid content also increases iron turnover and leads to iron loading of the hepatocyte (33).…”

Iron Dysregulation Combined with Aging Prevents Sepsis-Induced Apoptosis1

“…First, iron loading before CLP had no impact on any variable examined in Hfe Ϫ/Ϫ mice except for TNF␣ levels at 24 h. This was surprising given that a high iron diet given 2 weeks before CLP in young animals with this genetic abnormality causes increased mortality over those given a low iron diet [19]. We do not have a good explanation for this unexpected result.…”

“…The cecum was punctured once with a 25-gauge needle and gently squeezed to extrude some stool, then replaced into the abdomen, which was closed in layers. Published data demonstrates that double-puncture with a 25-gauge needle results in 30 to 60% 7-day survival in young Hfe Ϫ/Ϫ or WT mice given high or iron deficient diet 2 weeks before the onset of sepsis [19]. The reason a smaller injury was used is this study is based upon the fact that aged (24 month) C57Bl/6 WT mice have a three-fold increase in mortality compared to young (4 months) WT mice subjected to the same insult [22].…”

“…CLP was performed on male and female mice by the methods of Baker et al and as described previously [15,19,33]. Briefly, a midline laparotomy was performed, the cecum was externalized and ligated distal to the ileocecal valve, taking care to prevent intestinal obstruction.…”

“…The disease normally does not cause symptoms in those who are affected until the fourth to sixth decade of life, and the number of patients with the genetic abnormality who progress to organ damage is unclear [17,18]. While the effect of chronic iron dysregulation in acutely ill middle aged or elderly patients is unknown, iron overload given before CLP causes increased mortality in young Hfe Ϫ/Ϫ mice [19], suggesting that both acute and chronic abnormalities in iron metabolism affect outcome in critical illness.…”