Impaired intestinal iron absorption in Crohn's disease correlates with disease activity and markers of inflammation

Approximately 30% to 80% of subjects with Crohn’s disease (CD) develop anemia as a complication of their illness (77% in a recent pediatric cohort).1–3 The anemia in these subjects is multifactorial and may be caused by lack of intake, chronic blood loss, micronutrient deficiency (iron, folate, and vitamin B12), hemolysis, and medication-induced myelosuppression. However, the 2 most common causes of anemia in CD subjects are iron deficiency and anemia of inflammation (ACI; also referred to as the anemia of chronic disease). Typical laboratory features of ACI include a normocytic or microcytic anemia, low serum iron level, low total iron binding capacity (TIBC), normal or high serum ferritin level, and high reticuloendothelial stores relative to the amount of total body iron. Oral iron therapy may be of limited or no benefit in subjects with ACI. Although the exact pathogenesis of ACI is unknown, one hypothesis suggests that ACI arises in part as a result of a defect in the ability of enterocytes to transport iron and the of inability reticuloendothelial cells to recycle iron. Ferroportin (FPN), an iron export protein at the basolateral membrane of the enterocyte, is internalized and degraded under the influence of inflammatory cytokines (hepcidin and tumor necrosis factor-α), thus blocking iron absorption at the intestinal level.4,5 The impaired transport of iron by the enterocyte results in a net decrease in intestinal iron absorption into the systemic circulation. In addition, there is increased phagocytosis of red cells by macrophages and impaired release of iron from cells of the reticuloendothelial system (e.g. macrophages) into the circulation.6 As a result, serum transferrin is decreased, and iron delivery to erythroid precursors is impaired, leading to a blunted erythropoietin response and a decreased response to iron therapy. Hepcidin, a circulating peptide hormone produced by the liver and detectable in the urine, has been found to be induced by inflammation and iron overload.7,8 Animal studies have shown that loss of hepcidin causes iron overload, and excess hepcidin causes iron-deficiency anemia.9–11 Excessive hepcidin production associated with large hepatic adenomas in patients with type Ia glycogen storage disease results in a severe refractory iron-deficiency anemia. These glycogen storage disease subjects do not respond to oral iron supplementation and have a limited response to intravenous iron dextran, similar to subjects with ACI.12 Thus, animal and human data indicate that hepcidin is a mediator of ACI acting on FPN to exert its effect.5,9 Hepcidin is induced by the cytokine interleukin-6 (IL-6), which is increased in subjects with CD and other inflammatory conditions.13–16 We hypothesized that iron absorption is impaired in subjects with active CD because inflammatory cytokines released by the inflamed bowel stimulate hepcidin release by the liver. The released hepcidin in turn impairs enterocyte iron absorption by downstream effects on DMT-1 and internalization and degradation of FPN, which leads to anemia. In this study, we compared iron absorption of subjects with active and inactive CD disease. To evaluate iron absorption in ACI, we used a diagnostic test previously developed to study iron-deficiency anemia in children.17,18 We found that subjects with moderate to severe CD have impaired oral iron absorption and elevated IL-6 levels compared with subjects with inactive disease.