Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation

Abstract

Iron transport in the reticuloendothelial (RE) system plays a central role in iron metabolism, but its regulation has not been characterized physiologically in vivo in humans. In particular, why serum iron is elevated and RE cells are much less iron-loaded than parenchymal cells in idiopathic hemochromatosis is not known. The processing of erythrocyte iron by the RE system was studied after intravenous (IV) injection of 59Fe heat-damaged RBCs (HDRBCs) and 55Fe transferrin in normal subjects and in patients with iron deficiency, idiopathic hemochromatosis, inflammation, marrow aplasia, or hyperplastic erythropoiesis. Early release of 59Fe by the RE system was calculated from the plasma iron turnover and the 59Fe plasma reappearance curve. Late release was calculated from the ratio of 59Fe/55Fe RBC utilization in 2 weeks. The partitioning of iron between the early (release from heme catabolism) and late (release from RE stores) phases depended on the size of RE iron stores, as illustrated by the inverse relationship observed between early release and plasma ferritin (P less than .001). There was a strong correlation between early release and the rate of change of serum iron levels during the first three hours in normal subjects (r = .85, P less than .001). Inflammation produced a blockade of the early release phase, whereas in idiopathic hemochromatosis early release was considerably increased as compared with subjects with similar iron stores. Based on these results, we describe a model of RE iron metabolism in humans. We conclude that the RE system appears to determine the diurnal fluctuations in serum iron levels through variations in the immediate output of heme iron. In idiopathic hemochromatosis, a defect of the RE cell in withholding iron freed from hemoglobin could be responsible for the high serum iron levels and low RE iron stores.

Comparison of organ dysfunction in transfused patients with SCD or β thalassemia

“…Inflammation may help restrict iron to shielded sites within the reticuloendothelial system (RES), thereby decreasing injury [12,13]. Fillet and colleagues [14] demonstrated in humans that inflammation delayed the release of iron from the RE system. Transport and storage proteins may be different in these two diseases.…”

Translational regulation via iron-responsive elements by the nitric oxide/NO-synthase pathway.

“…For a further discussion, see the text. such as neopterin and tetrahydrobiopterin, as well as by multiple abnormalities in iron metabolism (Fillet et al, 1989;Cazzola et al, 1990;Fuchs et al, 1991). A blockage of iron utilization within the maturing red blood cell has been suggested to play a crucial role in the pathogenesis of this disease (Weinberg, 1984;Means and Krantz, 1992).…”

Regulation of iron metabolism in the acute‐phase response: interferon γ and tumour necrosis factor α induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients

“…Second, tissue iron release may be affected by cytokines. Ferrokinetic studies in humans have demonstrated that in inflammatory conditions iron release by the MPS is impaired, which correlates negatively with serum ferritin [25]. In rats with turpentine-induced inflammation an increase in ferritin synthesis precedes the fall in serum iron [26].…”

“…This iron shift may result from an increased influx of iron into storage compartments [22,23]. Concurrently, iron release by MPS and liver might be impaired, which is associated with an increased ferritin synthesis as reflected by elevated serum ferritin levels [24][25][26][27]. It has been speculated that modulation of intracellular iron processing results in a diversion of labile iron into the enhanced apoferritin pool [26].…”