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.

Oxidative stress and inflammation in iron‐overloaded patients with β‐thalassaemia or sickle cell disease

“…Inflammation may also be contributing to the lower NTBI levels observed in SCD, further protecting against tissue injury by removing a source of circulating labile iron. In summary, we suggest that the unique inflammatory physiology of SCD may protect against organ injury by restricting iron to protected areas within the RE system (Fillet et al, 1989;Ludwiczek et al, 2003) and maintaining protective antioxidants.…”

“…Our results support these observations. Inflammation (Fillet et al, 1989) and cytokines (IL-10) stimulate the uptake and retention of iron into monocytes and reticuloendothelial (RE) cells (Ludwiczek et al, 2003). Recently, hepcidin that is increased in inflammation, has been identified as a critical participant in this cellular regulation of iron storage (Papanikolaou et al, 2005).…”

Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3)

“…The Val 162 deletion in ferroportin gene appears therefore to represent a loss-of-function mutation that mainly impairs reticuloendothelial iron metabolism, although it has no major impact on intestinal iron absorption in heterozygous individuals. The alteration in reticuloendothelial iron metabolism is the opposite of that found in HFE-related genetic haemochromatosis, a condition characterized by increased macrophage iron release (Fillet et al, 1989). Protein topology modelling predicts 9-10 transmembrane region for ferroportin protein (Devalia et al, 2002).…”

Effect of repeated apotransferrin administrations on serum iron parameters in patients undergoing myeloablative conditioning and allogeneic stem cell transplantation

“…Furthermore, the administration of large doses of apotransferrin to animals did not modify iron donation by tissue (Lipschitz et al, 1971;Finch et al, 1982). In human studies no correlation between transferrin saturation level and release of radioactive iron to plasma has been observed (Stefanelli et al, 1984;Fillet et al, 1989). Bradley et al (1997) originally suggested that the appearance of NTBI after high-dose chemotherapy is the consequence of suspension of the erythropoietic activity.…”