Albertine Donker

Chapter 1 28 PATHOPHYSIOLOGY OF SYSTEMIC AND CELLULAR IRON METABOLISM Various genetic and acquired disorders of iron metabolism may result in iron deficiency or iron loading As described in the previous section, iron homeostasis is tightly regulated on the systemic and cellular level in order to ensure adequate organ supply in a hierarchical manner, with prioritization of the erythroblasts over the brain, heart, skeletal muscle and other organ systems in descending order. 12,91 However, various genetic and acquired conditions may result in a failure of these regulatory systems to maintain adequate systemic and/or cellular iron levels. On one side of the spectrum, ID occurs when iron demands exceed iron supply. If iron stores are fully depleted, IDA develops. On the systemic level, the mechanisms of adaption to (imminent) ID are centered on the suppression of hepcidin synthesis in order to allow increased enteral iron absorption and iron recycling from the macrophages. MT2, encoded by TMPRSS6 is essential for this process as described in the previous section. At the cellular level, the IRE/IRP system post-transcriptionally regulates cellular proteins resulting in increased iron import and decreased iron storage and export, and a reduction in heme synthesis in response to (imminent) ID and tissue hypoxia. Furthermore, tissue hypoxia due to anemia induces the kidneys to produce erythropoietin (EPO) in response to enhanced levels of HIF2α. As a consequence of this EPO production, erythropoiesis is increased, resulting in a further decrease of hepcidin production. Mice studies suggest that ERFE, secreted by the erythroblasts, plays a critical role in this pathway. 92 Apart from its effects on the EPO production by the kidneys, HIF2α also increases iron absorption by the intestine via direct transcriptional activation of DMT1, DCYTB and FPN. These mechanisms indicate that hypoxia links erythropoiesis with iron homeostasis. 93 Once stores are exhausted, levels of circulating iron decrease, even if absorption from the enteral lumen is increased. Reduced levels of iron in the liver trigger an increase in the synthesis of the apo-transferrin, further decreasing levels of TBI. Consequently, the uptake of iron from TfRs by all cells and organs is reduced. Owing to the low availability of iron, hypochromic, microcytic erythrocytes are produced, characteristic of IDA. 94,95