Cellular and systemic mechanisms are active in responses to iron deficiency to compensate for the lack of iron. When compensatory mechanisms are overwhelmed depletion of total body iron and iron deficiency anemia occur. The cell iron sensor and regulatory proteins (IRPs) increase the synthesis of the iron importer transferrin receptor to take up more iron, while the translation of the iron store ferritin and iron exporter ferroportin is suppressed. “Ferritinophagy,” a process of degradation of ferritin in lysosomes, mediated by the cargo protein Nuclear Receptor Coactivator 4 (NCOA4), is activated to recover iron stored in ferritin. Suppression of hepcidin production to increased iron supply is a key mechanism to compensate for iron deficiency. With increased ferroportin activity macrophages recycle more iron to transferrin and iron absorption is enhanced. Inhibition of hepcidin expression is more marked in iron deficiency with than without anemia because the tissue hypoxia accompanying anemia further contributes to hepcidin suppression.
In the duodenal mucosa the effect of hepcidin on ferroportin is coupled to the function of hypoxia inducible factor-2alpha (HIF-2α). In the presence of anemia tissue hypoxia stabilizes HIF-2α, which controls the expression of iron transporters divalent metal transporter 1 (DMT1) and duodenal cytochrome B (DCYTB) on luminal and ferroportin on the basolateral membrane, increasing the flux of iron into the circulation. Microorganisms compete with the human host for iron, leading to the hypothesis that gut microbiota might contribute to systemic iron homeostasis. Studies in mice suggest that some Lactobacillae species increased in iron deficiency produce metabolites that inhibit HIF-2α function in duodenal mucosa to favor bacterial iron acquisition when availability is limited. Whether a similar competition occurs also in humans has to be verified.
The synthesis of erythropoietin (EPO) is modulated not only by hypoxia but also by iron. In iron deficiency without anemia EPO synthesis is attenuated because high IRPs partially suppressed translation of HIF-2α; this limits erythropoiesis, saving iron for other vital functions. In the presence of anemia, the need for oxygen delivery by erythroid cells prevails, HIF-2α is fully stabilized, and EPO is strongly increased. The sensitivity of erythroid cells to EPO may be iron-modulated also via transferrin receptor 2, which contributes to hepcidin activation in the liver and is a partner of the EPO receptor in erythroid cells. In absolute iron deficiency, erythroblasts and erythrocytes release excess iron to plasma through ferroportin, a mechanism of protection from oxidative stress that likely becomes a compensatory mechanism in iron deficiency.
Deficiency of iron for mitochondrial function is likely the most important event that affects skeletal muscle, cardiomyocytes, and brain. The hematological effects of iron deficiency are easily recognizable. Reduction of transferrin bound iron impairs the iron uptake by maturing erythroblasts and anemia develops, paralleling the severity of iron deficiency. Initially red cell count is preserved, although erythrocytes become smaller with reduced Hb content (Fig. 1).
Fig1. IRON DEFICIENCY ANEMIA. Peripheral blood smear (A, B), bone marrow (BM) aspirate (C), and Prussian blue stain of BM aspirate (D) from a 16-year-old girl with hemoglobin 6.7 g/dL, hematocrit 22.6%, and mean corpuscular volume 59.2 fL. Peripheral smear shows hypochromic microcytic red blood cells (A), with widening of the central pallor and “pencil” cells (B). Polychromatophilic erythroid precursors in the aspirated specimen have scanty cytoplasm that is irregular and vacuolated (C). The Prussian blue-stained aspirate shows no iron stores in multiple spicules (D).
Signs of iron deficiency may be evident in epithelial cells that require iron for continuous renewal; the recognition of the consequences of iron deficiency in other organs is more difficult in the lack of specific laboratory tests.
In inflammation the enhanced expression of hepcidin induced by pro-inflammatory cytokines like IL-6 withholds iron in macrophages and decreases plasma iron. Hypoferremia coupled with inappropriate EPO production impairs erythroid activity11. When true iron deficiency develops in the context of inflammation, adaptation to iron deficiency prevails and hepcidin decreases, provided the inflammatory trigger is not too powerful.
