Hepcidin and Anemia: A Tight Relationship

Abstract

Hepcidin, the master regulator of systemic iron homeostasis, tightly influences erythrocyte production. High hepcidin levels block intestinal iron absorption and macrophage iron recycling, causing iron restricted erythropoiesis and anemia. Low hepcidin levels favor bone marrow iron supply for hemoglobin synthesis and red blood cells production. Expanded erythropoiesis, as after hemorrhage or erythropoietin treatment, blocks hepcidin through an acute reduction of transferrin saturation and the release of the erythroblast hormone and hepcidin inhibitor erythroferrone. Quantitatively reduced erythropoiesis, limiting iron consumption, increases transferrin saturation and stimulates hepcidin transcription. Deregulation of hepcidin synthesis is associated with anemia in three conditions: iron refractory iron deficiency anemia (IRIDA), the common anemia of acute and chronic inflammatory disorders, and the extremely rare hepcidin-producing adenomas that may develop in the liver of children with an inborn error of glucose metabolism. Inappropriately high levels of hepcidin cause iron-restricted or even iron-deficient erythropoiesis in all these conditions. Patients with IRIDA or anemia of inflammation do not respond to oral iron supplementation and show a delayed or partial response to intravenous iron. In hepcidin-producing adenomas, anemia is reverted by surgery. Other hepcidin-related anemias are the “iron loading anemias” characterized by ineffective erythropoiesis and hepcidin suppression. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias, congenital sideroblastic anemias, and some forms of hemolytic anemias as pyruvate kinase deficiency. The paradigm is non-transfusion-dependent thalassemia where the release of erythroferrone from the expanded pool of immature erythroid cells results in hepcidin suppression and secondary iron overload that in turn worsens ineffective erythropoiesis and anemia. In thalassemia murine models, approaches that induce iron restriction ameliorate both anemia and the iron phenotype. Manipulations of hepcidin might benefit all the above-described anemias. Compounds that antagonize hepcidin or its effect may be useful in inflammation and IRIDA, while hepcidin agonists may improve ineffective erythropoiesis. Correcting ineffective erythropoiesis in animal models ameliorates not only anemia but also iron homeostasis by reducing hepcidin inhibition. Some targeted approaches are now in clinical trials: hopefully they will result in novel treatments for a variety of anemias.

Iron Deficiency and Iron Deficiency Anemia: Implications and Impact in Pregnancy, Fetal Development, and Early Childhood Parameters

“…A detailed discussion of the regulation of iron balance is outside the scope of this review, and the reader is referred to recent reviews [23][24][25]. Iron content in the human body is carefully regulated Nutrients 2020, 12, 447 3 of 15 and is normally maintained at about 40 mg/kg in women and about 50 mg/kg in men.…”

“…When hepcidin levels are increased, iron is retained in enterocytes or macrophages and is not available for red cell production. When hepcidin is decreased, either because of ID or by increased erythropoiesis, absorbed iron in the enterocytes or stored iron in macrophages are mobilized into the circulation [23,24].…”

Age-Related Changes and Sex-Related Differences in Brain Iron Metabolism

“…Hepcidin expression decreases the iron absorption from the duodenal enterocytes, iron release from macrophages and its transport across the placenta [92,93]. The iron exporter required for iron egress from enterocytes, macrophages, as well as all other iron exporting cells including placental syncytiotrophoblasts and hepatocytes, is FPN1.…”

A Family Affected by a Life-Threatening Erythrocyte Defect Caused by Pyruvate Kinase Deficiency With Normal Iron Status: A Case Report

“…This is due to anemic stress which provokes ineffective erythropoiesis causing increased absorption and tissue accumulation of iron. Ineffective erythropoiesis and low or inappropriately normal hepcidin levels are noted in so called iron-loading anemias (Pagani et al, 2019). Indeed, low levels of hepcidin have been found in PK-deficient patients reflecting the effect of ineffective erythropoiesis on hepcidin production (Mojzikova et al, 2014).…”