The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance

Abstract

Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA.

Keywords: erythropoiesis; ineffective erythropoiesis; iron metabolism; iron overload.

Figure 1

Simplified overview of iron homeostasis. Thickness of arrows reflects amount of iron per compartment. In humans, daily absorption of iron, as well as iron loss, is minimal. Most iron is either stored, used for cellular processes or is present in the erythroid compartment. (A) Iron recycling within the erythroid compartment. Iron is incorporated in hemoglobin and recycling of iron occurs due to splenic clearance of senescent red blood cells. (B) Iron absorption, transport and storage. Enteral absorption is facilitated by divalent metal transporter 1 (DMT1). Iron is processed and secreted to the circulation via ferroportin (FPN), the carrier protein through which stored iron is also secreted from within macrophages and hepatocytes. In the circulation iron binds to transferrin (Tf) and cellular uptake occurs upon binding of Tf to transferrin receptor 1 (TfR1). Iron is primarily stored as ferritin within cells. (C) Hepcidin-ferroportin axis. Hepcidin expression is predominantly induced by the bone morphogenetic protein (BMP)/Smad signaling pathway, upon increased serum iron levels. Alternatively, the Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is activated upon inflammation through interleukin-6 (IL-6). Hepcidin blocks FPN-dependent iron export, and induces FPN degradation, resulting in a limitation of iron absorption and iron efflux from body iron storages [16].

Figure 2

Simplified overview of connecting factors in erythropoiesis and iron metabolism. (A) Healthy situation. Normal production of red blood cells (RBCs) to prevent tissue hypoxia, erythropoietin (EPO) levels are low. erythroferrone (ERFE) levels are normal, little impact on iron metabolism. (B) Acute anemia or EPO injection. Low levels of oxygen lead to increased EPO levels. EPO stimulates erythroblast proliferation and maturation and subsequently upregulation of soluble transferrin receptor 1 (sTfr1) and ERFE levels. Hepcidin levels are suppressed via ERFE, allowing increased iron uptake, followed by incorporation in hemoglobin in erythroblasts. This results in an increase in RBCs and compensation for the anemia. (C) Iron loading anemia. This is characterized by ineffective erythropoiesis, resulting in suboptimal compensation for anemia, leading to a constitutively hyperactive bone marrow and a persistent increase in EPO and sTfR levels, with or without high reticulocyte numbers. Iron levels are sufficient to cover for erythroid demand. Hepcidin levels are persistently low, partially due to high ERFE levels, leading to iron overload.