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.

Juvenile Hemochromatosis With Non-transfused Hemolytic Anemia Caused by a De Novo PIEZO1 Gene Mutation

“…13 In such adult cases of DHS1, organ damages induced by iron overload are severe, including the liver, pancreas, heart, and hypophysis. 11,13,18 However, in this juvenile case in which diagnosis was made early, iron overload was still limited at the liver and skin. Accordingly, though this case may be a mild phenotype, preventing further progression to multiorgan iron overload is essential.…”

“…Accordingly, the diagnosis could be delayed until late in adulthood after the development of diabetes mellitus by pancreatic iron overload 13. In such adult cases of DHS1, organ damages induced by iron overload are severe, including the liver, pancreas, heart, and hypophysis 11,13,18. However, in this juvenile case in which diagnosis was made early, iron overload was still limited at the liver and skin.…”

“…In terms of the mechanisms underlying iron overload in DHS1, particularly in the liver, gain-of-function mutations in PIEZO1 are assumed to directly suppress serum hepcidin levels and impair hepatic iron metabolism. 11,18 Ma et al 19 also found that constitutive or macrophage expression of a gain-of-function PIEZO1 allele disrupts levels of hepcidin and causes iron overload in a mouse model. Patients with a severe DHS1 phenotype harbor mutations in the pore domain (p.2189-2547) rather than in the non-pore domain of the PIEZO1 gene.…”

“…The case presented herein was confirmed as a de novo one. In terms of the mechanisms underlying iron overload in DHS1, particularly in the liver, gain-of-function mutations in PIEZO1 are assumed to directly suppress serum hepcidin levels and impair hepatic iron metabolism 11,18. Ma et al19 also found that constitutive or macrophage expression of a gain-of-function PIEZO1 allele disrupts levels of hepcidin and causes iron overload in a mouse model.…”

Molecular Pathways Involved in the Development of Congenital Erythrocytosis

“…TRF2 functions as a sensor for the circulating transferrin-bound iron, and it is highly expressed in the liver. TFR1 is responsible for iron uptake from plasma transferrin to the cells and is ubiquitously expressed in most of the cells, especially in erythroid precursors [146,147]. However, in erythrocyte production, hepcidin synthesis is additionally regulated through erythroferrone hormone (ERFE) secreted by EPO-stimulated erythroblasts in JAK2/STAT5 dependent manner [141,147].…”