title: Erythropoiesis-driven regulation of hepcidin in human red  cell disorders is better reflected through concentrations of  soluble transferrin receptor rather than growth  differentiation factor 15.
abstract: Growth differentiation factor 15 (GDF-15) is a bone marrow-derived cytokine whose ability to suppress iron regulator hepcidin in vitro and increased concentrations found in patients with ineffective erythropoiesis (IE)suggest that hepcidin deficiency mediated by GDF-15 may be the pathophysiological explanation for nontransfusional iron overload. We aimed to compare GDF-15 production in anemic states with different types of erythropoietic dysfunction. Complete blood counts, biochemical markers of iron status, plasma hepcidin, GDF-15, and known hepcidin regulators [interleukin-6 and erythropoietin (EPO)] were measured in 87 patients with red cell disorders comprising IE and hemolytic states: thalassemia, sickle cell anemia, and cobalamin deficiency. Healthy volunteers were also evaluated for comparison. Neither overall increased EPO,nor variable GDF-15 concentrations correlated with circulating hepcidin concentrations (P = 0.265 and P = 0.872). Relative hepcidin deficiency was found in disorders presenting with concurrent elevation of GDF-15 and soluble transferrin receptor (sTfR), a biomarker of erythropoiesis, and sTfR had the strongest correlation with hepcidin (r(s) = 0.584, P < 0.0001). Our data show that high concentrations of GDF-15 in vivo are not necessarily associated with pathological hepcidin reduction, and hepcidin deficiency was only found when associated with sTfR overproduction. sTfR elevation may be a necessary common denominator of erythropoiesis-driven mechanisms to favor iron absorption in anemic states and appears a suitable target for investigative approaches to iron disorders.
authors.affiliation: Instituto Nacional de Ciência e Tecnologia do Sangue (INCTS), Hematology and Hemotherapy Center, University of Campinas, Campinas, Brazil.
authors.forename: Kleber Yotsumoto
authors.initials: KY
authors.lastname: Fertrin
authors.forename: Carolina
authors.initials: C
authors.lastname: Lanaro
authors.forename: Carla Fernanda
authors.initials: CF
authors.lastname: Franco-Penteado
authors.forename: Dulcinéia Martins
authors.initials: DM
authors.lastname: de Albuquerque
authors.forename: Mariana Rezende Bandeira
authors.initials: MR
authors.lastname: de Mello
authors.forename: Flávia Rubia
authors.initials: FR
authors.lastname: Pallis
authors.forename: Marcos André Cavalcanti
authors.initials: MA
authors.lastname: Bezerra
authors.forename: Betania Lucena Domingues
authors.initials: BL
authors.lastname: Hatzlhofer
authors.forename: Gordana
authors.initials: G
authors.lastname: Olbina
authors.forename: Sara Terezinha Olalla
authors.initials: ST
authors.lastname: Saad
authors.forename: Aderson
authors.initials: A
authors.lastname: da Silva Araújo
authors.forename: Mark
authors.initials: M
authors.lastname: Westerman
authors.forename: Fernando Ferreira
authors.initials: FF
authors.lastname: Costa
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000097:blood; D016022:Case-Control Studies; D004912:Erythrocytes / Q000378:metabolism*; D004920:Erythropoiesis; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006402:Hematologic Diseases / Q000097:blood*; D064451:Hepcidins / Q000097:blood*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism; D000090463:Iron Deficiencies; D019190:Iron Overload / Q000097:blood; D008297:Male; D011990:Receptors, Transferrin / Q000097:blood*; D014168:Transferrin / Q000378:metabolism*
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D064451:Hepcidins; D011990:Receptors, Transferrin; D014168:Transferrin; D007501:Iron