Hepcidin Levels and Their Determinants in Different Types of Myelodysplastic Syndromes

Abstract

Iron overload may represent an additional clinical problem in patients with Myelodysplastic Syndromes (MDS), with recent data suggesting prognostic implications. Beyond red blood cells transfusions, dysregulation of hepcidin, the key iron hormone, may play a role, but studies until now have been hampered by technical problems. Using a recently validated assay, we measured serum hepcidin in 113 patients with different MDS subtypes. Mean hepcidin levels were consistently heterogeneous across different MDS subtypes, with the lowest levels in refractory anemia with ringed sideroblasts (RARS, 1.43 nM) and the highest in refractory anemia with excess blasts (RAEB, 11.3 nM) or in chronic myelomonocytic leukemia (CMML, 10.04 nM) (P = 0.003 by ANOVA). MDS subtypes remained significant predictors of hepcidin in multivariate analyses adjusted for ferritin and transfusion history. Consistently with current knowledge on hepcidin action/regulation, RARS patients had the highest levels of toxic non-transferrin-bound-iron, while RAEB and CMML patients had substantial elevation of C-Reactive Protein as compared to other MDS subtypes, and showed lost of homeostatic regulation by iron. Growth differentiation factor 15 did not appear as a primary hepcidin regulator in this series. If confirmed, these results may help to calibrate future treatments with chelating agents and/or hepcidin modulators in MDS patients.

Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis

“…Our observations reveal that hepcidin levels are significantly dysregulated in PMF; despite this, there was evidence of relatively preserved homeostatic control of hepcidin by iron, as reflected by the strongly positive correlation between hepcidin and ferritin levels. This correlation was independent of DIPSS-plus risk stratification, unlike what has been observed in MDS patients stratified by WHO subtype [16,17]; the latter analysis suggested relatively preserved homeostatic control in some MDS subtypes such as refractory anemia, refractory anemia with ringed sideroblasts, and 5q-syndrome but near complete loss of regulation in others such as refractory anemia with excess blasts and chronic myelomonocytic leukemia. The positive correlation between hepcidin and ferritin levels in PMF was found regardless of whether patients were RBC transfusion requiring at the time of sample collection.…”

Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

“…Furthermore, it has been shown that this erythropoietic signaling pathway can override hepcidin regulation by iron, as shown by the paradoxical association of low serum hepcidin levels and tissue iron overload both in mouse models 22,33,34 and patients 5,35 with b thalassemia, congenital dyserythropoietic anemia, 36 or myelodysplastic syndrome. 4 The normal Tf saturation seemed to limit iron loading of hepatocytes, on the contrary to what is observed in hemochromatosis with normal erythropoiesis or in ironloading anemia with ineffective erythropoiesis, where hepcidin is also fully suppressed but leads to heavy hepatocyte iron overload. 22,33,34 In hemolytic conditions, hemeand Hb-derived iron contributes to tissue iron loading independently of Tf-bound iron.…”

“…3 Since low hepcidin levels favor intestinal iron absorption and mobilization of tissue iron stores, its repression accounts for the paradoxical condition known as iron loading anemia. 4,5 In hemolytic anemia, much less is known about hepcidin expression and the pattern of iron loading compared to anemia with ineffective erythropoiesis. Intravascular hemolysis leads to massive red blood cell (RBC)-free Hb and heme, which are chaperoned by haptoglobin (Hp) and hemopexin (Hpx), respectively, and cleared by spleen and liver macrophages via CD163 and CD91, respectively.…”

Iron overload in myelodysplastic syndromes (MDS)

“…Iron overload (IOL) in MDS starts before patients become transfusion-dependent because ineffective erythropoiesis suppresses hepcidin production in the liver and thus leads to unrestrained intestinal iron uptake [1]. However, the most important cause of iron overload in MDS is chronic transfusion therapy.…”