The Relationship Between Erythropoetic Activity and Iron Burden In Patients With Myelodysplastic Syndrome

Although prolonged red blood cells (RBC) transfusion therapy appears to be the main contributor to iron overload, many patients have developed it at an early stage of the disease, before the onset of transfusions in MDS. Growth differentiation factor 15 (GDF-15), a protein produced by erythroid precursors, has been proposed to be a major hepcidin suppressor in ß-thalassemia, but data in the expression of hepcidin and GDF15 levels in MDS are less conclusive. To determine whether the erythropoetic activity affect the iron burden though GDF15 in patients with MDS, we determined the GDF15 levels as well as other markers of erythropoiesis and iron overload (soluble transferrin receptor [sTfR], erythropoietin [EPO], ferritin and hepcidin) in MDS without transfution.

One hundred and seven consecutive patients (mean age 50 years; 62% males) with MDS diagnosed between April, 2011 and March, 2013 at the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences (CAMS) were included. To be enrolled in this study, patients had to be previously treated without transfusion. To do a comparison with respect to serum hepcidin levels, the hepcidin/ferritin ratio and GDF15 levels, a group of forty healthy individuals (45% males) with rigorous definition of normal iron status were used as controls.

MDS patients had significantly higher levels of serum SF, GDF-15, and EPO as compared to the controls. GDF15 concentrations significant positively correlated with percent of bone marrow erythroblasts (P <0.001), sTfR (P = 0.018), ISAT (P =0.038) and negatively correlated with TRF (P=0.008). The hepcidin to ferritin ratio was strongly decreased in MDS patients as compared to the controls (P<0.001). The hepcidin to ferritin ratio also showed a significant variability across different MDS subtypes (P = 0.011), with the lowest values in patients with refractory anemia with ringed sideroblasts (RARS). GDF15 levels consistently heterogeneous across different MDS subtypes (P=0.005), with the highest levels in patients with RARS and the lowest levels in the RAEB and RCMD cohorts. A negative correlation between the hepcidin/SF ratio and GDF15 was found(r=-0.279, P=0.014). Both hepcidin and hepcidin/SF ratio were negatively correlated with EPO in MDS patients (r=-0.250, P=0.022 and r=-0.449, P<0.001 respectively). Furthermore, a negative correlation between hepcidin levels and HIF-1α mRNA expression was found in 28 MDS patients(r=-0.377, P=0.048), but there was no relationship in terms of hepcidin and HIF-2α mRNA expression. The hepcidin to ferritin ratio was independently associated with GDF15 concentration and WHO subtype in multivariable analysis (β=-0.292，P =0.029 and β=-0.390，P =0.006).

Iron overload occurs in MDS patients even without transfusion. Hepcidin concentrations are inappropriately low considering the severe iron overload. High level of GDF15 is a feature of ineffective erythropiesis in MDS. GDF15 is among the erythroid factors down-regulating hepcidin and contributes to iron overload in conditions of dyserythropoiesis in MDS.

No relevant conflicts of interest to declare.