Regulation of iron metabolism through GDF15 and hepcidin in pyruvate kinase deficiency

Department of Medicine II, Medical University of Innsbruck, Innsbruck, Austria.
British Journal of Haematology (Impact Factor: 4.71). 03/2009; 144(5):789-93. DOI: 10.1111/j.1365-2141.2008.07535.x
Source: PubMed


Iron absorption is inadequately increased in patients with chronic haemolytic anaemia, which is commonly complicated by iron overload. Growth differentiation factor 15 (GDF15) has been identified as a bone marrow-derived factor that abrogates hepcidin-mediated protection from iron overload under conditions of increased erythropoiesis. Increased concentrations of GDF15 have been reported in beta-thalassaemia patients and GDF15 has been found to suppress hepcidin expression in vitro. To further study the interdependencies of iron metabolism and erythropoiesis in vivo, the concentrations of hepcidin and GDF15 were determined in sera from 22 patients with pyruvate kinase deficiency (PKD) and 21 healthy control subjects. In PKD patients, serum hepcidin levels were 13-fold lower than in controls (2.0 ng/ml vs. 26.2 ng/ml) and GDF15 was significantly higher (859 pg/ml vs. 528 pg/ml). Serum hepcidin concentrations correlated positively with haemoglobin and negatively with serum GDF15. These results suggest that GDF15 contributes to low hepcidin expression and iron loading in PKD.

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Available from: Anthony T Murphy, Sep 25, 2015
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    • "Pyruvate kinase deficiency results in defective glycolysis resulting in erythroblast apoptosis and peripheral blood hemolysis [28] [29]. Pyruvate kinase deficiency is being investigated as a separate cause of ineffective erythropoiesis, but iron overloading is less consistent among these patients [30]. Other erythroid disorders associated with some degree of ineffective erythropoiesis include chronic pernicious anemia, hereditary spherocytosis, and sickle cell anemia [31] [32]. "
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    ABSTRACT: Erythropoiesis describes the hematopoietic process of cell proliferation and differentiation that results in the production of mature circulating erythrocytes. Adult humans produce 200 billion erythrocytes daily, and approximately 1 billion iron molecules are incorporated into the hemoglobin contained within each erythrocyte. Thus, iron usage for the hemoglobin production is a primary regulator of plasma iron supply and demand. In many anemias, additional sources of iron from diet and tissue stores are needed to meet the erythroid demand. Among a subset of anemias that arise from ineffective erythropoiesis, iron absorption and accumulation in the tissues increases to levels that are in excess of erythropoiesis demand even in the absence of transfusion. The mechanisms responsible for iron overloading due to ineffective erythropoiesis are not fully understood. Based upon data that is currently available, it is proposed in this review that loading and overloading of iron can be regulated by distinct or combined mechanisms associated with erythropoiesis. The concept of erythroid regulation of iron is broadened to include both physiological and pathological hepcidin suppression in cases of ineffective erythropoiesis.
    Advances in Hematology 05/2010; 2010(4, supplement 1):358283. DOI:10.1155/2010/358283
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    • "when compared with patients suffering from thalassaemia major ( mean 66AE000 pg / ml ) ( Tanno et al , 2007 ) . Although GDF15 levels in ACD patients were higher than those reported for PKD and sickle cell disease patients ( mean 880 pg / ml ) ( Tanno et al , 2007 ; Finkenstedt et al , 2009 ) we believe that , in contrast to patients with b - thalassaemia , GDF15 levels in ACD are too low to effectively suppress inflammation and iron - triggered hepci - din expression . Recently Lakhal et al ( 2009 ) demonstrated significantly increased GDF15 levels in patients with serum iron levels <8 lmol / l when compared to patients with iron concentra - tions of more than 14 lmol / l . "
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    ABSTRACT: Recently, the iron and erythropoiesis-controlled growth differentiation factor 15 (GDF15) has been shown to inhibit the expression of hepcidin in beta-thalassaemia patients, thereby increasing iron absorption despite iron overload. To access the diagnostic and pathogenic impact of GDF15 in inflammatory anaemia the association of GDF15 expression with serum iron parameters and hepcidin was studied in patients suffering from iron deficiency anaemia (IDA), anaemia of chronic disease (ACD) and ACD subjects with true iron deficiency (ACD/IDA). GDF15 was significantly increased in both ACD and ACD/IDA, but not in IDA subjects as compared to controls. In contrast, hepcidin levels were significantly lower in IDA and ACD/IDA subjects than in ACD patients. IDA and ACD/IDA, but not ACD, showed an association between GDF15 and soluble transferrin receptor, an indicator of iron requirement for erythropoiesis. However, GDF15 did not correlate to hepcidin in either patient group. While GDF15 levels were linked to the needs for erythropoiesis and iron homeostasis in IDA, the immunity-driven increase of GDF15 may not primarily affect iron homeostasis and hepcidin expression. This indicates that other ACD-related factors may overcome the regulatory effects of GDF15 on hepcidin expression during inflammation.
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