Soluble transferrin receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis

Abstract

Summary. Congenital anaemias due to ineffective erythropoiesis may be associated with excessive iron absorption and progressive iron loading. We investigated whether the soluble transferrin receptor (TfR) level was related to the degree of iron overload in 20 patients with thalassaemia intermedia, six patients with congenital dyserythropoietic anaemia type II (CDA II) and four patients with X-linked congenital sideroblastic anaemia (XLSA). All but two patients had increased serum ferritin levels (median 601 mg/l, range 105±2855 mg/l). Multiple regression analysis showed that 62% (P < 0´0001) of the variation in serum ferritin was explained by age and by changes in soluble TfR.Keywords: anaemia, erythropoiesis, erythropoietin, iron overload, soluble transferrin receptor.Congenital anaemias due to ineffective erythropoiesis can be associated with excessive iron absorption and progressive iron loading (Finch, 1994). Life-threatening iron overload may occur in non-transfused patients with thalassaemia intermedia (Pippard et al, 1979), congenital dyserythropoietic anaemia type II (CDA II) (Cazzola et al, 1983) and X-linked congenital sideroblastic anaemia (XLSA) (Cazzola et al, 1983;Peto et al, 1983). The degree of anaemia has been shown to be a poor predictor of iron loading, which correlates better with erythroid marrow activity. In fact studies of erythropoiesis and iron balance in anaemic patients have shown that expanded erythropoiesis is associated with increased iron absorption (Pootrakul et al, 1988).The mechanism by which the erythroid marrow expansion induces a positive iron balance is unknown (Finch, 1994). Recent observations suggest that HFE, an MCHrelated protein which is mutated in genetic haemochromatosis (Feder et al, 1996), may regulate iron homeostasis by interacting with transferrin receptor (TfR). HFE protein, in fact, binds to TfR with high af®nity and decreases binding of diferric transferrin . In addition, soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles (Lebron et al, 1998).A soluble form of TfR, probably representing a truncated form of tissue receptor, is present in human plasma (Huebers et al, 1990). The erythroid marrow is its main source and the soluble TfR concentration is increased in conditions with erythroid hyperplasia. We investigated whether the level of soluble TfR was related to the degree of iron overload in a group of patients with congenital anaemia due to ineffective erythropoiesis. PATIENTS AND METHODSWe studied 20 patients with thalassaemia intermedia, six patients with CDA II and four patients with XLSA who had received no or only occasional blood transfusions; their ages ranged from 7 to 66 years. The 20 patients with thalassaemia intermedia were followed at the Haematology Department of the Istituto di Clinica e Biologia dell'Eta Á Evolutiva, University of Cagliari, Sardinia, Italy. All were of Sardinian descent and ful®lled accepted criteria for a diagnosis of thalassaemia intermedia. The six patie...

Elevated growth differentiation factor 15 expression in patients with congenital dyserythropoietic anemia type I

“…Consistent with a previous study of dyserythropoietic anemia patients, 12 significantly higher levels of serum erythropoietin were detected among the CDA I population (EPO; CDA I, 118 Ϯ 59 IU/ dL; HV, 2.0 Ϯ 1.5 IU/dL, P ϭ 2.3 ϫ 10 Ϫ7 ; Figure 1B). Soluble transferrin receptor levels were also elevated (sTfR; CDA I, 86.4 Ϯ 14.0 nmol/L; HV, 21.4 Ϯ 6.2 nmol/L, P ϭ 7.4 ϫ 10 Ϫ15 ; Figure 1C).…”

Therapeutic effects of induced pluripotent stem cells in chimeric mice with -thalassemia

“…[24][25][26][27][28][29] The sTfR expression levels are found to be normal in β Figure S4A), suggesting improved erythropoiesis in the chimeras.…”

Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin

“…The membrane bound form of this receptor binds holotransferrin leading to iron uptake by erythroid precursors and is subsequently shed during further red cell maturation -its circulating levels are therefore generally proportional to iron uptake, 23 and it has been suggested as a mediator of iron regulation in effective and ineffective erythropoiesis. 24 After erythropoietin administration, however, sTFR levels remained constant throughout the week, only beginning to rise from day 8 (23.5±0.6 vs. 18.3±0.5 pmol/mL, P=0.002, Figure 1F). …”