Iron overload across the spectrum of non‐transfusion‐dependent thalassaemias: role of erythropoiesis, splenectomy and transfusions

Abstract

SummaryNon‐transfusion‐dependent thalassaemias (NTDT) encompass a spectrum of anaemias rarely requiring blood transfusions. Increased iron absorption, driven by hepcidin suppression secondary to erythron expansion, initially causes intrahepatic iron overload. We examined iron metabolism biomarkers in 166 NTDT patients with β thalassaemia intermedia (n = 95), haemoglobin (Hb) E/β thalassaemia (n = 49) and Hb H syndromes (n = 22). Liver iron concentration (LIC), serum ferritin (SF), transferrin saturation (TfSat) and non‐transferrin‐bound iron (NTBI) were elevated and correlated across diagnostic subgroups. NTBI correlated with soluble transferrin receptor (sTfR), labile plasma iron (LPI) and nucleated red blood cells (NRBCs), with elevations generally confined to previously transfused patients. Splenectomised patients had higher NTBI, TfSat, NRBCs and SF relative to LIC, than non‐splenectomised patients. LPI elevations were confined to patients with saturated transferrin. Erythron expansion biomarkers (sTfR, growth differentiation factor‐15, NRBCs) correlated with each other and with iron overload biomarkers, particularly in Hb H patients. Plasma hepcidin was similar across subgroups, increased with >20 prior transfusions, and correlated inversely with TfSat, NTBI, LPI and NRBCs. Hepcidin/SF ratios were low, consistent with hepcidin suppression relative to iron overload. Increased NTBI and, by implication, risk of extra‐hepatic iron distribution are more likely in previously transfused, splenectomised and iron‐overloaded NTDT patients with TfSat >70%.

Investigation and management of a raised serum ferritin

“…A variety of red cell disorders, characterised by ineffective erythropoiesis or haemolysis, are associated with increased iron absorption from the gastrointestinal tract and the resultant increased SF, even in the absence of red cell transfusion therapy (Porter et al , ); these include thalassaemic disorders, such as thalassaemia intermedia, pyruvate kinase deficiency, hereditary spherocytosis (Bolton‐Maggs et al , ), and inherited or acquired sideroblastic anaemias. Prolonged or chronic transfusion therapy, for example in patients with major haemoglobinopathies, myelodysplastic syndromes, or during treatment for haematological malignancies, will also cause transfusional iron overload.…”

Thalassemias: An Overview

“…Interestingly, causative factors of NTDT are variable, including mostly β-thalassemia intermedia and HbE/β-thalassemia but also HbH disease (which belongs to the α-thalassemia group). There are differences in both the biomarkers of iron metabolism and erythropoiesis as well as in the clinical manifestations among the various causative factors [39]. For instance, HbH disease in the Mediterranean has the mildest effects but can be severe in South East Asia.…”

Is there a difference in phenotype between males and females with non-transfusion-dependent thalassemia? A cross-sectional evaluation

“…Non-transfusion-dependent thalassemia (NTDT) encompasses a phenotypical and genotypical heterogeneous group of hemoglobinopathies, rarely requiring regular transfusion therapy. Despite relative independence from transfusions these patients experience a wide range of comorbidities and complications, which are the consequence of complex interactions of multiple pathophysiological factors: chronic anemia, ineffective erythropoiesis, hypercoagulability, and iron overload [1,2]. The treatment of NTDT relies on occasional or more frequent blood transfusions (during severe infection, pregnancy, and surgery), iron chelation, splenectomy, and hydroxyurea (HU).…”