Hepcidin is suppressed by erythropoiesis in hemoglobin E β-thalassemia and β-thalassemia trait

Abstract

Key Points• Expanded erythropoiesis strongly drives hepcidin suppression in severe transfusion-dependent HbE b-thalassemia.• b-thalassemia carriers, but not HbE carriers, have enhanced erythropoiesis associated with mildly suppressed hepcidin.Hemoglobin E (HbE) b-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE b-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE b-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, b-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE b-thalassemia and indicates that the epidemiology of b-thalassemia trait requires consideration when planning public health iron interventions. (Blood. 2015;125(5):873-880)

Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits

“…However, they showed reduced hepcidin levels and reduced hepcidin/ferritin ratio (both parameters approximately twice). These results are consistent with the data obtained on pediatric β-thalassemia carriers from Sri Lanka 22 . On the other hand, Guimaraes et al 20 found that only adult α-thalassemia carriers had significantly decreased hepcidin, while hepcidin of adult β-thalassemia carriers was insignificantly higher than in controls.…”

“…Elevated sTfR and GDF15 indicate increased but ineffective erythropoiesis in the bone marrow. Similar data were recently published for schoolchildren with β-thalassemia trait from Sri Lanka 22 and also for adult thalassemia carriers 20 . However, the study on adult thalassemia carriers showed that the β-thalassemia trait is associated with more profound negative effects on erythropoiesis than the α-thalassemia trait 20 .…”

“…On the other hand, the primary cause of iron overload in β-thalassemia major is regular transfusion therapy; hepcidin is higher than in β-thalassemia intermedia due to the suppressive effect of transfusions on ineffective erythropoiesis 19 . Recently, it was shown that carriers of β-or α-thalassemia allele too, have altered iron metabolism parameters and erythropoiesis despite the absence of clinical symptoms 20,22 .…”

Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia

“…8,9 In contrast to human patients who have dramatically reduced hepcidin production even in adulthood, [2][3][4][5] in the Th3/1 model, liver hepcidin mRNA expression is only low in young mice compared with wild-type (WT) mice of the same age; in adult Th3/1 mice, hepcidin expression becomes similar to that of WT mice. 10,11 However, even in adult Th3/1 mice, hepcidin levels are inappropriately low, considering their iron overload, consistent with the concept that inadequate levels of hepcidin cause the iron overload in thalassemic mice.…”

“…1 In b-thalassemia intermedia, patients do not require regular blood transfusions. 1 Even without the added iron load of transfusions, pathological suppression of the iron-regulatory hormone hepcidin [2][3][4][5] in patients with b-thalassemia syndromes results in excessive iron absorption. Subsequent iron accumulation in the liver, endocrine glands, and other organs leads to oxidative damage and severe clinical complications predominantly involving hepatic, endocrine, and vascular systems, but sparing the heart, at least compared with transfused patients.…”