b-Thalassemia is an inherited anemia in which synthesis of the hemoglobin b-chain is decreased. The excess unmatched a-globin chains accumulate in the growing erythroid precursors, causing their premature death (ineffective erythropoiesis). Clinical features of b-thalassemia include variably severe anemia and iron accumulation due to increased intestinal iron absorption. The most anemic patients require regular blood transfusions, which exacerbate their iron overload and result in damage to vital organs. The hepatic peptide hepcidin, a key regulator of iron metabolism in mammals, was recently found to be low in the urine of b-thalassemia patients, compared with healthy controls, despite their iron overload. In our work, we measured by RQ-PCR the liver mRNA expression of hepcidin and other iron regulatory genes in b-thalassemia major mouse model (C57Bl/6 Hbb th3/th3 ), and compared it with b-thalassemia intermedia mouse model (C57Bl/6 Hbb th3/þ ) and control mice. We found decreased expression of hepcidin and TfR2 and increased expression of TfR1 and NGAL in the b-thalassemia mouse models, compared with the control mice. Significant down-regulation of hepcidin expression in b-thalassemia major, despite iron overload, might explain the increased iron absorption typically observed in thalassemia. Am. J. Hematol. 81:479-483, 2006. V V C 2006 Wiley-Liss, Inc.

Summary β‐Thalassaemia represents a group of diseases, in which ineffective erythropoiesis is accompanied by iron overload. In a mouse model of β‐thalassaemia, we observed that the liver expressed relatively low levels of hepcidin, which is a key factor in the regulation of iron absorption by the gut and of iron recycling by the reticuloendothelial system. It was hypothesised that, despite the overt iron overload, a putative plasma factor found in β‐thalassaemia might suppress liver hepcidin expression. Sera from β‐thalassaemia and haemochromatosis (C282Y mutation) patients were compared with those of healthy individuals regarding their capacity to induce changes the expression of key genes of iron metabolism in human HepG2 hepatoma cells. Sera from β‐thalassaemia major patients induced a major decrease in hepcidin (HAMP) and lipocalin2 (oncogene 24p3) (LCN2) expression, as well as a moderate decrease in haemojuvelin (HFE2) expression, compared with sera from healthy individuals. A significant correlation was found between the degree of downregulation of HAMP and HFE2 induced by β‐thalassaemia major sera (r = 0·852, P < 0·0009). Decreased HAMP expression was also found in HepG2 cells treated with sera from β‐thalassaemia intermedia patients. In contrast, the majority of sera from hereditary haemochromatosis patients induced an increase in HAMP expression, which correlated with transferrin (Tf) saturation (r = 0·765, P < 0·0099). Our results suggest that, in β‐thalassaemia, serum factors might override the potential effect of iron overload on HAMP expression, thereby providing an explanation for the failure to arrest excessive intestinal iron absorption in these patients.