Background: Pro-hepcidin is 10 kDa peptide localized at the basolateral membrane of hepatocytes which is also present in plasma and is believed to be a hepcidin precursor (

Kulaksis et al,
Gut
2004
;
53
). Experimental hepatic iron loading in mice up-regulates hepcidin mRNA while iron deficiency has the reverse effect (
Pigeon et al,
JBC
2001
;
276
). Paradoxically mice with a thalassaemia intermedia phenotype had reduced liver hepcidin mRNA. Furthermore, presentation of non-transferrin bound iron (NTBI) to human liver cells (
Nemeth,
Blood
2003
;
101
)(Rafique, 2004 in preparation) decreased hepcidin mRNA. Patients and methods: 3 groups of patients were compared (thalassaemia major (TM), thalassaemia intermedia (TI) and sickle cell anaemia (HbSS)) to examine if variations in pro-hepcidin expression could account for the differences in iron loading. Pro-hepcidin measurements were performed at 1:1 dilutions in duplicate with a Pro-hepcidin ELISA (DRG diagnostics) using a previously published method (Kulakis, 2004). Iron status was evaluted by liver CMR , serum ferritin and NTBI; C reactive protein (CRP) was measured to exclude inflammation. All patients with a raised creatinine were excluded from the analysis. Results: TI patients (n=20) had a significantly lower serum pro-hepcidin (77 ± 40ng/ml) ( p<0.001) compared to HbSS (n=26) (111 ± 53 ng/ml), TM (n=27) (107 ± 44.5ng/ml) or control subjects (n=9) (119 ± 45ng/ml). The difference in serum pro-hepicidin between TI and HbSS persisted when patients were matched for serum ferritin (p = 0.02) or liver iron (p < 0.001). NTBI was significantly lower in HbSS (1.06 ± 0.27umol/l) than TI (2.49 ± 2.01 umol/l) even when patients were matched for serum ferritin (p <0.001) or for liver iron (p <0.05). Hb values were not significantly different between TI (8.6 g/dl) and HbSS patients (8.9g/dl). When all patients with a Hb <8g/dl were compared to those with a Hb > 10g/dl serum pro-hepcidin was not significantly different. No correlation between serum pro-hepcidin and liver iron, serum ferritin, CRP or Hb in any of the three groups was seen. Conclusion: Pro-hepcidin is significantly lower in TI than TM or HbSS patients and this cannot be accounted for by levels of anemia. We propose that NTBI, present early in TI secondary to high ineffective erythropoiesis, may lead to a similar paradoxical decrease in hepcidin synthesis reported in model systems and that this is reflected by reduced serum pro-hepcidin. Although levels of NTBI and liver iron did not differ significantly in TI and TM , transfusion and chelation therapy in TM may overide the NTBI mediated down regulation of pro-hepcidin. In HbSS, NTBI is lower than in TI or TM at matched levels of iron loading, resulting in less inhibition of pro-hepcidin synthesis and less duodenal iron absorption than in TI.

Topics:
hepcidin, iron, thalassemia intermedia, serum ferritin level result, c-reactive protein, rna, messenger, anemia, cardiac mri, chelation therapy, cooley's anemia

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2005, The American Society of Hematology
2004
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