Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis

Bridle, K. R., Frazer, D. M., Wilkins, S. J., Dixon, J. L., Purdie, D. M., Crawford, D. H. G., Subramaniam, V. N, Powell, L. W., Anderson, G. J. and Ramm, G. A. (2003) Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet, 361 9358: 669-673. doi:10.1016/S0140-6736(03)12602-5

Author Bridle, K. R.
Frazer, D. M.
Wilkins, S. J.
Dixon, J. L.
Purdie, D. M.
Crawford, D. H. G.
Subramaniam, V. N
Powell, L. W.
Anderson, G. J.
Ramm, G. A.
Title Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis
Journal name Lancet   Check publisher's open access policy
ISSN 0140-6736
Publication date 2003-02-22
Year available 2003
Sub-type Article (original research)
DOI 10.1016/S0140-6736(03)12602-5
Open Access Status Not yet assessed
Volume 361
Issue 9358
Start page 669
End page 673
Total pages 5
Place of publication London
Publisher Lancet
Language eng
Subject C1
321006 Gastroenterology and Hepatology
730118 Organs, diseases and abnormal conditions not elsewhere classified
Abstract Background The mechanisms responsible for disturbed iron homoeostasis in hereditary haemochromatosis are poorly understood. However, results of some studies indicate a link between hepcidin, a liver-derived peptide, and intestinal iron absorption, suggesting that this molecule could play a part in hepatic iron overload. To investigate this possible association, we studied the hepatic expression of the gene for hepcidin (HAMP) and a gene important in iron transport (IREG1) in patients with haemochromatosis, in normal controls, and in Hfe-knockout mice. Methods We extracted total RNA from the liver tissue of 27 patients with HFE-associated haemochromatosis, seven transplant donors (controls), and Hfe-knockout mice. HAMP and IREG1 mRNA concentrations were examined by ribonuclease protection assays and expressed relative to the housekeeping gene GAPD. Findings There was a significant decrease in HAMP expression in untreated patients compared with controls (5.4-fold, 95% CI 3.3-7.5; p<0.0001) despite significantly increased iron loading. Similarly, we noted a decrease in Hamp expression in iron-loaded Hfe-knockout mice. Hepatic IREG1 expression was greatly upregulated in patients with haemochromatosis (1.8-fold, 95% CI 1.5-2.2; p=0.002). There was a significant correlation between hepatic iron concentration and expression of HAMP (r=0.59, p=0.02) and IREG1 (r=0.67, p=0.007) in untreated patients. Interpretation Lack of HAMP upregulation in HFE-associated haemochromatosis despite significant hepatic iron loading indicates that HFE plays an important part in the regulation of hepcidin expression in response to iron overload. Our results imply that the liver is important in the pathophysiology of HFE-associated haemochromatosis. Furthermore, the increase in hepatic IREG1 expression in haemochromatosis suggests that IREG1 could function to facilitate the removal of excess iron from the liver.
Keyword Medicine, General & Internal
Autosomal-dominant Hemochromatosis
Hereditary Hemochromatosis
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID R01 DK57648-02
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2004 Higher Education Research Data Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 432 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 15 Aug 2007, 11:24:11 EST