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Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.
Lancet. 2003 Feb 22; 361(9358):669-73.Lct

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.

Authors+Show Affiliations

Hepatic Fibrosis Group, Queensland Institute of Medical Research, Royal Brisbane Hospital, Queensland, Herston, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12606179

Citation

Bridle, Kim R., et al. "Disrupted Hepcidin Regulation in HFE-associated Haemochromatosis and the Liver as a Regulator of Body Iron Homoeostasis." Lancet (London, England), vol. 361, no. 9358, 2003, pp. 669-73.
Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361(9358):669-73.
Bridle, K. R., Frazer, D. M., Wilkins, S. J., Dixon, J. L., Purdie, D. M., Crawford, D. H., Subramaniam, V. N., Powell, L. W., Anderson, G. J., & Ramm, G. A. (2003). Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet (London, England), 361(9358), 669-73.
Bridle KR, et al. Disrupted Hepcidin Regulation in HFE-associated Haemochromatosis and the Liver as a Regulator of Body Iron Homoeostasis. Lancet. 2003 Feb 22;361(9358):669-73. PubMed PMID: 12606179.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. AU - Bridle,Kim R, AU - Frazer,David M, AU - Wilkins,Sarah J, AU - Dixon,Jeanette L, AU - Purdie,David M, AU - Crawford,Darrell H G, AU - Subramaniam,V Nathan, AU - Powell,Lawrie W, AU - Anderson,Gregory J, AU - Ramm,Grant A, PY - 2003/2/28/pubmed PY - 2003/3/15/medline PY - 2003/2/28/entrez SP - 669 EP - 73 JF - Lancet (London, England) JO - Lancet VL - 361 IS - 9358 N2 - 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. SN - 0140-6736 UR - https://www.unboundmedicine.com/medline/citation/12606179/Disrupted_hepcidin_regulation_in_HFE_associated_haemochromatosis_and_the_liver_as_a_regulator_of_body_iron_homoeostasis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(03)12602-5 DB - PRIME DP - Unbound Medicine ER -