Duodenal expression of iron transport molecules in untreated haemochromatosis subjects

Abstract

Gut 2003;52:953-959 Background and aims: In HFE associated hereditary haemochromatosis, the duodenal enterocyte behaves as if iron deficient and previous reports have shown increased duodenal expression of divalent metal transporter 1 (DMT1) and iron regulated gene 1 (Ireg1) in affected subjects. In those studies, many patients had undergone venesection, which is a potent stimulus of iron absorption. Our study investigated duodenal expression of DMT1 (IRE and non-IRE), Ireg1, hephaestin, and duodenal cytochrome-b (Dyctb) in untreated C282Y homozygous haemochromatosis patients, iron deficient patients, and iron replete subjects. Methods: Total RNA was extracted from duodenal biopsies and expression of the iron transport genes was assessed by ribonuclease protection assay. Results: Expression of DMT1 (IRE) and Ireg1 was increased 3-5-fold in iron deficient subjects compared with iron replete subjects. Duodenal expression of DMT1 (IRE) and Ireg1 was similar in haemochromatosis patients and iron replete subjects but in haemochromatosis patients with elevated serum ferritin concentrations, both DMT1 (IRE) and Ireg1 expression were inappropriately increased relative to serum ferritin concentration. Hephaestin and Dcytb levels were not upregulated in haemochromatosis. DMT1 (IRE) and Ireg1 levels showed significant inverse correlations with serum ferritin concentration in each group of patients. Conclusions: These findings are consistent with DMT1 (IRE) and Ireg1 playing primary roles in the adaptive response to iron deficiency. Untreated haemochromatosis patients showed inappropriate increases in DMT1 (IRE) and Ireg1 expression for a given level of serum ferritin concentration, although the actual level of expression of these iron transport genes was not significantly different from that of normal subjects.

Increased duodenal expression of divalent metal transporter 1 and iron-regulated gene 1 in cirrhosis

“…Rather, we showed an inappropriate increase in the level of DMT1 and Ireg1 expression for a given SF level. 22 A preliminary report by Kelleher et al 28 found that untreated subjects with HHC did not have increased DMT1 levels, but phlebotomy therapy resulted in marked increases in DMT1 levels similar to that observed in patients with iron deficiency anemia. The duodenal expression of these iron transporters has been studied in only a few patients with nonhemochromatosis chronic liver disease.…”

“…The expression of DMT1 or Ireg1 in the 46 subjects with cirrhosis did not correlate with hemoglobin levels as it did in controls, suggesting that the degree of anemia was not a significant factor causing increased expression of these iron transport genes in cirrhosis. Iron deficiency-an important cause of increased iron absorption and intestinal iron transporter expression 19,22,28 -is common in patients with cirrhosis and frequently is occult. 10,31 Iron deficiency was diagnosed in four subjects with cirrhosis and the expression of the iron transport genes in these four subjects was similar to that observed in the iron-deficient controls.…”

“…Ribonuclease protection assays were performed as previously described using 2-g samples of total RNA. 22 The riboprobes used corresponded to the following complementary DNA sequences (the data in parentheses indicate the section of complementary DNA and GenBank accession number, respectively): DMT1 (nucleotide [nt] 1501-1773, AF064484), Ireg1 (nt1190-1362, AF231121), hephaestin (nt1207-1396, AF148860), Dcytb (nt272-513, XM015916), and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; nt580-734, M33197). The DMT1 riboprobe is based on the non-iron-responsive element (IRE) splice variant but can also detect the IRE form as it crosses the splice site that distinguishes the two transcripts.…”

Hereditary hemochromatosis is reflected in the iron isotope composition of blood

“…According to our hypothesis, this finding would indicate that iron absorption is up-regulated more distinctly in patients with hemochromatosis undergoing phlebotomy therapy than in untreated patients. Prior studies showed that intestinal expression of DMT-1 is increased in treated 26 but not in untreated 27 patients with hemochromatosis. Other studies have shown that phlebotomy therapy per se causes a significant increase of intestinal iron absorption in patients with hemochromatosis.…”

Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation

“…In haemochromatosis duodenal DMT1 and ferroportin expression are raised, leading to excess iron absorption and gradual accumulation of iron. [18][19][20] The recently identified protein hepcidin is central to the pathophysiology of haemochromatosis. Hepcidin is a circulating hormone synthesised in the liver and levels of expression are regulated by iron stores and inflammation.…”