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

Abstract

Hepatic hemosiderosis and increased iron absorption are common findings in cirrhosis. It has been proposed that a positive relation exists between intestinal iron absorption and the development of hepatic hemosiderosis. The current study investigated the duodenal expression of the iron transport molecules divalent metal transporter 1 (DMT1 [IRE]), ironregulated gene 1 (Ireg1 [ferroportin]), hephaestin, and duodenal cytochrome b (Dyctb) in 46 patients with cirrhosis and 20 control subjects. Total RNA samples were extracted from duodenal biopsy samples and the expression of the iron transport genes was assessed by ribonuclease protection assays. Expression of DMT1 and Ireg1 was increased 1.5 to 3-fold in subjects with cirrhosis compared with iron-replete control subjects. The presence of cirrhosis per se and serum ferritin (SF) concentration were independent factors that influenced the expression of DMT1. However, only SF concentration was independently associated with Ireg1 expression. In cirrhosis, the expression of DMT1 and Ireg1 was not related to the severity of liver disease or cirrhosis type. There was no correlation between the duodenal expression of DMT1 and Ireg1 and the degree of hepatic siderosis. In conclusion, the presence of cirrhosis is an independent factor associated with increased expression of DMT1 but not Ireg1. The mechanism by which cirrhosis mediates this change in DMT1 expression has yet to be determined. Increased expression of DMT1 may play an important role in the pathogenesis of cirrhosis-associated hepatic iron overload. (HEPATOLOGY 2004;39: 492-499.)

Deciphering the iron isotope message of the human body

“…This observation is consistent with a stronger expression of DMT1, the primary transporter of iron in the brush border membrane (see Fig. 5, step B), in treated hemochromatosis patients when compared to untreated patients [56][57][58]. In treated hemochromatotic patients, the body senses apparently that blood-letting results in a drop in iron stores which are lower compared to the untreated state and responds by up-regulating iron absorption to re-establish the original condition.…”

“…In a three isotope ratio space ( 56 Fe/ 54 Fe, 57 Fe/ 54 Fe, 58 Fe/ 54 Fe) the measured samples' composition is positioned on a triangular surface that is constrained by the (known) composition of the spike, the (known) composition of a natural reference material (e.g., the standard used as the reference for calculating delta values), and a curve that describes the natural mass fractionation process. This surface is intersected by a mixing line connecting the pure, unfractionated spike with the true sample's composition.…”

“…In principle, the sample is spiked with two enriched iron isotopes (e.g., 57 Fe, 58 Fe) of which the isotope ratio is exactly known. In a three isotope ratio space ( 56 Fe/ 54 Fe, 57 Fe/ 54 Fe, 58 Fe/ 54 Fe) the measured samples' composition is positioned on a triangular surface that is constrained by the (known) composition of the spike, the (known) composition of a natural reference material (e.g., the standard used as the reference for calculating delta values), and a curve that describes the natural mass fractionation process.…”

Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis?

“…If so, hepatocyte DMT1 may be particularly important in cirrhosis, as duodenal expression of iron transporters is increased in cirrhotics, thus creating the potential for iron uptake to exceed the binding capacity of transferrin, leading to the presence of NTBI in the portal circulation. 16 The decrease in DMT1 protein in the cirrhotic livers appears unlikely to play a primary role in the development of hemosiderosis, but may contribute to the increase in circulating levels of NTBI reported in cirrhotic patients. 36 In contrast to DMT1, we speculate that the decrease in Fpn in the cirrhotic livers may be mechanistically linked to the pathogenesis of hemosiderosis.…”

“…Stuart et al 16 have reported that duodenal expression of DMT1 and Fpn, the iron transporters at the apical and basolateral surfaces of the enterocyte, respectively, are increased in cirrhotic patients. These alterations would be predicted to increase intestinal iron absorption, potentially contributing to hepatic iron deposition.…”