Defect In Iron Absorption Research Articles

Isolated Defect of Intestinal Iron Absorption in Siblings of Iron Deficiency Anemia

Iron deficiency anemia (IDA) is the commonest type of anemia all over the world. It is easily treatable with oral iron therapy, but a minority of patients does remain unresponsive. This may be related to inappropriate compliance, manifest or occult blood loss, worm infestations, helicobacter infection, known malabsorption syndromes or paroxysmal nocturnal hemoglobinuria (PNH). We observed six such patients with non-responsive recurrent classical IDA who did not show any of the above conditions on specific investigations. Iron tolerance test (as an index of oral iron absorption) was performed on these patients. All of them showed negligible or no iron absorption, suggesting a defect in intestinal oral iron absorption as the cause of non-responsive IDA. This contention was supported by a dramatic response to parenteral iron therapy in all of them. Since the tests for known malabsorption syndromes were negative, it would be assumed that these subjects had an isolated defect in oral iron absorption that has been only scantily reported in the literature. Five of the six patients were siblings of two families. This raises the possibility of the defect in iron absorption to have a genetic connotation. Pending the complete work up for genetic studies, including the gene mutation for membrane bound serum protease type 6 (TMPRSS6) in these subjects and their families, this presentation is a short communication to expose and share our small experience of what looks to be an isolated defect in intestinal iron absorption.

Mutation of the gastric hydrogen-potassium ATPase alpha subunit causes iron-deficiency anemia in mice

AbstractIron is an essential component of heme and hemoglobin, and therefore restriction of iron availability directly limits erythropoiesis. In the present study, we report a defect in iron absorption that results in iron-deficiency anemia, as revealed by an N-ethyl-N-nitrosourea–induced mouse phenotype called sublytic. Homozygous sublytic mice develop hypochromic microcytic anemia with reduced osmotic fragility of RBCs. The sublytic phenotype stems from impaired gastrointestinal iron absorption caused by a point mutation of the gastric hydrogen-potassium ATPase α subunit encoded by Atp4a, which results in achlorhydria. The anemia of sublytic homozygotes can be corrected by feeding with a high-iron diet or by parenteral injection of iron dextran; rescue can also be achieved by providing acidified drinking water to sublytic homozygotes. These findings establish the necessity of the gastric proton pump for iron absorption and effective erythropoiesis.

Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease

The anemia of chronic disease is a prevalent, poorly understood condition that afflicts patients with a wide variety of diseases, including infections, malignancies, and rheumatologic disorders. It is characterized by a blunted erythropoietin response by erythroid precursors, decreased red blood cell survival, and a defect in iron absorption and macrophage iron retention, which interrupts iron delivery to erythroid precursor cells. We noted that patients with large hepatic adenomas had severe iron refractory anemia similar to that observed in anemia of chronic disease. This anemia resolved spontaneously after adenoma resection or liver transplantation. We investigated the role of the adenomas in the pathogenesis of the anemia and found that they produce inappropriately high levels of hepcidin mRNA. Hepcidin is a peptide hormone that has been implicated in controlling the release of iron from cells. We conclude that hepcidin plays a major, causative role in the anemia observed in our subgroup of patients with hepatic adenomas, and we speculate that it is important in the pathogenesis of the anemia of chronic disease in general.

Adaptive Response of Iron Absorption to Anemia, Increased Erythropoiesis, Iron Deficiency, and Iron Loading in β2-Microglobulin Knockout Mice

Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that beta2-microglobulin knockout (beta2m-/-) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorption in response to altered iron metabolism in the absence of beta2m-dependent molecule(s). Mucosal uptake, mucosal transfer and retention of iron were measured in control and beta2m-/- mice with altered iron metabolism. Mucosal uptake of Fe(III), but not of Fe(II), by the mutant mice was significantly higher when compared with B6 control mice. Mucosal transfer in the beta2m-/- mice was higher, independent of the iron form tested. No significant differences were found in iron absorption between control and beta2m-/- mice when anemia was induced either by repetitive bleeding or by hemolysis through phenylhydrazine treatment. However, iron absorption in mice made anemic by dietary deprivation of iron was significantly higher in the mutant mice. Furthermore, the beta2m-/- mice manifested an impaired capacity to downmodulate iron absorption when dietary or parenterally iron-loaded. The expression of the defect in iron absorption in the beta2m-/- mice is quantitative, with iron absorption being excessively high for the size of body iron stores. The higher iron absorption capacity in the beta2m-/- mice may involve the initial step of ferric mucosal uptake and the subsequent step of mucosal transfer of iron to the plasma.

Defective iron uptake by the duodenum of Belgrade rats fed diets of different iron contents.

Homozygous Belgrade rats have an inherited hypochromic, microcytic anemia that is due to impaired iron transport into immature erythrocytes. There is also evidence for abnormal iron transport in other tissues such as the intestine. This study was aimed at investigating the intestinal defect in rats that had been fed diets for 12 days that are normal, low, or high in iron. The duodenal uptake, transfer, and absorption of Fe(III)-nitrilotriacetate and Fe(II)-ascorbate were studied using in vivo tied-off gut sacs in genetically normal rats and in heterozygous or homozygous Belgrade rats. In normal and heterozygous Belgrade rats, the handling of Fe(III) and Fe(II) was similar; uptake, transfer, and absorption of Fe(III) and Fe(II) changed inversely with the iron content of the diet. In contrast, in homozygous Belgrade rats the uptake of both Fe(III) and Fe(II) was markedly reduced and absorption of Fe(III) did not change when animals were fed an iron-deficient diet. Since absorption of Fe(II) was similar to Fe(III), there is no evidence that the defect in iron absorption is due to failure of a mechanism for reduction of Fe(III). The lowered uptake of Fe(III) and Fe(II) in homozygous Belgrade rats probably involves a defective iron carrier associated with the microvillous membrane of the duodenum.

Ultrastructure of the duodenal mucosa of mice with a hereditary defect in iron absorption.

The Journal of PathologyVolume 104, Issue 1 p. 45-51 Article Ultrastructure of the duodenal mucosa of mice with a hereditary defect in iron absorption Y. C. Bédard, Y. C. Bédard Department of Pathology, University of Toronto, Toronto, CanadaSearch for more papers by this authorP. H. Pinkerton, P. H. Pinkerton Department of Pathology, University of Toronto, Toronto, CanadaSearch for more papers by this authorG. T. Simon, G. T. Simon Department of Pathology, University of Toronto, Toronto, CanadaSearch for more papers by this author Y. C. Bédard, Y. C. Bédard Department of Pathology, University of Toronto, Toronto, CanadaSearch for more papers by this authorP. H. Pinkerton, P. H. Pinkerton Department of Pathology, University of Toronto, Toronto, CanadaSearch for more papers by this authorG. T. Simon, G. T. Simon Department of Pathology, University of Toronto, Toronto, CanadaSearch for more papers by this author First published: May 1971 https://doi.org/10.1002/path.1711040106Citations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume104, Issue1May 1971Pages 45-51 RelatedInformation

Iron Metabolism and Absorption Studies in the X‐linked Anaemia of Mice

Summary. The X‐linked anaemia of mice (gene symbol, sla) is hypochromic and microcytic, and the stainable iron stores are reduced. Chemical estimates of total body iron content and serum iron concentration show low values and the total serum iron binding capacity is elevated in anaemic mice. Rapid plasma iron clearance and increased iron utilization provide further confirmation of iron deficiency in anaemic animals. Alterations in activity of haem‐containing enzymes have been sought in the heart, liver and kidney of anaemic mice, and slightly decreased activity found only in kidney cytochrome oxidase.The blood volume of mice with X‐linked anaemia is increased in spite of decreased red cell mass, and thus the anaemia is in part due to dilution. The cause of the increased blood volume has not been elucidated, but it may be related to splenic enlargement. In contrast to iron depleted humans and experimental animals, mice with X‐linked anaemia show impaired rather than increased intestinal iron absorption, indicating that the anaemia is a consequence of iron malabsorption. The defect in iron absorption may be an isolated one, since evidence of impaired retention of orally administered radio‐iodinated triolein, radio‐zinc, radio‐copper and radio‐cobalt has not been found. It is suggested that the genetically‐determined defect in the intestinal mucosa of mice with X‐linked anaemia may be due to deficiency of either an enzyme or a carrier substance necessary for the normal transfer of iron from the intestinal mucosal cell to the plasma.

Evidence for a Humoral Factor Influencing Iron Absorption

A series of studies was carried out to determine the effect of various serum preparations on iron absoprtion in the rat. Serum obtained from normal or previously iron-repleted and iron-depleted rats was injected intravenously into normal rats, and the intestinal transport of of iron determined utilizing isolated intestinal loops in vivo and everted duodenal gut sacs in vitro. In normal rats injected with serum from iron-loaded rats there was a significantly decreased absorption of radioactive iron in intestinal loops as well as a decreased mucosal to serosal transfer of radioactive iron in duodenal gut sacs. The factor in serum from iron-loaded rats causing decreased iron transport was found to be heat-stable. Three additional observations indicated that this defect in iron transport was not due to the infusion of iron per se. First, there was no increase in the nonheme iron content of the gut after injection of iron-repleted serum. Second, the intravenous injection of 15 µg of iron as FeSO4, similar to the amount of iron contained in an injection of iron-loaded serum, did not cause decreased absorption of radioiron from intestinal loops. Third, there was no increase in the serum iron level or saturation of transferrin in normal animals given iron-loaded serum. It was also observed that the defect in iron absorption induced by iron-loading rats with iron dextran could be partially corrected by the intravenous injection of normal serum or serum from iron-deficient rats. It is postulated that the serum injections may have resulted in dilution of a humoral inhibitory factor. The data obtained indicate that humoral stimulation and depression of iron absorption is demonstrable by the injection of normal or iron-deficient serum into iron-loaded rats and the injection of iron- loaded serum into normal rats. These observations suggest that a humoral mechanism may participate in the regulation of inorganic iron absorption in the rat.

Hereditary defect in iron absorption in mice.

SEX linked anaemia, which is hypochromic and microcytic1, was first observed in the male descendants of an irradiated mouse, and was shown to be an X linked recessive trait2. The gene symbol has been designated sla and its locus lies close to Tabby (Ta) and Brindled (Mobr) in linkage group XX2.