Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron deficiency affects 30% of the world's population. Iron metabolism is tightly regulated, with both gut transport and storage being coordinated. Hereditary haemochromatosis due to mutations in the HFE gene leads to increased absorption of iron and multiple end-organ damage. Myelodysplastic disorders are acquired clonal stem-cell disorders that cause ineffective erythropoiesis. Aplastic anaemia is caused by an intrinsic defect of haemopoietic stem cells; both inherited and acquired forms occur. Primary polycythaemia is a myeloproliferative disorder, a non-malignant stem-cell disease.
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PMID:Red cells II: acquired anaemias and polycythaemia. 1096 23

Iron absorption involves two carriers, one involved in the uptake of iron across the microvillus membrane of the enterocyte and the other in its transfer to the plasma at the basolateral surface. The uptake phase is thought to involve divalent metal transporter-1 (DMT1) which may move from the cytoplasm to the microvillus membrane under conditions of iron deficiency. To examine this possibility we used fasted animals previously fed an iron-deficient diet and then gavaged with iron. We measured the processes of iron absorption using in vivo gut sacs and correlated the changes observed with the intensity of DMT1 staining and gene expression in the duodenum. Fasting resulted in increased iron absorption, whereas gavage with iron decreased absorption. These changes were due to alterations in the uptake phase of absorption but not the transfer phase. There was also a highly significant correlation between the reduction in iron absorption, microvillus DMT1 staining and messenger ribonucleic acid (mRNA) expression. The loss of DMT1 from the microvillus membrane was not associated with an increase in cytoplasmic staining, suggesting that its loss was due to destruction of the carrier protein. It is concluded that DMT1 functional activity is determined by de novo synthesis and that the latter is regulated post-transcriptionally by enterocyte iron levels.
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PMID:Gastrointestinal function, divalent metal transporter-1 expression and intestinal iron absorption. 1095 38

Fecal occult blood (FOB) tests have been evaluated primarily for the application of colorectal cancer screening. Less is known about the performance characteristics of FOB tests for the evaluation of iron deficiency, the most common other application. As most clinically important occult gastrointestinal bleeding arises from the proximal gut, it is critical that FOB tests target analytes that are stable during the enteric transit. Available data indicate that guaiac-type and immunochemical tests are insensitive for the detection of proximal gut bleeding, and their use may confound the evaluation of iron deficiency. In contrast, the heme porphyrin test is sensitive for both proximal and distal sources of occult gastrointestinal bleeding, and this FOB test would appear to be the most rational selection for use in patients with iron deficiency or anemia. Outcome data are needed to better assess the impact of FOB testing on algorithms for evaluation of iron deficiency.
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PMID:Fecal occult blood testing for iron deficiency: a reappraisal. 1106 Apr 70

Iron overload is highly prevalent, but its molecular pathogenesis is poorly understood. Recently, DMT1 was shown to be a major apical iron transporter in absorptive cells of the duodenum. In vivo, it is the only transporter known to be important for the uptake of dietary non-heme iron from the gut lumen. The expression and subcellular localization of DMT1 protein in 3 mouse models of iron overload were examined: hypotransferrinemic (Trf(hpx)) mice, Hfe knockout mice, and B2m knockout mice. Interestingly, in Trf(hpx) homozygotes, DMT1 expression was strongly induced in the villus brush border when compared to control animals. This suggests that DMT1 expression is increased in response to iron deficiency in the erythron, even in the setting of systemic iron overload. In contrast, no increase was seen in DMT1 expression in animals with iron overload resembling human hemochromatosis. Therefore, it does not appear that changes in DMT1 levels are primarily responsible for iron loading in hemochromatosis.
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PMID:Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders. 1115 49

DMT1 has four names, transports as many as eight metals, may have four or more isoforms and carries out its transport for multiple purposes. This review is a start at sorting out these multiplicities. A G185R mutation results in diminished gastrointestinal iron uptake and decreased endosomal iron exit in microcytic mice and Belgrade rats. Comparison of mutant to normal rodents is one analytical tool. Ectopic expression is another. Antibodies that distinguish the isoforms are also useful. Two mRNA isoforms differ in the 3' UTR: +IRE DMT1 has an IRE (Iron Responsive Element) but -IRE DMT1 lacks this feature. The +/-IRE proteins differ in the distal 18 or 25 amino acid residues after shared identity for the proximal 543 residues. A major function is serving as the apical iron transporter in the lumen of the gut. The +IRE isoform appears to have that role. Another role is endosomal exit of iron. Some evidence indicts the -IRE isoform for this function. In our ectopic expression assay for metal uptake, four metals--Fe2+, Mn2+, Ni2+ and Co2+--respond to the normal DMT1 cDNA but not the G185R mutant. Two metals did not--Cd2+ and Zn2+--and two--Cu2+ and Pb2+--remain to be tested. In competition experiments in the same assay, Cd2+, Cu2+ and Pb2+ inhibit Mn2+ uptake but Zn2+ did not. In rodent mutants, Fe and Mn appear more dependent on DMT1 than Cu and Zn. Experiments based on ectopic expression, specific antibodies that inhibit metal uptake and labeling data indicate that Fe3+ uptake depends on a different pathway in multiple cells. Two isoforms localize differently in a number of cell types. Unexpectedly, the -IRE isoform is in the nuclei of cells with neuronal properties. While the function of -IRE DMT1 in the nucleus is speculative, one may safely infer that this localization identifies new role(s) for this multifunctional transporter. Management of toxic challenges is another function related to metal homeostasis. Airways represent a gateway tissue for metal entry. Preliminary evidence using specific PCR primers and antibodies specific to the two isoforms indicates that -IRE mRNA and protein increase in response to exposure to metal in lungs and in a cell culture model; the +IRE form is unresponsive. Thus the -IRE form could be part of a detoxification system in which +IRE DMT1 does not participate. How does iron status affect other metals' toxicity? In the case of Mn, iron deficiency may enhance cellular responses.
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PMID:DMT1: a mammalian transporter for multiple metals. 1257 63

Iron regulatory proteins (IRP) modulate the use of mRNA-encoding proteins that are involved in the transport, storage and use of iron. Several new potential mRNA targets for IRP were recently identified: divalent metal transporter-1 (DMT-1) and ferroportin, which are critical regulators of iron absorption in the gut and of iron cycling between various tissues of the body. Although this may extend the reach of IRP to other processes that are important for maintaining body iron homeostasis, the extent to which IRP modulate other physiological processes that are altered in response to changes in iron availability is not clear. However, in the past several years, targets for IRP and IRP-like proteins were identified in eukaryotes and prokaryotes in the tricarboxylic acid (TCA) cycle and electron-transport chain. In mammals, this includes the mRNA that encodes the TCA-cycle enzyme mitochondrial aconitase (m-acon). Recent work established that m-acon expression is translationally regulated by iron in a manner that is strongly correlated with IRP RNA-binding activity. Interestingly, these studies also demonstrate that IRP regulate their mRNA targets in a hierarchical manner. The changes in m-acon synthesis and abundance in liver during iron deficiency fail to affect TCA-cycle capacity but are associated with a significant upregulation of mitochondrial export of radiolabeled citrate. We conclude that IRP are required for the regulation of physiological pathways that include but are not limited to iron metabolism, and as such, IRP are critical factors in the adaptive response to iron deficiency.
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PMID:Novel roles for iron regulatory proteins in the adaptive response to iron deficiency. 1273 Apr 55

Rickets, once thought vanquished, is reappearing. In some less developed countries it hardly went away. This seminar reviews the effects of genes, stage of development, and environment on clinical expression of the disease. Rickets can be secondary to disorders of the gut, pancreas, liver, kidney, or metabolism; however, it is mostly due to nutrient deficiency and we concentrate on this form. Although calcium deficiency contributes in communities where little cows' milk is consumed, deficiency of vitamin D is the main cause. There are three major problems: the promotion of exclusive breastfeeding for long periods without vitamin D supplementation, particularly for babies whose mothers are vitamin D deficient; reduced opportunities for production of the vitamin in the skin because of female modesty and fear of skin cancer; and the high prevalence of rickets in immigrant groups in more temperate regions. A safety net of extra dietary vitamin D should be re-emphasised, not only for children but also for pregnant women. The reason why many immigrant children in temperate zones have vitamin D deficiency is unclear. We speculate that in addition to differences in genetic factors, sun exposure, and skin pigmentation, iron deficiency may affect vitamin D handling in the skin or gut or its intermediary metabolism.
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PMID:Rickets. 1458 42

One of the major causes of anemia in childhood worldwide is iron deficiency. Its prevalence depends mainly on age, being higher in infancy and adolescence. Its etiology varies, but poor iron diet is considered the commonest causative factor. Better tactics may be needed, like the targeted screening of children who belong to high-risk groups, to eradicate childhood iron deficiency. The amount of the body iron regulates its absorption from the gut through mechanisms that are still poorly understood. Early identification of iron deficiency is essential for the prevention not only of anemia but also the numerous and long-term consequences caused by the lack of iron. Many tests are available for the diagnosis of the disease. Some of them seem very promising for the early detection of iron deficiency, but further research is needed before they become widely acceptable in clinical practice. Treatment is based on oral iron salts, which do not have any serious side effects.
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PMID:Clinicolaboratory findings and treatment of iron-deficiency anemia in childhood. 1555 16

Manganese transport into the blood can result from inhaling metal-containing particles. Intestinal manganese and iron absorption is mediated by divalent metal transporter 1 (DMT1) and is upregulated in iron deficiency. Since iron status alters absorption of Fe and Mn in the gut, we tested the hypothesis that iron status may alter pulmonary transport of these metals. DMT1 expression in the lungs was evaluated to explore its role in metal transport. The pharmacokinetics of intratracheally instilled 54Mn or 59Fe in repeatedly bled or iron oxide-exposed rats were compared with controls. Iron oxide exposure caused a reduction in pulmonary transport of 54Mn and 59Fe, and decreased uptake in other major organs. Low iron status from repeated bleeding also reduced pulmonary transport of iron but not of manganese. However, uptake of manganese in the brain and of iron in the spleen increased in bled rats. DMT1 transcripts were detected in airway epithelium, alveolar macrophages, and bronchial-associated lymphoid tissue in all rats. Focal increases were seen in particle-containing macrophages and adjacent epithelial cells, but no change was observed in bled rats. Although lung DMT1 expression did not correlate with iron status, differences in pharmacokinetics of instilled metals suggest that their potential toxicity can be modified by iron status.
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PMID:Effects of iron status on transpulmonary transport and tissue distribution of Mn and Fe. 1634 1

Previous studies revealed novel genetic changes in the duodenal mucosa of iron-deprived rats during postnatal development. These observations are now extended to compare the genetic response to iron deficiency in the duodenum versus jejunum of 12-wk-old rats. cRNA samples were prepared from the duodenal and jejunal mucosa of three groups each of control and iron-deficient rats and hybridized with RAE 230A and 230B gene chips (Affymetrix). Stringent data reduction strategies were employed. Results showed that several genes were similarly induced in both gut segments, including DMT1, Dcytb, transferrin receptor 1, heme oxygenase 1, metallothionein, the Menkes copper ATPase (ATP7A), tripartitie motif protein 27, and the sodium-dependent vitamin C transporter. However, a subset of genes showed regulation in only one or the other gut segment. In duodenum only, gastrokine 1, trefoil factor 1 and claudin 2 were induced by iron-deficiency. Other genes previously identified were only regulated in the duodenum. Overall, these studies demonstrate similarities and distinct differences in the genetic response to iron deprivation in the duodenum versus jejunum and provide evidence that more distal gut segments also may play a role in increasing iron absorption in iron-deficiency anemia.
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PMID:Gene chip analyses reveal differential genetic responses to iron deficiency in rat duodenum and jejunum. 1662 62


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