Adaptive changes of duodenal iron transport proteins in celiac disease

2004 â—½  
Vol 17 (3) â—½  
pp. 316-325 â—½  
Author(s):  
Donatella Barisani â—½  
Antonina Parafioriti â—½  
Maria Teresa Bardella â—½  
Heinz Zoller â—½  
Dario Conte â—½  
...  
Keyword(s):  
Celiac Disease â—½  
Iron Deficiency â—½  
Protein Expression â—½  
Iron Transport â—½  
Basolateral Membrane â—½  
Deficiency Anemia â—½  
Mrna Levels â—½  
Divalent Metal Transporter 1 â—½  
Iron Stores â—½  
Iron Deficient

Iron deficiency is a manifestation of celiac disease (CD) usually attributed to a decreased absorptive surface, although no data on the regulation of iron transport under these conditions are currently available. Our aim was to evaluate divalent metal transporter 1 (DMT1), duodenal cytochrome b (Dcytb), ferroportin 1 (FP1), hephaestin, and transferrin receptor 1 (TfR1) expression, as well as iron regulatory protein (IRP) activity in duodenal biopsies from control, anemic, and CD patients. We studied 10 subjects with dyspepsia, 6 with iron-deficiency anemia, and 25 with CD. mRNA levels were determined by real-time PCR, protein expression by Western blotting or immunohistochemistry, and IRP activity by gel shift assay. Our results showed that DMT1, FP1, hephaestin, and TfR1 mRNA levels were significantly increased in CD patients with reduced body iron stores compared with controls, similar to what was observed in anemic patients. Protein expression paralleled the mRNAs changes. DMT1 protein expression was localized in differentiated enterocytes at the villi tips in controls, whereas with iron deficiency it was observed throughout the villi. FP1 expression was localized on the basolateral membrane of enterocytes and increased with low iron stores. TfR1 was localized in the crypts in controls but also in the villi with iron deficiency. These changes were paralleled by IRP activity, which increased in all iron-deficient subjects. We conclude that duodenal DMT1, FP1, hephaestin, and TfR1 expression and IRP activity, thus the iron absorption capacity, are upregulated in CD patients as a consequence of iron deficiency, whereas the increased enterocyte proliferation observed in CD has no effect on iron uptake regulation.

scholarly journals The Treatment of Iron Deficiency Anemia

Blood â—½  
1955 â—½  
Vol 10 (6) â—½  
pp. 567-581 â—½  
Author(s):  
DANIEL H. COLEMAN â—½  
ALEXANDER R. STEVENS â—½  
CLEMENT A. FINCH
Keyword(s):  
Iron Deficiency â—½  
Gastrointestinal Symptoms â—½  
The Body â—½  
Deficiency Anemia â—½  
Deficient Diet â—½  
Significant Group â—½  
Body Iron â—½  
Iron Stores â—½  
Iron Deficient â—½  
Full Complement

Abstract In the normal individual the amount of iron absorbed and lost from the body each day is exceedingly small. There are certain periods during life when body iron requirements are increased; the most important of these is infancy. Here, existing iron stores are rapidly depleted, and a deficient diet can soon produce iron deficiency. Once a full complement of body iron has been accrued, the adult is independent of iron intake and becomes iron deficient only through blood loss. In the production of iron deficiency, iron stores are exhausted before anemia appears. If any question in diagnosis from usual laboratory tests exists, the direct. examination of marrow for hemosiderin will establish the diagnosis. It is of obvious importance to confirm the diagnosis by specific therapy and to determine the cause of the iron depletion. Response to oral iron is highly predictable and failure of response usually in dictates a mistaken diagnosis. In a small but significant group of patients, either unable to take iron because of gastrointestinal symptoms, unable to absorb iron, or in need of iron reserves, parenteral administration of iron has distinct advantages. The saccharated oxide of iron is an effective preparation for this purpose.

scholarly journals Increased DMT1 and FPN1 expression with enhanced iron absorption in ulcerative colitis human colon

AJP Cell Physiology â—½  
2020 â—½  
Vol 318 (2) â—½  
pp. C263-C271 â—½  
Author(s):  
Emily A. Minor â—½  
Justin T. Kupec â—½  
Andrew J. Nickerson â—½  
Karthikeyan Narayanan â—½  
Vazhaikkurichi M. Rajendran
Keyword(s):  
Ulcerative Colitis â—½  
Iron Deficiency â—½  
Iron Absorption â—½  
Basolateral Membrane â—½  
Specific Inhibitor â—½  
Distal Colon â—½  
Human Colon â—½  
Deficiency Anemia â—½  
Divalent Metal Transporter 1 â—½  
Divalent Metal Transporter

Iron deficiency anemia is a common complication of ulcerative colitis (UC) that can profoundly impact quality of life. Most iron absorption occurs in the duodenum via divalent metal transporter 1 (DMT1)-mediated uptake and ferroportin-1 (FPN1)-mediated export across the apical and basolateral membranes, respectively. However, the colon also contains iron transporters and can participate in iron absorption. Studies have shown increased duodenal DMT1 and FPN1 in patients with UC, but there is conflicting evidence about whether expression is altered in UC colon. We hypothesized that expression of colonic DMT1 and FPN1 will also increase to compensate for iron deficiency. Quantitative RT-PCR and Western blot analyses were performed on duodenal and colonic segmental (right colon, transverse colon, left colon, and rectum) biopsies obtained during colonoscopy. DMT1 mRNA and protein abundances in colonic segments were approximately equal to those in the duodenum, whereas colonic FPN1 mRNA and protein abundances of colonic segments were about one-quarter of those of the duodenum. DMT1 specific mRNA and protein abundances were increased twofold, whereas FPN1 mRNA and protein expressions were increased fivefold in UC distal colon. Immunofluorescence studies revealed enhanced expression of apical membrane- and basolateral membrane-localized DMT1 and FPN1 in UC human colon, respectively. Increased DMT1 expression was associated with enhanced 2-(3-carbamimidoylsulfanylmethyl-benzyl)-isothiourea (CISMBI, DMT1 specific inhibitor)-sensitive 59Fe uptake in UC human colon. We conclude from these results that patients with active UC have increased expression of colonic iron transporters and increased iron absorption, which may be targeted in the treatment of UC-related anemia.

Iron Deficiency Anemia in Cancer Patients

2012 â—½  
Vol 08 (02) â—½  
pp. 74
Author(s):  
Mark Janis â—½  
Keyword(s):  
Iron Deficiency â—½  
Cancer Patients â—½  
Iron Deficiency Anemia â—½  
Iron Transport â—½  
The Body â—½  
Deficiency Anemia â—½  
Functional Iron Deficiency â—½  
Iron Stores â—½  
Iv Iron â—½  
Absolute Iron Deficiency

Anemia is highly prevalent, affecting approximately 40 % of cancer patients, and results in a significant decrease in health-related quality of life while also being associated with shorter cancer survival times. A recent survey of 15,000 cancer patients in Europe found that 39 % were anemic at the time of enrolment. In addition, anemia is a recognized complication of myelosuppressive chemotherapy, and it has been estimated that, in the US, around 1.3 million cancer patients who are not anemic at the time of diagnosis will develop anemia during the course of their disease. The etiology of anemia in cancer patients is variable and often multifactorial, and may be the result of an absolute or a functional iron deficiency. Cancer produces an enhanced inflammatory state within the body—causing hepcidin levels to increase and erythropoietin production to decrease—and results in a reduction in erythropoiesis due to impaired iron transport. This type of anemia is known as functional iron deficiency, where the body has adequate iron stores but there are problems with mobilization and transport of the iron. Absolute iron deficiency is when both iron stores and iron transport are low. The National Comprehensive Cancer Network (NCCN) treatment guidelines for cancer-related anemia recommend intravenous (IV) iron products alone for iron repletion in cancer patients with absolute iron deficiency, and erythropoiesis-stimulating agents (ESAs) in combination with IV iron in cancer patients (currently undergoing palliative chemotherapy) with functional iron deficiency. Although IV iron has been demonstrated to enhance the hematopoietic response to ESA therapy, the use of supplemental iron has not yet been optimized in oncology. Here we discuss the significance of iron deficiency anemia in cancer patients and the need to implement tools to properly diagnose this condition, and we provide an overview of the management strategies and recommendations for patients with iron deficiency anemia as outlined in the NCCN guidelines.

scholarly journals Expression of Duodenal Iron Transporter Proteins in Diabetic Patients with and without Iron Deficiency Anemia

2018 â—½  
Vol 2018 â—½  
pp. 1-4 â—½  
Author(s):  
Efrat Broide â—½  
Ram Reifen â—½  
Shay Matalon â—½  
Zipi Berkovich â—½  
Haim Shirin
Keyword(s):  
Iron Deficiency â—½  
Iron Deficiency Anemia â—½  
Iron Transport â—½  
Deficiency Anemia â—½  
Diabetic Patients â—½  
Divalent Metal Transporter 1 â—½  
Divalent Metal Transporter â—½  
Transporter Proteins â—½  
Group A â—½  
Group B

The role of iron transport proteins in the pathogenesis of anemia in patients with diabetes mellitus (T2DM) is still unclear. We investigated the expression of duodenal transporter proteins in diabetic patients with and without iron deficiency anemia (IDA). Methods. Overall, 39 patients were included: 16 with T2DM and IDA (group A), 11 with T2DM without IDA (group B), and 12 controls (group C). Duodenal mucosal expression of divalent metal transporter 1 (DMT1), ferroportin 1 (FPN), hephaestin (HEPH), and transferrin receptor 1 (TfR) was evaluated by Western blotting. Chronic disease activity markers were measured as well. Results. FPN expression was increased in group A compared to group B and controls: 1.17 (0.72–1.46), 0.76 (0.53–1.04), and 0.71 (0.64–0.86), respectively (p=0.011). TfR levels were over expressed in groups A and B compared to controls: 0.39 (0.26–0.61), 0.36 (0.24–0.43), and 0.18 (0.16–0.24), respectively, (p=0.004). The three groups did not differ significantly with regard to cellular HEPH and DMT1 expression. The normal CRP and serum ferritin levels, accompanied with normal FPN among diabetic patients without IDA, do not support the association of IDA with chronic inflammatory state. Conclusion. In patients with T2DM and IDA, duodenal iron transport protein expression might be dependent on body iron stores rather than by chronic inflammation or diabetes per se.

scholarly journals Effects of Pregnancy and Lactation on Iron Metabolism in Rats

10.1155/2015/105325 â—½  
2015 â—½  
Vol 2015 â—½  
pp. 1-9 â—½  
Author(s):  
Guofen Gao â—½  
Shang-Yuan Liu â—½  
Hui-Jie Wang â—½  
Tian-Wei Zhang â—½  
Peng Yu â—½  
...  
Keyword(s):  
Iron Deficiency â—½  
Iron Metabolism â—½  
Serum Iron â—½  
Late Pregnancy â—½  
Deficiency Anemia â—½  
Iron Level â—½  
Lactation Period â—½  
Divalent Metal Transporter 1 â—½  
Iron Stores â—½  
Pregnancy And Lactation

In female, inadequate iron supply is a highly prevalent problem that often leads to iron-deficiency anemia. This study aimed to understand the effects of pregnancy and lactation on iron metabolism. Rats with different days of gestation and lactation were used to determine the variations in iron stores and serum iron level and the changes in expression of iron metabolism-related proteins, including ferritin, ferroportin 1 (FPN1), ceruloplasmin (Cp), divalent metal transporter 1 (DMT1), transferrin receptor 1 (TfR1), and the major iron-regulatory molecule—hepcidin. We found that iron stores decline dramatically at late-pregnancy period, and the low iron store status persists throughout the lactation period. The significantly increased FPN1 level in small intestine facilitates digestive iron absorption, which maintains the serum iron concentration at a near-normal level to meet the increase of iron requirements. Moreover, a significant decrease of hepcidin expression is observed during late-pregnancy and early-lactation stages, suggesting the important regulatory role that hepcidin plays in iron metabolism during pregnancy and lactation. These results are fundamental to the understanding of iron homeostasis during pregnancy and lactation and may provide experimental bases for future studies to identify key molecules expressed during these special periods that regulate the expression of hepcidin, to eventually improve the iron-deficiency status.

scholarly journals ASSOCIATION OF POTENTIAL CELIAC DISEASE AND REFRACTORY IRON DEFICIENCY ANEMIA IN CHILDREN AND ADOLESCENTS

2018 â—½  
Vol 55 (1) â—½  
pp. 78-81 â—½  
Author(s):  
Mahdi SHAHRIARI â—½  
Naser HONAR â—½  
Ali YOUSEFI â—½  
Hazhir JAVAHERIZADEH
Keyword(s):  
Celiac Disease â—½  
Iron Deficiency â—½  
Iron Deficiency Anemia â—½  
Pediatric Care â—½  
Deficiency Anemia â—½  
Serologic Test â—½  
Care Clinic â—½  
Number Of Patients â—½  
Iron Deficient â—½  
Serologic Screening

ABSTRACT BACKGROUND: Celiac disease is an enteropathy caused by dietary gluten. The combination of serologic, genetic and histologic data has led to description of other categories of this disease. OBJECTIVE: There are a number of patients with iron deficiency anemia (IDA) that do not respond to iron treatment and may be repeated for many times, Therefore, we aimed to investigate celiac disease in this group. METHODS: In this cross sectional transverse prospective study from August 2011 to February 2013, in a Pediatric care clinic affiliated to Shiraz University of Medical Sciences, 184 children including 92 IDA patients who responded to treatment using iron supplement, 45 non-responding iron deficient patients, and 47 healthy individuals, with the maximum age of 18 years, with written consent from their parents, participated in serologic screening (with Anti-TTG antibody and anti-Endomysial antibody) for celiac disease. Patients with at least one positive serology test underwent multiple mucosal biopsy from bulb and duodenum. RESULTS: Among 184 participants, 19 (10.3%) subjects had positive serologic test for celiac disease, including 13 (28.9%) patients in the group with refractory IDA, 5 (5.4%) patients in the group with treated IDA, and 1 patient in the healthy group. The frequency of positive serologic test in the group with IDA resistant to treatment was prominently higher than the other two groups (P<0.001). Among the patients with positive serologic celiac test who underwent endoscopy and biopsy, no histologic evidence of celiac disease was seen. They were diagnosed as potential celiac disease. CONCLUSION: Frequency of potential celiac disease in patients with refractory IDA was higher than control the subjects. Therefore, we recommend serologic screening for early detection and minimizing the complications of celiac disease and repeated iron therapy for this group.

Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats

2005 â—½  
Vol 288 (5) â—½  
pp. L887-L893 â—½  
Author(s):  
Elizabeth Heilig â—½  
Ramon Molina â—½  
Thomas Donaghey â—½  
Joseph D. Brain â—½  
Marianne Wessling-Resnick
Keyword(s):  
Iron Deficiency â—½  
Iron Absorption â—½  
Iron Status â—½  
Mrna Levels â—½  
Blood Clearance â—½  
Divalent Metal Transporter 1 â—½  
Divalent Metal Transporter â—½  
Pulmonary Uptake â—½  
Iron Deficient â—½  
Metal Absorption

High levels of airborne manganese can be neurotoxic, yet little is known about absorption of this metal via the lungs. Intestinal manganese uptake is upregulated by iron deficiency and is thought to be mediated by divalent metal transporter 1 (DMT1), an iron-regulated factor known to play a role in dietary iron absorption. To better characterize metal absorption from the lungs to the blood and test whether iron deficiency may modify this process, the pharmacokinetics of pulmonary manganese and iron absorption by control and iron-deficient rats were compared. Levels of DMT1 expression in the lungs were determined to explore potential changes induced by iron deficiency that might alter metal absorption. The pharmacokinetic curves for intratracheally instilled54Mn and59Fe were significantly different, suggesting that pulmonary uptake of the two metals involves different mechanisms. Intratracheally instilled iron-deficient rats had significantly higher blood54Mn levels, whereas blood59Fe levels were significantly reduced compared with controls. The same trend was observed when radioisotopes were delivered by intravenous injection, indicating that iron-deficient rats have altered blood clearance of manganese. In situ analysis revealed the presence of DMT1 transcripts in airway epithelium; however, mRNA levels did not change in iron deficiency. Although lung DMT1 levels and metal absorption did not appear to be influenced by iron deficiency, the differences in blood clearance of instilled manganese identified by this study support the idea that iron status can influence the potential toxicity of this metal.

scholarly journals Supplemental Microalgal Iron Helps Replete Blood Hemoglobin in Moderately Anemic Mice Fed a Rice-Based Diet

Nutrients â—½  
10.3390/nu12082239 â—½  
2020 â—½  
Vol 12 (8) â—½  
pp. 2239
Author(s):  
Rohil S. Bhatnagar â—½  
Dennis D. Miller â—½  
Olga I. Padilla-Zakour â—½  
Xin Gen Lei
Keyword(s):  
Heme Iron â—½  
Deficiency Anemia â—½  
Free Access â—½  
Mrna Levels â—½  
Divalent Metal Transporter 1 â—½  
Minute Amount â—½  
Divalent Metal Transporter â—½  
Non Heme Iron â—½  
Blood Hemoglobin â—½  
Iron Deficient

Iron deficiency anemia affects 1.2 billion people globally. Our objectives were to determine if (1) supplemental iron extracted from defatted microalgae (Nannochloropsis oceanica, DGM) and (2) a combination of minute amount of plant phytase and inulin could help replete hemoglobin in anemic mice. Mice (7 weeks old) were fed a control diet (6 mg Fe/kg). After 10 weeks, the mice were assigned to three treatments: control, control + DGM iron (Fe-DGM, 39 mg Fe/kg), or control + 1% inulin + 250 units of phytase/kg (INU−PHY, 6 mg Fe/kg). The mice had free access to diets and water for 6 weeks. The Fe-DGM group had elevated blood hemoglobin (p < 0.01) and a two-fold greater (p < 0.0001) liver non-heme iron over the control. Strikingly, the INU-PHY group had 34% greater non-heme iron than the control, despite the same concentrations of iron in their diets. Fe-DGM group had altered (p < 0.05) mRNA levels of hepcidin, divalent metal transporter 1, transferrin and transferrin receptor 1. Iron extracted from defatted microalgae seemed to be effective in alleviating moderate anemia, and INU-PHY enhanced utilization of intrinsic iron present in the rice diet. Our findings may lead to a novel formulation of these ingredients to develop safer and bioavailable iron supplements for iron-deficient populations.

scholarly journals Serum ceruloplasmin protein expression and activity increases in iron-deficient rats and is further enhanced by higher dietary copper intake

Blood â—½  
2011 â—½  
Vol 118 (11) â—½  
pp. 3146-3153 â—½  
Author(s):  
Perungavur N. Ranganathan â—½  
Yan Lu â—½  
Lingli Jiang â—½  
Changae Kim â—½  
James F. Collins
Keyword(s):  
Iron Deficiency â—½  
Protein Expression â—½  
Iron Homeostasis â—½  
Amine Oxidase â—½  
Mrna Levels â—½  
Hepatic Copper â—½  
Liver Copper â—½  
Iron Deprivation â—½  
Iron Deficient â—½  
Expression And Activity

AbstractIncreases in serum and liver copper content are noted during iron deficiency in mammals, suggesting that copper-dependent processes participate during iron deprivation. One point of intersection between the 2 metals is the liver-derived, multicopper ferroxidase ceruloplasmin (Cp) that is important for iron release from certain tissues. The current study sought to explore Cp expression and activity during physiologic states in which hepatic copper loading occurs (eg, iron deficiency). Weanling rats were fed control or low iron diets containing low, normal, or high copper for ∼ 5 weeks, and parameters of iron homeostasis were measured. Liver copper increased in control and iron-deficient rats fed extra copper. Hepatic Cp mRNA levels did not change; however, serum Cp protein was higher during iron deprivation and with higher copper consumption. In-gel and spectrophotometric ferroxidase and amine oxidase assays demonstrated that Cp activity was enhanced when hepatic copper loading occurred. Interestingly, liver copper levels strongly correlated with Cp protein expression and activity. These observations support the possibility that liver copper loading increases metallation of the Cp protein, leading to increased production of the holo enzyme. Moreover, this phenomenon may play an important role in the compensatory response to maintain iron homeostasis during iron deficiency.

Ceruloplasmin Is Essential for the Mobilization of Tissue Iron Stores.

Blood â—½  
2005 â—½  
Vol 106 (11) â—½  
pp. 3581-3581
Author(s):  
Seth Rivera â—½  
Miguel Lopez â—½  
Dina Farshidi â—½  
Victoria Gabayan â—½  
Tomas Ganz
Keyword(s):  
Iron Deficiency â—½  
Serum Iron â—½  
Iron Homeostasis â—½  
Extracellular Fluid â—½  
Deficiency Anemia â—½  
Dietary Iron â—½  
Deficient Diet â—½  
Iron Stores â—½  
High Iron â—½  
Iron Deficient

Abstract In extracellular fluid, iron is in the ferric (oxidized form) but the intracellular form is ferrous iron (reduced). The outflow of iron from cells is dependent on oxidase activity that converts ferrous to ferric iron. Iron-absorbing enterocytes possess a unique iron oxidase, hephaestin. It is presumed that the circulating hephaestin paralog ceruloplasmin fulfils this role in hepatocytes and macrophages. The DiSnA mouse lacks ceruloplasmin. We hypothesized that iron homeostasis in this mouse would be unusually dependent on dietary iron because the mouse would not be able to mobilize iron from tissue stores in hepatocytes and macrophages. We fed 4-week-old DiSnA and wildtype (WT) mice a high iron (1%) diet for 4 weeks to load tissue stores. We then switched them to an iron-deficient diet and analyzed them weekly to measure iron and hemoglobin concentrations. Even on the high iron diet, DiSnA mice had lower serum iron concentrations than WT control (32.9±17.9 vs. 53.5±17.6 μM, p=0.05) but after two weeks on the iron deficient diet, the DiSnA mice had almost undetectable serum iron (4.2±1.8 μM) whereas the WT controls had only declined slightly (43.2±9.6 μM, p&lt;0.001). Iron saturation followed a similar trend. Neither WT nor DiSnA mice were anemic at baseline (Hgb = 13.9±0.3 and 13.9±1.1 g/dL, respectively; p=0.994) but by the end of two weeks, the DiSnA mice had developed anemia whereas the WT mice had not (Hgb = 10.4±0.5 vs. 12.6±0.5 g/dL; p&lt;0.001). The difference in hemoglobin concentrations persisted to the 6-week timepoint (Hgb = 8.4±0.5 vs. 12.6±1.4; p&lt;0.001). After 6-weeks on a low iron diet, iron was still present in livers and spleens of both groups. Ceruloplasmin is essential for the mobilization of iron stores to protect against iron deficiency anemia in response to periods of dietary iron deficiency.

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