Iron Deficiency Caused by Intestinal Iron Loss-Novel Candidate Genes for Severe Anemia.
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ABSTRACT:
SUBMITTER: Huettmann C
PROVIDER: S-EPMC8700796 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein. In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia. In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase-2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment. A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients. The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration; in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach.
| S-EPMC3669438 | biostudies-literature
Project description:Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the "atypical" microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field.
| S-EPMC4439901 | biostudies-literature
Project description:Heme is an efficient source of iron in the diet, and heme preparations are used to prevent and cure iron deficiency anemia in humans and animals. However, the molecular mechanisms responsible for heme absorption remain only partially characterized. Here, we employed young iron-deficient piglets as a convenient animal model to determine the efficacy of oral heme iron supplementation and investigate the pathways of heme iron absorption. The use of bovine hemoglobin as a dietary source of heme iron was found to efficiently counteract the development of iron deficiency anemia in piglets, although it did not fully rebalance their iron status. Our results revealed a concerted increase in the expression of genes responsible for apical and basolateral heme transport in the duodenum of piglets fed a heme-enriched diet. In these animals the catalytic activity of heme oxygenase 1 contributed to the release of elemental iron from the protoporphyrin ring of heme within enterocytes, which may then be transported by the strongly expressed ferroportin across the basolateral membrane to the circulation. We hypothesize that the well-recognized high bioavailability of heme iron may depend on a split pathway mediating the transport of heme-derived elemental iron and intact heme from the interior of duodenal enterocytes to the bloodstream.
| S-EPMC5514692 | biostudies-literature
Project description:ImportanceHearing loss in the US adult population is linked to hospitalization, poorer self-reported health, hypertension, diabetes, and tobacco use. Because iron deficiency anemia (IDA) is a common and easily correctable condition, further understanding of the association between IDA and all types of hearing loss in a population of US adults may help to open new possibilities for early identification and appropriate treatment.ObjectiveTo evaluate the association between sensorineural hearing loss (SNHL) and conductive hearing loss and IDA in adults aged 21 to 90 years in the United States.Design, setting, and participantsThe prevalence of IDA and hearing loss (International Classification of Diseases, Ninth Revision codes 389.1 [SNHL], 389.0 [conductive hearing loss], and 389 [combined hearing loss]) was identified in this retrospective cohort study at the Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania. Iron deficiency anemia was determined by low hemoglobin and ferritin levels for age and sex in 305 339 adults aged 21 to 90 years. Associations between hearing loss and IDA were evaluated using χ2 testing, and logistic regression was used to model the risk of hearing loss among those with IDA. The study was conducted from January 1, 2011, to October 1, 2015.Main outcomes and measuresHearing loss.ResultsOf 305 339 patients in the study population, 132 551 were men (43.4%); mean (SD) age was 50.1 (18.5) years. There was a 1.6% (n = 4807) prevalence of combined hearing loss and 0.7% (n = 2274) prevalence of IDA. Both SNHL (present in 26 of 2274 individuals [1.1%] with IDA; P = .005) and combined hearing loss (present in 77 [3.4%]; P < .001) were significantly associated with IDA. Logistic regression analysis confirmed increased odds of SNHL (adjusted odds ratio [OR], 1.82; 95% CI, 1.18-2.66) and combined hearing loss (adjusted OR, 2.41; 95% CI, 1.90-3.01) among adults with IDA, after adjusting for sex.Conclusions and relevanceIron deficiency anemia was associated with SNHL and combined hearing loss in a population of adult patients. Further research is needed to better understand the potential links between IDA and hearing loss and whether screening and treatment of IDA in adults could have clinical implications in patients with hearing loss.
| S-EPMC5787694 | biostudies-literature
Project description:Idiopathic pulmonary hemosiderosis is a potentially fatal disease that results from episodes of alveolar hemorrhage of unknown origin. The clinical spectrum is varied, and anemia may constitute the only manifestation of illness, preceding other signs and symptoms by several months. We present the case of a 4 year-old child presenting with fever, vomiting and prostration, associated with pallor. He had microcytic and hypochromic anemia refractory to iron therapy. Gastrointestinal bleeding was ruled out after negative extensive etiological investigation. Subsequently, pulmonary infiltrates suggestive of alveolar hemorrhage were observed in the chest radiography. The cytological exam of the bronchoalveolar lavage showed hemosiderin-laden macrophages. After the etiological study, the diagnosis of idiopathic pulmonary hemosiderosis was made by exclusion. He was initiated on corticosteroid therapy, later associated to an immunosuppressive agent, with subsequent correction of anemia and of the radiological pattern. The patient is currently asymptomatic.
| S-EPMC6276813 | biostudies-other
Project description:Purpose: The goal of this study was to probe for the effects of iron-deficiency anemia on the cardiac transciprtome using RNA-seq Methods: C57B6 mice were weaned onto a control or iron-deficient diet for 6 weeks. Hearts were removed and total mRNA was submitted for RNA-seq. Sequencing data was aligned using STAR and differetial gene expression analysis conducted in R using EdgeR and DESeq2. qRT–PCR validation for genes of interest was performed using TaqMan and SYBR Green assays. Results: We mapped about 24 million sequence reads per sample to the mouse genome (build mm10) and identified 13,590 transcripts in the hearts of control and iron-deficient mice after removing lowly expressed genes and PCR duplicates. Differential gene expression analysis showed approximately 78% downregulated and 22% upregulated genes in iron-deficiency anemia compared to controls. PCA plot showed control and iron-deficient hearts clustering in two distinct and separate clusters. Conclusions: Our study represents the first whole-transcriptomic study on cardiac samples obtained from iron-deficient and anemic mice, with biologic replicates, generated by RNA-seq technology. The RNA-seq data presented here can be used by others to explore which pathways are affected by iron-deficiency anemia
2020-12-03 | GSE162493 | GEO
Project description:Pathogenic TMPRSS6 variants impairing matriptase-2 function result in inappropriately high hepcidin levels relative to body iron status, leading to iron refractory iron deficiency anemia (IRIDA). As diagnosing IRIDA can be challenging due to its genotypical and phenotypical heterogeneity, we assessed the transferrin saturation (TSAT)/hepcidin ratio to distinguish IRIDA from multi-causal iron deficiency anemia (IDA). We included 20 IRIDA patients from a registry for rare inherited iron disorders and then enrolled 39 controls with IDA due to other causes. Plasma hepcidin-25 levels were measured by standardized isotope dilution mass spectrometry. IDA controls had not received iron therapy in the last 3 months and C-reactive protein levels were <10.0 mg/L. IRIDA patients had significantly lower TSAT/hepcidin ratios compared to IDA controls, median 0.6%/nM (interquartile range, IQR, 0.4-1.1%/nM) and 16.7%/nM (IQR, 12.0-24.0%/nM), respectively. The area under the curve for the TSAT/hepcidin ratio was 1.000 with 100% sensitivity and specificity (95% confidence intervals 84-100% and 91-100%, respectively) at an optimal cut-off point of 5.6%/nM. The TSAT/hepcidin ratio shows excellent performance in discriminating IRIDA from TMPRSS6-unrelated IDA early in the diagnostic work-up of IDA provided that recent iron therapy and moderate-to-severe inflammation are absent. These observations warrant further exploration in a broader IDA population.
| S-EPMC8836508 | biostudies-literature
Project description:Microalgae are used as a source of lipids for the production of biofuels. Most algae produce neutral lipids under stress conditions. Here, lipid accumulation by the unicellular alga Chlamydomonas reinhardtii was examined during cultivation under iron-limiting conditions. Severe iron stress caused the cells to accumulate a significant amount of lipid, specifically triacylglycerols (TAGs), by compromising the growth. Semi-quantitative measurements by Fourier transform infrared (FTIR) spectroscopy showed an increase in both carbohydrate and lipid content in iron-stressed C. reinhardtii cells compared to control. Analysis by flow cytometry and thin layer chromatography confirmed that severe iron deficiency-induced TAG accumulation to fourfold higher than in iron-replete control cells. This accumulation of TAGs was mostly degraded from chloroplast lipids accompanied by overexpression of diacylglycerol acyltransferase (DGAT2A) protein. Furthermore, liquid chromatography-mass spectrometry (LC-MS) analysis demonstrated significantly enhanced levels of C16:0, C18:2, and C18:3 fatty acids (FAs). These results indicate that iron stress triggers the rapid accumulation of TAGs in C. reinhardtii cells. The enhanced production of these lipids caused by the iron deficiency may contribute to the efficient production of algal biofuels if we escalate to the photobioreactor's growth conditions.
| S-EPMC8076870 | biostudies-literature
Project description:Iron deficiency contributes to anemia after transplantation. The magnitude of iron loss from blood loss in the peri-transplantation period has not been quantified. We prospectively estimated phlebotomy and surgical losses over the first 12-weeks following transplantation in 39 consecutive renal transplant recipients on hemodialysis (HD), peritoneal dialysis (PD), or chronic kidney disease (CKD). At transplant, ferritin levels were <200 ng/ml in 51% of the patients, and iron saturation was </=20% in 44%. CKD patients more commonly had ferritin levels <200 ng/ml than either HD or PD patients (100% vs. 21% vs. 67%, P < 0.0002, respectively). Blood loss was similar among HD, PD and CKD patients (833 +/- 194 vs. 861 +/- 324 vs. 755 +/- 79 ml respectively, P = NS), and no difference between deceased and living donor transplant recipients (881 +/- 291 vs. 788 +/- 162 ml, P = 0.33). Based on baseline hemoglobin (Hgb) of 11.8 g/dl, we estimated that an additional 330 mg of iron was needed to normalize hemoglobin to 13 g/dl, and 605 mg to increase hemoglobin to 14 g/dl. Blood and iron losses over the first 12 weeks post-transplant are substantial and may warrant early administration of intravenous iron.
| S-EPMC2754723 | biostudies-literature
Project description:BackgroundPrevious trials of prenatal iron supplementation had limited measures of maternal or neonatal iron status.ObjectiveThe purpose was to assess effects of prenatal iron-folate supplementation on maternal and neonatal iron status.MethodsEnrollment occurred June 2009 through December 2011 in Hebei, China. Women with uncomplicated singleton pregnancies at ≤20 wk gestation, aged ≥18 y, and with hemoglobin ≥100 g/L were randomly assigned 1:1 to receive daily iron (300 mg ferrous sulfate) or placebo + 0.40 mg folate from enrollment to birth. Iron status was assessed in maternal venous blood (at enrollment and at or near term) and cord blood. Primary outcomes were as follows: 1) maternal iron deficiency (ID) defined in 2 ways as serum ferritin (SF) <15 μg/L and body iron (BI) <0 mg/kg; 2) maternal ID anemia [ID + anemia (IDA); hemoglobin <110 g/L]; and 3) neonatal ID (cord blood ferritin <75 μg/L or zinc protoporphyrin/heme >118 μmol/mol).ResultsA total of 2371 women were randomly assigned, with outcomes for 1632 women or neonates (809 placebo/folate, 823 iron/folate; 1579 mother-newborn pairs, 37 mothers, 16 neonates). Most infants (97%) were born at term. At or near term, maternal hemoglobin was significantly higher (+5.56 g/L) for iron vs. placebo groups. Anemia risk was reduced (RR: 0.53; 95% CI: 0.43, 0.66), as were risks of ID (RR: 0.74; 95% CI: 0.69, 0.79 by SF; RR: 0.65; 95% CI: 0.59, 0.71 by BI) and IDA (RR: 0.49; 95% CI: 0.38, 0.62 by SF; RR: 0.51; 95% CI: 0.40, 0.65 by BI). Most women still had ID (66.8% by SF, 54.7% by BI). Adverse effects, all minor, were similar by group. There were no differences in cord blood iron measures; >45% of neonates in each group had ID. However, dose-response analyses showed higher cord SF with more maternal iron capsules reported being consumed (β per 10 capsules = 2.60, P < 0.05).ConclusionsPrenatal iron supplementation reduced anemia, ID, and IDA in pregnant women in rural China, but most women and >45% of neonates had ID, regardless of supplementation. This trial was registered at clinicaltrials.gov as NCT02221752.
| S-EPMC4516762 | biostudies-literature