Iron supplementation in suckling piglets: how to correct iron deficiency anemia without affecting plasma hepcidin levels.
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ABSTRACT:
SUBMITTER: Starzynski RR
PROVIDER: S-EPMC3667775 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:A novel polysaccharide named Angelica sinensis polysaccharide (ASP) was obtained from the powdered and defatted roots of A. sinensis (Oliv.) Diels. The molecular weight of ASP was determined to be 78 kDa and was 95.0% sugars consisting of mostly arabinose, glucose, and galactose with a molar ratio of 1:5.68:3.91. A previous study indicated that ASP may increase plasma iron levels by suppressing the expression of hepcidin, a negative regulator of body iron metabolism, in the liver. The present study aims to clarify the inhibitory effect of ASP on hepcidin expression in rat models of iron deficiency anemia (IDA), and clarify the mechanisms involved. It was demonstrated that ASP significantly reduced hepcidin expression by inhibiting the expression of mothers against decapentaplegic protein 4 (SMAD4) in liver and stimulating the secretion of erythropoietin, which further downregulated hepcidin by repressing CCAAT/enhancer-binding protein α (C/EBPα) and the phosphorylation of signal transducer and activator of transcription 3/5. The results indicate that ASP can suppress the expression of hepcidin in rats with IDA, and may be useful for the treatment of IDA.
| S-EPMC3466919 | biostudies-literature
Project description:Hemolysis occurring in hematologic diseases is often associated with an iron loading anemia. This iron overload is the result of a massive outflow of hemoglobin into the bloodstream, but the mechanism of hemoglobin handling has not been fully elucidated. Here, in a congenital erythropoietic porphyria mouse model, we evaluate the impact of hemolysis and regenerative anemia on hepcidin synthesis and iron metabolism. Hemolysis was confirmed by a complete drop in haptoglobin, hemopexin and increased plasma lactate dehydrogenase, an increased red blood cell distribution width and osmotic fragility, a reduced half-life of red blood cells, and increased expression of heme oxygenase 1. The erythropoiesis-induced Fam132b was increased, hepcidin mRNA repressed, and transepithelial iron transport in isolated duodenal loops increased. Iron was mostly accumulated in liver and spleen macrophages but transferrin saturation remained within the normal range. The expression levels of hemoglobin-haptoglobin receptor CD163 and hemopexin receptor CD91 were drastically reduced in both liver and spleen, resulting in heme- and hemoglobin-derived iron elimination in urine. In the kidney, the megalin/cubilin endocytic complex, heme oxygenase 1 and the iron exporter ferroportin were induced, which is reminiscent of significant renal handling of hemoglobin-derived iron. Our results highlight ironbound hemoglobin urinary clearance mechanism and strongly suggest that, in addition to the sequestration of iron in macrophages, kidney may play a major role in protecting hepatocytes from iron overload in chronic hemolysis.
| S-EPMC5286934 | 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
Project description:Iron deficiency is the most common mammalian nutritional disorder. However, among mammalian species iron deficiency anemia (IDA), occurs regularly only in pigs. To cure IDA, piglets are routinely injected with high amounts of iron dextran (FeDex), which can lead to perturbations in iron homeostasis. Here, we evaluate the therapeutic efficacy of non-invasive supplementation with Sucrosomial iron (SI), a highly bioavailable iron supplement preventing IDA in humans and mice and various iron oxide nanoparticles (IONPs). Analysis of red blood cell indices and plasma iron parameters shows that not all iron preparations used in the study efficiently counteracted IDA comparable to FeDex-based supplementation. We found no signs of iron toxicity of any tested iron compounds, as evaluated based on the measurement of several toxicological markers that could indicate the occurrence of oxidative stress or inflammation. Neither SI nor IONPs increased hepcidin expression with alterations in ferroportin (FPN) protein level. Finally, the analysis of the piglet gut microbiota indicates the individual pattern of bacterial diversity across taxonomic levels, independent of the type of supplementation. In light of our results, SI but not IONPs used in the experiment emerges as a promising nutritional iron supplement, with a high potential to correct IDA in piglets.
| S-EPMC8466487 | biostudies-literature
Project description:We examined changes in hepcidin (closely associated with anemia of chronic inflammation (ACI)) and upstream regulatory pathways after intravenous (IV) iron supplementation in an ACI animal model. ACI was induced in male Sprague-Dawley rats by intraperitoneally administering complete Freund's adjuvant (CFA). Two weeks after starting CFA treatment, ACI rats received IV iron (CFA-iron) or vehicle (CFA-saline). Three days after IV iron treatment, iron profiles, hepcidin levels, and expression of proteins involved in the signaling pathways upstream of hepcidin transcription in the liver were measured. In CFA-treated rats, anemia with a concomitant increase in the levels of serum inflammatory cytokines and reactive oxygen species occurred. In CFA-iron rats, hemoglobin (Hb) concentration was still lower than that in control rats. In CFA-saline rats, hepatic hepcidin and ferritin levels increased compared with those in control rats and were further increased in CFA-iron rats. In CFA-saline rats, NADPH oxidase- (NOX-) 2, NOX-4, and superoxide dismutase levels in the liver were upregulated compared with those in control rats and their levels were further increased in CFA-iron rats. In CFA-saline rats, activities of the IL-6/STAT and BMP/SMAD pathways were enhanced in the liver compared with those in control rats and their levels were further increased in CFA-iron rats, whereas IL-6 expression remained unaffected after IV iron administration. In HepG2 cells, iron caused phosphorylation of STAT-3 and SMAD1/5 and knockdown of STAT-3 and SMAD1/5 using siRNAs reduced iron-induced hepcidin upregulation to levels similar to those in corresponding control cells. Renal erythropoietin expression and serum erythroferrone concentration were lower in CFA-iron rats than those in control rats. In ACI rats, IV iron supplementation did not recover Hb within three days despite an increase in hepatic ferritin levels, which might be attributable to an additional increase in hepcidin levels that was already upregulated under ACI conditions. Both STAT-3 phosphorylation and SMAD1/5 phosphorylation were associated with hepcidin upregulation after IV iron treatment, and this seems to be linked to iron-induced oxidative stress.
| S-EPMC8643261 | biostudies-literature
Project description:Hepatic hepcidin synthesis is stimulated by inflammation but inhibited during iron deficiency anemia (IDA). In humans, the relative strength of these opposing signals on serum hepcidin and the net effect on iron absorption and systemic iron recycling is uncertain. In this prospective, 45-day study, in young women (n=46; age 18-49 years) with or without IDA, we compared iron and inflammation markers, serum hepcidin and erythrocyte iron incorporation from 57Fe-labeled test meals, before and 8, 24 and 36 hours (h) after influenza/DPT vaccination as an acute inflammatory stimulus. Compared to baseline, at 24-36 h after vaccination: 1) interleukin-6 increased 2-3-fold in both groups (P<0.001); 2) serum hepcidin increased >2-fold in the non-anemic group (P<0.001), but did not significantly change in the IDA group; 3) serum iron decreased in the non-anemic group (P<0.05) but did not change in the IDA group; and 4) erythrocyte iron incorporation did not change in either of the two groups, but was approximately 2-fold higher in the IDA group both before and after vaccination (P<0.001). In this study, mild acute inflammation did not increase serum hepcidin in women with IDA, suggesting low iron status and erythropoietic drive offset the inflammatory stimulus on hepcidin expression. In non-anemic women, inflammation increased serum hepcidin and produced mild hypoferremia, but did not reduce dietary iron absorption, suggesting iron-recycling macrophages are more sensitive than the enterocyte to high serum hepcidin during inflammation. The study was registered as a prospective observational trial at clinicaltrials.gov identifier: 02175888 The study was funded by the International Atomic Energy Agency.
| S-EPMC6545852 | biostudies-literature
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:Background/objectivesScreening and diagnosis of iron deficiency anemia (IDA) is cumbersome as it may require testing for hemoglobin, ferritin, and an inflammatory biomarker. The aim of this study was to compare the diagnostic capacity of hematologic biomarkers to detect IDA among pregnant women in Tanzania.Subjects/methodsWe pooled data from an iron supplementation trial of 1500 iron-replete pregnant woman and a prospective cohort of 600 iron-deficient pregnant women. Receiver operating characteristic curves (ROC) for hematologic biomarkers were used to assess the sensitivity, specificity, and area under the curve (AUC) for iron deficiency (ID) and iron deficiency anemia (IDA), crude, or corrected for inflammation. Regression models assessed the relationship of baseline biomarker categories (gestational age <27 weeks) and IDA at delivery.ResultsHemoglobin had the largest AUC for crude ID (0.96), while hepcidin had the largest AUC for corrected ID (0.80). The optimal hepcidin cutoff for the diagnosis of corrected IDA based on maximal sensitivity and specificity was ≤1.6 µg/L. An hepcidin cutoff of <4.3 µg/L had a sensitivity of 95% for regression-corrected ID. Among iron-replete women who did not receive iron, the association of baseline hemoglobin >110 g/L with IDA at delivery (RR = 0.73; 95% CI: 0.47, 1.13) was attenuated. Baseline hepcidin >1.6 µg/L was associated with reduced risk of anemia at delivery by 49% (95% CI: 27%, 45%).ConclusionsAscertaining hemoglobin and hepcidin levels may improve the targeting of iron supplementation programs in resource-limited countries, though hepcidin's high costs may limit its use.
| S-EPMC7162716 | biostudies-literature