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Supplémentation en fer : indications, limites et modalités
Abstract
During the past 10 years, the knowledge of iron metabolism has been revolutionized by the discovery of the main regulatory hormone of body iron: hepcidin. Meanwhile, new formulations of intravenous iron have been developed and are already or readily available. In this article, we review the recent pathophysiological mechanisms underlying anemia of chronic disease or due to iron deficiency. We describe the various treatment modalities of iron deficiency anemia using oral or intravenous route and the emerging indications of treatment with iron. Finally, we discuss the situations in which iron supplementation may be harmful.
Copyright © 2012. Published by Elsevier SAS.
... Les propositions thérapeutiques sont résumées dans l'encadré 1, mais ne repo- sent pas sur des études réalisées en réanimation. Les lecteurs peuvent se rapporter à une revue récente pour plus de détails [61]. ...
La fréquence de la carence martiale en réanimation est probablement sous-évaluée du fait d’un diagnostic difficile en présence d’inflammation. La découverte de l’hepcidine, principal régulateur du métabolisme du fer, a ouvert des perspectives pour le diagnostic et l’intérêt du traitement martial en réanimation.
... Enfin, l'ensemble des patients ayant une carence martiale (16 patients) ont été traités avec du fer par voie orale, comme le recommandent les dernières recommandations. En effet, les principales indications du fer par voie orale sont l'anémie par carence martiale, la fatigue chez des femmes jeunes (< 55 ans) sans anémie avec une ferritinémie dans des valeurs basses et la carence martiale chez des adolescentes, sans anémie[23]. Tous les patients carencés en vitamine B12 ont d'autre part été traités par cyanocobalamine, soit injectable (intra-musculaire), soit administrée per os. ...
Objectives: Iron deficiency anemia represents a public health issue which is usually managed by midwives. Because it is associated with maternal and fetal risks, a treatment is warranted. Oral iron represents the main option for treating this condition. Despite the existence of national and international guidelines no consensus about its modality of use has emerged so far. The primary objective of this study was to analyze midwives’practice with regards to iron deficiency anemia treatment using oral iron formulations.
Methods: We conducted an observational and descriptive cross-sectional in a sample of midwives from the Gironde administrative region using a questionnaire.
Results: We obtained 85 questionnaires from midwives working in private or public health facilities. Doses of iron and duration of treatment seem insufficient for a majority of responders. Folic acid and vitamin C are often associated with oral iron. Most midwives assess the efficacy of oral iron at one month with hemoglobin and ferritin levels. A significant fraction of these midwives shares similar practices which are in good accordance with the literature such as patient counselling with regards to drug intake, management of gastrointestinal side effects and inefficacity of oral iron. Noticeably, some of these midwives don’t follow any guidelines.
Conclusion: The majority of participants demonstrated practices in accordance with various national guidelines although no precise therapeutic algorithm is available as reference. Larger studies on the management of iron deficiency anemia in pregnancy by health professionals and harmonization of practices are necessary.
Résumé
La carence en fer est un problème de santé publique dans le monde avec une mortalité pédiatrique non négligeable. Elle reste fréquente chez les femmes réglées en Europe et pose parfois un problème thérapeutique : un traitement progestatif peut alors être proposé. Le diagnostic repose sur le dosage de la ferritine, dont la norme inférieure doit être modifiée selon le terrain : de 20 μg/L chez la femme jeune à 100 μg/L en cas de pathologie inflammatoire, ou d’insuffisance cardiaque ou rénale. Chez les hommes et les femmes ménopausées, la réalisation d’une coloscopie d’excellente qualité et d’une fibroscopie œso-gastro-duodénale est obligatoire pour rechercher un saignement digestif : ulcérations hautes, cancer colique, cancer gastrique, angiodysplasies, etc. Le traitement par fer oral entraîne systématiquement une coloration noire des selles et doit être prolongé pour une durée d’au moins trois mois. Les formes intraveineuses de fer sont réservées aux anémies ferriprives résistantes au traitement par fer oral, car elles comportent des risques exceptionnels d’anaphylaxie, de bronchospasme ou d’hypophosphorémie retardée.
Surgeries of THA (total hip arthroplasty) and TKA (total knee arthroplasty) are operations with high potential bleeding. Preoperative anemia is a risk factor for acute postoperative anaemia which themselves driving many deleterious effects, including the risks associated with transfusion. So, it is necessary to strengthen the management of patients in perioperative period by appropriate martial prevention. Purpose: The objective is to evaluate the impact of a systematic prescription of oral iron preoperatively before surgery THA or TKA. Materials and method: Both studies included patients who underwent total hip or knee arthoplasty (THA-TKA). S1 was proceeded retrospectively on all patients operated in 2011, and S2 prospectively on patients who have been prescribed preoperative iron in September-October 2012. We collected data: surgery, iron prescriptions, haemoglobin levels, transfusions and durations of stay. Results: Surgery: 327 (S1): 205 THA/122 TKA vs. 30 (S2): 13 THA/17 TKA. Postoperative iron prescription: 69% of patients (S1): oral iron 32%, intravenous iron 20%, both oral and intravenous iron 17% vs. 43% of patients (S2): oral iron 23%, intravenous iron 13%, both oral and intravenous iron 7%. Haemoglobin levels: between preoperative and immediate postoperative periods, mean decrease was from 12.9±0.2g/dL to 11.1±0.1g/dL (S1) vs. 13.3±0.2g/dL to 11.7±0.2g/dL (S2), between preoperative period and hospital discharge, mean loss was 2.2±0.2g/dL (S1) vs. 1.9±0.17g/dL (S2) (p<10-3). Transfusion: 29% of patients (S1) vs. 20% (S2) (p<10-3). Duration of stay: mean was 10.6±0.8days (S1) vs. 8.3±0.3days (S2) (p<0.005). Conclusion: Preventive treatment with oral iron significantly improves postoperative acute anemia.
The aim of this study was to determine the prevalence of iron deficiency among patients with pernicious anemia. We realized a retrospective study from 2000 to 2010 including 55 patients suffering from pernicious anemia who were followed in Reims and Strasbourg university hospitals. Inclusion criteria were histological diagnosis of immune atrophic fundic gastritis and criteria of gastric autoimmuninty, and for which ferritin was measured. Iron deficiency is defined as serum ferritin level <20 μg/L in women and <30 μg/L in men. 45 (81.8%) patients were female. The mean age was 61 ± 17 years (range: 25/98).There was anemia in 32 patients (58.2%). Macrocytosis was noted, with or without anemia, in 30 patients (54.5%); microcytosis, with or without anemia, was noted in 8 (14.5%) patients. 17 patients (30.9%) had normal mean corpuscular volume. Vitamin B12 deficiency was objectived in 42 patients (76.4%) in our series. 16 patients (29%) had iron deficiency. 14 patients were female. They were significantly younger than female subjects without iron deficiency (p =0.004). In conclusion, iron deficiency is not rare in patients with pernicious anemia. It could be a complication of achlorhydria. We suggest a dosage of serum ferritin for all patients with pernicious anemia.
Préciser les éléments d’orientation et de dépistage en population générale des patientes à risque d’hémorragie du post-partum (HPP), ainsi que les éléments de prise en charge anténatale de l’anémie sévère, des thrombopénies, des patientes avec une pathologie de l’hémostase ou traitées par anticoagulants.
This is the first study to investigate the efficacy of intravenous iron in treating fatigue in nonanemic patients with low serum ferritin concentration. In a randomized, double-blinded, placebo-controlled study, 90 premenopausal women presenting with fatigue, serum ferritin ≤ 50 ng/mL, and hemoglobin ≥ 120 g/L were randomized to receive either 800 mg of intravenous iron (III)-hydroxide sucrose or intravenous placebo. Fatigue and serum iron status were assessed at baseline and after 6 and 12 weeks. Median fatigue at baseline was 4.5 (on a 0-10 scale). Fatigue decreased during the initial 6 weeks by 1.1 in the iron group compared with 0.7 in the placebo group (P = .07). Efficacy of iron was bound to depleted iron stores: In patients with baseline serum ferritin ≤ 15 ng/mL, fatigue decreased by 1.8 in the iron group compared with 0.4 in the placebo group (P = .005), and 82% of iron-treated compared with 47% of placebo-treated patients reported improved fatigue (P = .03). Drug-associated adverse events were observed in 21% of iron-treated patients and in 7% of placebo-treated patients (P = .05); none of these events was serious. Intravenous administration of iron improved fatigue in iron-deficient, nonanemic women with a good safety and tolerability profile. The efficacy of intravenous iron was bound to a serum ferritin concentration ≤ 15 ng/mL. This study was registered at the International Standard Randomized Controlled Trial Number Register (www.isrctn.org) as ISRCTN78430425.
Iron deficiency is the single most prevalent nutritional deficiency worldwide. It accounts for anemia in 5% of American women and 2% of American men. The goal of this review article is to assist practitioners in understanding the physiology of iron metabolism and to aid in accurately diagnosing iron deficiency anemia. The current first line of therapy for patients with iron deficiency anemia is oral iron supplementation. Oral supplementation is cheap, safe, and effective at correcting iron deficiency anemia; however, it is not tolerated by some patients and in a subset of patients it is insufficient. Patients in whom the gastrointestinal blood loss exceeds the intestinal ability to absorb iron (e.g. intestinal angiodysplasia) may develop iron deficiency anemia refractory to oral iron supplementation. This population of patients proves to be the most challenging to manage. Historically, these patients have required numerous and frequent blood transfusions and suffer end-organ damage resultant from their refractory anemia. Intravenous iron supplementation fell out of favor secondary to the presence of infrequent but serious side effects. Newer and safer intravenous iron preparations are now available and are likely currently underutilized. This article discusses the possible use of intravenous iron supplementation in the management of patients with severe iron deficiency anemia and those who have failed oral iron supplementation.
Main disorders of iron metabolism Increased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron deficiency anaemia. In chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, resulting in hypoferraemia and iron restricted erythropoiesis, despite normal iron stores (functional iron deficiency), and finally anaemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD+ID). In contrast, low hepcidin expression may lead to hereditary haemochromatosis (HH type I, mutations of the HFE gene) and type II (mutations of the hemojuvelin and hepcidin genes). Mutations of transferrin receptor 2 lead to HH type III, whereas those of the ferroportin gene lead to HH type IV. All these syndromes are characterised by iron overload. As transferrin becomes saturated in iron overload states, non-transferrin bound iron appears. Part of this iron is highly reactive (labile plasma iron), inducing free radical formation. Free radicals are responsible for the parenchymal cell injury associated with iron overload syndromes.
Role of laboratory testing in diagnosis In iron deficiency status, laboratory tests may provide evidence of iron depletion in the body or reflect iron deficient red cell production. Increased transferrin saturation and/or ferritin levels are the main cues for further investigation of iron overload. The appropriate combination of different laboratory tests with an integrated algorithm will help to establish a correct diagnosis of iron overload, iron deficiency and anaemia.
Review of treatment options Indications, advantages and side effects of the different options for treating iron overload (phlebotomy and iron chelators) and iron deficiency (oral or intravenous iron formulations) will be discussed.
In addition to occasional autoimmune hemolytic anemia, unexplained iron-deficiency anemia has been reported in childhood Castleman disease (CD). The recent discovery of hepcidin has regenerated the research on iron metabolism. This hormone is a key regulator of iron homeostasis, mainly by inhibiting intestinal iron absorption. Liver expression of hepcidin increases in response to interleukin 6 (IL-6). With chronic overproduction of IL-6 as a hallmark, CD could be an interesting human model for studying the contribution of the IL-6/hepcidin pathway in the pathogenesis of anemia of chronic disease. We report here the case of a 16-year-old boy with chronic iron-deficiency anemia (plasma ferritin: 19 μg/L; plasma iron: 2.2 μmol/L; negative bone marrow Perls' Prussian blue stain), inflammatory syndrome (C-reactive protein: 108 mg/L), and growth retardation for the previous 2 years. Diagnostic workup revealed a large mesenteric mass corresponding to localized CD of mixed histologic type. Resection of the tumor resulted in complete resolution of iron-deficiency anemia and inflammatory syndrome. Parallel variations of plasma IL-6, C-reactive protein, and hepcidin concentrations, together with tumor immunohistochemistry, strongly suggested that IL-6 synthesized by the tumor caused both the inflammation and iron deficiency through enhancement of hepcidin production by the liver. The results of this unique case study (1) explain the mechanism of iron deficiency observed in some children with CD, (2) confirm in vivo the regulatory effect of IL-6 in human hepcidin production, and (3) suggest that iron deficiency is a causal link between IL-6 and anemia of chronic disease.
Purpose:
To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.
Methods:
An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched.
Results:
The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews.
Recommendations:
For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.
Beyond erythropoiesis, iron is involved in numerous biological processes crucial for maintenance of homeostasis. Patients with chronic heart failure (CHF) are prone to develop iron deficiency (ID), and iron supplementation improves their functional status and quality of life. We sought to examine the relationship between ID and survival in patients with systolic CHF.
In a prospective observational study, we evaluated 546 patients with stable systolic CHF [age: 55 +/- 11 (mean +/- standard deviation) years, males: 88%, left ventricular ejection fraction: 26 +/- 7%, New York Heart Association (NYHA) class (I/II/III/IV): 57/221/226/42]. Iron deficiency was defined as: ferritin <100 microg/L, or 100-300 microg/L with transferrin saturation <20%. The prevalence of ID was 37 +/- 4% [+/-95% confidence intervals (CI)] in the entire CHF population (32 +/- 4 vs. 57 +/- 10%-in subjects without vs. with anaemia defined as haemoglobin level <12 g/dL in women and <13 g/dL in men, P < 0.001). In a multiple logistic model, ID was more prevalent in women, those in the advanced NYHA class, with higher plasma N-terminal pro-type B natriuretic peptide and higher serum high-sensitivity C-reactive protein (all P < 0.05). At the end of follow-up (mean duration: 731 +/- 350 days), there were 153 (28%) deaths and 30 (6%) heart transplantations (HTX). In multivariable models, ID (but not anaemia) was related to an increased risk of death or HTX (adjusted hazard ratio 1.58, 95% CI 1.14-2.17, P < 0.01).
In patients with systolic CHF, ID is common and constitutes a strong, independent predictor of unfavourable outcome. Iron supplementation may be considered as a therapeutic approach in these patients to improve prognosis.
Differentiating agents have been proposed to overcome the impaired cellular differentiation in acute myeloid leukemia (AML). However, only the combinations of all-trans retinoic acid or arsenic trioxide with chemotherapy have been successful, and only in treating acute promyelocytic leukemia (also called AML3). We show that iron homeostasis is an effective target in the treatment of AML. Iron chelating therapy induces the differentiation of leukemia blasts and normal bone marrow precursors into monocytes/macrophages in a manner involving modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). 30% of the genes most strongly induced by iron deprivation are also targeted by vitamin D3 (VD), a well known differentiating agent. Iron chelating agents induce expression and phosphorylation of the VD receptor (VDR), and iron deprivation and VD act synergistically. VD magnifies activation of MAPK JNK and the induction of VDR target genes. When used to treat one AML patient refractory to chemotherapy, the combination of iron-chelating agents and VD resulted in reversal of pancytopenia and in blast differentiation. We propose that iron availability modulates myeloid cell commitment and that targeting this cellular differentiation pathway together with conventional differentiating agents provides new therapeutic modalities for AML.
Iron maldistribution has been implicated in multiple diseases, including the anemia of inflammation (AI), atherosclerosis, diabetes, and neurodegenerative disorders. Iron metabolism is controlled by hepcidin, a 25-amino acid peptide. Hepcidin is induced by inflammation, causes iron to be sequestered, and thus, potentially contributes to AI. Human hepcidin (hHepc) overexpression in mice caused an iron-deficient phenotype, including stunted growth, hair loss, and iron-deficient erythropoiesis. It also caused resistance to supraphysiologic levels of erythropoiesis-stimulating agent, supporting the hypothesis that hepcidin may influence response to treatment in AI. To explore the role of hepcidin in inflammatory anemia, a mouse AI model was developed with heat-killed Brucella abortus treatment. Suppression of hepcidin mRNA was a successful anemia treatment in this model. High-affinity antibodies specific for hHepc were generated, and hHepc knock-in mice were produced to enable antibody testing. Antibody treatment neutralized hHepc in vitro and in vivo and facilitated anemia treatment in hHepc knock-in mice with AI. These data indicate that antihepcidin antibodies may be an effective treatment for patients with inflammatory anemia. The ability to manipulate iron metabolism in vivo may also allow investigation of the role of iron in a number of other pathologic conditions.
Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia.
We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 microg per liter or between 100 and 299 microg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life.
Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups.
Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780).
Intake of supplements containing iron or a combination of iron and folic acid by pregnant women may improve maternal health and pregnancy outcomes. Recently, intermittent supplementation regimens have been proposed as alternatives to daily regimens.
To assess the effectiveness and safety of daily and intermittent use of iron or iron+folic acid supplements by pregnant women.
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2009) and contacted relevant organisations for the identification of ongoing and unpublished studies.
All randomised or quasi-randomised trials evaluating the effect of supplementation with iron or iron+folic acid during pregnancy.
We assessed the methodological quality of trials using the standard Cochrane criteria. Two authors independently assessed which trials to include in the review and one author extracted data.
We included 49 trials, involving 23,200 pregnant women. Overall, the results showed significant heterogeneity across most prespecified outcomes and were analysed assuming random-effects. The trials provided limited information related to clinical maternal and infant outcomes.Overall, daily iron supplementation was associated with increased haemoglobin levels in maternal blood both before and after birth and reduced risk of anaemia at term. These effects did not differ significantly between women receiving intermittent or daily iron or iron+folic acid supplementation. Women who received daily prenatal iron supplementation with or without folic acid were less likely to have iron deficiency at term as defined by current cut-off values than those who received no treatment or placebo. Side effects and haemoconcentration (a haemoglobin level greater than 130 g/L) were more common among women who received daily iron or iron+folic acid supplementation than among those who received no treatment or placebo. The risk of haemoconcentration during the second and third trimester was higher among those on a daily regimen of iron supplementation. The clinical significance of haemoconcentration remains uncertain.
Universal prenatal supplementation with iron or iron+folic acid provided either daily or weekly is effective to prevent anaemia and iron deficiency at term. We found no evidence, however, of the significant reduction in substantive maternal and neonatal adverse clinical outcomes (low birthweight, delayed development, preterm birth, infection, postpartum haemorrhage). Associated side effects and particularly haemoconcentration during pregnancy may suggest the need for revising iron doses and schemes of supplementation during pregnancy and adjust preventive iron supplementation recommendations.
Up to 25% of adolescent girls in the USA are iron deficient. This double-blind, placebo-controlled clinical trial assessed the effects of iron supplementation on cognitive function in adolescent girls with non-anaemic iron deficiency.
716 girls who enrolled at four Baltimore high schools were screened for non-anaemic iron deficiency (serum ferritin < or = 12 micrograms/L with normal haemoglobin). 98 (13.7%) girls had non-anaemic iron deficiency of whom 81 were enrolled in the trial. Participants were randomly assigned oral ferrous sulphate (650 mg twice daily) or placebo for 8 weeks. The effect of iron treatment was assessed by questionnaires and haematological and cognitive tests, which were done before treatment started and repeated after the intervention. We used four tests of attention and memory to measure cognitive functioning. Intention-to-treat and per-protocol analyses were done.
Of the 81 enrolled girls with non-anaemic iron deficiency, 78 (96%) completed the study (39 in each group). Five girls (three control, two treatment) developed anaemia during the intervention and were excluded from the analyses. Thus, 73 girls were included in the per-protocol analysis. Ethnic distribution, mean age, serum ferritin concentrations, haemoglobin concentrations, and cognitive test scores of the groups did not differ significantly at baseline. Postintervention haematological measures of iron status were significantly improved in the treatment group (serum ferritin 27.3 vs 12.1 micrograms/L, p < 0.001). Regression analysis showed that girls who received iron performed better on a test of verbal learning and memory than girls in the control group (p < 0.02).
In this urban population of non-anaemic iron-deficient adolescent girls, iron supplementation improved verbal learning and memory.
To determine the subjective response to iron therapy in non-anaemic women with unexplained fatigue.
Double blind randomised placebo controlled trial.
Academic primary care centre and eight general practices in western Switzerland.
144 women aged 18 to 55, assigned to either oral ferrous sulphate (80 mg/day of elemental iron daily; n=75) or placebo (n=69) for four weeks.
Level of fatigue, measured by a 10 point visual analogue scale.
136 (94%) women completed the study. Most had a low serum ferritin concentration; <or= 20 microg/l in 69 (51%) women. Mean age, haemoglobin concentration, serum ferritin concentration, level of fatigue, depression, and anxiety were similar in both groups at baseline. Both groups were also similar for compliance and dropout rates. The level of fatigue after one month decreased by -1.82/6.37 points (29%) in the iron group compared with -0.85/6.46 points (13%) in the placebo group (difference 0.95 points, 95% confidence interval 0.32 to 1.62; P=0.004). Subgroups analysis showed that only women with ferritin concentrations <or= 50 microg/l improved with oral supplementation.
Non-anaemic women with unexplained fatigue may benefit from iron supplementation. The effect may be restricted to women with low or borderline serum ferritin concentrations.
Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
Evidence suggests that brain iron deficiency at any time in life may disrupt metabolic processes and subsequently change cognitive and behavioral functioning. Women of reproductive age are among those most vulnerable to iron deficiency and may be at high risk for cognitive alterations due to iron deficiency.
We aimed to examine the relation between iron status and cognitive abilities in young women.
A blinded, placebo-controlled, stratified intervention study was conducted in women aged 18-35 y of varied iron status who were randomly assigned to receive iron supplements or a placebo. Cognition was assessed by using 8 cognitive performance tasks (from Detterman's Cognitive Abilities Test) at baseline (n = 149) and after 16 wk of treatment (n = 113).
At baseline, the iron-sufficient women (n = 42) performed better on cognitive tasks (P = 0.011) and completed them faster (P = 0.038) than did the women with iron deficiency anemia (n = 34). Factors representing performance accuracy and the time needed to complete the tasks by the iron-deficient but nonanemic women (n = 73) were intermediate between the 2 extremes of iron status. After treatment, a significant improvement in serum ferritin was associated with a 5-7-fold improvement in cognitive performance, whereas a significant improvement in hemoglobin was related to improved speed in completing the cognitive tasks.
Iron status is a significant factor in cognitive performance in women of reproductive age. Severity of anemia primarily affects processing speed, and severity of iron deficiency affects accuracy of cognitive function over a broad range of tasks. Thus, the effects of iron deficiency on cognition are not limited to the developing brain.
To review the potential risks of administering intravenous iron to patients with infection.
Literature was accessed through MEDLINE (1977-June 2007) and Google Scholar, using the terms intravenous iron, iron sucrose, ferric gluconate, iron dextran, and infection. In addition, reference citations from publications identified were reviewed.
All English-language articles identified from the data sources were evaluated. Studies that provided data relevant to the objective were used, including in vitro and animal studies.
The role of iron in bacterial growth and the pathophysiology of cellular immunity create legitimate, yet theoretical, concerns that active infection may be exacerbated by the administration of intravenous iron. Human data relating to this issue are limited. A few small, human studies in a population with chronic kidney disease suggest a possible increased risk of developing an infection associated with intravenous iron; however, prospective human data directly linking intravenous iron to exacerbation of existing infection or infection-related mortality are lacking. In vitro data suggest that increased transferrin saturation related to iron administration may result in polymorphonuclear leukocyte dysfunction and decreased inhibition of bacterial growth. Sparse animal data have linked intravenous iron therapy with morbidity and mortality in sepsis models.
Despite the limited human data, careful consideration of risk versus benefit should be used when administering intravenous iron to patients with ongoing infection. Additional clinical data are needed to determine whether intravenous iron administration worsens outcomes of patients with infection.
Ferric carboxymaltose (Ferinject®), a novel iron complex that consists of a ferric hydroxide core stabilized by a carbohydrate shell, allows for controlled delivery of iron to target tissues. Administered intravenously, it is effective in the treatment of iron-deficiency anaemia, delivering a replenishment dose of up to 1000 mg of iron during a minimum administration time of ≤15 minutes. Results of several randomized trials have shown that intravenously administered ferric carboxymaltose rapidly improves haemoglobin levels and replenishes depleted iron stores in various populations of patients with iron-deficiency anaemia, including those with inflammatory bowel disease, heavy uterine bleeding, postpartum irondeficiency anaemia or chronic kidney disease. It was well tolerated in clinical trials. Ferric carboxymaltose is, therefore, an effective option in the treatment of iron-deficiency anaemia in patients for whom oral iron preparations are ineffective or cannot be administered.
Pharmacological Properties
Ferric carboxymaltose is a macromolecular ferric hydroxide carbohydrate complex, which allows for controlled delivery of iron within the cells of the reticuloendothelial system and subsequent delivery to the iron-binding proteins ferritin and transferrin, with minimal risk of release of large amounts of ionic iron in the serum. Intravenous administration of ferric carboxymaltose results in transient elevations in serum iron, serum ferritin and transferrin saturation, and, ultimately, in the correction of haemoglobin levels and replenishment of depleted iron stores.
The total iron concentration in the serum increased rapidly in a dose-dependent manner after intravenous administration of ferric carboxymaltose. Ferric carboxymaltose is rapidly cleared from the circulation and is distributed primarily to the bone marrow (≈80%) and also to the liver and spleen. Repeated weekly administration of ferric carboxymaltose does not result in accumulation of transferrin iron in patients with iron-deficiency anaemia.
Therapeutic Efficacy
Intravenously administered ferric carboxymaltose was effective in the treatment of iron-deficiency anaemia in several 6- to 12-week, randomized, open-label, controlled, multicentre trials in various patient populations, including those with inflammatory bowel disease, heavy uterine bleeding or postpartum irondeficiency anaemia, and those with chronic kidney disease not undergoing or undergoing haemodialysis. In most trials, patients received either ferric carboxymaltose equivalent to an iron dose of ≤1000mg (or 15mg/kg in those weighing <66kg) administered over ≤15 minutes (subsequent doses administered at 1-week intervals) or oral ferrous sulfate at a dose equivalent to 65 mg iron three times daily or 100mg iron twice daily. In one trial, patients with chronic kidney disease undergoing haemodialysis received 200 mg of iron intravenously either as ferric carboxymaltose or iron sucrose administered into the haemodialysis line two to three times weekly. In all trials, ferric carboxymaltose was administered until each patient had received his or her calculated total iron replacement dose.
Haemoglobin-related outcomes improved in patients with iron-deficiency anaemia receiving ferric carboxymaltose. Treatment with ferric carboxymaltose was associated with rapid and sustained increases from baseline in haemoglobin levels. Ferric carboxymaltose was considered to be as least as effective as ferrous sulfate with regard to changes from baseline in haemoglobin levels or the proportion of patients achieving a haematopoietic response at various timepoints. In general, improvements in haemoglobin levels were more rapid with ferric carboxymaltose than with ferrous sulfate. In patients with chronic kidney disease undergoing haemodialysis, ferric carboxymaltose was at least as effective as iron sucrose.
Ferric carboxymaltose also replenished depleted iron stores and improved health-related quality-of-life (HR-QOL) in patients with iron-deficiency anaemia. Recipients of ferric carboxymaltose demonstrated improvements from baseline in serum ferritin levels and transferrin saturation, as well as improvements from baseline in HR-QOL assessment scores. Ferric carboxymaltose was at least as effective as ferrous sulfate with regard to endpoints related to serum ferritin levels, transferrin saturation and HR-QOL.
Tolerability
Ferric carboxymaltose was well tolerated in clinical trials in patients with irondeficiency anaemia, with most drug-related adverse events considered to be mild to moderate in severity. Commonly reported drug-related adverse events include headache, dizziness, nausea, abdominal pain, constipation, diarrhoea, rash and injection-site reactions.
The incidence of drug-related adverse events in patients receiving intravenous ferric carboxymaltose was generally similar to that in patients receiving oral ferrous sulfate. In general, rash and local injection-site reactions were more common with ferric carboxymaltose, whereas gastrointestinal adverse events were more frequent with ferrous sulfate. In patients with chronic kidney disease undergoing haemodialysis, a lower proportion of ferric carboxymaltose than iron sucrose recipients experienced at least one drug-related adverse event.
Les femmes en âge de procreer ont un faible niveau de reserves en fer. La supplementation systematique ameliore les parametres biologiques maternels mais est sans effet sur le foetus et le nouveau-ne. Au contraire, une supplementation selective s'adressant a des femmes anemiees (10 a 20 % des grossesses) parfois denutries a des effets benefiques. Le risque potentiel majeur d'une supplementation inutile est la majoration du stress oxydant implique dans un certain nombre de pathologies gravidiques (pre-eclampsie, diabete gestationnel). Une augmentation trop importante de la masse erythrocytaire peut aussi avoir un effet deletere sur les echanges uteroplacentaires. Le principe de precaution doit nous faire reserver la supplementation martiale aux femmes anemiees ou a risque d'anemie. Pour les autres femmes, des conseils nutritionnels adaptes doivent permettre un apport en fer suffisant (recommandation du CNGOF).
Purpose:
Advances towards the understanding of gene regulation and protein function recently discovered through iron metabolism disorders are the subject of this review.
Current knowledge and key points:
Within a few years the discovery of genes that determine heritable defects of cellular iron uptake or regulation in mice as in humans have provided new insights for investigation into iron metabolism pathways.
Future prospects and projects:
It is still unclear how connections are made between new proteins in iron uptake, trafficking and regulation of iron homeostasis. Gene expression studies using microarrays technology in different iron conditions should help to explore iron homeostasis further.
Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads
to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin
is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here
we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded,
leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete
a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the
cell surface.
Iron deficiency anemia (IDA) is common in chronic diseases and intravenous iron is an effective and recommended treatment. However, dose calculations and inconvenient administration may affect compliance and efficacy. We compared the efficacy and safety of a novel fixed-dose ferric carboxymaltose regimen (FCM) with individually calculated iron sucrose (IS) doses in patients with inflammatory bowel disease (IBD) and IDA.
This randomized, controlled, open-label, multicenter study included 485 patients with IDA (ferritin <100 μg/L, hemoglobin [Hb] 7-12 g/dL [female] or 7-13 g/dL [male]) and mild-to-moderate or quiescent IBD at 88 hospitals and clinics in 14 countries. Patients received either FCM in a maximum of 3 infusions of 1000 or 500 mg iron, or Ganzoni-calculated IS dosages in up to 11 infusions of 200 mg iron. Primary end point was Hb response (Hb increase ≥ 2 g/dL); secondary end points included anemia resolution and iron status normalization by week 12.
The results of 240 FCM-treated and 235 IS-treated patients were analyzed. More patients with FCM than IS achieved Hb response (150 [65.8%] vs 118 [53.6%]; 12.2% difference, P = .004) or Hb normalization (166 [72.8%] vs 136 [61.8%]; 11.0% difference, P = .015). Both treatments improved quality of life scores by week 12. Study drugs were well tolerated and drug-related adverse events were in line with drug-specific clinical experience. Deviations from scheduled total iron dosages were more frequent in the IS group.
The simpler FCM-based dosing regimen showed better efficacy and compliance, as well as a good safety profile, compared with the Ganzoni-calculated IS dose regimen.
Iron deficiency may exacerbate symptoms in the Restless Legs Syndrome (RLS). We investigated the effect of intravenous iron sucrose or placebo on symptoms in patients with RLS and mild to moderate iron deficit. Sixty patients with primary RLS (seven males, age 46 (9) years, S-ferritin < or =45 microg/L) recruited from a cohort of 231 patients were randomly assigned in a 12-months double-blind, multi-centre study of iron sucrose 1000 mg (n = 29) or saline (n = 31). The primary efficacy variable was the RLS severity scale (IRLS) score at week 11. Median IRLS score decreased from 24 to 7 (week 11) after iron sucrose and from 26 to 17 after placebo (P = 0.123, N.S. for between treatment comparison). The corresponding scores at week 7 were 12 and 20 in the two groups (P = 0.017). Drop out rate because of lack of efficacy at 12 months was 19/31 after placebo and 5/29 patients after iron sucrose (Kaplan-Meier estimate, log rank test P = 0.0006) suggesting an iron induced superior long term RLS symptom control. Iron sucrose was well tolerated. This study showed a lack of superiority of iron sucrose at 11 weeks but found evidence that iron sucrose reduced RLS symptoms both in the acute phase (7 weeks) and during long-term follow up in patients with variable degree of iron deficiency. Further studies on target patient groups, dosing and dosing intervals are warranted before iron sucrose could be considered for treatment of iron deficient patients with RLS.
Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer.
Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups.
Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42).
Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits.
German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).
Ferric carboxymaltose (Ferinject®, Injectafer®) is an intravenous iron preparation approved in numerous countries for the treatment of iron deficiency. A single high dose of ferric carboxymaltose (up to 750 mg of iron in the US and 1,000 mg of iron in the EU) can be infused in a short time frame (15 min). Consequently, fewer doses of ferric carboxymaltose may be needed to replenish iron stores compared with some other intravenous iron preparations (e.g. iron sucrose). Ferric carboxymaltose improved self-reported patient global assessment, New York Heart Association functional class and exercise capacity in patients with chronic heart failure and iron deficiency in two randomized, placebo-controlled trials (FAIR-HF and CONFIRM-HF). In other randomized controlled trials, ferric carboxymaltose replenished iron stores and corrected anaemia in various populations with iron-deficiency anaemia, including patients with chronic kidney disease, inflammatory bowel disease or heavy uterine bleeding, postpartum iron-deficiency anaemia and perioperative anaemia. Intravenous ferric carboxymaltose was generally well tolerated, with a low risk of hypersensitivity reactions. It was generally better tolerated than oral ferrous sulfate, mainly reflecting a lower incidence of gastrointestinal adverse effects. The most common laboratory abnormality seen in ferric carboxymaltose recipients was transient, asymptomatic hypophosphataemia. The higher acquisition cost of ferric carboxymaltose appeared to be offset by lower costs for other items, with the potential for cost savings. In conclusion, ferric carboxymaltose is an important option for the treatment of iron deficiency.
Restless Legs Syndrome (RLS) is a primary disorder of sensation that affects sleep and has been associated with iron deficiency. The purpose of this study was to determine if symptomatic RLS patients with low-normal serum ferritin levels benefit from oral iron replacement.
This was a randomized, placebo-controlled, double-blinded study. Eligible patients were randomized to oral iron therapy vs. appearance-matched placebo and followed over a 12 week period.
Baseline International Restless Leg Scale (IRLS) scores for the treatment (24.8+/-5.72) and placebo (23.0+/-5.03) groups were similar. Baseline ferritin levels for the treatment (40.6+/-15.3ng/ml) and placebo (36.7+/-20.8ng/ml) groups were also similar. After 12 weeks, IRLS scores decreased more in the treatment arm (10.3+/-7.40) than in the placebo arm (1.14+/-5.64), (p=0.01). Ferritin levels increased more in the treatment arm (25.1+/-20.3ng/ml) than in the placebo arm (7.5+/-13.7ng/ml), (p=0.04). We observed a nonsignificant trend toward improved quality of life in the treated patients, (p=0.07).
This is the first double-blinded, placebo-controlled study to demonstrate statistically significant improvement in RLS symptoms using oral iron therapy in patients with low-normal ferritin. The findings from this study suggest that additional larger randomized placebo-controlled trials of iron as treatment for patients with low-normal ferritin are warranted.
Use of erythropoietin (EPO) therapy and iron supplementation has improved the management of anemia in patients with end-stage renal disease (ESRD). As more patients receive supplemental iron, however, concerns are being raised about a potential link between iron and infection. There is biologic plausibility for this link, since iron is a growth factor for bacteria and certain host defense mechanisms are iron-sensitive. Animal models show that injection of iron leads to increased susceptibility to bacterial infection. In some studies, patients with high serum ferritin levels have reduced neutrophil function. However, these studies did not determine whether serum ferritin levels were elevated because of increased iron stores or because of infection. If infection is present, it might cause both the elevated serum ferritin levels and the neutrophil dysfunction. Several clinical studies have found an association between high serum ferritin levels and increased infectious risk. In studies that control for important covariates such as use of catheters and previous infections, the infectious risk associated with iron administration or elevated serum ferritin levels is reduced or eliminated. Collectively, these studies suggest that our current understanding of the relationship between iron and infection is incomplete and further studies are needed. There is no reason to alter current iron treatment strategies based on this literature.
Beyond its role in hemoglobin synthesis, iron plays an important part in host defense mechanisms. Sequestration of iron is a mechanism to control bacterial proliferation and virulence. However, uremia results in several immunologic deficits, including impaired lymphocyte mitogenic response and granulocyte function abnormalities such as impaired phagocytosis, respiratory burst, and myeloperoxidase activity. At the other end of the spectrum, iron overload can impair immune function and stimulate bacterial growth and virulence. Overtreatment with iron increases the preexisting risk of infectious complications for uremic patients, as indicated by hyperferritinemia in hemodialysis patients who have impaired polymorphonuclear leukocyte (PMNL)-induced bacterial killing. These results suggest that maintaining iron status within normal range is important to control potential increased risk of infection in patients with end-stage renal disease (ESRD).
Restless legs syndrome (RLS) is a common disorder in patients with end-stage renal disease (ESRD) that causes motor agitation and insomnia. Because RLS has been associated with iron deficiency, we sought to investigate the effects of intravenous (IV) iron dextran on symptoms of RLS in a double-blind placebo-controlled trial.
Patients determined to have RLS by International RLS Study Group criteria were administered either iron dextran, 1,000 mg, or normal saline IV in a blinded fashion. Patient demographic data were collected, and blood chemistry tests, liver function studies, serum iron levels, ferritin levels, and total iron-binding capacity were obtained at baseline and 1, 2, and 4 weeks postinfusion. Side effects or adverse events to interventions were monitored, and RLS symptoms were assessed by a rating scale at the same intervals.
Eleven patients were randomly assigned to the administration of iron dextran, and 14 patients to the administration of saline. RLS severity scores were slightly higher in the placebo group at baseline, but hemoglobin levels, iron stores, and other biochemical parameters did not differ. Although no change in symptoms were seen in the placebo-treated group, significant improvement in RLS symptom scores in response to iron dextran was seen 1 week after infusion (-2; interquartile range [IQR], -6 to -1; P = 0.03, Wilcoxon's rank sums), but was greatest at 2 weeks (-3; IQR, -5 to -2 compared with -1 to 0; P = 0.01). Salutary effects of iron persisted at 4 weeks, but were no longer statistically significant. The significant increase in serum ferritin levels and iron saturation observed in the iron dextran-treated group was not seen in the placebo-treated group. No differences in adverse events were noted between groups.
High-dose iron dextran infusion is associated with a significant, but transient, reduction in symptoms of RLS in patients with ESRD.
The chelator currently used to treat iron (Fe) overload disease, desferrioxamine (DFO), has shown anti-proliferative activity against leukemia and neuroblastoma cells in vitro, in vivo and in clinical trials. Collectively, these studies suggest that Fe-deprivation may be a useful anti-cancer strategy. However, the efficacy of DFO is severely limited due to its poor ability to permeate cell membranes and bind intracellular Fe pools. These limitations have encouraged the development of other Fe chelators that are far more effective than DFO. One group of ligands that have been extensively investigated are those of the pyridoxal isonicotinoyl hydrazone (PIH) class. In this review the marked anti-proliferative effects of the PIH analogs are discussed with reference to their mechanisms of action and structure-activity relationships. In particular, we discuss the activity of a novel group of ligands that are "hybrid" chelators derived from our most effective PIH analogs and thiosemicarbazones. The anti-tumor activity of the PIH analogs and other chelators such as tachpyridine, O-trensox and the desferrithiocin analogs have been well characterized in vitro. However, further studies in animals are critical to evaluate their selective anti-tumor activity and potential as therapeutic agents.
This review focuses on advances and strategies in the use of iron chelators as anti-tumor therapies. Although the development of iron chelators for human disease has focused primarily on their use in the treatment of secondary iron overload, chelators may also be useful anti-tumor agents. They can deplete iron or cause oxidative stress in the tumor due to redox perturbations in its environment. Iron chelators have been tested for their anti-tumor activity in cell culture experiments, animal models and human clinical trials. Largely for pragmatic reasons, clinical studies of the anti-tumor activity of iron chelators have generally focused on desferrioxamine (DFO), a drug approved for the treatment of iron overload. These studies have shown that DFO can retard tumor growth in many different experimental contexts. However, the activity of DFO is modest, and advances in the use of chelators as anti-cancer agents will require the development of new chelators based on new paradigms. Examples of iron chelators that have shown promising anti-tumor activity (in various stages of development) include heterocyclic carboxaldehyde thiosemicarbazones, analogs of pyridoxal isonicotinoyl hydrazone, tachpyridine, O-trensox, desferrithiocin, and other natural and synthetic chelators. Apart from their use as single agents, chelators may also synergize with other anti-cancer therapies. The development of chelators as anticancer agents is largely an unexplored field, but one with extraordinary potential to impact human cancer.
Iron deficiency anemia is common in people with chronic kidney disease (CKD) and its importance in supporting erythropoiesis is unquestioned especially in those patients treated with erythropoietin. Clinical symptomatology such as fatigability, cold intolerance, failure to concentrate and poor effort intolerance is often attributed to anemia or uremia. That iron deficiency, per se, can cause these symptoms is poorly recognized. Clinical and animal studies that support the benefits of iron supplementation, independent of increasing hemoglobin, such as those on immune function, physical performance, thermoregulation, cognition, and restless leg syndrome and aluminum absorption is the subject of this narrative review.
Pathophysiology and differential diagnosis of anaemia Disorders of erythropoie-sis, erythrocytes and iron metabolism. The Handbook, 4. Paris: ESH
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Lambert JF, Beris P. Pathophysiology and differential diagnosis of anaemia. In: Beaumont C, Beris P, Beuzard Y, Brugnara C, editors. Disorders of erythropoie-sis, erythrocytes and iron metabolism. The Handbook, 4. Paris: ESH; 2009. p. 109–39.
Iron therapy Disorders of erythropoiesis, erythrocytes and iron metabolism. The Handbook, 21. Paris: ESH
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Brugnara C, Beris P. Iron therapy. In: Beaumont C, Beris P, Beuzard Y, Brugnara C, editors. Disorders of erythropoiesis, erythrocytes and iron metabolism. The Handbook, 21. Paris: ESH; 2009. p. 513–26.