Expected hepcidin levels in individuals with iron deficiency and anemia are lower than the values measured in this study.

Other potential mediators of refractoriness to oral iron in heart failure seem less likely to have affected our findings. Use of anticoagulants and antiplatelet agents was prevalent, but the rate of expected loss of iron Therefore, in the absence of overt gastrointenstinal bleeding, which did not occur in any of the participants treated with oral iron during the trial, blood loss would not be expected to account for the observed minimal increases in iron stores with oral iron treatment.

The choice of iron polysaccharide formulation for this study was based on its offering the highest dose of elemental iron among available oral supplements, coupled with its tolerance profile to aid in adherence and minimize risk of unblinding participants.

Polysaccharide iron preparations have been shown to provide comparable iron repletion to iron salts. Hence, even after accounting for limited gastrointestinal iron absorption, the fold increase in oral iron exposure, compared with the recommended daily intake, served to adequately test the hypothesis that oral iron supplementation would improve iron stores and functional capacity in HFrEF.

The selection of change in peak V̇ o 2 for the primary end point, as previously described, 15 was based on the fact that peak V̇ o 2 is the gold standard indicator of functional capacity in heart failure and has been shown to improve with iron repletion in non—heart failure populations.

The lack of treatment effect on quality of life, NT-proBNP, and other physiological end points is consistent with the observed lack of treatment effect on maximal exercise capacity. Submaximum exercise capacity, indicative of endurance and independent of volitional effort, may be more sensitive to subtle changes in iron bioavailability as opposed to peak V̇ o 2.

This trial complements recent studies about intravenous iron treatment in informing the appropriate approach to iron repletion in HFrEF. However, the correlates observed between baseline iron indices and exercise capacity, as well as changes in Tsat being related to improvement in peak V̇ o 2 are consistent with results of recent trials suggesting beneficial effects of intravenous iron on functional capacity in HFrEF.

This study has some important limitations. This study was not powered to detect differences in clinical events or safety end points. There was also no direct comparison between intravenous vs oral iron repletion. Given the relatively short duration of the trial, it is possible that longer duration or higher dose of exposure may have led to more significant improvement in iron stores and increased exercise capacity, particularly among those participants with appropriately low hepcidin levels.

In addition, this study was confined to patients with HFrEF and findings may differ in heart failure with preserved ejection fraction. Among participants with iron deficiency and HFrEF, high-dose oral iron minimally augmented iron stores and did not improve exercise capacity over 16 weeks.

These findings do not support the use of oral iron supplementation to treat iron deficiency in patients with HFrEF. Corresponding Author: Gregory D. Lewis, MD, Pulmonary Critical Care Unit, Cardiology Division, Massachusetts General Hospital, 55 Fruit St, Bigelow , Boston, MA glewis partners.

Correction: This article was corrected for data and typographical errors on May 25, Author Contributions: Drs Lewis and Braunwald had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Lewis, Malhotra, Hernandez, Felker, Tang, Redfield, Semigran, Givertz, Whellen, Anstrom, Shah, Desvigne-Nickens, Butler, Braunwald. Acquisition, analysis, or interpretation of data: Lewis, Malhotra, Hernandez, McNulty, Smith, Felker, Tang, LaRue, Semigran, Givertz, Van Buren, Whellen, Shah, Desvigne-Nickens, Butler, Braunwald.

Critical revision of the manuscript for important intellectual content: All authors. Administrative, technical, or material support: Hernandez, LaRue, Givertz, Shah, Desvigne-Nickens, Braunwald. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Dr Lewis reports receipt of grants to the institution from Abbott, Novartis, Shape Systems, and Stealth BioTherapeutics; personal fees for consultancies from Ironwood and Cheetah Medical; and unpaid consultancies from Luitpold and Sonivie. Dr Malhotra reports receipt of personal fees for consultancies from Akros Pharma and Third Pole and for advisory board participation from Mallinckrodt Pharmaceuticals outside the submitted work.

Dr Hernandez reports receipt of grant support from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold, Merck, and Novartis; and personal fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boston Scientific, Luitpold, and Novartis outside the submitted work.

Dr Felker reports receipt of grant support from NHLBI during the conduct of the study , Novartis, Amgen, Merck, Roche Diagnostics, and American Heart Association; and personal fees from Novartis, Amgen, Bristol-Myers Squibb, GlaxoSmithKline, and Myokardia outside the submitted work.

Dr Tang reports receipt of grants from NIH during the conduct of the study and also outside the submitted work. Dr Semigran reports receipt of grant support from NHLBI during the conduct of the study. Dr Van Buren reports receipt of grant support from NIH and personal fees for consultancy services from Medtronic.

Dr Anstrom reports receipt of grant support from the Heart Failure Clinical Research Network during the conduct of the study. Dr Butler reports receipt of grant support from the NHLBI and receipt of personal fees for consultancy services from Luitpold.

Dr Braunwald reports grant support to his institution from Duke University for his role as chair of the NHLBI Heart Failure Network , Merck, AstraZeneca, Novartis, Daiichi Sankyo, and GlaxoSmithKline; personal fees for consultancies from The Medicines Company and Theravance; personal fees for lectures from Medscape, Menarini International, and Daiichi Sankyo; and uncompensated consultancies and lectures for Merck and Novartis.

The NHLBI was not able to prevent manuscript submission. IRONOUT HF Trial Members, Investigators, and Committees: In addition to the Writing Committee, the following individuals participated in the IRONOUT HF study: HFN Member Clinical Centers—Boston VA Healthcare System: N.

Lakdawala, S. Ly, M. Quinn; Brigham and Women's Hospital: S. Anello, K. Brooks; Cleveland Clinic Foundation: T. Fonk, K. Meera; Duke University Medical Center: P. Adams, S. Chavis, A. Mbugua; Emory University Hospital: G. Snell, T. Burns, T. Dickson, N.

Islam; Johns Hopkins Hospital: R. Tedford, A. Bacher; Lancaster General Hospital: T. Nossuli, C. Forney, S. Pointer, H. Testa; Massachusetts General Hospital: D. Cocca-Spofford; Mayo Clinic: S.

Cho, S. Decker, J. Gatzke; Metro Health System: M. Dunlap, J. Nichols, P. Leo; Northwestern Memorial Hospital: S. Shah, H.

Mkrdichian, C. Sanchez; Saint Louis University Hospital: P. Hauptman, M. Lesko, E. Weber; Stony Brook University Medical Center: I. Caikauskaite, N. Nayyar, L. Papadimitriou; Thomas Jefferson University Hospital: S.

Adams, M. Fox, B. Gallagher, M. McCarey, K. Murphy; Tufts Medical Center: G. Huggins, A. Cronkright, G. Jamieson, R. Oliveira, T. Cheutzow; University of Missouri Health System: C.

Danila, S. Collins; University of Pennsylvania Health System: K. Margulies, T. Coppola, T. Wahlen VA Medical Center: S. Drakos, J. Nativi-Nicolau, J. Gibbs, J. Gutierrez; University of Vermont Medical Center: M.

LeWinter, M. Rowen; VA St. Louis Health Care System: I. Halatchev, C. Rowe; Washington University School of Medicine: V. Davila-Roman, J. Flanagan, D. Whitehead; HFN Data and Safety Monitoring Board—D.

Vaughan chair , R. Agarwal, J. Ambrose, D. DeGrazia, K. Kennedy, M. Johnson, J. Parrillo, M. Penn, M. Powers, E. Rose; Protocol Review Committee—W. Abraham chair , R. Cai, D. McNamara, J. Rose, D. Vaughan, R. Virmani; Biomarker Core Lab—University of Vermont: R. Tracy, R. Boyle; CPET Core Lab—L.

Wooster, C. Bailey, A. Dress, D. Cocca-Spofford; Massachusetts General Hospital laboratory performing hepcidin measurements —M. Buswell, G. Shelton, K. This article is also focused on adult athletes and the information discussed may not apply to children.

Iron is a mineral that has several important roles in the body including energy metabolism, oxygen transport, and acid-base balance. Red blood cells transport oxygen throughout the body and are filled with proteins called hemoglobin.

Each hemoglobin molecule contains iron. Oxygen picked up in the lungs binds to the iron inside hemoglobin and then is carried all over the body to supply oxygen to organs and tissues. Iron comes from our diet. Dietary iron can be classified into heme iron and non-heme iron.

Heme iron is found in meat, poultry, and fish. Red meat contains about three times as much iron as both poultry and fish making it one of the richest sources of dietary iron. Heme iron is absorbed by the digestive tract about twice as well as non-heme iron.

Sources of non-heme iron includes fruits, vegetables, and iron fortified foods. Vitamin C assists with the absorption of non-heme iron in the digestive tract so mixing foods rich in vitamin C with non-heme iron containing foods can increase the amount of iron the body absorbs.

Athletes need more iron than the general population. Iron is lost through sweat, skin, urine, the gastrointestinal GI tract, and menstruation.

Athletes lose more iron due to heavy sweating as well as increased blood loss in the urine and GI tract. The mechanical force of a footstrike during endurance running, for example, can increase the destruction of red blood cells in the feet, leading to a shorter red blood cell life span.

Female athletes are at even higher risk for iron deficiency as compared to males due to monthly blood loss associated with menstruation. Athletes may also be at risk for iron deficiency due to insufficient dietary iron intake. Remember, the body is not very effective at absorbing dietary iron. Those following a strict vegetarian or vegan diet can be at even higher risk for iron deficiency due to the decreased absorption of non-heme iron found in plants and fortified foods.

Because iron is necessary for oxygen transport and energy metabolism, both of which are critical for fueling aerobic exercise, endurance athletes can experience a decline in exercise capacity and VO2 max, the maximal amount of oxygen the body can use, with iron deficiency.

As iron deficiency becomes more severe, the body cannot make a sufficient number of red blood cells and anemia, meaning low red blood cells, develops.

Athletes with iron deficiency anemia will generally have more pronounced symptoms than those with iron deficiency alone. A craving for ice chips is actually pretty specific to iron deficiency, so any athletes out there who find themselves wanting to eat a lot of ice should definitely have their iron levels checked.

Iron deficiency is diagnosed through blood tests. The most useful of the typical iron study panel is ferritin, which is a marker of iron stores. In the sports nutrition community, there is no clear ferritin goal for athletes. If a ferritin is dropping significantly during the course of a training cycle, this can also be indicative of developing iron deficiency and the need to intervene, even if the ferritin is within what is generally considered a normal range.

It is also worth mentioning that ferritin levels can quickly increase when the body is under stress so results may be falsely high during periods of active infection or inflammation.

The other traditional iron panel tests can be useful in distinguishing iron deficiency from poor iron utilization states. A complete blood count CBC measures the levels of red blood cell in the body and determines whether or not someone is anemic.

Pregnant women with low iron may be more prone to infection because iron also supports the immune system. It is clear that iron supplements are needed for women who are both pregnant and iron-deficient. However, research is ongoing as to the possibility of recommending additional iron to all pregnant women, even those with normal iron levels.

It is argued that all pregnant women should take 30 to 60 milligrams mg of iron supplements on every day of their pregnancy, regardless of their iron levels.

Insufficient iron in the diet can affect the efficiency with which the body uses energy. Iron carries oxygen to the muscles and brain and is crucial for both mental and physical performance. Low iron levels may result in a lack of focus, increased irritability, and reduced stamina.

Iron deficiency is more common among athletes, especially young female athletes, than in individuals who do not lead an active lifestyle. This appears to be particularly true in female endurance athletes, such as long-distance runners.

Some experts suggest that female endurance athletes should add an additional 10 mg of elemental iron per day to the current RDA for iron intake. Iron deficiency in athletes decreases athletic performance and weakens immune system activity.

For more in-depth resources about vitamins, minerals, and supplements, visit our dedicated hub. Iron has a low bioavailability, meaning that the small intestine does not readily absorb large amounts. This decreases its availability for use and increases the likelihood of deficiency.

There are two types of dietary iron, known as heme and non-heme. Animal sources of food, including meat and seafood, contain heme iron. Heme iron is more easily absorbed by the body. Non-heme iron, the type found in plants, requires that the body take multiple steps to absorb it.

Plant-based sources of iron include beans, nuts, soy, vegetables, and fortified grains. The bioavailability of heme iron from animal sources can be up to 40 percent. Non-heme iron from plant-based sources, however, has a bioavailability of between 2 and 20 percent.

For this reason, the RDA for vegetarians is 1. Consuming vitamin-C-rich foods alongside non-heme sources of iron can dramatically increase iron absorption. When following a vegetarian diet, it is also important to consider components of food and medications that block or reduce iron absorption, such as:.

Calcium can slow both heme and non-heme iron absorption. In most cases, a typical varied, Western-style diet is considered balanced in terms of enhancers and inhibitors of iron absorption. In adults, doses for oral iron supplementation can be as high as 60 to mg of elemental iron per day.

These doses typically apply to women who are pregnant and severely iron-deficient. An upset stomach is a common side effect of iron supplementation, so dividing doses throughout the day may help. Adults with a healthy digestive system have a very low risk of iron overload from dietary sources.

People with a genetic disorder called hemochromatosis are at a high risk of iron overload as they absorb far more iron from food when compared to people without the condition. This can lead to a buildup of iron in the liver and other organs. It can also cause the creation of free radicals that damage cells and tissues, including the liver, heart, and pancreas, as well increasing the risk of certain cancers.

Frequently taking iron supplements that contain more than 20 mg of elemental iron at a time can cause nausea, vomiting, and stomach pain, especially if the supplement is not taken with food. In severe cases, iron overdoses can lead to organ failure, internal bleeding, coma , seizure, and even death.

It is important to keep iron supplements out of reach of children to reduce the risk of fatal overdose. According to Poison Control, accidental ingestion of iron supplements was the most common cause of death from an overdose of medication in children less than 6 years old until the s.

Changes in the manufacture and distribution of iron supplements have helped reduce accidental iron overdoses in children, such as replacing sugar coatings on iron tablets with film coatings, using child-proof bottle caps, and individually packaging high doses of iron.

Penn, M. Powers, E. Rose; Protocol Review Committee—W. Abraham chair , R. Cai, D. McNamara, J. Rose, D. Vaughan, R.

Virmani; Biomarker Core Lab—University of Vermont: R. Tracy, R. Boyle; CPET Core Lab—L. Wooster, C. Bailey, A. Dress, D. Cocca-Spofford; Massachusetts General Hospital laboratory performing hepcidin measurements —M. Buswell, G. Shelton, K. Allen, D.

Bloch; Coordinating Center—Duke Clinical Research Institute: E. Velazquez, A. Devore, L. Cooper, J. Kelly, P. Monds, M. Sellers, T. Atwood, K. Hwang, T. full text icon Full Text. Download PDF Top of Article Key Points Abstract Introduction Methods Results Discussion Conclusions Article Information References.

Figure 1. Flow of Participants for the IRONOUT HF Study. View Large Download. a Data on patients screened for eligibility were not available. Figure 2. Relationships Between Quartiles of Baseline Plasma Hepcidin Levels and Response in Participants Treated With Iron Polysaccharide.

Table 1. Baseline Characteristics of Participants in the IRONOUT HF Study a. Table 2. Primary, Secondary, and Safety End Points. Table 3. Levels of Iron Metabolism Markers According to Treatment Group. Supplement 1. Supplement 2. IRONOUT HF Inclusion and Exclusion Criteria eTable 1. Serious Adverse Events Listed by Body System for the 2 Treatment Groups eTable 2.

Multicenter Trials That Evaluated Iron Supplementation for Treatment of Iron Deficiency in Patients With Heart Failure eFigure 1. Forest Plot For Prespecified Subgroup Analysis Relative to the Primary End Point of Change in Peak VO2 at Week 16 eFigure 2.

Panel A: Time to First Serious and Nonserious Adverse Event Panel B: Time to Death or Cardiovascular Hospitalization eReferences.

Supplement 3. Statistical Analysis. Pasricha SR. Anemia: a comprehensive global estimate. PubMed Google Scholar Crossref.

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J Card Fail. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. Dong F, Zhang X, Culver B, Chew HG Jr, Kelley RO, Ren J. Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release.

Clin Sci Lond. Toblli JE, Lombraña A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol.

Dunn LL, Suryo Rahmanto Y, Richardson DR. Iron uptake and metabolism in the new millennium. Trends Cell Biol. Haas JD, Brownlie T 4th. Iron deficiency and reduced work capacity. J Nutr. PubMed Google Scholar. Andrews NC. Disorders of iron metabolism.

Melenovsky V, Petrak J, Mracek T, et al. Myocardial iron content and mitochondrial function in human heart failure. Eur J Heart Fail. Georgieva Z, Georgieva M.

Compensatory and adaptive changes in microcirculation and left ventricular function of patients with chronic iron-deficiency anaemia. Clin Hemorheol Microcirc. Jankowska EA, Ponikowski P.

Molecular changes in myocardium in the course of anemia or iron deficiency. Heart Fail Clin. Anker SD, Comin Colet J, Filippatos G, et al; FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency.

Ponikowski P, van Veldhuisen DJ, Comin-Colet J, et al; CONFIRM-HF Investigators. Beneficial effects of long-term intravenous iron therapy with ferric carboxymaltose in patients with symptomatic heart failure and iron deficiency.

Eur Heart J. Lewis GD, Semigran MJ, Givertz MM, et al. Oral iron therapy for heart failure with reduced ejection fraction: design and rationale for oral iron repletion effects on oxygen uptake in heart failure.

Circ Heart Fail. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire.

Chatterjee NA, Murphy RM, Malhotra R, et al. Prolonged mean V̇o 2 response time in systolic heart failure. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein.

Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. Ganz T. Hepcidin and iron regulation, 10 years later. Nemeth E, Tuttle MS, Powelson J, et al.

Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Franchini M, Montagnana M, Lippi G.

Hepcidin and iron metabolism. Clin Chim Acta. Swank AM, Horton J, Fleg JL, et al; HF-ACTION Investigators. Modest increase in peak V̇o 2 is related to better clinical outcomes in chronic heart failure patients. Cardiopulmonary exercise testing in heart failure.

JACC Heart Fail. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF. Beck-da-Silva L, Piardi D, Soder S, et al.

IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. Int J Cardiol. van Santen S, van Dongen-Lases EC, de Vegt F, et al.

Hepcidin and hemoglobin content parameters in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum. Choi HS, Song SH, Lee JH, Kim HJ, Yang HR. Serum hepcidin levels and iron parameters in children with iron deficiency.

Korean J Hematol. Jacobs P, Fransman D, Coghlan P. Comparative bioavailability of ferric polymaltose and ferrous sulphate in iron-deficient blood donors.

J Clin Apher. Here, look at how to get more iron in the…. Iron deficiency anemia is prevalent among older people. Find out the reasons behind this and learn about the causes, symptoms, and treatment of iron…. Hemochromatosis causes the body to absorb too much iron.

Learn about the causes, symptoms, and treatments here. Hemochromatosis causes people to absorb too much iron from food. In this article, we look at whether and how making dietary changes can help treat….

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Medical News Today. Health Conditions Health Products Discover Tools Connect. Everything you need to know about iron. Medically reviewed by Judith Marcin, M. Recommended intake Benefits Foods Risks Iron is a mineral vital to the proper function of hemoglobin, a protein needed to transport oxygen in the blood and perform other various processes.

Fast facts on iron The Recommended Daily Allowance RDA varies between ages, but women who are pregnant require the most. Iron promotes healthy pregnancy, increased energy, and better athletic performance. Iron deficiency is most common in female athletes.

Canned clams, fortified cereals, and white beans are the best sources of dietary iron. Too much iron can increase the risk of liver cancer and diabetes. Was this helpful? Recommended intake. Share on Pinterest Iron is important for maintaining a healthy pregnancy.

Further resources For more in-depth resources about vitamins, minerals, and supplements, visit our dedicated hub. Share on Pinterest Clams are an excellent source of iron.

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Atlantic diet may help prevent metabolic syndrome. Related Coverage. What to know about iron deficiency anemia. Medically reviewed by Alana Biggers, M. Hypoxia-inducible factor 2α HIF2α upregulates the expression of both the brush border machinery DMT1 and DCYTB that uptakes iron from the lumen and the iron exporter FPN at the basolateral membrane by binding hypoxia-responsive elements of these gene promoters.

Macrophages rapidly recycle iron derived from the phagocytosis of senescent red cells Figure 1. However, the absolute amount of iron recycled from hypochromic erythrocytes by heme-oxygenase 1 decreases in parallel with the severity of iron deficiency, because Hb content per cell mean corpuscular Hb [MCH] is reduced.

A novel mechanism related to erythrocyte FPN, which is highly expressed in iron deficiency, may contribute to maintaining circulating iron levels. Cellular iron content is controlled by IRPs that in iron deficiency bind stem-loop sequences IREs in the untranslated regions UTRs of iron genes to posttranscriptionally coordinate proteins of iron absorption, export, use, and storage.

Other IRP-independent mechanisms optimize iron use in low-iron states. mTOR inhibition activates tristetraprolin, which reduces both TFR1 and FPN expression to save iron for tissue metabolic needs. In iron deficiency, ferritin is delivered to autophagosomes for degradation ferritinophagy by nuclear receptor coactivator 4, which in contrast is proteasome degraded in iron-replete cells.

Although serum ferritin is the best biomarker of iron deficiency, the mechanisms of its release as well as its function in the circulation remain mysterious.

Iron restriction limits the expansion of early erythropoiesis and optimizes iron use by terminal erythropoiesis. In vitro iron deprivation blunts the EPO responsiveness of early progenitors through inactivation of iron-dependent aconitase, which suppresses isocitrate production.

The same phenotype, expression of increased EPO sensitivity, is recapitulated by the genetic loss of the EPOR partner TFR2 in mice; this condition mimics iron deficiency, 27 because TFR2 is lost from the membrane when diferric TF is reduced. With the development of anemia and hypoxia, EPO levels increase exponentially, and multiple mediators, such as erythroferrone, 13 GDF15, 29 and PDGF-BB, 30 suppress hepcidin to enhance iron supply.

In this process, a role of soluble TFR sTFR , an accepted biomarker of iron deficiency, 31 although reasonable, remains unproven. Because of the increased number of erythroblasts and limited iron supply, heme content per cell is reduced. Globin translation is also impaired by low heme; the stress sensor heme-regulated inhibitor HRI phosphorylates the elongation initiation factor 2a eIF2A to block translation, concomitantly increasing ATF4, which inhibits the translation regulator mTOR.

The optimization of erythropoiesis might preserve iron for vital functions within a global body economy. However, the mechanism is not fully effective, because even in the absence of anemia, other organs may become iron deficient.

In Western countries, other healthy individuals may be at risk. These include vegetarians, especially vegans, because of diet restriction and blood donors. Females are more affected in all the groups listed here.

Iron deficiency with or without anemia may be isolated or secondary to a causative disorder or occur in the context of multiple pathological conditions eg, in the elderly.

Iron deficiency is usually acquired and exceptionally inherited. In developing countries, iron deficiency anemia is nutritional, resulting from reduced intake of bioavailable iron Table 1 , and often associated with infections causing hemorrhages, such as hookworm infestation or schistosomiasis.

ESA, erythropoiesis-stimulating agent; H 2 antagonists, histamine receptor blockers; IRIDA, iron-refractory iron deficiency anemia; PNH, paroxysmal nocturnal hemoglobinuria.

Rarely resulting from gene mutations other than TMPRSS6. Absolute iron deficiency may be masked by comorbidities eg, in the elderly, and in the setting of renal failure. Anemia in the elderly has multiple causes. Unfortunately, being obscured by comorbidities, it often remains undiagnosed, 38 while even mild anemia worsens the outcome of associated disorders and influences mortality.

A recognized cause of dysregulation of iron metabolism is obesity, which may lead to iron deficiency, especially after bariatric surgery because of global absorption impairment Table 1. Considering the need for balancing iron demand and supply, specific clinical settings are characterized by acute restriction of iron for erythropoiesis.

The best-known example is treatment with erythropoiesis-stimulating agents. Another example is postoperative anemia that follows major surgery.

IRIDA 43 is a rare recessive condition resulting from mutations of TMPRSS6 , 44 , 45 leading to an inability to cleave the BMP coreceptor HJV and inhibit hepcidin.

IRIDA patients are refractory to oral iron supplementation. In adults, especially men, anemia may be less evident than in children, while iron deficiency and microcytosis persist. Populations studies suggest that susceptibility to iron deficiency is in part influenced by genetics.

Studies of blood donors have strengthened the hypothesis that genetic variants of iron genes, especially TMPRSS6 and HFE , reported to influence iron parameters 49 , 50 and hepcidin, 51 may predispose to or protect individuals from iron deficiency.

Iron deficiency anemia characterizes both germinal and intestinal conditional Bpnt 1 knockout mice, establishing a novel link between sulfur and iron homeostasis.

Clinical signs and symptoms of iron deficiency anemia are limited and often neglected. The most important, fatigue, is unspecific. Alterations of epithelial cells such as dry mouth, cheilitis, atrophic glossitis, Plummer-Vinson pharyngeal webs, and hair loss are observed in longstanding deficiency.

Restless leg syndrome reveals iron deficiency in a proportion of cases. For a detailed discussion of symptoms in iron deficiency anemia, readers are referred elsewhere.

A correct diagnosis requires laboratory tests. Low serum ferritin levels are the hallmark of absolute iron deficiency, reflecting exhausted stores. Measuring serum hepcidin may be diagnostic of this atypical iron deficiency, provided that inflammation is excluded. Reticulocyte Hb content may reveal rapid changes in erythropoietic activity.

All tissues are assumed to be iron deficient when ferritin is low. No specific test assesses tissue eg, cardiac or muscle iron deficiency when ferritin is unreliable, such as in inflammation. Perception of this deficiency by patients is highly variable.

Clinical diagnosis relies on deterioration of the specific organ eg, heart function or on unspecific symptoms, the most popular being fatigue. Alternatively, the diagnosis is based on a positive outcome after iron supplementation, such as in heart failure.

The etiological cause of iron deficiency should be addressed in all cases and, whenever possible, eliminated.

Iron treatment should be started immediately, even in the absence of anemia, especially in symptomatic patients. The choice of iron compound and the route of administration are largely dependent on the presence and degree of anemia, reversibility of the underlying cause, clinical status age, sex, longstanding vs recent onset , and in some instances patient preference.

Iron salts such as iron sulfate, fumarate, and gluconate remain a mainstay of therapy in absolute iron deficiency.

Mounting evidence indicates that low doses are more effective and better tolerated than the traditionally recommended to mg of elementary iron per day. Importantly, even a mild increase in serum iron activates hepcidin to limit iron absorption. This physiological response was exploited to design the most appropriate dose and schedule of oral iron administration in iron-deficient nonanemic women.

In short-term studies that used stable iron isotopes, supplementation with iron sulfate mg induced hepcidin increase for up to 48 hours, limiting the absorption of the subsequent doses.

In a study comparing 2 groups of women who were receiving mg of iron sulfate per day either as a single or 2 divided doses, the first group showed smaller serum hepcidin increases.

An ongoing study in women with iron deficiency anemia 70 is assessing whether the alternate-day protocol should also be recommended in the presence of anemia, 71 when hypoxia further increases intestinal iron absorption and fully suppresses hepcidin.

Other adverse effects of unabsorbed iron include alterations in the composition of the gut microbiome, with reduction of beneficial Lactobacillus and Bifidobacterium bacteria, enhancement of potential pathogens Enterobacteriaceae , and increased inflammation and diarrhea, as shown in African children.

The minimal dose used for iron supplementation is 60 mg per day. Lower doses A prophylactic treatment with iron sulfate 60 mg in adults and 30 mg in children has been recommended in world areas characterized by high prevalence of iron deficiency anemia.

Epidemiological 75 and in vitro studies have shown that iron deficiency is an adaptation process protecting from Plasmodium virulence and that its correction may increase infection severity. This would increase erythrocyte iron content, favoring the parasite growth. To avoid the latter effects, a future solution is the development of iron compounds bioavailable only to humans and not to pathogens.

There is great interest in the development of compounds better tolerated than iron salts; numerous compounds have been proposed eg, sucrosomial iron, heme iron polypeptide, iron containing nanoparticles , but studies are limited. In the same condition, the phosphate binder iron ferric citrate simultaneously corrects both hyperphosphatemia and iron deficiency; its double effect is being tested in a clinical trial in CKD.

The natural compound extracted from the bark of the Taiwanese tree hinokitiol restores iron transport in cells lacking transporters, such as DMT1 or FPN. The alternative for patients intolerant or unresponsive to oral compounds is IV iron.

Advantages are the more rapid effect and the negligible gastrointestinal toxicity. IV iron is available in different forms; iron gluconate and iron sucrose require repeated infusions, whereas ferric carboxymaltose, ferumoxytol, low molecular weight iron dextran, and iron isomaltoside may be administered in high doses to rapidly replace the total iron deficit usually However, this decision should be carefully made on an individual basis.

High-dose IV iron may increase Hb or iron stores before surgery predicted to induce heavy bleeding. This is a kind of prevention of acute postoperative anemia and an alternative to blood transfusions, which are associated with several postoperative complications, including infections. Patient blood management programs that limit blood transfusions by perioperative iron use reduce morbidity and negative prognoses in high-risk interventions.

An important issue concerning IV iron is safety. Because iron is a growth factor for several pathogens, iron therapy is contraindicated in infections. The risk of infection after IV iron is still a matter of controversy.

Increased risk was found in a meta-analysis evaluating trials of IV iron to spare transfusions, 93 and caution was suggested in dialysis patients. Hypophosphatemia after ferricarboxymaltose is usually transient and reversible, although rarely, severe cases have been reported after repeated infusions.

The superior efficacy of IV vs oral iron is undisputable and expected; the long-term adverse effects of ROS generation in cases of therapy-induced positive iron balance have been scarcely explored, although overtreatment might occur in functional rather than in absolute iron deficiency.

A recent analysis in CKD concluded that patients seemed to tolerate positive iron balance, because iron that was not used was safely stored in reticule-endothelial cells.

Although advances in understanding iron metabolism and regulation are systematically providing novel insights, additional studies are needed before iron therapy becomes a personalized approach in all cases.

These studies should aim at discovering markers of tissue iron deficiency, investigate novel schedules of iron administration based on iron physiology, provide clearer indications to high-dose IV iron, and contribute long-term evaluations of treatment outcomes.

The author thanks Domenico Girelli for his valuable advice and criticism and Alessia Pagani for help with the figure. Conflict-of-interest disclosure: C. is an advisor for Vifor Iron Core and has received honoraria from Vifor Pharma.

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About About Blood Editorial Board and Staff Subscriptions Public Access Copyright Alerts Blood Classifieds. Skip Nav Destination Content Menu. Close Abstract. Pathophysiology of iron deficiency. Etiology of iron deficiency. Diagnosing iron deficiency. Advances and controversies in the treatment of iron deficiency.

Future perspectives. Article Navigation. Iron Metabolism and Its Disorders January 3, Clara Camaschella Clara Camaschella. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy. This Site. Google Scholar. Blood 1 : 30— Article history Submitted:.

Connected Content. A related article has been published: Introduction to a review series on iron metabolism and its disorders. A companion article has been published: The molecular genetics of sideroblastic anemia.

A companion article has been published: Iron metabolism under conditions of ineffective erythropoiesis in β-thalassemia. View more. A companion article has been published: Liver iron sensing and body iron homeostasis.

A companion article has been published: Anemia of inflammation. An erratum has been published: Camaschella C. Iron deficiency. View less. Split-Screen Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Request Permissions.

Cite Icon Cite. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Figure 1. View large Download PPT. Table 1. Type of cause. Pathophysiologic mechanism. View Large. Table 2. Indication for IV iron therapy. Contribution: C.

conceived, wrote, and reviewed the paper. GBD Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for diseases and injuries for countries, a systematic analysis for the Global Burden of Disease Study Search ADS.

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Heart failure , Iron deficiency , Soluble transferrin receptor , Hepcidin , Prognosis , Exercise capacity. Figure 1. Open in new tab Download slide. Figure 2. Major pools of utilized and stored iron in the body. Figure 3. The concept of absolute and functional iron deficiency.

Figure 4. Figure 5. Table 1 Summary of seven studies with intravenous iron therapy administered in patients with heart failure. Studied groups. Iron therapy.

Major results. Inclusion criteria: clinical status. Inclusion criteria: Hb and iron status. Study design. Iron preparation.

Hb and iron status. QoL, HF symptoms. Exercise capacity. CV events. Bolger et al. during 17 days mg i. placebo 20 vs. placebo 24 vs. three times weekly for 3 weeks Maintenance phase: mg iron i. none 27 vs. placebo vs. iron week until repletion dose is achieved Maintenance phase: mg i. Open in new tab.

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Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. Published by Oxford University Press on behalf of European Society of Cardiology. For commercial re-use, please contact journals.

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Maximum mg iron i. iron on Days 15, Okonko et al.