When was iron deficiency discovered

The diagnosis of certainty is determined by hemoglobin electrophoresis: increased amount of fetal hemoglobin HbF or hemoglobin A2. Elements of differential diagnosis: Normal or increased serum iron. Bone marrow cytology with Perls staining: ring-shaped sideroblasts the iron is placed in the mitochondria with a ring around its core. Difficulties in diagnosis: Previous treatment with iron supplements. Association with an anemia from chronic diseases [ 52 , 53 , 54 ].

The correction of anemia is vital; depending on its severity, anemia could trigger cardiovascular complications, sometimes severe [ 55 , 56 ].

Treatment of IDA has two major objectives: Substitution treatment with iron products, aiming to correct anemia and replenishing the iron reserves. Intramuscular administration of iron is rarely used due to local complications such as pain at administration site, uneven absorption, skin pigmentation, and even development of sarcomas at the injection site as some authors have reported [ 57 , 58 ]. Transdermal administration has been experimented in animal models, but there is no evidence that it would be effective and safe in humans [ 59 ].

Treatment with oral iron products is preferable due to the low cost and lack of anaphylactic side effect. Usually, it is used to treat iron-deficiency anemia in children and adolescents.

The main indications of oral iron are treatment of IDA, treatment of iron deficiency, and prophylaxis of iron deficiency in subjects with high needs such as pregnant women, adolescents, and preterm children.

A wide range of iron products is available in forms of tablets or liquid. Liquid iron products have the advantage of allowing titration of the dose. The most commonly used oral iron products are polysaccharide iron complex, ferrous gluconate, ferrous sulfate, and ferrous fumarate.

Regarding the dosage, various over-the-counter tablets exist depending on the products, but generally, there are no differences between these products in effectiveness or adverse events. The daily dose needed to correct iron deficiency depends on age, iron deficiency, and urgency.

In general, daily dose for the correction of IDA with oral products is — mg elemental iron. Reports show that this dose taken every other day is most effective and has a better absorption and fewer side effects [ 60 , 61 ]. Toxicity of iron products is more important in elderly patients, so doses are smaller. In a randomized study of 90 patients, of over 80 years old with iron deficiency, doses of 10, 15, or mg for 2 months were equally effective [ 62 ]. The bioavailability and absorption of oral iron products may be influenced by food e.

This is why iron products are administered 2 hours before and 4 hours after the administration of antacid absorption of iron as ferrous iron depending on acidic environment.

In general, iron product administration is associated with acidic foods orange juice or vitamin C to promote iron absorption, but there are no studies that show a positive effect of vitamin C in the absorption of iron [ 63 ]. There is no consensus on the duration of treatment with oral iron products. Some experts end treatment after correcting anemia to allow early detection of secondary anemia, due to recurrent blood loss.

Others recommend continuing treatment for 6 months after correction of anemia in order to supplement iron reserves. Generally, 6 weeks of treatment are needed to correct anemia, followed by 6 months to replenish the reserves.

Side effect of oral therapy:. Black stools create anxiety as they may be misinterpreted as gastrointestinal bleeding. Some measures can be taken in order to diminish iron side effects and increase tolerability as increasing the time between administrations given every other day, not daily , changing diet concomitant administration of food, even if absorption is reduced , reducing daily dose of elemental iron, switching from tablets to liquid preparations that allow titration of doses, or switching from tables to IV administration.

There are some specific indications for IV administered iron products when oral administration is inefficient or contraindicated see Table 5 : Patients who do not tolerate oral products due to gastrointestinal symptoms especially elderly, pregnant women, and patients with gastrointestinal disorders for which the administration of these products may aggravate symptoms.

Patients with uncontrollable chronic blood loss that cannot be corrected by oral treatment Rendu-Osler disease and other vascular malformations, cancer, etc. Patients who have undergone surgery of the digestive tract that affects the absorption: gastrectomies and surgical bypass. Patients with pathology associating malabsorption or inflammatory disease like celiac disease, Whipple disease, etc.

Patients who require replenishing iron reserves in one to two sessions instead of prolonged treatments. Treatment of iron deficiency and prophylaxis of iron deficiency in subjects with high needs such as pregnant women, adolescents, and children. Administration of IV products leads to reduced transfusion requirements for certain patients reducing the risk of posttransfusion adverse reactions.

Differences between these products consist in cost and the number of visits required for the administration of the total dose, namely, the time of administration and the number of doses required. The total amount of iron required depends on the intended purpose, correcting anemia or supplementing the iron reserves. In clinical practice, a mg dose of iron is generally enough to treat anemia. Generally, no premedication prior to IV administration is needed, except for patients with a history of asthma or drug allergies or patients with inflammatory arthritis for which mg of methylprednisolone before iron administration is recommended [ 64 ].

Generally, antihistamines are not used in preventing side effects [ 65 , 66 , 67 ]. Administration and dosing of various iron products:. LMW Fe Dextran : It can be given in a single dose of mg in ml of saline, 1 hour infusion, or multiple doses of 2 ml, i.

If single dose is preferred, a test dose of 0. Ferric gluconate Ferrlecit : It is administered in a 10—15 ml dose, the equivalent of — In patients with drug allergies, it is recommended to administer a test dose prior to infusion. Each dose can be given by bolus or infusion of 20—30 minutes. It is recommended to administer a 1. Ferumoxytol : It consists of superparamagnetic iron oxide nanoparticles coated with a low molecular weight semisynthetic carbohydrate.

Ferumoxytol may interfere with magnetic resonance imagery MRI , which can lead to errors in interpreting the results. Doses are given in a 15 minute infusion. It is efficient and safe [ 68 , 69 , 70 , 71 ]. It can sometimes cause hypophosphatemia. It does not require a test dose. Efficacy has been demonstrated in inflammatory bowel disease, chronic renal disease, heart surgery, and chemotherapy-induced anemia [ 72 , 73 , 74 , 75 , 76 ].

Side effects of IV iron products:. The most common side effects consist in allergic reactions, sometimes anaphylactic shock. However, these reactions are extremely rare and often overestimated. Patients with inflammatory arthritis rheumatoid arthritis may experience an exacerbation of symptoms during iron infusion, which can be prevented by administering mg of methylprednisolone.

Reducing the risk of allergic reactions can be achieved through the following measures: Avoidance of administration of parenteral iron products to patients known for hypersensitivity reactions in the past. Preventing the exacerbation of the symptoms of inflammatory arthritis patients by administering methylprednisolone.

Nonallergic reactions may occur, which include located rash, heart palpitations, dizziness, muscle spasms of the neck, scapula-vertebral region, etc. The risk of infection may be increased because iron acts as a growth factor for bacteria.

This is supported by some authors but denied by others [ 77 , 78 ]. Monitoring the response to iron therapy depends on the severity of anemia and on the way of iron administration. For patients treated with oral products, reassessment is done after 2 weeks of treatment by checking Hb levels and reticulocytes.

For parenteral treatment, reevaluation is done after 4—8 weeks. Iron treatment is continued until ferritin and transferrin return to normal. There are some either clinical or laboratory criteria used to monitor the efficacy of treatment with iron. Amelioration of asthenia and installation of a well-being state in the first days of treatment besides the increased level of hemoglobin within 1—2 weeks of treatment seem to be the most important parameters related to iron-deficiency correction.

In patients with severe anemia, a modest reticulocytic crisis occurs within 7—10 days after the initiation of treatment.

In those with mild anemia, this reticulocytosis is not encountered. After iron treatment, erythropoiesis with reticulocytosis efficiency occurs after 1—2 weeks of treatment, followed by an increase in hemoglobin levels. This increase the so-called reticulocyte crisis is not as expressed as in vitamin B12 or folic acid anemia treatment in megaloblastic anemia.

With treatment, anemia is corrected in about 1—2 months, but for replenishing the iron reserves, it is necessary to continue for about 4—6 months of treatment. Prognosis of patients with IDA depends mainly on the underlying condition that caused iron deficiency and on the cardiovascular status of patients.

Failure to respond to treatment with iron may occur in several circumstances, the more frequent observed being: Reduced patient compliance and treatment interruptions.

Celiac disease and Helicobacter pylori infection may reduce the absorption of iron, thus being a frequent cause of failure to oral iron treatment. Red blood cell transfusion is not generally required in iron-deficiency anemia, but in severe cases such as symptomatic patients associating cardiac pathology, transfusion is required in order to ameliorate symptoms until iron deficits are corrected.

Multiple factors can contribute to iron imbalance in the human organism. Often such factors can coexist requiring a complex management of the consequent anemia.

Treatment of underlying conditions is an important step toward reducing iron-deficiency-anemia-associated morbidity. All authors have read and approved this version of the book chapter, and due care has been taken to ensure the integrity of the work. No part of this work has been published or submitted elsewhere. No financial conflict of interest exists in the submission of this manuscript.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications.

Natural History, Complications and Prognosis. Diagnostic Study of Choice. History and Symptoms. Physical Examination. Laboratory Findings. Echocardiography or Ultrasound.

Other Imaging Findings. Other Diagnostic Studies. Medical Therapy. Primary Prevention. Secondary Prevention. Cost-Effectiveness of Therapy. Future or Investigational Therapies. Case 1. Most recent articles. Most cited articles. Review articles. 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.

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 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.