iron deficiency anemia case study pdf

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Patient Case Presentation

Patient  Overview

M.J. is a 25-year-old, African American female presenting to her PCP with complaints of fatigue, weakness, and shortness of breath with minimal activity. Her friends and family have told her she appears pale, and combined with her recent symptoms she has decided to get checked out. She also states that she has noticed her hair and fingernails becoming extremely thin and brittle, causing even more concern. The patient first started noticing these symptoms a few months ago and they have been getting progressively worse. Upon initial assessment, her mucosal membranes and conjunctivae are pale. She denies pain at this time, but describes an intermittent dry, soreness of her tongue.

Vital Signs:

Temperature – 37 C (98.8 F)

HR – 95

BP – 110/70 (83)

Lab Values:

Hgb- 7 g/dL

Serum Iron – 40 mcg/dL

Transferrin Saturation – 15%

Medical History

• Diagnosed with peptic ulcer disease at age 21 – controlled with PPI pharmacotherapy
• IUD placement 3 months ago – reports an increase in menstrual bleeding since placement

Surgical History

• No past surgical history reported

Family History

• Diagnosis of iron deficiency anemia at 24 years old during pregnancy with patient – on daily supplement
• Otherwise healthy
• Diagnosis of hypertension – controlled with diet and exercise
• No siblings

Social History

• Vegetarian – patient states she has been having weird cravings for ice cubes lately
• Living alone in an apartment close to work in a lower-income community
• Works full time at a clothing department store

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Introduction

Epidemiology, pathophysiology of iron deficiency, etiology of iron deficiency, diagnosing iron deficiency, advances and controversies in the treatment of iron deficiency, future perspectives, acknowledgments, iron deficiency.

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Clara Camaschella; Iron deficiency. Blood 2019; 133 (1): 30–39. doi: https://doi.org/10.1182/blood-2018-05-815944

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Iron deficiency anemia affects >1.2 billions individuals worldwide, and iron deficiency in the absence of anemia is even more frequent. Total-body (absolute) iron deficiency is caused by physiologically increased iron requirements in children, adolescents, young and pregnant women, by reduced iron intake, or by pathological defective absorption or chronic blood loss. Adaptation to iron deficiency at the tissue level is controlled by iron regulatory proteins to increase iron uptake and retention; at the systemic level, suppression of the iron hormone hepcidin increases iron release to plasma by absorptive enterocytes and recycling macrophages. The diagnosis of absolute iron deficiency is easy unless the condition is masked by inflammatory conditions. All cases of iron deficiency should be assessed for treatment and underlying cause. Special attention is needed in areas endemic for malaria and other infections to avoid worsening of infection by iron treatment. Ongoing efforts aim at optimizing iron salts–based therapy by protocols of administration based on the physiology of hepcidin control and reducing the common adverse effects of oral iron. IV iron, especially last-generation compounds administered at high doses in single infusions, is becoming an effective alternative in an increasing number of conditions because of a more rapid and persistent hematological response and acceptable safety profile. Risks/benefits of the different treatments should be weighed in a personalized therapeutic approach to iron deficiency.

Iron balance is essential for all cell life. Iron homeostatic mechanisms evolved to avoid iron excess and the generation of harmful reactive oxygen species by reutilizing body iron and limiting its uptake from the environment. The inevitable other side of the coin is the easy development of iron deficiency.

Iron deficiency is the depletion of total-body iron, especially of macrophage and hepatocyte iron stores. Because the largest amount of iron is consumed for hemoglobin (Hb) synthesis to produce 200 billion erythrocytes daily, anemia is the more evident sign of iron deficiency, and iron deficiency anemia is often considered synonymous with iron deficiency. However, iron deficiency is a broader condition that often precedes the onset of anemia or indicates deficiency in organs/tissues other than those involved in erythropoiesis, such as skeletal muscles and the heart, the latter highly iron dependent for myoglobin and energy production to sustain mechanical contraction.

This article reviews the mechanisms of adaptation to iron deficiency and related anemia, examines how improved knowledge is influencing treatment, and discusses areas that remain uncertain from the biological and clinical perspectives.

According to the Global Burden of Disease Study 2016, iron deficiency anemia is 1 of the 5 leading causes of years lived with disability burden and is the first cause in women. 1   Adopting the World Health Organization–recommended cutoff for anemia (Hb <13 g/dL in males, <12 g/dL in females, <11g/dL during pregnancy), a worldwide survey showed that in 2010, anemia still affected one third of the population, with approximately half of the cases resulting from iron deficiency. The estimate is that ∼1.24 billion individuals experience iron deficiency anemia, although with huge variations from low- to high-income countries. 2   The global prevalence of iron deficiency without anemia remains elusive, although the suggested figure is at least double that of iron deficiency anemia. The problem becomes even more relevant if we take into account functional iron deficiency, which occurs when iron is hardly mobilized from stores, as in chronic inflammations/infections or when the vigorous erythropoietic expansion by exogenous or endogenous erythropoietin (EPO) causes an acute disproportion between iron demand and supply.

Globally, iron deficiency anemia has relevant medical and social impacts, accounting for impairment of cognitive performance in young children, 3   adverse outcomes of pregnancy for both mothers and newborns, 4   decreased physical and working capacities in adults, and cognitive decline in the elderly. 5 , 6   From available data, the relative contribution of iron deficiency to these negative outcomes is difficult to disassociate from that of anemia.

Iron deficiency deeply affects iron homeostasis, inducing adaptive mechanisms on the hepcidin-ferroportin (FPN) axis, the iron regulatory protein (IRP)/iron responsive element (IRE) machinery, and other regulators. The aim is to optimize iron usage by erythropoiesis and to counteract the physiological inhibition of iron absorption.

Mechanisms of adaptation

Systemic regulation.

Liver hepcidin is the master hormone that physiologically limits iron entry into plasma. Binding to its receptor FPN, hepcidin blocks iron export both by occluding the exporter central cavity 7   and by inducing its degradation. 8   Because of the high FPN expression on professional iron exporter cells, such as enterocytes and macrophages, hepcidin suppression in iron deficiency enhances both iron absorption and its release from macrophages to plasma. Multiple factors downregulate hepcidin transcription ( Figure 1 ). The BMP-SMAD signaling pathway is repressed, because in iron deficiency, expression of BMP6 ligand is low, 9   the BMP coreceptor HJV is cleaved by TMPRSS6, 10   and TFR2 is removed from the cell surface. 11   In addition, the histone deacetylase HDAC3 erases activation markers from the hepcidin locus, 12   providing an epigenetic contribution to hormone suppression. The function of ERFE, released by erythroid cells stimulated by erythropoietin, 13   is less relevant in iron deficiency without anemia, because hepcidin is downregulated when iron deficiency is induced in Erfe −/− mice. 12   However, ERFE plays a role in the presence of anemia and hypoxia. 13  

Mechanisms of hepcidin inhibition in iron deficiency anemia. Main cells/organs involved in hepcidin (HAMP) inhibition in iron deficiency are illustrated. In the hepatocytes, bone morphogenic protein (BMP)-SMAD signaling, the main activator of hepcidin, is low because low levels of BMP6 are produced by liver sinusoidal endothelial cells (L-SEC), the BMP coreceptor hemojuvelin (HJV) is cleaved from the hepatocyte surface by the transmembrane serine protease 6 (TMPRSS6), and the second transferrin receptor (TFR2) is not stabilized on the cell surface in the absence of the ligand diferric transferrin (TF). Low hepcidin levels increase iron absorption by enterocytes and recycling by macrophages through increased activity of the iron exporter FPN. In mild iron deficiency in the absence of hypoxia, increased EPO sensitivity is due to the loss of TFR2 on erythroblast surfaces. Histone deacetylase 3 (HIDAC3) participates in hepcidin suppression by erasing markers of activation at the hepcidin locus. In iron deficiency anemia, hypoxia increases EPO. Increased ERFE fully blocks the hepcidin pathway, although the molecular mechanism of hepcidin inhibition by ERFE remains unknown (?). BMPR, BMP receptor; CP, ceruloplasmin; DCYTB, duodenal cytochrome B; DMT1, divalent metal transporter 1; EPOR, EPO receptor; HEPH, hephestin.

Local mechanisms increase intestinal iron absorption. 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. 14  

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. 15   Low serum hepcidin levels ultimately determine the amount of iron entering the circulation ( Figure 1 ).

Cellular regulation

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. 16   Binding to 3′UTR IREs, IRPs stabilize the messenger RNA of TFRC and DMT1 ; binding to 5′UTR IREs, they repress translation of ferritin, FPN, 5′-aminolevulinate synthase 2 (ALAS2), and HIF2α. To avoid deleterious iron retention in iron-deficient enterocytes and maturing erythroblasts, an alternative isoform of FPN lacking 5′UTR IRE escapes IRP control 15   while remaining sensitive to the hepcidin effect.

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. 17   Cells may recover their own iron stored in ferritin. 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. 18   Reduced ferritinophagy makes NcoA4 knockout mice susceptible to hypoferremia and iron deficiency. 19   Ferritinophagy has been shown to provide iron for erythroid differentiation in vitro 20   and in zebrafish. 21   It has not been assessed whether ferritin is reduced in plasma when it undergoes ferritinophagy. 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. 22  

Iron-restricted erythropoiesis

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. 23   Accordingly, iron or isocitrate treatment restores erythroid lineage differentiation. 24   EPO is not elevated in mice with iron deficiency without anemia. 25 , 26   However, in the same condition, terminal erythropoiesis is modified, with decreased apoptosis and increased number of late erythroblasts. 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. 11 , 28  

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. 32   The heme/globin coordination improves erythropoiesis, producing microcytic (low mean corpuscular volume)/hypochromic (low MCH) erythrocytes. 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.

Individuals at risk

Reflecting high iron requirements, infants, preschool children (age <5 years), young menstruating women, and women in the second/third trimester of pregnancy and postpartum are the most affected groups. 33 , 34   Adolescents also are susceptible to iron deficiency because of rapid growth.

In Western countries, other healthy individuals may be at risk. These include vegetarians, especially vegans, because of diet restriction and blood donors. 35   The RISE study, which evaluated the iron status of >2000 frequent blood donors in the United States, showed that two thirds of women and half of men were iron deficient. 36   Elite endurance athletes are at risk because of inflammation-induced increased hepcidin and blood losses. 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.

Acquired iron deficiency

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. In Western societies, other than in individuals at risk, iron depletion results from chronic bleeding and/or reduced iron absorption, disorders that may be more relevant than anemia itself ( Table 1 ). For this reason, considering age, sex, clinical history, and symptoms, identification of the underlying cause is an essential part of the patient’s workup. 33 , 34  

Main causes of absolute iron deficiency/iron deficiency anemia

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

More common in developing countries.

Rarely resulting from gene mutations other than TMPRSS6 . 100  

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. 37   Iron deficiency accounts for ∼30% of cases, resulting from low intake, reduced absorption (atrophic gastritis, use of proton pump inhibitors), gastrointestinal blood losses (antithrombotic drugs, angiodysplasia, peptic ulcer, hemorrhoids, and even colorectal cancer). Unfortunately, being obscured by comorbidities, it often remains undiagnosed, 38   while even mild anemia worsens the outcome of associated disorders and influences mortality. 39   Patients with chronic kidney disease (CKD) are prone to absolute iron deficiency because of reduced absorption 40   and blood loss at dialysis, at an estimated rate of up to 2 to 3 g per year. 41   However, high hepcidin levels and inflammation, which reduce iron mobilization from stores, may mask absolute deficiency. 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 ). 42   In Western countries, as a result of increased life expectancy, these types of iron deficiency are expected to increase in coming years.

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. Recovery from anemia may be limited or delayed because of preexisting unrecognized iron deficiency that becomes evident after surgery and/or cytokine-induced defective iron mobilization.

Genetics of iron deficiency

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. 10   High hepcidin in IRIDA patients impairs iron absorption, counteracting an essential compensatory mechanism to sustain erythropoiesis. IRIDA patients are refractory to oral iron supplementation. 46 , 47   IV iron is indicated when anemia is severe, but it may be only partially effective. In adults, especially men, anemia may be less evident than in children, while iron deficiency and microcytosis persist. 48  

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. 52  

In a novel murine model, genetic iron deficiency anemia was caused by loss of the enzyme of the sulfur assimilation pathway bisphosphate-3′-nucleotidase (Bpnt1). Iron deficiency anemia characterizes both germinal and intestinal conditional Bpnt 1 knockout mice, establishing a novel link between sulfur and iron homeostasis. 53  

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. 54 , 55   In the elderly, iron deficiency anemia may cause heart failure or angina. For a detailed discussion of symptoms in iron deficiency anemia, readers are referred elsewhere. 34 , 56  

A correct diagnosis requires laboratory tests. Low serum ferritin levels are the hallmark of absolute iron deficiency, reflecting exhausted stores. Levels <30 mg/L are the accepted threshold that identifies mild cases; in the presence of anemia, ferritin levels are usually lower (<10-12 mg/L). In the absence of inflammations/infections, serum ferritin shows the best correlation with bone marrow stainable iron, once the gold standard in assessing depletion of iron stores. 33 , 34  

Measuring TF saturation (<16%) is unnecessary for diagnosis, although it has diagnostic value in functional deficiency when serum ferritin is unreliable. Hepcidin levels, which are low/undetectable in absolute iron deficiency, are also unnecessary. Exceptions are the rare IRIDA patients who show low TF saturation and normal/high hepcidin and serum ferritin levels, reflecting increased macrophage iron. Measuring serum hepcidin may be diagnostic of this atypical iron deficiency, provided that inflammation is excluded. 57  

sTFR and its relationship to ferritin (sTFR/logFt index) are good indicators of iron-deficient erythropoiesis, 58 , 59   but tests to measure these indicators are scarcely available in clinics. Reduction of MCH and mean corpuscular volume and increased (>6% in CKD) hypochromic red cells (with MCH <28 pg) occur relatively late because of the erythrocyte lifespan. Reticulocyte Hb content may reveal rapid changes in erythropoietic activity. Early reduction (<26 pg) may occur after erythropoiesis-stimulating agent treatment and early increase after iron supplementation. 60   When heme is low, zinc is incorporated into protoporphyrin-IX, levels of which become elevated and measurable in mature erythrocytes. 60  

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. 61  

To correctly diagnose iron deficiency in the context of multiple comorbidities, such as in inflammation, ferritin threshold <100 mg/L or even higher values are suggested, in combination with low (<20%) TF saturation. 62   Although these arbitrary cutoffs likely overestimate iron deficiency, they are largely used for therapeutic decisions. The diagnosis of absolute iron deficiency is also challenging in the elderly; proposed cutoffs between >30 and <100 mg/L are based on small studies. 37 , 38   This supports the need for well-designed prospective clinical trials and development of biomarkers for tissue iron deficiency.

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. 63 , 64   A systematic review of the efficacy of iron supplementation in iron-deficient nonanemic individuals concluded that treatment (any type) increased Hb and ferritin and reduced self-reported fatigue but did not improve physical performance or maximal oxygen consumption. 65  

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.

Oral iron supplementation

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 100 to 200 mg of elementary iron per day. Because absorption of nonheme iron is modest (5% to 28% at the fastest), 66   high doses may result in ROS-mediated toxicity of nonabsorbed iron on intestinal mucosa. Common adverse effects, such as nausea, vomiting, constipation, or diarrhea, may lead to noncompliance with therapy in 30% to 70% of cases 67   and jeopardize the prolonged (several months) treatment planned. 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 (60-240 mg) induced hepcidin increase for up to 48 hours, limiting the absorption of the subsequent doses. 68   In another trial in which participants were randomly assigned to receive 60 mg of iron per day for 14 days or on alternate day for 28 days, fractional iron absorption was significantly greater in the latter group (21.8% vs 16.3%). In a study comparing 2 groups of women who were receiving 120 mg of iron sulfate per day either as a single or 2 divided doses, the first group showed smaller serum hepcidin increases. 69   Altogether these elegant studies indicate that changing the administration from daily to alternate-day schedules and from divided to single doses increases the efficacy of treatment in iron-deficient nonanemic individuals and has the potential to improve tolerability. 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. 14  

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. 72 , 73  

The minimal dose used for iron supplementation is 60 mg per day. Lower doses (37.5 mg per day) of oral iron have proven useful in blood donors to limit deferrals from donations. 36  

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. 74   However, the validity of universal supplementation in countries with high prevalence of malaria and/or other infections is controversial. 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. 76 , 77   Recent evidence shows that FPN expressed in erythrocytes is functional and reduced by the high hepcidin levels induced by iron supplementation. This would increase erythrocyte iron content, favoring the parasite growth. 15   In these cases, iron supplementation should occur in association with antimalarial treatment. 78   Another problem is related supplemented iron causing gut dysbiosis and diarrhea. 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. 79   Sucrosomial iron has been tested in patients with CKD, 80   but the mechanism of absorption and the real benefits are uncertain. 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. 81   A phase 3 trial of ferric maltol provided positive results on iron deficiency anemia in inflammatory bowel diseases. 82   Rigorously designed clinical trials are needed to confirm the efficacy of these iron preparations.

The natural compound extracted from the bark of the Taiwanese tree hinokitiol restores iron transport in cells lacking transporters, such as DMT1 or FPN. 83   Exploiting the iron gradient that, in the absence of the transporter, is formed across membranes, hinokitiol restores transport direction both in vitro and in zebrafish, but no data are available on its chronic use in mice.

The alternative for patients intolerant or unresponsive to oral compounds is IV iron. 47   Once limited by the risk of severe hypersensitivity reactions, this route of administration is currently more widely used as a result of the improved safety profile of last-generation compounds. Established indications to IV iron are reduced absorption capacity in the presence of gastrointestinal disorders or bariatric surgery, severe anemia (Hb <7-8 g/dL), high hepcidin resulting from concomitant inflammation, and rarely IRIDA and when a fast recovery is desirable ( Table 2 ). Advantages are the more rapid effect and the negligible gastrointestinal toxicity. 67   IV iron is more effective than oral iron in CKD patients treated with erythropoiesis-stimulating agents 41 , 84   and avoids oxidative damage to the intestinal mucosa in active inflammatory bowel diseases. 85   In the latter disorders, IV iron preserves the normal microbiome, which would be disrupted by oral iron. 40   The European Crohn’s and Colitis Organization recommends IV iron as a first-line therapy for patients with active disease and Hb <10 g/dL and oral iron in inactive disease/mild anemia patients, 86   the latter being more likely to have absolute iron deficiency.

Indication for IV iron therapy

IBD, inflammatory bowel disease.

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 1-1.5 g) in 1 or 2 infusions. 56   The stable carbohydrate shell of the latter compounds prevents free iron release, a feature that increases their safety. 56   The high-dose schedule avoids repeated hospital visits (eg, for patients with reduced mobility, such as the elderly, for whom oral therapy can be particularly disturbing) 38   and is convenient when a fast recovery is needed (such as in the second and third trimesters of pregnancy or in postpartum anemia 87   and the prevention of repeated cycles of therapy [eg, in heavy uterine bleeding]). 88   In addition to the prompt Hb increase, this protocol rapidly reconstitutes stores, 89   making the advantages (single access, accelerated recovery, limited need for blood tests) outweigh the disadvantages (cost, invasiveness, risk of reactions). 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. 90   A randomized trial of IV iron administration at postoperative day 1 vs standard care showed less anemia and reduction of transfusions and infections in the iron arm in major orthopedic and abdominal surgeries. 91   The iron infusion approach might be especially valuable in surgery candidates prone to iron deficiency, such as young women or patients with colorectal cancer. 92  

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. 94   Another meta-analysis of >10 000 patients receiving different IV compounds or oral iron or placebo did not find different risks of infection. 95   Long-term studies are needed in patients with different disorders.

Hypophosphatemia after ferricarboxymaltose is usually transient and reversible, although rarely, severe cases have been reported after repeated infusions. 96   Minor/moderate infusion reactions (nausea, pruritus, urticaria, flushing, back or thoracic pain), often self-limited, may be observed in 1:200 infusions and more serious reactions (hypotension, dyspnea) in 1:200 000. 95   Although globally IV treatment seems safe, the number of reported patients is usually too limited to detect extremely rare anaphylactic reactions, such as those once caused by high molecular weight iron dextran. Their unclear pathogenesis is ascribed to the release of iron particles in the circulation and has been interpreted as a “complement activation-related pseudo-allergy.” 97 (p5029) Personnel who administer IV iron must be prepared to manage any type of reaction, including exceptionally severe ones. 98  

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. 99   However, in the absence of data and iron toxicity tests, it is advisable to regularly assess iron status when high doses are repeatedly administered.

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.

Contribution: C.C. conceived, wrote, and reviewed the paper.

Conflict-of-interest disclosure: C.C. is an advisor for Vifor Iron Core and has received honoraria from Vifor Pharma.

Correspondence: Clara Camaschella, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Via Olgettina, 58, 20132 Milan, Italy; e-mail: [email protected] .

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MATTHEW W. SHORT, LTC, MC, USA, AND JASON E. DOMAGALSKI, MAJ, MC, USA

Am Fam Physician. 2013;87(2):98-104

Patient information : See related handout on iron deficiency anemia , written by the authors of this article.

Author disclosure: No relevant financial affiliations to disclose.

Iron deficiency is the most common nutritional disorder worldwide and accounts for approximately one-half of anemia cases. The diagnosis of iron deficiency anemia is confirmed by the findings of low iron stores and a hemoglobin level two standard deviations below normal. Women should be screened during pregnancy, and children screened at one year of age. Supplemental iron may be given initially, followed by further workup if the patient is not responsive to therapy. Men and postmenopausal women should not be screened, but should be evaluated with gastrointestinal endoscopy if diagnosed with iron deficiency anemia. The underlying cause should be treated, and oral iron therapy can be initiated to replenish iron stores. Parenteral therapy may be used in patients who cannot tolerate or absorb oral preparations.

Iron deficiency anemia is diminished red blood cell production due to low iron stores in the body. It is the most common nutritional disorder worldwide and accounts for approximately one-half of anemia cases. 1 , 2 Iron deficiency anemia can result from inadequate iron intake, decreased iron absorption, increased iron demand, and increased iron loss. 3 Identifying the underlying etiology and administering the appropriate therapy are keys to the evaluation and management of this condition.

Diagnosis of iron deficiency anemia requires laboratory-confirmed evidence of anemia, as well as evidence of low iron stores. 4 Anemia is defined as a hemoglobin level two standard deviations below normal for age and sex ( Table 1 ) . 5

A complete blood count can be helpful to determine the mean corpuscular volume or red blood cell size. Although iron deficiency is the most common cause of microcytic anemia, up to 40 percent of patients with iron deficiency anemia will have normocytic erythrocytes. 2 As such, iron deficiency should still be considered in all cases of anemia unless the mean corpuscular volume is greater than 95 μm 3 (95 fL), because this cutoff has a sensitivity of 97.6 percent. 6 Other causes of microcytosis include chronic inflammatory states, lead poisoning, thalassemia, and sideroblastic anemia. 1

The following diagnostic approach is recommended in patients with anemia and is outlined in Figure 1 . 2 , 6 – 11 A serum ferritin level should be obtained in patients with anemia and a mean corpuscular volume less than 95 μm 3 . Ferritin reflects iron stores and is the most accurate test to diagnose iron deficiency anemia. 7 Although levels below 15 ng per mL (33.70 pmol per L) are consistent with a diagnosis of iron deficiency anemia, using a cutoff of 30 ng per mL (67.41 pmol per L) improves sensitivity from 25 to 92 percent, and specificity remains high at 98 percent. 8 , 12 Ferritin is also an acute phase reactant and can be elevated in patients with chronic inflammation or infection. In patients with chronic inflammation, iron deficiency anemia is likely when the ferritin level is less than 50 ng per mL (112.35 pmol per L). 7 Ferritin values greater than or equal to 100 ng per mL (224.70 pmol per L) generally exclude iron deficiency anemia. 9 , 10

In patients with no inflammatory states and in whom the ferritin level is indeterminate (31 to 99 ng per mL [69.66 to 222.45 pmol per L]), further tests can be performed to ascertain iron status. Values consistent with iron deficiency include a low serum iron level, low transferrin saturation, and a high total iron-binding capacity. 2

Soluble transferrin receptor and erythrocyte protoporphyrin testing, or bone marrow biopsy can be considered if the diagnosis remains unclear. 2 The soluble transferrin receptor level is an indirect measure of erythropoiesis and is increased in patients with iron deficiency anemia. 8 Another benefit of this test is that the soluble transferrin receptor level is unaffected by inflammatory states and can help identify concomitant iron deficiency anemia in patients with anemia of chronic disease. 12 Erythrocyte protoporphyrin is a heme precursor and accumulates in the absence of adequate iron stores. 11 If other tests are indeterminate and suspicion for iron deficiency anemia persists, the absence of stainable iron in a bone marrow biopsy is considered the diagnostic standard. 2

MEN AND POSTMENOPAUSAL WOMEN

Asymptomatic men and postmenopausal women should not be screened for iron deficiency anemia. Testing should be performed in patients with signs and symptoms of anemia, and a complete evaluation should be performed if iron deficiency is confirmed. 13

PREGNANT WOMEN

The American Academy of Family Physicians, U.S. Preventive Services Task Force, and Centers for Disease Control and Prevention recommend routine screening of asymptomatic pregnant women for iron deficiency anemia. 4 , 11 , 14 The American College of Obstetricians and Gynecologists recommends screening for anemia and implementing iron therapy if iron deficiency anemia is confirmed. 15 The defined values consistent with anemia in pregnancy are hemoglobin levels less than 11 g per dL (110 g per L) in the first or third trimester, or less than 10.5 g per dL (105 g per L) in the second trimester. 16 A maternal hemoglobin level of less than 6 g per dL (60 g per L) has been associated with poor fetal outcomes, including death. 15

The American Academy of Pediatrics recommends universal hemoglobin screening and evaluation of risk factors for iron deficiency anemia in all children at one year of age. 16 Risk factors include low birth weight, history of prematurity, exposure to lead, exclusive breastfeeding beyond four months of life, and weaning to whole milk and complementary foods without iron-fortified foods. 16 The Centers for Disease Control and Prevention recommends screening children from low-income or newly immigrated families at nine to 12 months of age, and consideration of screening for preterm and low-birth-weight infants before six months of age if they are not given iron-fortified formula. 14 The U.S. Preventive Services Task Force found insufficient evidence for screening in asymptomatic children six to 12 months of age and does not make recommendations for other ages. 4 A meta-analysis showed that infants in whom cord clamping was delayed for up to two minutes after birth had a reduced risk of low iron stores for up to six months. 17 Larger randomized studies that include maternal outcomes are needed before delayed cord clamping can be recommended for general practice.

Once iron deficiency anemia is identified, the goal is to determine the underlying etiology. Causes include inadequate iron intake, decreased iron absorption, increased iron demand, and increased iron loss ( Table 2 ) . 5 , 7 , 18 , 19

Iron Therapy

Premenopausal women with a negative evaluation for abnormal uterine bleeding can be given a trial of iron therapy. In children and pregnant women, iron therapy should be tried initially. Current guidelines recommend empiric treatment in children up to two years of age and in pregnant women with iron deficiency anemia; however, if the hemoglobin level does not increase by 1 g per dL (10 g per L) after one month of therapy in children or does not improve in pregnant women, further evaluation may be indicated. 4 , 15 , 16 In pregnant patients, poor compliance or intolerance should be considered, and parenteral iron may produce a better response. 15

The evaluation should begin with a thorough history and physical examination to help identify the cause of iron deficiency. The history should focus on potential etiologies and may include questions about diet, gastrointestinal (GI) symptoms, history of pica or pagophagia (i.e., compulsive consumption of ice), signs of blood loss (e.g., epistaxis, menorrhagia, melena, hematuria, hematemesis), surgical history (e.g., gastric bypass), and family history of GI malignancy. Patients with iron deficiency anemia are often asymptomatic and have limited findings on examination. Further evaluation should be based on risk factors ( Figure 2 ) . 10 , 15 , 17 – 21

PREMENOPAUSAL WOMEN

Excessive menstruation is a common cause of iron deficiency anemia in premenopausal women in developed countries; however, a GI source (particularly erosive lesions in the stomach or esophagus) is present in 6 to 30 percent of cases. 20 , 22 , 23 If the gynecologic workup is negative and the patient does not respond to iron therapy, endoscopy should be performed to exclude an occult GI source. 20 , 22 , 23

Excessive or irregular menstrual bleeding affects 9 to 14 percent of all women and can lead to varying degrees of iron deficiency anemia. 24 Etiologies include thyroid disease, uncontrolled diabetes mellitus, polycystic ovary syndrome, coagulopathies, uterine fibroids, endometrial hyperplasia, hyperprolactinemia, and use of antipsychotics or antiepileptics. Initial evaluation includes a history, physical examination, and pregnancy and thyroid-stimulating hormone tests. An endometrial biopsy should be considered in women 35 years and younger who have conditions that could lead to unopposed estrogen exposure, in women older than 35 years who have suspected anovulatory bleeding, and in women with abnormal uterine bleeding that does not respond to medical therapy. 25

In men and postmenopausal women, GI sources of bleeding should be excluded. Current recommendations support upper and lower endoscopy; however, there are no clear guidelines about which procedure should be performed first or if the second procedure is necessary if a source is found on the first study. 18 Lesions that occur simultaneously in the upper and lower tracts are rare, occurring in only 1 to 9 percent of patients. 18 However, one study showed that 12.2 percent of patients diagnosed with celiac disease and iron deficiency anemia had a secondary source of anemia, including three cases of colon cancer. 26 A study of patients with iron deficiency anemia of unknown etiology in the primary care setting found that 11 percent had newly diagnosed GI cancer. 27 Additionally, a cohort study found that 6 percent of patients older than 50 years and 9 percent of those older than 65 years will be diagnosed with a GI malignancy within two years of a diagnosis of iron deficiency anemia. 28 Celiac serology should also be considered for all adults presenting with iron deficiency anemia. 18 Upper endoscopy with duodenal biopsies should be performed to confirm the diagnosis after positive serologic testing and to evaluate for additional etiologies. 29

In patients in whom endoscopy may be contraindicated because of procedural risk, radiographic imaging may offer sufficient screening. The sensitivity of computed tomographic colonography for lesions larger than 1 cm is greater than 90 percent. 7 The use of barium enema is less reliable, but may be of use if colonoscopy or computed tomographic colonography is not available.

If initial endoscopy findings are negative and patients with iron deficiency anemia do not respond to iron therapy, repeat upper and lower endoscopy may be justified. In some instances, lesions may not be detected on initial examination (e.g., missed mucosal erosions in a large hiatal hernia, suboptimal preparation for colonoscopy, inadequate biopsy of a suspected lesion). 13 Colonoscopy can fail to diagnose up to 5 percent of colorectal tumors. 13

Additional evaluation of the small intestine is not necessary unless there is inadequate response to iron therapy, the patient is transfusion dependent, or fecal occult blood testing suggests that the patient has had obscure GI bleeding with the source undiscovered on initial or repeat endoscopy. 30 In these cases, further evaluation with capsule endoscopy should be considered. 30 Enteroscopy is an upper endoscopy procedure using a longer scope to visualize the proximal jejunum; it should be reserved to treat or biopsy lesions identified by capsule endoscopy. This test is a second-line technique for evaluating the small bowel because it is complicated by the level of sedation and duration of procedure. 13 Magnetic resonance imaging enteroclysis, computed tomographic enterography, or barium studies may also be considered, but have a limited ability to identify most small bowel lesions, which are mucosal and flat. 7

UNDERLYING CAUSE

Patients with an underlying condition that causes iron deficiency anemia should be treated or referred to a subspecialist (e.g., gynecologist, gastroenterologist) for definitive treatment.

ORAL IRON THERAPY

The dosage of elemental iron required to treat iron deficiency anemia in adults is 120 mg per day for three months; the dosage for children is 3 mg per kg per day, up to 60 mg per day. 1 An increase in hemoglobin of 1 g per dL after one month of treatment shows an adequate response to treatment and confirms the diagnosis. 16 In adults, therapy should be continued for three months after the anemia is corrected to allow iron stores to become replenished 7 ( Figure 3 6 , 28 , 31 ) .

Adherence to oral iron therapy can be a barrier to treatment because of GI adverse effects such as epigastric discomfort, nausea, diarrhea, and constipation. These effects may be reduced when iron is taken with meals, but absorption may decrease by 40 percent. 1 Medications such as proton pump inhibitors and factors that induce gastric acid hyposecretion (e.g., chronic atrophic gastritis, recent gastrectomy or vagotomy) are associated with reduced absorption of dietary iron and iron tablets. 31

PARENTERAL IRON THERAPY

Parenteral therapy may be used in patients who cannot tolerate or absorb oral preparations, such as those who have undergone gastrectomy, gastrojejunostomy, bariatric surgery, or other small bowel surgeries. The most common indications for intravenous therapy include GI effects, worsening symptoms of inflammatory bowel disease, unresolved bleeding, renal failure–induced anemia treated with erythropoietin, and insufficient absorption in patients with celiac disease. 32

Parenteral treatment options are outlined in Table 3 . 2 , 16 Serious adverse effects have occurred in up to 0.7 percent of patients receiving iron dextran, with 31 recorded fatalities reported between 1976 and 1996. 32 , 33 Iron sucrose and sodium ferric gluconate (Ferrlecit) have greater bio-availability and a lower incidence of life-threatening anaphylaxis compared with iron dextran. 2 Approximately 35 percent of patients receiving iron sucrose have mild adverse effects (e.g., headache, nausea, diarrhea). 7 One small study cited similar adverse effect profiles between intravenous iron dextran and sodium ferric gluconate, with only one serious adverse effect reported in the iron dextran group. 34 If this finding is duplicated in larger studies, it could support the use of iron dextran over sodium ferric gluconate, because the total dose can be given in one sitting. A newer formulation, ferumoxytol, can be given over five minutes and supplies 510 mg of elemental iron per infusion, allowing for greater amounts of iron in fewer infusions compared with iron sucrose. 2

There are no standard recommendations for follow-up after initiating therapy for iron deficiency anemia; however, one suggested course is to recheck complete blood counts every three months for one year. If hemoglobin and red blood cell indices remain normal, one additional complete blood count should be obtained 12 months later. A more practical approach is to recheck the patient periodically; no further follow-up is necessary if the patient is asymptomatic and the hematocrit level remains normal. 7

BLOOD TRANSFUSION

There is no universally accepted threshold for transfusing packed red blood cells in patients with iron deficiency anemia. Guidelines often specify certain hemoglobin values as indications to transfuse, but the patient's clinical condition and symptoms are an essential part of deciding whether to transfuse. 35 Transfusion is recommended in pregnant women with hemoglobin levels of less than 6 g per dL because of potentially abnormal fetal oxygenation resulting in non-reassuring fetal heart tracings, low amniotic fluid volumes, fetal cerebral vasodilation, and fetal death. 15 If transfusion is performed, two units of packed red blood cells should be given, then the clinical situation should be reassessed to guide further treatment. 35

Data Sources: A PubMed search was completed in Clinical Queries using the key terms iron deficiency and anemia. The search included meta-analyses, randomized controlled trials, controlled trials, and reviews. Searches were also performed using Essential Evidence Plus, the Cochrane database, the National Guideline Clearinghouse database, the Trip Database, DynaMed, and the Agency for Healthcare Research and Quality evidence reports. Search date: January 10, 2012.

World Health Organization. Iron Deficiency Anaemia: Assessment, Prevention, and Control: A Guide for Programme Managers . Geneva, Switzerland: World Health Organization; 2001.

Johnson-Wimbley TD, Graham DY. Diagnosis and management of iron deficiency anemia in the 21st century. Therap Adv Gastroenterol. 2011;4(3):177-184.

WHO Global Database on Anaemia. Worldwide Prevalence of Anaemia 1993–2005 . Geneva, Switzerland: World Health Organization; 2008.

U. S. Preventive Services Task Force. Screening for iron deficiency anemia, including iron supplementations for children and pregnant women: recommendation statement. Am Fam Physician. 2006;74(3):461-464.

Van Vranken M. Evaluation of microcytosis. Am Fam Physician. 2010;82(9):1117-1122.

Ioannou GN, Spector J, Scott K, Rockey DC. Prospective evaluation of a clinical guideline for the diagnosis and management of iron deficiency anemia. Am J Med. 2002;113(4):281-287.

Goddard AF, James MW, McIntyre AS, Scott BB British Society of Gastroenterology. Guidelines for the management of iron deficiency anaemia. Gut. 2011;60(10):1309-1316.

Mast AE, Blinder MA, Gronowski AM, Chumley C, Scott MG. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem. 1998;44(1):45-51.

Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev. 2009;23(3):95-104.

Galloway MJ, Smellie WS. Investigating iron status in microcytic anaemia. BMJ. 2006;333(7572):791-793.

Assessing the iron status of populations: report of a joint World Health Organization/Centers for Disease Control and Prevention technical consultation on the assessment of iron status at the population level, Geneva, Switzerland, 6–8 April 2004. Geneva: World Health Organization, Centers for Disease Control and Prevention; 2005.

Skikne BS, Punnonen K, Caldron PH, et al. Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. Am J Hematol. 2011;86(11):923-927.

Bermejo F, García-López S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol. 2009;15(37):4638-4643.

Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep. 1998;47(RR-3):1-29.

American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 95: anemia in pregnancy. Obstet Gynecol. 2008;112(1):201-207.

Baker RD, Greer FR Committee on Nutrition, American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0–3 years of age). Pediatrics. 2010;126(5):1040-1050.

Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297(11):1241-1252.

Liu K, Kaffes AJ. Iron deficiency anaemia: a review of diagnosis, investigation and management. Eur J Gastroenterol Hepatol. 2012;24(2):109-116.

British Columbia Ministry of Health. Iron deficiency—investigation and management. http://www.bcguidelines.ca/guideline_iron_deficiency.html . Accessed November 13, 2012.

Carter D, Maor Y, Bar-Meir S, Avidan B. Prevalence and predictive signs for gastrointestinal lesions in premenopausal women with iron deficiency anemia. Dig Dis Sci. 2008;53(12):3138-3144.

American College of Obstetricians and Gynecologists Committee on Adolescent Health Care; American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. ACOG committee opinion no. 451: Von Willebrand disease in women. Obstet Gynecol. 2009;114(6):1439-1443.

Green BT, Rockey DC. Gastrointestinal endoscopic evaluation of pre-menopausal women with iron deficiency anemia. J Clin Gastroenterol. 2004;38(2):104-109.

Park DI, Ryu SH, Oh SJ, et al. Significance of endoscopy in asymptomatic premenopausal women with iron deficiency anemia. Dig Dis Sci. 2006;51(12):2372-2376.

Fraser IS, Langham S, Uhl-Hochgraeber K. Health-related quality of life and economic burden of abnormal uterine bleeding. Expert Rev Obstet Gynecol. 2009;4(2):179-189.

ACOG Committee on Practice Bulletins—Gynecology, American College of Obstetricians and Gynecologists. ACOG practice bulletin: management of anovulatory bleeding. Int J Gynaecol Obstet. 2001;72(3):263-271.

Hopper AD, Leeds JS, Hurlstone DP, Hadjivassiliou M, Drew K, Sanders DS. Are lower gastrointestinal investigations necessary in patients with coeliac disease?. Eur J Gastroenterol Hepatol. 2005;17(6):617-621.

Yates JM, Logan EC, Stewart RM. Iron deficiency anaemia in general practice: clinical outcomes over three years and factors influencing diagnostic investigations. Postgrad Med J. 2004;80(945):405-410.

Ioannou GN, Rockey DC, Bryson CL, Weiss NS. Iron deficiency and gastrointestinal malignancy: a population-based cohort study. Am J Med. 2002;113(4):276-280.

Lewis NR, Scott BB. Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests). Aliment Pharmacol Ther. 2006;24(1):47-54.

Sidhu R, Sanders DS, Morris AJ, McAlindon ME. Guidelines on small bowel enteroscopy and capsule endoscopy in adults. Gut. 2008;57(1):125-136.

Ajmera AV, Shastri GS, Gajera MJ, Judge TA. Suboptimal response to ferrous sulfate in iron-deficient patients taking omeprazole. Am J Ther. 2012;19(3):185-189.

Maslovsky I. Intravenous iron in a primary-care clinic. Am J Hematol. 2005;78(4):261-264.

Silverstein SB, Rodgers GM. Parenteral iron therapy options. Am J Hematol. 2004;76(1):74-78.

Eichbaum Q, Foran S, Dzik S. Is iron gluconate really safer than iron dextran?. Blood. 2003;101(9):3756-3757.

Murphy MF, Wallington TB, Kelsey P, et al.; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the clinical use of red cell transfusions. Br J Haematol. 2001;113(1):24-31.

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• Volume 9, Issue 1
• Iron deficiency anaemia: pathophysiology, assessment, practical management
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• http://orcid.org/0000-0003-1026-3173 Aditi Kumar 1 ,
• Esha Sharma 2 ,
• Alexandra Marley 1 ,
• Mark A Samaan 2 ,
• http://orcid.org/0000-0002-8782-0292 Matthew James Brookes 1 , 3
• 1 Department of Gastroenterology , The Royal Wolverhampton NHS Trust , Wolverhampton , UK
• 2 Inflammatory Bowel Disease Unit , Guys and St Thomas' NHS Foundation Trust , London , UK
• 3 Research Institue , Faculty of Science and Engineering, University of Wolverhampton , Wolverhampton , UK
• Correspondence to Dr Aditi Kumar; aditikumar{at}nhs.net

The WHO has recognised iron deficiency anaemia (IDA) as the most common nutritional deficiency in the world, with 30% of the population being affected with this condition. Although the most common causes of IDA are gastrointestinal bleeding and menstruation in women, decreased dietary iron and decreased iron absorption are also culpable causes. Patients with IDA should be treated with the aim of replenishing iron stores and returning the haemoglobin to a normal level. This has shown to improve quality of life, morbidity, prognosis in chronic disease and outcomes in pregnancy. Iron deficiency occurs in many chronic inflammatory conditions, including congestive cardiac failure, chronic kidney disease and inflammatory bowel disease. This article will provide an updated overview on diagnosis and management of IDA in patients with chronic conditions, preoperative and in pregnancy. We will discuss the benefits and limitations of oral versus intravenous iron replacement in each cohort, with an overview on cost analysis between the different iron formulations currently on the market.

• iron deficiency
• inflammatory bowel disease
• iron absorption
• iron metabolism

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https://doi.org/10.1136/bmjgast-2021-000759

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Introduction

The WHO has recognised iron deficiency anaemia (IDA) as the most common nutritional deficiency in the world, with 30% of the population being affected with this condition. 1 While IDA is more prevalent in children and women, adult men are also susceptible depending on their socioeconomic status and health conditions. 2 Although the most common causes of IDA are gastrointestinal (GI) bleeding and menstruation in women, decreased dietary iron intake and absorption are also culpable causes. 3

Iron is required for various cellular functions, including but not limited to enzymatic processes, DNA synthesis, oxygen transport and mitochondrial energy generation. 4 5 As such, the symptoms of IDA can vary over a wide range. Shortness of breath, fatigue, palpitations, tachycardia and angina can result from reduced blood oxygen levels. This resultant hypoxemia can subsequently cause a compensatory decrease in intestinal blood flow, leading to motility disorder, malabsorption, nausea, weight loss and abdominal pain. Central hypoxia can cause headaches, vertigo and lethargy as well as cognitive impairment with several studies showing an improvement in cognitive functions once anaemia has normalised. 6–9 It is well known that IDA significantly affects quality of life (QoL) 9 with recent evidence demonstrating that treating IDA improves QoL, regardless of the underlying cause for anaemia. 8 10

In this review, we will discuss the pathophysiology, diagnosis, treatment and complications in the management of IDA. The investigative criteria for IDA are beyond the scope of this article and have been comprehensively outlined in the recent British Society of Gastroenterology guidelines. 11

Pathophysiology

Iron is an essential element and is controlled primarily by dietary intake, intestinal absorption and iron recycling. 12 Dietary iron can be found in two forms: haem and non-haem iron. Haem iron is easily absorbable and arises from haemoglobin (Hb) and myoglobin in the form of animal meat, poultry and fish. Non-haem iron is mostly found in plant food but is not as easily absorbable. Compounds such as phytate, oxalate, polyphenols and tannin, which are found in plants, diminish the uptake of non-haem iron, as do some drugs, such as proton pump inhibitors. 13 14 Ascorbic acid, citrate and gastric acid, conversely, facilitate iron absorption. 15 In a healthy diet, approximately 5–15 mg of elemental iron and 1–5 mg of haem iron are ingested daily although only 1–2 mg is ultimately absorbed into the intestine, predominantly in the duodenum and proximal jejunum. 16 Please see figure 1 for details on the iron absorption pathways.

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The two different iron absorption pathways. Non-haem absorption pathway (left): insoluble ferric iron (Fe 3+ ) is reduced to absorbable ferrous iron (Fe 2+ ), which is carried out by the enzyme duodenal cytochrome B (DcytB). The divalent metal transporter 1 (DMT1) imports Fe 2+ across the apical surface and into the cell, which can then be either stored as ferritin or exported into circulation through ferroportin. Prior to exiting the enterocyte, Fe 2+ must be oxidised back to Fe 3+ by hephaestin or ceruloplasmin. Haem absorption pathway (right): the haem carrier protein (HCP1) transports haem iron directly into the enterocyte. Once inside the enterocyte, haem iron can either be released into plasma via the haem exporter FLVCR1 or be converted back into Fe 2+ via the haem oxidase (HO) enzyme. The ferroportin receptor then releases Fe 2+ into the plasma. Hepcidin, a hepatic peptide hormone, controls ferroportin, the sole iron exporter, by promoting its endocytosis. Hepcidin production and circulation are regulated by plasma iron concentration and iron stores. Hepcidin is increased in the presence of inflammation, which then promotes the degradation of ferroportin and subsequently impairs the exportation of cellular iron into plasma. Figure taken with permission from Kumar and Brookes. 84

Assessment and diagnosis

The WHO defines anaemia as blood Hb level below 130 g/L in men and 120 g/L in women. 1 In isolated iron deficiency, serum ferritin (the storage molecule for iron) should be less than 30 ug/L. 17 However, ferritin is an acute phase protein and can be increased in the presence of inflammation. 18 Thus, if there is evidence of concomitant inflammation, such as elevated C reactive protein, ferritin less than 100 ug/L is indicative of IDA. 19 Transferrin, the iron transporter, is generally elevated; however, it is a negative acute phase protein and, therefore, can be normal or reduced in chronic inflammatory states. 20 Serum iron and transferrin saturations (TSAT) will be reduced with TSAT less than 20% required for the diagnosis of IDA. 17 See table 1 for the breakdown of diagnostic criteria for IDA. It is crucial to note that iron deficiency should not be excluded in the presence of a normal Hb as a significant amount of iron must be lost before the Hb levels begin to decline. Thus, a low mean corpuscular Hb with a normal Hb or an increase in red cell distribution width signifies mild iron deficiency without anaemia. 21

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Diagnostic criteria for iron deficiency anaemia

Patients with IDA should be treated with the aim of replenishing iron stores and returning the Hb to a normal level. This has been shown to improve QoL, morbidity, prognosis in chronic disease and outcomes in pregnancy. 22 Iron replenishment can occur via three routes: oral iron, parenteral oral and transfusion of packed red cells. Each route has its benefits and limitations, which will be discussed below in greater detail.

Conventional oral iron formulations

The British Society of Gastroenterology recommends ferrous preparations, specifically ferrous sulphate, as first-line therapy for iron replenishment as they are cheap, have good bioavailability, available in multiple preparations and have been shown to replenish iron stores and correct anaemia effectively. 11 However, there are also many limitations to their use, with the most common being the frequency and severity of side effects. A systematic review demonstrated that GI side effects were the most problematic with constipation being the most frequent complaint, followed by nausea and diarrhoea. 23 This will have a resultant effect on patient adherence, likely leading to cessation and, thus, inadequate treatment. 24

The appropriate dosing of ferrous iron preparations is also a contentious issue between clinicians. To adequately replenish iron stores, therapeutic treatment of IDA was initially felt to require 200 mg of iron sulphate 2–3 times per day in order to raise Hb by 20 g/L over a 4-week period, with treatment continuing for 3 months. 25 However, the daily doses of elemental iron should not be greater than 100 mg/day 26 as the body can only absorb 10–20 mg of iron per day. 26 It should be noted that 200 mg of ferrous sulphate is equivalent to 65 mg of elemental iron. 27

A recent study compared oral iron dosing regimens in women with mild anaemia with divided daily, once daily and alternate-day dosing. The results demonstrated superiority with alternate-day dosing, with 33% greater fractional iron absorption over 14 doses. 28 In addition, a randomised trial of elderly patients with IDA received 15 mg, 50 mg or 150 mg of elemental iron per day. After 2 months, the mean increase in Hb was the same in all groups (1.4 g/dL); however, adverse effects were significantly greater with higher doses. 29 It is, therefore, an evolving view that a single daily dose (40–60 mg) or a slightly higher alternate-day dose (80–100 mg) is the preferred dosing regimen in order to reduce the side effects and optimise the proportion of elemental iron absorbed. 28–30

Sodium feredetate is a water-soluble EDTA compound with higher bioavailability than the ferrous iron salt preparations. In the UK, it is available as a liquid preparation (Sytron); however, it is also available in tablet form (Ecofer, not currently licensed in the UK) often in combination with B12 and folate. 31 In a study looking at treatment of IDA in pregnant women, sodium feredetate increased Hb by 1.28 g/dL after 1 month of treatment and 2.11 g/dL after 2 months of treatment. This was in comparison to the group of women who received ferrous sulphate, where the mean Hb rose by 1 g/dL after 1 month and 1.58 g/dL after 2 months. As well as a significantly greater increase in Hb, there were significantly fewer side effects seen with sodium feredetate than ferrous sulphate. 32 This study also highlighted the improved bioavailability of sodium feredetate as this cohort was given one 231 mg tablet once per day for 2 months (equivalent to 33 mg of elemental iron) compared with the ferrous sulphate cohort who were given 200 mg tablets two times per day for 2 months (equivalent to 60 mg of elemental iron).

Novel oral iron formulations

Ferric maltol, a novel preparation, is a non-salt oral iron formulation composed of stable ferric iron complexed with a sugar derivative, tri-maltol. It is licenced in the European Union and the USA and sold under the brand names Feraccru and Accrufer, respectively. When absorbed, the maltol ligand remains complexed to iron, which reduces the formation of free iron and facilitates iron transport across the enterocyte. 33 This subsequently increases the bioavailability of iron such that lower doses of elemental iron are required to treat IDA compared with the ferrous iron preparations. 34 Furthermore, ferric maltol has been shown to have less of an effect on the gut microbiome. 35 Studies on the use of ferric maltol has been limited to patients with inflammatory bowel disease (IBD), with results demonstrating improvement in Hb levels beyond 12 weeks with sustained normal Hb levels up to 64 weeks when compared with placebo. 36 37 When compared with intravenous ferric carboxymaltose, however, ferric maltol was shown to be inferior and did not meet the primary endpoint of increasing Hb by 2 g/L or Hb normalisation by 12 weeks (85% vs 68%, respectively). 38

Finally, sucrosomial iron is an innovative oral iron-containing carrier, in which ferric pyrophosphate is within a phospholipid bilayer membrane forming the ‘sucrosome’, creating a gastroresistant complex, which can be transported to the intestinal mucosa where it is absorbed without free iron interacting with the gut wall. 39 40 This unique structure protects iron from the acidic environment in the stomach, increases intestinal epithelial absorption and ensures high bioavailability while reducing the risk for potential adverse GI effects. 39 Despite lower doses of elemental iron, this newer oral iron preparation (30–60 mg/day) has also shown greater efficacy in increasing Hb and ferritin concentrations compared with ferrous sulphate (105–210 mg/day), with a mean Hb increase in 2.7 g/dL and 1.4 g/dL, respectively, over a 12-week course of treatment. 39

Recent studies have demonstrated sucrosomial iron to be non-inferior to parenteral iron in patients with anaemia secondary to coeliac disease, cancer, bariatric surgery and chronic kidney disease (CKD). 41–43 In a study looking at patients with IDA as a result of benign GI or gynaecological bleeding who had previously not responded to or not tolerated ferrous sulphate were randomised to receive a high dose of either sucrosomial iron or intravenous ferrous gluconate. Results demonstrated that patients were comparable at baseline and rise in Hb was not significantly different between the two groups, with the number of weeks required to achieve an Hb target value of 12 g/dL was four in the sucrosomial iron group and 3.5 in the ferrous gluconate group. 44

Intravenous iron

An alternative to oral iron supplementation is parenteral administration. Intravenous iron is the preferred route of administration in some patients and is increasingly favoured due to its rapid correction of Hb, fewer side effects and improved safety profile. The primary advantage of intravenous iron is that it bypasses the GI tract absorption, thereby avoiding further mucosal aggravation and inflammation and producing less side effects. 45 Clinicians also do not have to worry about patient’s adherence to medication.

There are a variety of intravenous iron preparations with selection of the agent dependent on multiple factors including cost considerations, patient and physician preference and product availability. It is important to note that clinical studies of the various formulations follow different protocols, and as of yet, there are no large head-to-head trials between these formulations comparing efficacy and safety profile.

Older intravenous iron preparations such as high-molecular weight dextran iron (Dexferrum) have been discontinued due to their unfavourable safety profiles with relatively high incidence of anaphylaxis. 46 The lower molecular weight dextran compounds such as Cosmofer are, however, still in use and have been shown to be effective with a much lower incidence of anaphylactoid reactions. 47 While there has not been a study comparing the different preparations, a meta-analysis looking at the overall rate of anaphylaxis with intravenous dextran was 0.61%, 48 which is significantly greater than with the newer non-dextran intravenous preparations. 49

Ferric derisomaltose (Monofer) is an alternative intravenous iron preparation, which is often preferred to Cosmofer due to its shorter infusion time, thereby optimising the use of medical infusion units and nursing time as these drugs are often given as day-case procedures. Monofer is also preferred by some as it can be given as one infusion rather than two infusions. Ferric carboxymaltol (Ferinject) is a preparation widely used in the UK. It can be safely administered at a single dose of 1000 mg within 15 min; however, two infusions may be required in some patients, depending on their weight and Hb levels. Finally, iron sucrose (Venofer) is given by a slow injection of 100–200 mg 2–3 times a week. 50 It has been shown to be effective, although a comparison study showed Ferinject to be superior. In this study, Ferinject was associated with a higher rate of achieving a 2 g/dL increase in Hb concentration in comparison to iron sucrose by a relative risk of 1.65. 51 While Venofer has been extensively studied, the major drawback in its use is the need for multiple infusions, which can not only be less acceptable to patients but also made difficult for overstretched healthcare services.

Red blood cell transfusion

It is advised that transfusions should be reserved for patients with severe anaemia, haemodynamically unstable and/or have associated comorbid conditions. 26 However, while severe anaemia is defined as Hb <70 g/dL, many of these patients may be haemodynamically stable and rather have chronic anaemia, remaining asymptomatic. Although a unit of blood contains approximately 200 mg of iron, 22 these patients are very likely to require further iron supplementation to adequately replenish their iron stores, particularly if the cause for their anaemia is chronic and not easily treatable, for example, advanced malignancy or haematological disease.

Clinicians are rightly reluctant to transfuse patients unnecessarily as it is associated with not insignificant risks. These include an increased mortality with liberal blood transfusion in the setting of upper GI bleeding. 52 There is also increased incidence of transfusion-related reactions. This includes the risk of Transfusion Related Acute Lung Injury, which is one of the most serious reactions, the incidence of which is approximately 1 in 5000 transfusions. 53 Furthermore, there remains a small risk for transmitting infections, both viral and bacterial. 54–56

Considerations in management

Comorbidities.

IDA occurs in many chronic inflammatory conditions, including congestive cardiac failure (CCF), CKD and IBD ( table 2 ). To complicate matters, symptoms such as fatigue are commonly seen in these conditions, which can mimic and be confused with symptoms of IDA. Consequently, the management of IDA can often be overlooked. Untreated IDA can have greater consequences in these conditions causing an exacerbation of the underlying disease. 6

A list of common conditions and patient groups who have an increased risk of developing iron deficiency anaemia

Congestive cardiac failure

In CCF, IDA is one of the most prevalent comorbid conditions 57 and can be a result of multiple factors including reduced appetite, increased GI blood losses as a result of antiplatelet or anticoagulant medication and decreased GI absorption due to oedema. 58

The median dose of iron needed to replete iron sufficiently in patients with CCF with IDA is 1000 mg. 59 If patients were given ferrous sulphate, the first-line oral preparation, the bioavailability is only 10% at best, 60 and, thus, patients would need a minimum of 50 days at a dose of 200 mg/day to correct the iron deficit. Realistically, considering missed doses or non-adherence, it can take up to 6 months to adequately replenish iron stores. 58 Thus, intravenous iron should be considered first line for the treatment of iron deficiency in CCF. 6 The Ferinject Assessment in Patients with Iron Deficiency and Heart Failure (FAIR-HF) and Ferric Carboxymaltose Evaluation on Performance in Patients with Iron Deficiency in Combination with Chronic Heart Failure (CONFIRM-HF) trials demonstrated the benefit of ferric carboxymaltose compared with placebo in correcting IDA by improving exercise capacity, cardiac function, symptom severity and QoL. 61

Chronic kidney disease

The causes of IDA in CKD are similar to those in CCF, namely, reduced GI iron absorption, poor nutrition and blood loss caused by dialysis and frequent blood sampling. A recent meta-analysis and systematic review demonstrated intravenous iron to be more effective than oral iron in treating IDA in CKD, regardless of requirement for dialysis. 6 62 The Kidney Disease: Improving Global Outcomes clinical practice guidelines also recommend intravenous iron as first-line treatment for patients with stage 5 CKD. 63 However, ferric citrate might be an alternative oral preparation with a recent trial of 203 patients given 1 g three times per day showing fewer hospitalisation rates and lower incidence of death, dialysis or transplantation. 64 Despite the evidence provided for intravenous preparations, oral iron remains first-line therapy for many clinicians and patients as it is readily available, inexpensive and avoids the need for intravenous access, which can cause injury to blood vessels that may be needed in the future for critical vascular access. 65 Furthermore, there are concerns regarding potential side effects with intravenous iron including anaphylaxis, hypersensitivity, susceptibility to infections and cardiovascular events, hypophosphataemia and iron overload. 66 While human erythropoietin (EPO) and EPO-stimulating agents (ESA) have been in use for decades, they are associated with worsening hypertension, seizures and dialysis access clotting. 67 68 Moreover, ESA has not shown to reduce adverse outcomes associated with anaemia, including mortality rate, hospitalisations and progression of kidney disease. 69

Inflammatory bowel disease

IDA has been acknowledged as one of the most common extra intestinal manifestations of IBD. 20 Impaired GI iron absorption is caused by chronically inflamed bowel, chronic blood losses, bowel resection and malnutrition. 6 Improvement in iron status through treatment with intravenous iron has led to significant improvement in QoL in patients with IBD. 10 Adverse effects from oral iron are well recognised but have greater consequences in patients with IBD. Absorption from the GI tract is limited (on average 10%–20% of ingested amount) and unabsorbed iron is exposed to the ulcerated intestinal surface, which can cause further mucosal damage as well as changes to gut microbiota, 70 although it is not yet established whether oral iron exacerbates IBD inflammation beyond animal models. The European Crohn’s and Colitis Organisation (ECCO) guidelines advise the use of intravenous iron as first-line therapy in patients with active disease, severe anaemia (Hb <100 g/L), if previously intolerant to oral iron and for patients in need of concomitant treatment with EPO. 26 However, there is a place for both oral and intravenous iron in patients with IBD, which is further outlined in figure 2 .

Iron deficiency treatment pathway in patients with IBD patients as followed by the South East London Clinical Commissioning Group. 85 Hb, haemoglobin; IBD, inflammatory bowel disease.

IDA is associated with multiple types of cancer, including GI (colorectal, pancreatic, oesophageal, gastric), lung, genitourinary (cervical, prostate, testicular), breast and haemotological (lymphoma, leukaemia, myeloma). 71 In cancer patients, iron deficiency is associated with fatigue and weakness irrespective of the presence of anaemia. 66 Iron deficiency can occur frequently by means of chemotherapy-induced anaemia and anaemia of chronic disease. 66 Blood transfusions, ESA therapy and intravenous iron are the potential treatment options for IDA in patients with cancer. The aim is to improve QoL and reduce reliance on blood transfusions that are often associated with further multiorgan complications. Beneficial effects of ESAs are limited and both the European medicines agency and Food and Drug Administration have recommended restricting their use to patients with symptomatic anaemia and those undergoing specific chemotherapy. 72 A consensus of cancer experts suggest intravenous iron should be used over oral iron supplementation due to reduced efficacy and poor tolerance and adherence in the latter. 72 This is corroborated by a meta-analysis of 11 randomised studies, where intravenous iron had an improved haematopoietic response in chemotherapy-induced anaemia with no safety concerns and an overall reduction in blood transfusion requirement, compared with oral iron. 73

Elderly population

Another high-risk population are the elderly where prevalence of iron deficiency increases rapidly with age due to reduce oral intake, poor absorption and excess loss. 74 A meta-analysis of trial data shows treatment of iron deficiency with both oral and intravenous iron reduces blood transfusion requirements and increases Hb levels but does not significantly impact mortality 68 Oral supplementation is recommended for treatment of IDA in this population, and lower doses of oral iron may be effective and better tolerated among elderly patients. For those whose oral treatment has been unsuccessful, intravenous treatment should be considered to avoid adverse effects and effectively treat anaemia. However, potential adaptations of oral therapy should also be considered such as liquid formulations or reducing dose frequency. 74

IDA in surgery

There is a growing field of evidence to focus on the impact of iron deficiency on morbidity and mortality in the perioperative period. Recently published national guidance recommends that IDA should be identified and treated pre and postoperatively, 75 whether that be via oral or intravenous iron supplementation. Intravenous iron is recommended for those who are unable to tolerate oral iron, those with functional iron deficiency and those with surgical procedures close to the time the IDA was diagnosed. 75 Further research is necessary to assess the impact of the timing of iron replacement prior to surgery.

Anaemia in pregnancy is defined as Hb <110 g/L with ferritin levels <100 μg/L. 11 The total iron loss in pregnancy approximately 1000 mg, and, thus, the recommended daily dietary allowance for iron in pregnancy is 27 mg compared with 8 mg in the adult non-pregnant population. 76 The usual recommended dose of elemental iron is 80 mg, which is equivalent to 250 mg of oral iron sulphate tablets. 76 Intermittent oral iron has been reported to be effective as daily iron dosing in raising Hb levels and is associated with a lower incidence of adverse effects. 77 However, a meta-analysis has demonstrated intravenous iron sucrose improved Hb (mean difference 7.17 g/L) and serum ferritin levels (mean difference 49.66 ug/L) while ferric carboxymaltose improved Hb levels (mean difference 8.52 g/L), compared with oral ferrous sulphate. 78 Furthermore, side effects were less common with the parenteral formulations, but included local pain, skin irritation and rarely allergic reactions.

Adverse effects

As previously discussed, the common adverse effects of oral iron are well known among healthcare professionals and patients. The potential adverse effects of intravenous iron have more recently been publicised as they become further researched and understood. The rare adverse effect of hypersensitivity reactions has been known for some time and have dictated specialised protocols and training for healthcare professionals routinely administering intravenous iron.

Hypophosphataemia is an increasingly recognised adverse effect of intravenous iron. The risk of persistent hypophosphataemia and osteomalacia is possibly higher with ferric carboxymaltose than with the other intravenous iron preparations. A key mechanism is the carbohydrate moieties in ferric carboxymaltose inhibit degradation of fibroblast growth factor 23, resulting in greater renal loss of phosphate. 79 Phosphate replacement is an ineffective management strategy due to this mechanism as any phosphate replaced is lost through greater renal wasting. 80 Although the clinical significance is not yet fully understood, it is expected to have more of an effect on those patients requiring higher doses, repeat courses and are at a higher risk of electrolyte imbalances due to malnutrition. 79

A less commonly recognised adverse effect is that of extravasation of intravenous iron that can cause long-lasting tattoo-like skin discolouration preceded by skin irritation and pain at the injection site. Though this adverse effect is considered to be rare (occurring at a rate of approximately 1.6%), the skin staining can last for several months after the initial infusion despite pharmacological interventions to resolve the reaction. 81 82 Though the extravasation of intravenous iron is not expected to cause harm, the long-lasting effects of the skin stain can have negative psychological and social impact on patients, so awareness of this phenomenon among healthcare professionals is imperative. Patients should be informed of this potential adverse effect prior to administration of intravenous iron.

Cost implications

It is important to consider both the cost of the impact of iron deficiency to the healthcare system and the cost of the individual treatments when assessing the overall cost of IDA management ( table 3 ). Oral treatment with standard ferric salts is by far the lowest cost option with convenient administration and low drug cost (a 12-week course is approximately £2). Conversely, intravenous iron preparations can cost approximately £1400 per patient infusion when based on the highest iron requirement and including costs to the healthcare system for patient day-case admission. However, the most significant cost to the healthcare system is that of untreated IDA, which can result in emergency hospitalisation and multiple blood transfusions, approximately £1700 per admission on average. Brookes et al reviewed management of IDA in England between 2012 and 2018 and identified that £42.4 million was spent on emergency hospital admissions. In comparison, £46 million was spent on day case admissions, although four times as many patients were treated in the outpatient setting. 83 Though intravenous iron administration can seem more expensive than oral treatment, these findings strongly suggest that there is a need for a national strategy for standardising and streamlining elective intravenous iron administration to prevent more costly emergency admissions. For those who have not tolerated standard oral supplementation, ferric maltol may offer a more suitable alternative than intravenous iron. The cost of ferric maltol is significantly more than the standard oral iron (approximately £170 for a 12-week course) but much less than intravenous iron. If oral intolerance is the drive for choosing intravenous treatment, then ferric maltol may offer an alternative choice with less potential adverse effects, although direct comparisons of this drug with other iron formulations still need to be studied.

Cost analysis per drug

Looking to the future: service development and redesign

IDA is the most common nutritional disorder globally and is associated with multiple comorbid states with severe implications in QoL. Despite national guidance on managing IDA, there is still wide variability in current practices, not just between National Health Service trusts but also between clinicians and departments. Choosing between intravenous and oral iron therapies is dependent on many factors, including the therapy goal, response to prior therapy, patient preference, cost and ease of access to an infusion centre. A standardised pathway steered by evidence-based medicine can reduce this variance in care, while simultaneously supporting cost-effective anaemia management across and between the new integrated care systems.

Ethics statements

Patient consent for publication.

Not applicable.

Ethics approval

This study does not involve human participants.

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Twitter @dr_dee_kumar

Contributors AK, AM and ES wrote the manuscript. MAS and MJB provided critical revisions of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests ES served as a speaker and/or an advisory board member for Takeda, Janssen and Pharmacosmos. MAS served as a speaker, a consultant and/or an advisory board member for Abbvie, Bristol Myers Squibb, Sandoz, Janssen, Takeda, MSD, Falk and Samsung Bioepis. MJB has received funding from Vifor International and Tillotts Pharma in the form of grants for research work and travel expenses, outside of the submitted work.

Provenance and peer review Commissioned; externally peer reviewed.

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A case of iron-deficiency anemia

2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

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Background and objectives: Video-capsule endoscopy (VCE) has shown a large range (38–83%) of diagnostic yield in unexplained iron deficiency anemia (IDA) and obscure-occult bleeding. Therefore, we retrospectively investigated the VCE-detected spectrum and the prevalence of small bowel injuries and associated risk factors in inpatients with both of the above reported conditions. Methods: We selected inpatients with IDA (hemoglobin &lt;12 g/dL in women, &lt;13 g/dL in men) and obscure-occult bleeding. We excluded VCE indications other than IDA. Complete medical histories and laboratory tests were collected. All subjects underwent PillCam SB2/SB3. The VCE feature Lewis score was calculated when appropriate. We used the t-test and Fisher’s exact test for continuous and categorical variables, respectively, in univariate analysis. For multivariate analysis, we used binomial logistic regression. Results: We retrieved 109 patients (female:male ratio of 53:56; age 63.4 ± 18.9 years). Eighty ...

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Ingestion of foreign bodies (FBs) is a relatively common problem in the United States and india with an estimated incidence of 120 per 1 million population (Ayantunde and Oke, 2006), and is the cause of almost 1500 deaths each year. FB ingestion is a common clinical problem in both adults and children. Swallowed objects may be true FBs such as coins, plastic toys, bones, pins, disc batteries and food bolus that impact in the esophagus (Ayantunde and Oke, 2006). Toddlers are the most affected. Although ingested FBs usually pass through the gastrointestinaltract without any problem, intestinal obstruction and, in less than 1%, perforation may occur (Cossavella et al., 1998). A 64 yr old male presented with hematamesis and melena on and off for 15 days duration. No H/o known psychiatric illness in the past. On evaluation chest x ray and Abdominal x ray erect abdomen revealed multiple foreign bodies from stomach to rectum. The FB are of open safety pins, nail, safety pin head. There is ...

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Introduction Ingesting a foreign body (FB) is not an uncommon occurrence. Most pass through the gastrointestinal (GI) tract uneventfully, and perforation is rare. The aim of this study was to report our experience with ingested FB perforations of the GI tract treated surgically at our institution. Methods A total of 62 consecutive patients who underwent surgery for an ingested FB perforation of the GI tract between 1990 and 2005 were retrospectively reviewed. Three patients with no definite FB demonstrated intraoperatively were included. Results The patients had a median age of 58 years, and 37 (60%) were male. Of the 59 FBs recovered, 55 (93%) were toothpicks and dietary FBs such as fish bones or bone fragments. A definitive preoperative history of FB ingestion was obtained for only two patients, and 36 of 52 patients (69%) wore dentures. Altogether, 18 (29%) perforations occurred in the anus or distal rectum, and 44 perforations were intraabdominal, with the most common abdominal site being the distal ileum (39%). Patients with FB perforations in the stomach, duodenum, and large intestine were significantly more likely to be afebrile (P = 0.043), to have chronic symptoms (> 3 days) (P P P Conclusions Ingested FB perforation in the adult population is most commonly secondary to unconscious accidental ingestion and is frequently caused by dietary FBs especially fish bones. A preoperative history of FB ingestion is thus rarely obtained, although wearing dentures is a common risk factor. FB perforations of the stomach, duodenum, and large intestine tend to present with a longer, more innocuous clinical picture than perforations in the jejunum or ileum.

Editor iajps

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• v.85(1); 2010 Jan

39-Year-Old Woman With an Obscure Case of Anemia

Shanique r. palmer.

* Resident in Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN

Gita Thanarajasingam

† Medical student, Mayo Medical School, Rochester, MN

Alexandra P. Wolanskyj

‡ Adviser to fellow and Consultant in Hematology, Mayo Clinic, Rochester, MN

A 39-year-old woman was referred to our institution for evaluation of anemia. She was known to have multiple comorbidities and had a baseline hemoglobin concentration of approximately 10.5 g/dL. About 6 months before her referral, the patient began having recurrent episodes of severe anemia, with hemoglobin values as low as 3.5 g/dL. She had become transfusion-dependent and had received about 30 units of packed red blood cells (RBCs) in the preceding 3 months. The patient denied any history of easy bruisability, menorrhagia, or overt evidence of bleeding from any site. Additionally, she denied any change in the appearance or color of her urine and had no history of jaundice. There was no family history of anemia or any other hematologic disorder. As an outpatient, she had undergone an extensive evaluation at another institution, but results failed to provide an explanation for her anemia.

The patient's medical history was remarkable for severe asthma, thought to be due to Churg-Strauss syndrome. She had a tunneled central venous catheter for self-administration of intravenous corticosteroids at the earliest sign of an asthmatic exacerbation. Her other medications included bronchodilators, weekly erythropoietin injections, intravenous iron therapy, an antidepressant, and an anxiolytic.

At presentation, the patient's vital signs were normal. Physical examination was unremarkable except for mild generalized pallor. A complete blood count on the day of admission revealed the following (reference ranges shown parenthetically): hemoglobin, 4.9 g/dL (12.0-15.5 g/dL); mean corpuscular volume (MCV), 94.4 fL (81.6-98.3 fL); hematocrit, 13.4% (34.9%-44.5%); leukocyte count, 6.0 × 10 9 /L (3.5-10.5 × 10 9 /L); and platelet count, 203 × 10 9 /L (150-450 × 10 9 /L). The patient's partial thromboplastin time and prothrombin time (PT)/international normalized ratio were normal. These results were obtained within 24 hours of her last transfusion.

• Chronic blood loss
• Acute hemolysis
• Chronic disease
• Myelodysplastic syndrome
• Acquired pure red cell aplasia

Anemia can be categorized as microcytic, normocytic, or macrocytic by examining the MCV. This patient clearly has a normocytic anemia, with her MCV of 94.4 fL, although this must be interpreted with some caution, given her history of multiple transfusions, which can normalize the MCV. Normocytic anemias are classically due to premature destruction or acute loss of RBCs or to decreased bone marrow production. With this in mind, we can approach the proposed list of differential diagnoses. Chronic blood loss usually leads to iron deficiency anemia, which is classically microcytic in nature; however, a normocytic anemia may also be seen. Hemolytic anemias usually result in a normocytic picture. Anemia of chronic disease is usually normocytic and is possible because of this patient's complicated medical history. The myelodysplastic syndromes refer to a heterogeneous group of stem cell disorders characterized by abnormal cellular maturation and, most commonly, chronic cytopenias. They result in macrocytosis, which is classically marked, with MCV sometimes greater than 110 fL. This is the only condition listed that classically results in a macrocytic anemia, rather than normocytic, and was therefore least likely to be the cause of the patient's anemia. Acquired pure red cell aplasia is a primary bone marrow disorder characterized by decreased reticulocytes and the virtual absence of erythroid precursors in the bone marrow. It is often idiopathic but may occur in association with various diseases, such as systemic lupus erythematosus and hematologic malignancies. Regardless of the underlying cause, the anemia is usually normocytic with absolute reticulocytopenia.

With the observation that the patient's anemia was normocytic with an MCV of 94.4 fL, the next task was to narrow the list of differential diagnoses and establish whether this was due to premature destruction or acute loss of RBCs vs decreased bone marrow production.

• Peripheral blood smear
• Absolute reticulocyte count
• Serum ferritin
• Erythropoietin
• Bone marrow biopsy and aspiration

The peripheral blood smear provides useful information that cannot be obtained with the usual complete blood count and can provide clues to a variety of bone marrow disorders, as well as systemic disorders that can have hematologic manifestations. However, it would not be the single best test to provide the necessary information at this point. We needed to establish whether there was an adequate or inadequate (ie, hypoproliferative) bone marrow response. An adequate response is usually due to hemolysis or acute loss of RBCs. The reticulocyte count is a good indicator of this and is the only test listed that could have directly provided this necessary piece of information. Anemia with an absolute reticulocyte count of less than 75 × 10 9 /L provides strong evidence of deficient production of RBCs, whereas a count of greater than 100 × 10 9 /L indicates a brisk and efficient response to hemolysis or blood loss. The region between these 2 limits remains a gray zone, and other clinical and laboratory parameters should be used to interpret the overall picture. The plasma ferritin level generally reflects overall iron storage and is typically used as a part of the panel to evaluate for iron deficiency anemia in a patient with microcytosis. Therefore, it would not be most useful in this patient with a normocytic anemia. Erythropoietin is a growth factor that is the primary stimulus for erythropoiesis. It would not be useful at this juncture in revealing whether the anemia is due to decreased production or increased loss of blood cells or premature destruction. A bone marrow biopsy would show erythroid hyperplasia, a nonspecific finding, if erythropoiesis is increased in response to the anemia. If there is a hypoproliferative state, the marrow may reveal a variety of findings, depending on the underlying diagnosis. Therefore, a bone marrow biopsy would be premature at this point. However, a bone marrow biopsy would be indicated if there was pancytopenia or if the peripheral smear showed abnormal cells, such as blast forms or dysplastic changes.

Our patient had a reticulocytosis of 13.3% (0.60%-1.83%), with an absolute reticulocyte count of 238.8 × 10 9 /L (29.5-87.3 × 10 9 /L).

• Total and indirect bilirubin levels, haptoglobin, lactate dehydrogenase (LDH)
• Direct Coombs test
• Indirect Coombs test
• Activated partial thromboplastin time (aPTT), PT, fibrinogen, soluble fibrin monomer complex, and D-dimers

In this patient with an absolute reticulocytosis, ie, an adequate bone marrow response, the next step would be in differentiating between hemolysis and acute blood loss. Hemolysis is usually characterized by elevated indirect bilirubin concentrations, decreased serum haptoglobin concentrations (with intravascular hemolysis in particular), and increased serum LDH levels, and this series of tests would be most useful in narrowing the differential diagnoses at this point. The peripheral blood smear is less specific, but in the presence of hemolysis, it may reveal abnormally shaped RBCs, including fragmented RBCs (schistocytes, helmet cells), spherocytes, elliptocytes, or RBC inclusions, which may be seen in certain hemolysis-producing infections, such as malaria, babesiosis, and Bartonella . Hemolytic anemias may be acquired and immune, in which case there is immunologic destruction of RBCs mediated by autoantibodies directed against antigens on the patient's RBCs. The direct and indirect Coombs tests detect antibodies on the surface of the patient's RBCs and in the patient's serum, respectively. However, the presence of hemolysis must first be established, especially since a patient may have a mildly positive Coombs test that is clinically insignificant if not associated with ongoing hemolysis. The laboratory findings in disseminated intravascular coagulation and intravascular coagulation and fibrinolysis (DIC/ICF) include elevated D-dimer and soluble fibrin monomer complex levels, low fibrinogen levels, and prolonged PT and aPTT. Therefore, these investigations should be performed when a diagnosis of DIC/ICF is suspected. However, this patient's clinical scenario and laboratory findings to date, ie, lack of thrombocytopenia and normal PT and aPTT, do not suggest underlying DIC/ICF.

The patient had a mildly reduced haptoglobin level at 14 mg/dL (30-200 mg/dL), likely secondary to her multiple transfusions. However, her LDH level was normal at 205 U/L (122-222 U/L), as were her total and direct bilirubin levels at 0.4 mg/dL (0.1-1.0 mg/dL) and 0.1 mg/dL (0.0-0.3 mg/dL), respectively. A peripheral blood smear showed no abnormally shaped RBCs. The overall picture was not in keeping with hemolysis. On the first day of her evaluation, the patient's hemoglobin concentration was 11.1 g/dL. By day 2 of her outpatient work-up, it had decreased to 5.6 g/dL, and she received 4 units of packed RBCs. Despite the transfusions, her hemoglobin concentration decreased further within 24 hours to 4.9 g/dL. At this point, the patient was admitted and received 3 more units of packed RBCs. During this time, she was asymptomatic, and her vital signs remained stable.

• Esophagogastroduodenoscopy
• Colonoscopy
• Computed tomography (CT) of the abdomen and pelvis
• Transfer to the intensive care unit
• Angiography of the gastrointestinal (GI) tract

The patient had no overt signs or symptoms of bleeding, and it would be unlikely for her to have occult GI bleeding that resulted in such dramatic decreases in her hemoglobin concentration. Also, results of fecal occult blood testing were negative. Therefore, neither upper nor lower GI endoscopy would be expected to reveal any useful information. However, the patient could have occult intra-abdominal bleeding, and noncontrast CT of her abdomen and pelvis would be crucial in ruling this out. The patient's mental status remained normal, and she was exhibiting no overt evidence of decreased perfusion or hemodynamic instability other than mild tachycardia. Therefore, she could be deemed clinically stable, and transferring her to the intensive care unit would be unnecessary at this time. She was well compensated despite the severity and acuteness of the anemia, no doubt in part due to her age and lack of other cardiac comorbidities. In this patient who is exhibiting no overt evidence of GI bleeding, angiography would not be the next best step.

Noncontrast CT of her abdomen and pelvis revealed normal findings. During the night of hospital day 2, an astute nurse noticed what appeared to be bloodstains on the patient's gown. The patient reported that she had spilled cranberry juice on the gown. Closer inspection of her room revealed several blood-soaked tissues and Styrofoam cups filled with fresh blood in her wastebasket. The patient was also found to have dried, crusted blood all over her fingernails, and a blood-stained 10-mL syringe, most of its labeling worn away by overuse, was found in her gown pocket ( Figure ).

10-mL syringe allegedly used by the patient for self-phlebotomy.

• Factitious disorder
• Munchausen by proxy
• Malingering
• Somatization disorder
• Hypochondriasis

With the discovery made in the patient's room, in particular the syringe, the patient's self-phlebotomy became evident, leading to a diagnosis of factitious anemia. The most chronic and extreme form of factitious illness, Munchausen syndrome, typically includes travel from hospital to hospital combined with the willingness to submit to multiple procedures for self-fabricated signs of illness, as occurred with our patient before her presentation at our institution. In Munchausen by proxy, caregivers (usually mothers) induce illness in their children to obtain care and support for themselves. In malingering, illness is feigned to gain such external incentives as money or drugs or to avoid such consequences as military service or criminal prosecution. Factitious disorder, in contrast, has no incentive other than being a patient in the sick role. Since we identified no incentive other than obtaining our care, our patient could not be said to be malingering. Somatization refers to the tendency to experience psychological distress in the form of somatic symptoms not intentionally produced, thus differentiating this disorder from factitious illness or malingering. Hypochondriasis refers to a preoccupation with believing one is ill as a result of misconstruing physical symptoms that are not self-generated. By her self-phlebotomizing activity, our patient could not be considered hypochondriacal.

The patient was seen by the psychiatry service, and although she was obviously at risk of purposeful self-harm, she denied suicidal or homicidal ideation. It became evident that she had a history of severe depression, borderline personality disorder, chemical dependency, and a history of repeated episodes of parasuicide by means of wrist cutting. She gave consent for her central line to be removed, and this was done before her dismissal. There was direct communication with her primary care physicians and primary psychiatrist, and she was then dismissed from the hospital with a plan for close and consistent medical attention.

Several cases of factitious anemia have been reported in the literature. 1 , 2 The patient is seldom caught in the act and usually denies the behavior, making the diagnosis difficult to establish incontrovertibly. Patients with this condition often have underlying psychiatric issues and constantly need to assume the sick role. Once the diagnosis is suspected, the patient should be confronted, and removal of any contributing medical device is essential. Early diagnosis is usually difficult but may prevent repeated hospitalizations and the risks associated with invasive diagnostic procedures. 2 Management is usually extremely difficult but should be centered around long-term psychotherapy. 2 A multidisciplinary approach is of utmost importance because patients usually become very uncooperative when they are discovered and may make attempts to break off relations with the current medical staff and seek medical attention elsewhere. Providing optimal management to an uncooperative patient may be difficult without violating the patient's autonomy. Therefore, a psychiatric consultation should be arranged as soon as possible, and seeking assistance from the institution's ethics and legal committees may be prudent.

The current case provides an opportunity to highlight an approach to the patient presenting with anemia. Anemia can be classified according to measurement of RBC size, as seen on the peripheral blood smear and as indicated by the MCV. This morphological approach categorizes the anemias as microcytic, normocytic, or macrocytic, providing a useful starting point to narrow the list of differential diagnoses. By definition, the MCV is normal (80-100 fL) in patients with normocytic anemia, low (<80 fL) in patients with microcytic anemia, and high (>100 fL) in patients with macrocytic anemia. 3

The presence of a microcytic anemia usually indicates a pathologic process involving hemoglobin synthesis. The most common cause is iron deficiency, but other classic causes include the thalassemias and other hemoglobinopathies, lead poisoning, sideroblastic anemia, and, less commonly, anemia of chronic disease. If microcytosis is identified, the next step would be to differentiate among these common causes, and this can be done by assessing serum iron studies, which include serum ferritin, iron, total iron-binding capacity, and transferrin saturation. In iron deficiency, the classic findings are a low serum ferritin value, which is diagnostic, elevated total iron-binding capacity, and low saturation. Other findings include a peripheral blood smear showing anisocytosis and poikilocytosis. If the serum ferritin level and other iron studies are normal, then thalassemia should be considered, and hemoglobin electrophoresis should be performed for the definitive diagnosis. Caution must be taken in interpreting the iron studies in anemia of chronic disease because findings are often inconsistent. The entire clinical scenario must be taken into account. 3 Sideroblastic anemias may be hereditary or acquired, and the latter is characterized by increased RBC distribution width, dimorphic RBCs, and bone marrow ringed sideroblasts.

If the anemia is found to be normocytic, the next step would be to differentiate between RBC destruction/loss and a hypoproliferative state. The presence of an increased reticulocyte response (>100 × 10 9 /L) suggests either loss or destruction of RBCs; thus, differentiation of these 2 conditions must be made. Hemolysis is characterized by elevated indirect bilirubin levels, decreased serum haptoglobin levels, and increased serum LDH levels. Also, the peripheral smear may reveal several abnormalities, such as fragmented RBCs and other abnormally shaped RBCs. If laboratory parameters or the peripheral smear is not suggestive of hemolysis, then a bleeding source should be sought. A normocytic anemia without reticulocytosis indicates an aplastic anemia; myelophthisis in which the bone marrow is replaced by fibrosis, tumor, or other abnormal cells; or lack of erythropoietin, which can be seen classically in renal failure.

The first step in evaluating a macrocytic anemia should be ruling out a marked reticulocytosis (polychromasia). Polychromasia may cause a regenerative macrocytosis. If this is found, evaluation for hemolysis or blood loss should be performed as outlined previously. Macrocytic anemias may be due to defects in DNA synthesis, resulting in oval macrocytes, or increase in the cholesterol/phospholipid ratio in membranes, resulting in round macrocytes.

Oval macrocytosis is classically due to vitamin B 12 or folate deficiency. If neither is present, then a bone marrow biopsy is warranted to look for the presence of a myelodysplastic syndrome. Round macrocytes may be due to severe alcoholism, liver disease, or hypothyroidism. Also, tobacco use and advanced age may result in round macrocytosis without anemia.

Factitious disorders are difficult to diagnose. However, our patient presented with several clues, including her previous psychiatric history and the recurrent dramatic decreases in her hemoglobin concentration, usually when she was unsupervised. Heightened suspicion is the first step in arriving at the correct diagnosis. Additionally, if anemia is approached in a logical stepwise manner, as outlined previously, multiple expensive, unnecessary, and invasive investigations can be avoided, and if due to a factitious disorder, necessary psychotherapy can be implemented in a more timely fashion.

Acknowledgments

We thank J. Michael Bostwick MD, Department of Psychiatry, Mayo Clinic, Rochester MN, for his expertise in the care of this patient and guidance in the preparation of the submitted manuscript.

See end of article for correct answers to questions.

Correct answers: 1. d , 2. b , 3. a , 4. c , 5. a