Seminar

Iron deficiency anaemia

Anthony Lopez, Patrice Cacoub, Iain C Macdougall, Laurent Peyrin-Biroulet

Anaemia affects roughly a third of the world’s population; half the cases are due to iron deficiency. It is a major and Lancet 2016; 387: 907–16
global public health problem that affects maternal and child mortality, physical performance, and referral to Published Online
health-care professionals. Children aged 0–5 years, women of childbearing age, and pregnant women are particularly August 25, 2015
http://dx.doi.org/10.1016/
at risk. Several chronic diseases are frequently associated with iron deficiency anaemia—notably chronic kidney
S0140-6736(15)60865-0
disease, chronic heart failure, cancer, and inflammatory bowel disease. Measurement of serum ferritin, transferrin
Department of Hepato-
saturation, serum soluble transferrin receptors, and the serum soluble transferrin receptors–ferritin index are more Gastroenterology and Inserm
accurate than classic red cell indices in the diagnosis of iron deficiency anaemia. In addition to the search for and U954, University Hospital of
treatment of the cause of iron deficiency, treatment strategies encompass prevention, including food fortification and Nancy, Lorraine University,
Vandoeuvre-lès-Nancy, France
iron supplementation. Oral iron is usually recommended as first-line therapy, but the most recent intravenous iron
(A Lopez MD,
formulations, which have been available for nearly a decade, seem to replenish iron stores safely and effectively. Prof L Peyrin-Biroulet MD);
Hepcidin has a key role in iron homoeostasis and could be a future diagnostic and therapeutic target. In this Seminar, Sorbonne Universités, UPMC
we discuss the clinical presentation, epidemiology, pathophysiology, diagnosis, and acute management of iron Univ Paris 06, UMR 7211, Paris,
France (Prof P Cacoub MD);
deficiency anaemia, and outstanding research questions for treatment.
Inflammation-
Immunopathology-Biotherapy
Introduction In severe cases patients might have dyspnoea at rest, Department, F-75005, Paris,
Iron deficiency occurs in two main forms: absolute or angina pectoris, and haemodynamic instability.8,11 France (Prof P Cacoub); AP-HP,
Groupe Hospitalier Pitié-
functional. Absolute iron deficiency arises when total Clinical features of iron deficiency anaemia depend on Salpêtrière, Department of
body iron stores are low or exhausted; functional iron the severity of the anaemia, age, comorbidities, and Internal Medicine and Clinical
deficiency is a disorder in which total body iron stores chronicity and speed of onset. In some cases, anaemia is Immunology, F-75013, Paris,
are normal or increased, but the iron supply to the asymptomatic and diagnosed only after laboratory France (Prof P Cacoub); and
Department of Renal Medicine,
bone marrow is inadequate. Absolute and functional measurement of haemoglobin concentrations. Iron King’s College Hospital,
deficiencies can coexist. Functional iron deficiency can deficiency especially affects epithelial cells with a rapid London, UK
be present in many acute and chronic inflammatory turnover, causing dryness and roughness of the skin, dry (Prof I C Macdougall MD)
states, and hepcidin—the master regulator of iron and damaged hair, diffuse and moderate alopecia,4 and Correspondence to:
homoeostasis—has a key role in pathogenesis. In this koilonychia (spoon-shaped finger nails). Loss of tongue Prof Laurent Peyrin-Biroulet,
Department of Hepato-
Seminar, we focus mainly on absolute iron deficiency. papillae occurs in patients with mild-to-moderate iron Gastroenterology, University
deficiency and is a good gauge of length of deficiency. Hospital of Nancy-Brabois,
Clinical presentation Université de Lorraine,
Patients with iron deficiency anaemia can present with Allée du Morvan,
Panel 1: Symptoms of iron deficiency anaemia 54511 Vandoeuvre-lès-Nancy,
symptoms that are associated with all anaemias, which France
are sometimes associated with specific signs due to iron Very frequent [email protected]
deficiency (panel 1). Pallor of the skin, conjunctivae, and • Paleness (45–50%)1
nail beds are common.1,11 The diagnostic usefulness of • Fatigue (44%)2
these signs is increased when clinicians can ascertain • Dyspnoea
whether their presence is a change from normal in the • Headache (63%)3
patient. Other symptoms and signs result from hypoxic
functioning: fatigue,2 exertional dyspnoea progressing Frequent
to breathlessness at rest, vertigo, syncope,9 headache,3 • Diffuse and moderate alopecia (30%)4
tachycardia,8 and a cardiac systolic flow murmur.7 • Atrophic glossitis (27%)5
• Restless legs syndrome (24%)6
• Dry and rough skin
Search strategy and selection criteria • Dry and damaged hair
• Cardiac murmur (10%)7
We searched the Cochrane Library, Medline, and Embase with
• Tachycardia (9%)8
the terms “anaemia”, “iron deficiency”, “epidemiology”,
• Neurocognitive dysfunction
“pathophysiology”, “ferritin”, “serum soluble transferrin
• Angina pectoris
receptors”, “hepcidin”, “supplementation”, “fortification”, and
• Vertigo
“review”. We selected work published in any language, largely
between Jan 1, 2010, and Dec 31, 2014, but did not exclude Rare
commonly referenced and highly regarded older publications. • Haemodynamic instability (2%)8
Our last search was on Jan 25, 2015. We also searched the • Syncope (0·3%)9
reference lists of articles identified by this search strategy and • Koilonychia
selected those that we judged relevant. • Plummer-Vinson syndrome (<0·1%)10

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Atrophic glossitis is noted in severe cases.5 Iron deficiency women (p=0∙002).17 A meta-analysis18 showed increased
has been reported to be associated with restless legs attention and concentration in children, adolescents, and
syndrome.6 However, in a meta-analysis12 evidence was women who received iron supplementation. Anger
insufficient to determine whether iron therapy is (p=0∙007) and fatigue (p=0∙017) were significantly higher
beneficial for restless legs syndrome (p=0∙06).12 in Japanese women with iron deficiency but who did not
Plummer-Vinson syndrome—which is also called have anaemia, than they were in controls with healthy
Kelly-Paterson syndrome—is rare and characterised by iron concentrations.19
dysphagia, iron deficiency anaemia, and oesophageal
webs.10 Accurate epidemiological data are not available Epidemiology
but analysis of case reports suggests that about 90% of In 2010, global anaemia prevalence was 32·9% (ie, more
cases are in women, with a mean age at diagnosis of than 2·2 billion people were affected); iron deficiency
47 years (range 28–80 years).10 The syndrome is associated was the most common cause.20 WHO estimated that,
with an increased risk of squamous cell carcinoma of the between 1993 and 2005, worldwide prevalence of anaemia
pharynx and the oesophagus, which occurs in 3–15% of was 24∙8% in the general population—from 12∙7% in
patients.10 Iron deficiency seems to be dominant in men to 47∙4% in children aged 0–5 years. Prevalence was
the pathogenesis of Plummer-Vinson syndrome, and 30∙2% in women, and 41∙8% in pregnancy. 23∙9% of
therefore iron supplementation is the main treatment.10 people older than 60 years were anaemic.21 Between 1995
Oesophageal webs can be endoscopically dilated if and 2011, worldwide prevalence of anaemia decreased by
dysphagia persists despite iron supplementation. Yearly 4–5% in children aged 0–5 years, non-pregnant women,
upper gastrointestinal endoscopies are recommended to and pregnant women aged 15–49 years.22 Prevalence of
detect prematurely neoplastic lesions.10 anaemia varies hugely around the world.21
Whatever its cause, anaemia can negatively affect Iron deficiency is the most common nutritional
physical performance, particularly work productivity, in deficiency, but robust, population-based studies are few.
adults, as a result of both the reduced oxygen transport Thus, in US studies prevalence of iron deficiency ranges
associated with anaemia and the reduced cellular oxidative from 4∙5% to 18∙0%.23–25 But at a global level, the lowest
capacity associated with iron deficiency.13 In a 2013 burden of anaemia associated with iron deficiency was
systematic review,14 a positive association was noted in noted in the USA and Canada (2·9% of envelope). In
older people (aged ≥65 years) between anaemia and global several regions—including central Asia (64·7%), south
cognitive decline and incidence of dementia. Perinatal Asia (54·8%), and Andean Latin America (62·3%)—a
iron deficiency is associated with delayed neurocognitive very high proportion of the anaemia burden was caused
development and psychiatric illness.15 Even after iron by iron deficiency.20
repletion in infancy, cognitive abnormalities can persist at Data for the epidemiology of iron deficiency anaemia
age 10 years.16 Low body iron stores were significantly are unreliable, especially because anaemia is often
associated with low performances in cognitive executive ascribed to iron deficiency, irrespective of its cause
planning function in 42 non-anaemic undergraduate (table 1). WHO estimates that 50% of cases worldwide are
due to iron deficiency,26 but regional and subgroup
Prevalence (%) disparities exist. In two studies from the past 3 years,
prevalence of iron deficiency anaemia was roughly 20%.27,28
Anaemia
General population20 32·9
Pathophysiology
Men (15–60 years)21 12·7 Iron is an essential component of haemoglobin in red
School-age children (>5 years)21 25·4 blood cells and of myoglobin in muscles, which contain
See Online for appendix Elderly (>60 years)21 23·9 around 60% of total body iron (appendix). It is also
Preschool children (0–5 years)22 43·0 necessary for the functioning of various cellular
Non-pregnant women and girls (15–49 years)22 29·0 mechanisms, including enzymatic processes, DNA
Pregnant women and girls (15–49 years)22 38·0 synthesis, and mitochondrial energy generation. In adults,
Iron deficiency the body contains 3–5 g of iron; 20–25 mg is needed daily
Children (<2 years)23 9·0 for production of red blood cells and cellular metabolism.29
Children (3–5 years)24 4·5 Because dietary intake is limited (1–2 mg per day), other
Adolescent girls (12–19 years)24 15·6 sources are needed for iron homoeostasis—eg, recycling
Women (20–49 years)24 15·7 of ageing erythrocytes in macrophages, exchange of iron
Pregnant women and girls (12–59 years)25 18·0 in iron-containing enzymes, and iron stores.29 About
Iron deficiency anaemia 1–2 mg of iron is lost daily as a result of menstrual
General population26 12·2 bleeding, sweating, skin desquamation, and urinary
Hospital-based population27 23·0 excretion.29 Because iron does not have an excretion
regulation pathway, dietary intake, intestinal absorption,
Table 1: Prevalence of anaemia, iron deficiency, and iron deficiency anaemia
and iron recycling have to be finely regulated.

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Dietary iron is available in two forms: haem and

non-haem iron. Iron is complexed as Fe²+ (ferrous iron) Panel 2: Physiological conditions and pathological disorders associated with iron
in haemoglobin in the haem form, which is present in deficiency anaemia
animal food sources, such as meat, poultry, and seafood.30 Physiological
Non-haem iron (Fe³+ or ferric iron) is present in the • Infancy41
vegetarian diet (black tea, cacao, cereals, dried fruit, etc).30 • Adolescence in girls42
Haem iron is estimated to contribute 10–15% of total iron • Pregnancy43
intake in meat-eating populations, but because it is • Regular blood donation44
generally better absorbed—with a rate of absorption • Being an elite athlete39
estimated at 15–35%—than non-haem iron, it can
account for more than 40% of total absorbed iron.31 Pathological
In iron homoeostasis, a small peptide called hepcidin, Blood loss
which is mainly secreted by hepatocytes and was first • Digestive tract: colonic carcinoma, gastric carcinoma, inflammatory bowel
described in 2001 in mice with iron overload,32 has a • Diseases, ulcers, angiodysplasia, parasites45
crucial role in the control of iron availability to tissues. • Gynaecological loss46
Outside the liver, other cell types and organs, such as • Surgery
macrophages,32 adipocytes,33 the heart,34 and the kidneys,35 • Haematuria, epistaxis, haemoptysis
can produce hepcidin. In plasma, hepcidin is bound to • Haemodialysis
α2-macroglobulin36 and albumin,37 and can be cleared via • Non-steroidal anti-inflammatory drugs, aspirin
the kidney.37 The main role of hepcidin is to control Malabsorption
surface expression of FPN1 by binding to the protein, • Coeliac disease47
which is then internalised and degraded by lysosomes.37 • Gastrectomy
FPN1 is the only known iron-exporting protein, so after • Helicobacter pylori48
its degradation enterocytes, macrophages, and hepato- • Gut resection, atrophic gastritis, bypass gastric surgery, bacterial overgrowth45
cytes can no longer export iron, which is sequestrated in • Interaction with food elements: tea, coffee, calcium, flavonoids, oxalates, phytates
these cells. • Pica syndrome, pagophagia
High expression of hepcidin decreases plasma iron • Proton-pump inhibitors and H2 antagonists
concentrations; low expression increases concentrations. Iron deficiency anaemia associated with anaemia of chronic disease
Hepcidin expression is upregulated by high con- • Chronic heart failure49
centrations of iron in the liver and plasma, inflammation, • Cancer50
and physical activity38,39 whereas it is downregulated by • Chronic kidney disease51
iron deficiency, erythropoiesis, hypoxia, and endocrine • Rheumatoid arthritis52
signals (testosterone, oestrogen, and growth factors). • Obesity53
A new hormone called erythroferrone was identified in • Inflammatory bowel diseases54
2014. It is produced by erythroblasts in response to
erythropoietin, and mediates hepcidin suppression Genetic disorders
during stress erythropoiesis.40 • Iron-refractory iron deficiency anaemia55
• Others (divalent metal transporter 1 deficiency anaemia, Fanconi anaemia, pyruvate
Risk factors kinase deficiency, etc)
Physiological and pathological conditions can promote
iron deficiency anaemia (panel 2). The maximum In relation to diet, ferritin concentrations do not seem
absorption of iron from the diet is less than the body’s to differ between omnivores and vegetarians.42 Some
requirements for iron, resulting in a risk of iron deficiency. components of diet directly affect iron bioavailability.
In infants and young children (aged 0–15 years), rapid Phytates (found in cereals and vegetables), polyphenols
growth consumes the iron stores that accumulate during (found in vegetables, fruits, some cereals and legumes,
gestation, which can, in turn, lead to an absolute deficiency.41 tea, coffee, and wine), calcium, and proteins inhibit iron
After childhood, adolescent girls are particularly at risk of absorption. By contrast, ascorbic acid and muscle tissue
iron deficiency anaemia, because of menstrual iron losses.42 enhance absorption.31
During pregnancy, iron needs are tripled because of Various drugs and abnormalities can lead to iron
expansion of maternal red cell mass and growth of the deficiency anaemia, including blood loss, malabsorption,
fetus and placenta. Daily iron supplementation is chronic disease (so-called iron deficiency anaemia
significantly associated with reduced risk of anaemia at associated with anaemia of chronic disases),57 and genetic
term.43 Mothers who breastfeed are less likely to be iron alterations. Blood loss is the most common, especially
deficient than pregnant women because iron concentration from the digestive tract. In UK guidelines,45 the most
in mature breastmilk is only 0·20–0·80 mg/L,56 and most common causes of blood loss were colonic carcinoma,
breastfeeders are amenorrhoeic. Regular blood donors are gastric carcinoma, benign gastric ulceration, and
at increased risk of iron deficiency.44 angiodysplasia. In developing countries, gastrointestinal

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target a subnormal concentration of haemoglobin to

Healthy Mild Moderate Severe
anaemia anaemia anaemia avoid the risk of iron overload.55
Boys and girls (0·5–4 years) ≥110 100–109 70–99 <70
Diagnostic investigations
Boys and girls (5–11 years) ≥115 110–114 80–109 <80
The diagnosis of anaemia is made after confirmation of a
Boys and girls (12–14 years) ≥120 110–119 80–109 <80
reduced blood haemoglobin concentration as shown by a
Non-pregnant women and girls (15 years or older) ≥120 110–119 80–109 <80
full blood count. Thresholds to define anaemia depend
Pregnant women and girls (≥15 years) ≥110 100–109 70–99 <70
on age, sex, pregnancy, altitude, and smoking. An adult
Men and boys (15 years or older) ≥130 110–129 80–109 <80
man is deemed anaemic when his haemoglobin
Table 2: Haemoglobin concentrations (in g/L) for diagnosis of anaemia, by population concentration is less than 130 g/L, whereas an adult
woman is judged anaemic when her haemoglobin
concentration is less than 120 g/L. In pregnancy, this
parasites such as Trichuris trichiura (whipworm) and cutoff is lowered to 110 g/L (table 2).63
Necator americanus (hookworm) account for about a third Diagnosis of iron deficiency is somewhat complex, and
of iron deficiency anaemia.58 Antihelminthic treatment use of several iron status indicators in combination seems
given every 3 months to Zanzibari children decreased the to provide the best assessment of iron sufficiency. Several
incidence of anaemia by 59%.59 Gynaecological loss is the laboratory markers of iron status might be available
next most frequent cause.46 Excessive surgical blood loss (appendix). First, red cell indices on full blood counts
without replacement can also lead to iron deficiency might show a reduced mean cell haemoglobin, which
anaemia. Other blood losses, such as haematuria, corresponds to hypochromia, and a reduced mean cell
epistaxis, or haemoptysis, occur much less frequently. volume, corresponding to microcytosis. Thresholds are
The most common causes of iron malabsorption are not universally agreed, and disparities exist between
coeliac disease,47 gastrectomy, bypass gastric surgery,60 laboratories.64 Mean cell haemoglobin and volume are
and Helicobacter pylori colonisation.48 Uncommon causes inexpensive, widely available, and sensitive measures, but
of malabsorption are substantial gut resection, atrophic become abnormal only in longstanding iron deficiency.
gastritis, and bacterial overgrowth, each of which cause These measures are also decreased in several chronic
less than 1% of iron deficiency anaemia.45 Pica is a disease states, including haemoglobinopathies (such as
compulsive disorder characterised by an appetite for thalassaemia) or sideroblastic anaemia. Moreover, mean
substances with no significant nutritional values (such as cell volume could be normal in combined nutrient
paper, clay, soil, glass, or sand) that can lead to iron deficiency. In cases of microcytosis, haemoglobin
malabsorption. A craving for ice, pagophagia, has similar electrophoresis is recommended in patients of appropriate
effects. Many drugs are associated with iron deficiency ethnic background (people from Mediterranean countries,
anaemia, either by increasing blood loss (eg, non-steroidal the Middle East, central Asia, India, southern China, and
anti-inflammatory drugs) or decreasing iron absorption east Asia) to eliminate a haemoglobinopathy such as
(eg, proton-pump inhibitors and H2 receptor antagonists). thalassaemia or sickle cell disease.45
Iron deficiency anaemia is frequently reported in chronic In the absence of inflammation, serum ferritin
disorders,57 including inflammatory bowel diseases measurement is the most specific test that correlates with
(IBD),54 chronic heart failure,49 chronic kidney disease,51 total body iron stores. It is a universally available and
cancer,50 rheumatoid arthritis,52 and obesity.53,61 standardised measurement. Iron deficiency is diagnosed
Anaemias caused by genetic defects are a large group below the cutoff of 15 μg/L in patients older than 5 years.26
of rare, heterogeneous disorders. The European In a systematic review,65 ferritin was the most effective test
Network of Rare Congenital Anaemias lists 62 rare to detect iron deficiency.65 However, other authors suggested
anaemia subtypes,62 including haemolytic anaemias and that the diagnostic accuracy of ferritin could be improved
anaemias arising from mutations in genes that control by increasing the cutoff to 30 μg/L. The sensitivity then
duodenal iron absorption (eg, SLC11A2), systemic increased from 25% to 92%, compared with the cutoff
iron homoeostasis (eg, TMPRSS6), or erythroid iron value of 12 μg/L.66 Specificity was unchanged at 98%.66
absorption and utilisation. Iron refractory iron Ferritin concentrations are increased independently of
deficiency anaemia is a microcytic anaemia that affects iron status in acute and chronic inflammatory disorders,
fewer than one in a million people.62 It is caused by a malignant disease, and liver disease—a serious diagnostic
defect in the TMPRSS6 gene encoding matriptase-2, limitation. In these situations, patients with a ferritin
which has a key role in the downregulation of hepcidin. concentration of 50 μg/L or higher could still be iron
Hepcidin concentrations are increased in the disorder, deficient.26,65 In chronic kidney disease, cutoffs of 100 μg/L
leading to iron deficiency.55 Oral iron is ineffective. have been suggested,67 and 200 μg/L in case of
Correction of iron refractory iron deficient anaemia by haemodialysis.68 Other assays can be helpful in these
parenteral iron is partial and much slower than that disorders, such as serum iron and serum transferrin
in patients with acquired iron deficiency.55 Some concentrations or total iron-binding capacity, which is
researchers recommend recombinant erythropoietin to needed to calculate the transferrin saturation.

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In cases of iron deficiency, serum iron is reduced and measurements are not widely available in most clinical
total iron-binding capacity is increased, resulting in a laboratories, partly because of the difficulty of automation
substantial reduction in transferrin saturation (ie, the of the assay.
ratio of serum iron to total iron-binding capacity). The Measurement of the proportion of circulating
threshold of 16% is generally used to screen for iron hypochromic red cells as a proportion of total red blood
deficiency,26 but a threshold of 20% is used in the cells is the most sensitive marker of iron deficiency in
presence of inflammation. patients with chronic kidney disease—6% is the cutoff.76
Serum soluble transferrin receptors (sTfR) derive from Unfortunately, a fresh blood sample is needed for this
proteolysis of the membrane transferrin receptor. This analysis, and automated analysers are not widely
process shows tissue iron deficiency and inversely the available. Reticulocyte haemoglobin content is a very
amount of iron available for erythropoiesis. In case of iron early indicator of iron status, and shows available iron for
deficiency, synthesis of transferrin receptors is increased, erythropoiesis during the 3–4 days before measurement.77
leading to a corresponding increase in sTfR. A substantial A reticulocyte haemoglobin content of less than 27·2 pg
advantage of measurement of sTfR compared with other is diagnostic. But access to this assay is poor, and false
assays is that sTfR concentrations are not affected by normal values can occur in patients with raised mean cell
inflammation.66 Concentrations of sTfR can be raised in volumes or thalassaemia.78 Measurement of reticulocyte
patients with disorders associated with increased haemoglobin content is being incorporated into several
erythropoiesis, such as haemolytic anaemia or chronic cell counters (eg, Siemens, Sysmex, Beckman-Coulter).
lymphocytic leukaemia, and in those who use recombinant
human erythropoietin. Another limitation is the absence Acute and long-term management
of standardised cutoffs worldwide, although UK The aim of treatment is to supply enough iron to
guidelines have been published.68 normalise haemoglobin concentrations and replenish
In 2012, a meta-analysis69 of ten studies of sTfR accuracy iron stores, and thereby to improve quality of life,
showed that the assay had a sensitivity of 86% and a symptoms, and the prognosis of many chronic
specificity of 75%. In routine practice, measurement of disorders. Two distinct approaches exist: prevention
sTfR is not needed for a diagnosis of iron deficiency strategies targeted at populations at risk and active
anaemia. The ratio between these receptors and the iron supplementation approaches in confirmed iron
logarithm of serum ferritin (ie, the sTfR–F index) seems deficiency anaemia.
to discriminate disease—particularly chronic disease— On a global level, food-based approaches—ie, promotion
better than either test individually.70 It is directly of access to, and consumption of, iron-rich foods such as
proportional to tissue deficit in patients with iron meat and organs from cattle, fowl, fish, and poultry, and
deficiency. When the sTfR–F index is low, anaemia is non-animal foods such as legumes and green leafy
probably caused by chronic disease. When it is high, iron vegetables—are recommended by WHO.26 The bio-
deficiency is probably the major cause of anaemia.71 availability of iron can be increased by absorption
Although thresholds are not clearly defined, a ratio enhancers, including ascorbic acid. Inhibitors of iron
greater than 2–3 can be used to diagnose iron deficiency absorption—eg, calcium; phytates, which are essentially
anaemia.57,72,73 Limitations of this index are the same as present in cereal; tannins, which are found in tea and
those of sTfR. coffee—should be reduced or removed from iron-rich
Bone marrow aspiration is still thought of as the gold meals. Tea can reduce iron absorption by 90%.79
standard for diagnosis of iron deficiency. It is not affected Deworming might increase people’s haemoglobin
by inflammation and is highly specific, but is invasive, concentrations.80,81 Enrichment of food with iron is an
uncomfortable for the patient, expensive, and affected by effective public health intervention to improve the iron
recombinant human erythropoietin. Thus, bone marrow status of populations.82 Iron should be incorporated in
aspiration is reserved for very specific cases, when other widely consumed food, organoleptic properties should not
techniques are negative or conflicting. be changed, and prices should not increase. Rice is fortified
In cases of iron depletion, zinc transport across the in the Philippines, bread in Chile, and flour in Venezuela.82
intestine increases. Thus, an increased concentration of After 6 months of breastfeeding, children need an
zinc protoporphyrin in erythrocytes (>80 μg/dL) is additional source of iron to maintain adequate iron
associated with iron deficiency anaemia.26 The ratio nutrition. WHO recommends micronutrient powders in
between zinc protoporphyrin and haem concentrations children aged 6–23 months if the prevalence of anaemia
provides similar information.74 Compared with bone is 20% or higher, with the aim of providing 12∙5 mg
marrow aspiration, zinc protoporphyrin assays had a elemental iron daily, preferably as ferrous fumarate.
sensitivity of 77∙8% and specificity of 69∙8.75 Disorders Thereafter, iron is added to children’s daily food.82 In a
other than iron deficiency can lead to increased 2013 meta-analysis,83 food fortification with micronutrient
concentrations, such as infection, inflammation, lead powder reduced anaemia by 31% and iron deficiency by
poisoning, haemolytic anaemia, increased bilirubin 51% compared with placebo in children younger than
concentrations, and haemodialysis. Zinc protoporphyrin 2 years.83

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in which oral and intravenous iron (ferric carboxymaltose)

Treat cause were compared,87 and as many as 70% of patients in
some studies.88,89 The stool often turns black, which is
• Oral iron supplementation (eg, 325 mg ferrous gluconate daily)
not harmful, and treatment does not have to be
• Measure haemoglobin, ferritin, and transferrin saturation monthly interrupted.
When side-effects occur, iron can be taken with meals,
Effective Not effective or poor tolerance but doing so decreases absorption to 40%. Alternatively,
smaller doses could be taken between meals and at
• Check adherence bedtime or ferrous sulphate could be replaced by 325 mg
• Investigate iron malabsorption
• Eradicate Helicobacter pylori
ferrous gluconate daily (35 mg of elemental iron). The
• Check drug history reticulocyte count should rise as soon as 4 days after
treatment is begun and reach a maximum at 7–10 days.
Continue oral iron
supplementation for 3 months Effective
Haemoglobin concentrations start rising by the second
week of therapy. Historically, a 20 g/L improvement
Not
effective in haemoglobin concentration has been deemed an
Check red cell indices and iron
appropriate response to iron supplementation, but
status monthly for 3 months
and then every 3 months for a serum ferritin concentration and zinc protoporphyrin
year; if symptoms persist,
Consider parenteral iron are significantly (p<0·001) correlated to haemoglobin,
further blood tests should be
done every 3 months for
supplementation and can be used as markers of effectiveness.90 Oral iron
another year and iron should be given for 3 months after iron deficiency has
supplements should be given
been corrected so that stores are replenished.
Yes When patients do not respond to treatment, the
No further investigation

Iron status maintained?

diagnosis of iron deficiency anaemia should be
reconfirmed and adherence should be assessed and
Consider further investigation
No improved. Then, the cause of iron deficiency should be
corrected, if possible. Malabsorption of iron can occur,
Figure: Algorithm for treatment of iron deficiency anaemia especially in cases of coeliac disease, bowel resection, or
H pylori infection. True malabsorption can be diagnosed
Iron supplementation by giving an oral dose of liquid ferrous sulphate (50–60 mg
Iron supplementation is used in two clinical scenarios: to iron) and measuring serum iron concentration 1–2 h
prevent iron deficiency anaemia in at-risk populations, or later. A serum iron concentration of less than 100 μg per
to treat patients with proven disease. In 2011, WHO 100 mL suggests iron malabsorption. A meta-analysis91
recommended daily iron supplementation with 60 mg of showed that eradication of H pylori accelerated the
elemental iron to prevent iron deficiency in menstruating improvement of ferritin concentrations. However, this
adolescent girls and women where the prevalence of benefit was not maintained after 3 months.91
anaemia is 20%.84,85 Similar recommendations were Iron chelates have also been assessed. Inulin, a natural
made for children aged 0–5 years (2 mg/kg daily) and fructose polymer, can be chelated with iron to enhance
children aged 5–12 years (30 mg daily).86 iron absorption within the colon.92 Similar results were
For therapeutic iron supplementation, four common reported for bisglycinate iron93 and liposomal iron.94
iron preparations are available: ferrous sulphate, ferrous Parenteral iron is indicated when blood loss exceeds
sulphate exsiccated, ferrous gluconate, and ferrous the absorptive capacity for iron, in case of iron
fumarate. No one compound seems better than the malabsorption, or oral treatment is unsuccessful or
others. The usual dosage is 325 mg (corresponding to poorly tolerated by the patient (figure). Six main forms of
65 mg of elemental iron) three times a day. But lower intravenous iron are available: iron sucrose, ferric
dosages—eg, 200 mg twice daily—seem as effective and gluconate, ferric carboxymaltose, iron isomaltoside-1000,
are associated with fewer side-effects.45 Iron absorption ferumoxytol, and iron dextran (low-molecular-weight
by enterocytes seems saturable; thus a dose of iron could forms). These compounds comprise a core containing an
prevent absorption of subsequent doses. iron salt, such as iron oxyhydroxide, surrounded by a
Ferrous sulphate should be taken between meals, and carbohydrate shell. The compound is processed by the
patients should avoid inhibitors of iron absorption when reticuloendothelial system. The iron is then released
taking the dose. Although ascorbic acid can improve the from the complex and either stored in ferritin or exported
bioavailability of dietary iron, it increases the frequency back to plasma, via ferroportin, and binds to transferrin.
of side-effects associated with oral iron supplements, The kinetics of iron release from the complex varies
such as epigastric discomfort, nausea, diarrhoea, and according to the iron preparation. Iron is most tightly
constipation, because it increases the amount of ferrous bound to iron dextran preparations, and most loosely
iron downstream. Side-effects occur in roughly about bound to iron gluconate. The speed of release also
32% of patients according to a meta-analysis87 of studies determines how much iron can be given as a single dose.

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Iron dextran products can be given in quantities of 1 g or measures are taken to minimise allergic reactions.103
more, whereas the maximum single dose of iron A guideline with recommendations about the manage-
gluconate is 125 mg. ment and prevention of hypersensitivity reactions to
Intravenous iron replenishes iron stores more effectively intravenous iron was published in 2014.104 The potential
than does oral iron post partum95 and in several disorders, of all intravenous iron preparations to exacerbate
including inflammatory bowel disease96 and chronic oxidative stress and increase susceptibility to infections
kidney disease.97 In the FERGIcor study,98 a randomised, is of concern. In their meta-analysis,105 Litton and
controlled, open-label, multicentre study of 485 patients colleagues105 reported a significant increase in the risk of
with inflammatory bowel disease and iron deficiency infection with intravenous iron (relative risk 1·33,
anaemia, ferric carboxymaltose and iron sucrose were 95% CI 1·10–1·64) compared with oral or no iron
compared.98 The primary endpoint—an increase in supplementation. We will not discuss alternative
haemoglobin concentrations of 20 g/L or more—was treatments, such as blood transfusions, but refer readers
achieved in 65∙8% of patients in the ferric carboxymaltose to Goodnough and colleagues’ 2013 review.106
group and 53∙6% in the iron sucrose group (p=0∙004).
High-molecular-weight iron dextran is associated with a Follow-up
higher frequency of serious anaphylactic reactions than Once the cause of iron deficiency anaemia has been treated
are other preparations. In a review99 of data from WHO and haemoglobin concentrations are healthy, full blood
and drug manufacturers, 31 deaths in the USA were count and markers of iron status should be measured
associated with this preparation between 1976 and 1996. regularly. The British Society of Gastroenterology
Thus, high-molecular-weight iron dextran has been recommends monthly measurements for 3 months, and
withdrawn from the market. However, low-molecular- then every 3 months for a year.45 If symptoms persist,
weight iron dextran and other newer formulations seem further blood tests should be done every 3 months for
to have the same safety profile as ferric gluconate.100 In another year, and iron supplements should be given. If
a multicentre, crossover, randomised, double blind, haemoglobin or red cell indices cannot be maintained in
placebo-controlled prospective study of 2534 patients this way, further investigations are necessary.45
undergoing haemodialysis, the frequency of drug
intolerance was 0∙44% with ferric gluconate (95% CI Outstanding research questions
0∙21–0∙71%) and 0∙1% with placebo (p=0∙02).101 No Because oral iron is associated with gastrointestinal
difference was noted between groups in the frequency of side-effects, new formulations have been developed. In a
serious adverse events. A life-threatening event (immediate trial107 of patients with inflammatory bowel disease and
reaction necessitating resuscitation measures) occurred in iron deficiency anaemia, ferric maltol was more effective
the ferric gluconate group (0∙04%, 95% CI 0∙00–0∙22%). than placebo at increasing haemoglobin at 12 weeks
35% of patients given iron sucrose have mild (p<0∙001), and had a similar safety profile. In
side-effects (abdominal pain, nausea, headache, non-dialysis-dependent patients with chronic kidney
diarrhoea); the frequency of serious adverse reactions is disease, oral haem iron polypeptide had similar efficacy
low (0∙03–0∙04%).45 In a meta-analysis87 the safety profile to intravenous iron sucrose in maintaining haemoglobin,
of ferric carboxymaltose was assessed, and serious with no differences in adverse events.108 Many studies of
adverse events occurred in roughly 3% of patients, which intravenous iron are of short duration and have small
did not differ significantly from the frequency in patients sample sizes. Large, randomised controlled studies with
given placebo.87 About 0∙4% of patients given ferric hard endpoints and long durations are needed to
carboxymaltose died—which was not significantly investigate the safety of these compounds.
different from the rate of death in patients given placebo. Hepcidin production decreases in iron deficiency
Ferumoxytol is a superparamagnetic iron oxide coated anaemia but increases in inflammatory states. Hepcidin
with carbohydrate that is used in iron deficiency anaemia could potentially be used to distinguish iron deficiency
and as a contrast agent for MRI. It has been approved for anaemia and anaemia of chronic disease. Because
use in patients with chronic kidney disease in the USA hepcidin assays are expensive and not routinely available,
since 2009, and in Europe since 2012. According to a an algorithm to predict hepcidin concentrations has
report102 from the Canadian Agency for Drugs and been proposed: transferrin saturation (%) – sTfR
Technologies in Health, ferumoxytol seems as effective (mg/L) + C-reactive protein (mg/L).109 Further studies
as other intravenous iron formulations. might validate the diagnostic accuracy of hepcidin in
Patients with self-limiting minor infusion reactions iron deficiency anaemia.110
are often inappropriately given pressors and anti- Hepcidin could also be a therapeutic target. Down-
histamines, which probably cause most of the serious regulation could prevent retention of iron within
adverse events associated with intravenous iron. The the reticuloendothelial system. Different approaches
European Medicines Agency’s Committee for Medicinal targeting different regulatory steps have been tried to
Products for Human Use concluded that the benefits of control hepcidin expression pharmacologically. They
intravenous iron exceed the risks provided that adequate include hepcidin-sequestering agents (antibodies,

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anticalins, and aptamers), inhibitors of the BMP/SMAD 16 Congdon EL, Westerlund A, Algarin CR, et al. Iron deficiency in
or IL6/STAT3 pathways, inhibitors of hepcidin infancy is associated with altered neural correlates of recognition
memory at 10 years. J Pediatr 2012; 160: 1027–33.
transduction (small interfering or small hairpin RNA), or 17 Blanton CA, Green MW, Kretsch MJ. Body iron is associated with
ferroportin stabilisers.111 In a pilot study,112 vitamin D cognitive executive planning function in college women.
supplementation was associated with a 34% decrease in Br J Nutr 2013; 109: 906–13.
18 Falkingham M, Abdelhamid A, Curtis P, Fairweather-Tait S, Dye L,
circulating concentrations of hepcidin (p<0·05).112 A fully Hooper L. The effects of oral iron supplementation on cognition in
human anti-hepcidin antibody affected iron metabolism older children and adults: a systematic review and meta-analysis.
in both mice and non-human primates,70 and early phase Nutr J 2010; 9: 4.
19 Sawada T, Konomi A, Yokoi K. Iron deficiency without anemia is
clinical studies are beginning to be reported.113 associated with anger and fatigue in young Japanese women.
Contributors Biol Trace Elem Res 2014; 159: 22–31.
AL did the literature search. AL, ICM, and LP-B edited the paper and PC, 20 Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis
ICM, and LP-B critically reviewed it. of global anemia burden from 1990 to 2010. Blood 2014; 123: 615–24.
21 De Benoist B, Egli I, Cogswell M. Worldwide prevalence of anaemia
Declaration of interests
1993–2005. Geneva: World Health Organization, 2008.
AL declares no competing interests. PC has done consultancy for, served
22 Stevens GA, Finucane MM, De-Regil LM, et al, and the Nutrition
on advisory boards for, or received honoraria or speakers’ fees from
Impact Model Study Group (Anaemia). Global, regional, and
Abbvie, AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, national trends in haemoglobin concentration and prevalence of
GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Pfizer, Roche, total and severe anaemia in children and pregnant and
Servier, and Vifor. He is an inventor of a patent application owned by his non-pregnant women for 1995–2011: a systematic analysis of
academic institution that is licensed to ILTOO, a biotechnology company population-representative data. Lancet Glob Health 2013; 1: e16–25.
developing low dose interleukin 2 in autoimmune diseases in which he 23 Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL.
holds shares. ICM has received speakers’ fees and honoraria from Prevalence of iron deficiency in the United States. JAMA 1997;
AMAG, Vifor Pharma, Pharmacosmos, and Takeda; consulting fees 277: 973–76.
from Amgen, Ortho Biotech, Roche, Bayer, Astellas, AstraZeneca, 24 Cogswell ME, Looker AC, Pfeiffer CM, et al. Assessment of iron
FibroGen; and research funding from AMAG, Vifor Pharma, Bayer, deficiency in US preschool children and nonpregnant females of
Astellas, and Noxxon. LP-B has received consulting fees from Merck, childbearing age: National Health and Nutrition Examination
Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Survey 2003–2006. Am J Clin Nutr 2009; 89: 1334–42.
Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, 25 Mei Z, Cogswell ME, Looker AC, et al. Assessment of iron status in
Celltrion, Takeda, Biogaran, Boehringer Ingelheim, Lilly, Pfizer, and US pregnant women from the National Health and Nutrition
HAC-Pharma, and lecture fees from Merck, Abbott, Takeda, Janssen, Examination Survey (NHANES), 1999–2006. Am J Clin Nutr 2011;
Ferring, Norgine, Tillots, Vifor, Therakos, and HAC-pharma. 93: 1312–20.
26 WHO. Iron deficiency anaemia assessment, prevention, and
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