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1832

ron deficiency and iron-deficiency anemia are global health 
problems and common medical conditions seen in everyday clinical practice. 
Although the prevalence of iron-deficiency anemia has recently declined some-
what, iron deficiency continues to be the top-ranking cause of anemia worldwide, 
and iron-deficiency anemia has a substantial effect on the lives of young children 
and premenopausal women in both low-income and developed countries.1 The 
diagnosis and treatment of this condition could clearly be improved.
Iron is crucial to biologic functions, including respiration, energy production, 
DNA synthesis, and cell proliferation.2 The human body has evolved to conserve 
iron in several ways, including the recycling of iron after the breakdown of red 
cells and the retention of iron in the absence of an excretion mechanism. How-
ever, since excess levels of iron can be toxic, its absorption is limited to 1 to 2 mg 
daily, and most of the iron needed daily (about 25 mg per day) is provided through 
recycling by macrophages that phagocytose senescent erythrocytes. The latter two 
mechanisms are controlled by the hormone hepcidin, which maintains total-body 
iron within normal ranges, avoiding both iron deficiency and excess.
Iron deficiency refers to the reduction of iron stores that precedes overt iron-
deficiency anemia or persists without progression. Iron-deficiency anemia is a 
more severe condition in which low levels of iron are associated with anemia and 
the presence of microcytic hypochromic red cells.
Iron-restricted erythropoiesis indicates that the delivery of iron to erythroid 
precursors is impaired, no matter how replete the stores.3,4 Stores may be normal 
or even increased because of iron sequestration in cases of anemia of chronic in-
flammation, which is observed in patients with autoimmune disorders, cancer, 
infections, and chronic kidney diseases.3,4 The presence of both iron deficiency and 
anemia of chronic disorders is common and may be seen in elderly patients5 and 
patients with chronic kidney disease.6 However, a substantial fraction of the ane-
mia that is typical in elderly patients occurs in the absence of iron deficiency or 
elevated hepcidin levels.7

Functional iron deficiency is a state of iron-poor erythropoiesis8 in which there 
is insufficient mobilization of iron from stores in the presence of increased de-
mands, as is observed after treatment with erythropoiesis-stimulating agents.9 (See 
the Glossary for definitions of terms related to iron-deficiency anemia.)
This review reconsiders iron deficiency and its anemia in light of advances in 
the understanding of systemic iron homeostasis and examines causes, patho-
physiological features, and treatment options in adults. Readers are referred else-
where for information on the presentation, symptoms, and diagnosis of iron-defi-
ciency anemia through laboratory tests and on issues that are specific to children 
or pregnancy.10-13

From Vita Salute University and San Raf-
faele Scientific Institute, Milan. Address 
reprint requests to Dr. Camaschella at 
Vita Salute University, San Raffaele Sci-
entific Institute, Via Olgettina, 58, 20132 
Milan, Italy, or at  camaschella . clara@ hsr . it.

N Engl J Med 2015;372:1832-43.
DOI: 10.1056/NEJMra1401038
Copyright © 2015 Massachusetts Medical Society.

Downloaded from nejm.org at EKU Libraries on January 28, 2019. For personal use only. No other uses without permission.

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Iron deficiency affects more than 2 billion people 
worldwide,1 and iron-deficiency anemia remains 
the top cause of anemia, as confirmed by the 
analysis of a large number of reports on the 
burden of disease in 187 countries between 1990 
and 201014 and by a survey on the burden of ane-
mia in persons at risk, such as preschool chil-
dren and young women.15 Prevention programs 
have decreased rates of iron-deficiency anemia 
globally; the prevalence is now highest in Cen-
tral and West Africa and South Asia.14,15 The esti-
mated prevalence of iron deficiency worldwide is 
twice as high as that of iron-deficiency anemia.
The reported prevalence of iron deficiency in 
the absence of dietary fortification is approxi-
mately 40% in preschool children, 30% in men-
struating girls and women, and 38% in pregnant 
women.14-16 These rates reflect the increased 
physiological need for dietary iron during spe-
cific life stages and according to sex. The 
growth spurt of adolescence is another critical 
period. For patients in any of these categories, 
pathologic causes of iron-deficiency anemia are 
often absent and extensive diagnostic workups 
are not advised. However, as discussed below, 
when the response to treatment is unsatisfacto-
ry, multiple causes should be considered, even in 
patients in these high-risk groups.
In developing countries, iron deficiency and 
iron-deficiency anemia typically result from in-
sufficient dietary intake, loss of blood due to 
intestinal worm colonization, or both. In high-
income countries, certain eating habits (e.g., a

vegetarian diet or no intake of red meat) and 
pathologic conditions (e.g., chronic blood loss or 
malabsorption) are the most common causes. 
Paradoxically, it appears to be more difficult to 
reduce the prevalence of iron-deficiency anemia 
in high-income countries than in lower-income 
countries. One reason for this seeming paradox 
is the high rate of iron deficiency in aging popu-
lations.14

Modifications of Iron 
Homeostasis in Iron Deficiency

The mechanisms of iron acquisition are tightly 
regulated by hepcidin-based homeostatic con-
trols.2 Hepcidin is a peptide hormone that is 
synthesized primarily in the liver. It functions as 
an acute-phase reactant that adjusts fluctuations 
in plasma iron levels caused by absorptive entero-
cytes and macrophages in the spleen by binding 
to and inducing the degradation of ferroportin, 
which exports iron from cells.17 Hepcidin expres-
sion increases in response to high circulating 
and tissue levels of iron and in persons with 
systemic inflammation or infection. Its produc-
tion is inhibited by the expansion of erythropoie-
sis, iron deficiency, and tissue hypoxia in response 
to signals originating in the bone marrow, the 
liver, and probably muscle tissue and adipo-
cytes.2,18 Increases in hepcidin levels that are 
induced by inflammatory cytokines, especially 
interleukin-6, explain the iron sequestration and 
reduced supply of erythropoietic iron that occurs 
in the anemia of chronic disease.
In the general population, hepcidin levels are

Anemia of chronic disorders or anemia of inflammation: Multifactorial anemia associated with increased cytokine pro-
duction, up-regulation of hepcidin, and abnormal iron homeostasis.

Functional iron deficiency: Insufficient mobilization of erythroid iron in the presence of increased requests, as occurs 
 after treatment with erythropoiesis-stimulating agents.

Iron deficiency: Depressed levels of total body iron, especially iron stores, with preservation of levels of erythroid iron.

Iron-deficiency anemia: Depressed levels of total body iron in the presence of anemia.

Iron-restricted erythropoiesis: A reduced supply of iron for the purpose of erythropoiesis, regardless of the level of iron 
stores, which are usually replete.

Iron-refractory iron-deficiency anemia (IRIDA): Iron-deficiency anemia that is unresponsive to oral iron treatment, in 
most cases referring to the genetic disease caused by a mutation in TMPRSS6, the gene encoding transmembrane 
protease, serine 6, also known as matriptase-2.

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1834
The new engl and jour nal of medicine
low in girls and young women and higher — 
similar to levels in men — in postmenopausal 
women; fluctuations in hepcidin levels have a 
strong direct correlation with serum levels of 
ferritin.19,20 In iron deficiency, the transcription 
of hepcidin is suppressed. This adaptive mecha-
Figure 1. The Iron Cycle — Mechanisms of Adaptation to Iron Deficiency.
The mechanisms of adaptation to iron deficiency are centered on the suppression of the hepatic hormone hepcidin 
and the tissue hypoxia that develops consequent to anemia. The production of erythropoietin (EPO) by the kidney 
increases in response to enhanced levels of hypoxia-inducible factor 2α (HIF-2α). As a consequence of the stimula-
tion of erythropoietin, erythropoiesis is increased and hypochromic microcytic red cells are produced owing to the 
low availability of iron. Senescent red cells are destroyed by macrophages, and their iron is recycled. The increase in 
erythropoiesis suppresses the production of hepcidin. In mice, this function is mediated by erythroferrone (ERFE), 
which is secreted by the erythroblasts21 to maintain adequate iron absorption and efficiency in erythropoiesis. HIF-2α 
increases the expression of the duodenal divalent metal transporter 1 (DMT1)22 on the apical surface of enterocytes 
to increase the transfer of dietary iron from the lumen to enterocytes. Hepcidin levels are depressed in response to 
a reduction in the physiologic signals that maintain its production (e.g., increases in levels of iron-bound transferrin 
and in the iron content of the liver),2,18 to the increased activity of the inhibitor transmembrane protease, serine 6 
(TMPRSS6),23 to the reduction in levels of the activator bone morphogenetic protein 6 (BMP6), and to increased in-
hibition from erythropoietin-stimulated erythropoiesis. Ferroportin (FPN), which is no longer being degraded because 
of the low levels of hepcidin, exports the available iron across the enterocyte basal membrane and from macrophage 
stores17 to the circulation. Once stores are exhausted, levels of circulating iron decrease, even if absorption from the 
lumen is increased. Reduced levels of iron in the liver trigger increases in the synthesis of the iron carrier transferrin 
(referred to as apotransferrin when not bound to iron), further decreasing levels of iron-bound transferrin, the ligand 
of the transferrin receptor. Consequently, the uptake of iron from transferrin receptors by all cells and organs (e.g., 
skeletal muscles and the heart) is reduced.
Hepatocyte
Enterocyte
FPN
FPN
DMT1
Heart
Skeletal
muscle
↓Fe
↓Fe
+
↑HIF-2α
↑HIF-2α
EPO
↓Fe
↓Fe
↑Fe
Fe
Fe
↑Fe
↑TMPRSS6
ERFE?
Erythropoiesis
Erythroblasts
Spleen
macrophage
Kidney
Red 
cells
BMP6
BMP6
Fe
Hepcidin
ERFE?
Hepcidin
Hepcidin
TMPRSS6
↓
Hepcidin
Hepcidin
Hepcidin
Hepcidin
↓
Fe
↓Fe
↓Fe
Apotransferrin
Fe
↓Fe
Apotransferrin
Apotransferrin
All
organs
↓
organs
organs
↓
Fe
Fe
↓
↓
↓
↓
↓
↓
↓
↓
The New England Journal of Medicine 
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 Copyright © 2015 Massachusetts Medical Society. All rights reserved.

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1835

nism facilitates the absorption of iron (Fig. 1) 
and the release of iron from body stores. Intes-
tinal iron uptake from the gut lumen through 
divalent metal transporter 1 (DMT1) is increased 
by the activation of hypoxia-inducible factor 
2α.22 The degree of store repletion determines 
the rapidity with which iron deficiency develops 
in cases of blood loss or a drastic reduction in 
iron absorption. Hepatocytes appear to be a 
long-term reservoir for iron and release it more 
slowly than macrophages.

Poverty, malnutrition, and famine are self-explan-
atory causes of anemia in the multitude of peo-
ple living with iron deficiency in developing 
countries, especially children and pregnant 
women. In addition, a cereal-based diet decreas-
es iron bioavailability because phytates in grains 
sequester iron in a poorly absorbable complex. 
Other common causes in developing countries 
include hookworm infections and schistosomia-
sis, which cause chronic blood loss.14 Strict vegan 
and vegetarian diets, malabsorption, and chron-
ic blood loss resulting from heavy menstrual

losses are well-known causes of iron-deficiency 
anemia in developed countries (Table 1). Chron-
ic blood loss from the gastrointestinal tract, in-
cluding occult blood, especially in male patients 
and elderly patients, may reveal the presence of 
benign lesions, angiodysplasia, or cancer. The 
origin of obscure gastrointestinal blood loss,24 
especially from the small bowel, may be clari-
fied by means of video-capsule endoscopy, which 
is increasingly used when conventional workups 
for iron-deficiency anemia return negative re-
sults.25 Persons who donate blood regularly are 
also at risk for iron deficiency, and their iron 
levels should be monitored.
In rare forms of intravascular hemolysis, iron 
is lost in the urine, and iron deficiency then ag-
gravates anemia (e.g., in paroxysmal nocturnal 
hemoglobinuria). Anemia in endurance athletes 
may be due to hemolysis, blood loss, and often 
mild inflammation. Nonsteroidal antiinflamma-
tory drugs and anticoagulants may contribute to 
blood loss, and proton-pump inhibitors are a 
frequently overlooked cause of impaired iron 
absorption (Table 1).26

The simultaneous occurrence of multiple 
causes of iron deficiency is common. In develop-
ing countries, low iron intake combined with

Increased demand
Infancy, rapid growth (adolescence), menstrual blood loss, pregnancy (second and 
third trimesters), blood donation

Environmental
Insufficient intake, resulting from poverty, malnutrition, diet (e.g., vegetarian, vegan, 
iron-poor)

Decreased absorption
Gastrectomy, duodenal bypass, bariatric surgery, Helicobacter pylori infection, celiac 
sprue, atrophic gastritis, inflammatory bowel diseases (e.g., ulcerative colitis, 
Crohn’s disease)*

Chronic blood loss
Gastrointestinal tract, including esophagitis, erosive gastritis, peptic ulcer, diverticuli-
tis, benign tumors, intestinal cancer, inflammatory bowel diseases, angiodysplasia, 
hemorrhoids, hookworm infestation, obscure source
Genitourinary system, including heavy menses, menorrhagia, intravascular hemoly-
sis (e.g., paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia 
with cold antibodies, march hemoglobinuria, damaged heart valves, microangio-
pathic hemolysis)
Systemic bleeding, including hemorrhagic telangiectasia, chronic schistosomiasis, 
Munchausen’s syndrome (e.g, self-induced hemorrhages)

Drug-related
Glucocorticoids, salicylates, NSAIDs, proton-pump inhibitors

Genetic
Iron-refractory iron-deficiency anemia

Iron-restricted erythropoietic
Treatment with erythropoiesis-stimulating agents, anemia of chronic disease, chronic 
kidney disease*

*  Inflammatory conditions may be associated with iron deficiency. NSAIDs denotes nonsteroidal antiinflammatory drugs.

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intestinal infections with nematodes may result 
in severe anemia, especially in young children. 
The severity of iron deficiency is also associated 
with Ancylostoma duodenale (hookworm) load, ac-
cording to the results of real-time polymerase-
chain-reaction assays of fecal samples.27 In 
chronic schistosomiasis, blood losses combine 
with the anemia of inflammation.28 Patients 
with hypermenorrhea may also have concomi-
tant malabsorption of iron.29 In end-stage kid-
ney disease, iron-deficiency anemia results from 
blood loss during dialysis, reduced hepcidin clear-
ance, inflammation, and certain drugs (e.g., 
proton-pump inhibitors and anticoagulants). In 
elderly persons, the prevalence of anemia corre-
lates with advanced age and multiple related 
conditions, including iron deficiency,5 inflam-
matory disorders, decreased levels of erythropoi-
etin, and cancer.30 Obesity may be associated 
with mild iron deficiency because of subclinical 
inflammation, increased hepcidin levels, and de-
creased iron absorption.31 Some studies report a 
high prevalence of iron deficiency (30 to 50%) in 
patients with congestive heart failure,32,33 prob-
ably because of impaired iron absorption and 
inflammation: increased serum levels of hepci-
din have been reported in the early stages of 
disease but not during disease progression.34

Iron-deficiency anemia is usually acquired. How-
ever, the elucidation of systemic iron homeosta-
sis has led to the recognition of a rare autosomal 
recessive disorder, iron-refractory iron-deficiency 
anemia (IRIDA) (Online Mendelian Inheritance 
in Man [OMIM] number, 206200).35 Iron-defi-
ciency anemia is defined as “refractory” when 
there is an absence of hematologic response 
(an increase of <1 g of hemoglobin) after 4 to 
6 weeks of treatment with oral iron.29 IRIDA is 
caused by a mutation in TMPRSS6,36 the gene en-
coding transmembrane protease, serine 6, also 
known as matriptase-2, which inhibits the sig-
naling pathway that activates hepcidin (Fig. 1).37 
Loss-of-function mutations in TMPRSS6 reported 
in more than 50 families38,39 have led to consti-
tutively high production of hepcidin, which 
blocks the intestinal absorption of iron. This 
type of anemia is variable, more severe in chil-
dren, and unresponsive to treatment with oral

iron. Typical findings include a striking micro-
cytosis and extremely low transferrin saturation 
in the presence of normal or borderline-low 
ferritin levels and high hepcidin levels.38 The 
diagnosis ultimately requires sequencing of 
TMPRSS6. IRIDA represents less than 1% of the 
cases of iron-deficiency anemia seen in medical 
practice. However, knowledge of this condition 
is valuable to clinicians, since it clarifies how 
essential the suppression of hepcidin is (Fig. 1) 
to the body’s response to pharmacologic iron. 
IRIDA also suggests the existence of genetic 
susceptibility to iron deficiency. Variants of 
TMPRSS6 have been associated with the modula-
tion of serum hepcidin levels in individual per-
sons,40 the variation in iron levels in population 
studies,41,42 and even with iron-deficiency anemia 
in elderly Chinese women.43 It is possible that 
coexisting acquired factors explain the ethnic 
specificity of the latter association.
In most cases, iron resistance is due to disor-
ders of the gastrointestinal tract29 (Table 1). 
Partial or total gastrectomy or any surgical pro-
cedure that bypasses the duodenum can cause 
resistance to oral iron. Bariatric surgery, such as 
laparoscopic Roux-en-Y gastric bypass, which is 
performed in selected obese patients to reduce 
caloric intake and to correct diabetes, is an 
emerging cause of iron deficiency and anemia 
because the procedure effectively removes an ac-
tive iron absorption site from the digestive pro-
cess and increases gastric pH.44 The limited fol-
low-up data on patients who have undergone the 
procedure indicate that iron deficiency develops 
in up to 45%,45 particularly in women; lifelong 
nutritional monitoring and iron supplementa-
tion are advised.46 Helicobacter pylori infection de-
creases iron absorption (Table 1) because the 
microorganism competes with its human host 
for available iron, reduces the bioavailability of 
vitamin C, and may lead to microerosions that 
cause bleeding.47 Since it is estimated that half 
the world’s population is infected with H. pylori, 
clinicians should be aware of the possibility of 
infection and provide treatment in order to 
eradicate this source of iron-resistant iron-defi-
ciency anemia. The prevalence of celiac disease 
and its atypical manifestations, which include 
iron-deficiency anemia, are increasingly recog-
nized worldwide.48 In one study, screening for 
the prevalence of gluten sensitivity with the use 
of anti-transglutaminase antibodies uncovered

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1837

negligible incidence among iron-replete partici-
pants, whereas 2.5% of participants with iron 
deficiency had sensitivity to gluten.49 In another 
study of a series of patients with iron-refractory 
iron-deficiency anemia, 5% of participants had 
gluten sensitivity.29 These findings suggest that 
gluten sensitivity may be associated with iron-
refractory iron-deficiency anemia. Similarly, au-
toimmune atrophic gastritis, another rare cause 
of iron-refractory deficiency anemia, which re-
sults from an immune reaction against gastric 
parietal cells and intrinsic factor, should be 
considered as a possible albeit unlikely cause of 
iron-refractory microcytic anemia.29 In patients 
with inflammatory bowel disease, anemia may 
be iron-resistant, but it is multifactorial, often 
resulting from a combination of deficiencies in 
iron, folate, and vitamin B12, inflammation, and 
side effects from drug therapy.

Iron-deficiency anemia is chronic and frequently 
asymptomatic and thus may often go undiag-
nosed. Weakness, fatigue, difficulty in concen-
trating, and poor work productivity are nonspe-
cific symptoms ascribed to low delivery of 
oxygen to body tissues and decreased activity of 
iron-containing enzymes. The extent to which 
these nonhematologic effects of iron deficiency 
are manifested before anemia develops is un-
clear. Signs of iron deficiency in tissue are subtle 
and may not respond to iron therapy. Iron defi-
ciency has been reported to decrease cognitive 
performance and to delay mental and motor 
development in children.
Severe iron-deficiency anemia in pregnancy is 
associated with an increased risk of preterm la-
bor, low neonatal weight, and increased new-
born and maternal mortality. Iron deficiency 
may predispose a person to infections, precipi-
tate heart failure, and cause restless leg syn-
drome. In patients with heart failure, iron defi-
ciency has a negative effect on the quality of life, 
irrespective of the presence of anemia.50

The traditional laboratory measures and results 
used to determine iron status and iron defi-
ciency and related conditions (e.g., functional 
iron deficiency, iron-deficiency anemia, IRIDA,

and anemia of chronic diseases) are well estab-
lished (Table 2). Serum ferritin level is the most 
sensitive and specific test used for the identifica-
tion of iron deficiency (indicated by a level of 
<30 μg per liter). Levels are lower in patients 
with iron-deficiency anemia; a transferrin satu-
ration level of less than 16% indicates an iron 
supply that is insufficient to support normal 
erythropoiesis. However, in determining iron 
status, it is important to consider the whole pic-
ture rather than relying on single test results. 
Guidelines for the differential diagnosis of mi-
crocytic anemias have recently been reviewed 
elsewhere.11,53 The diagnosis of iron-deficiency 
anemia in the context of inflammation is chal-
lenging and cannot be determined on the basis 
of the results of a single test (Table 2): signifi-
cantly higher cutoff levels for ferritin are used to 
define iron-deficiency anemia accompanied by 
inflammation,3 with the best predictor being a 
ferritin level of less than 100 μg per liter. High-
er cutoff levels for ferritin are used in the diag-
nosis of iron deficiency in other conditions (e.g., 
<300 μg per liter for heart failure50 and for 
chronic kidney disease in the presence of a 
transferrin saturation level of less than 30%54). 
The assessment of iron stores through iron 
staining of bone marrow specimens obtained by 
means of biopsy is an option that is not used 
frequently. At present, no reliable test for hepci-
din levels is available.

Cautions and General Guidelines
Patients with iron-deficiency anemia should re-
ceive iron supplementation. Caution must be 
used in areas in which malaria is endemic be-
cause supplementation may reverse the poten-
tially protective effects of iron deficiency55 or 
increase the susceptibility to coinfections.56 In 
vitro studies have shown that the malaria para-
site Plasmodium falciparum is less efficient in infect-
ing iron-deficient erythrocytes than in infecting 
iron-replete erythrocytes, a protection that is re-
versed with iron supplementation.57 Some stud-
ies support the view that measurement of hepci-
din levels could help to determine the best time 
(e.g., the end of malaria season) to provide 
children in these regions with iron supplementa-
tion.58 Emerging data suggest that nonabsorbed 
iron could be harmful to patients because it

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1838

Table 2. Laboratory Tests for the Measurement of Iron Status in Adults.

Test
Iron  
Deficiency
Functional  
Iron Deficiency
Iron-Deficiency 
Anemia
IRIDA
Anemia of Chronic 
Diseases

Iron-Deficiency 
Anemia and 
Anemia of Chronic 
Diseases
Normal Value

Iron — μmol/liter
Low
Low–normal
Low
Low
Low
Low
10–30

Transferrin saturation — %
≥16
Low– normal
<16*
<10
Low–normal
Low–normal
>16 to <45

Ferritin — μg/liter
<30†
Normal
<10
Variable
>100‡
<100‡

Hemoglobin — g/dl
Normal
Normal
Low
Low
Low
Low

Mean corpuscular volume — fl
Normal
Normal
<80
Very low
Low–normal
Low
80–95

Mean corpuscular hemoglobin — pg
Normal
Normal
<27
Very low
Low–normal
Low
27–34

sTFR — mg/liter§
High
High
High
High
Low–normal
Variable
Varies¶

sTFR/log ferritin index‖
NA
NA
>2
NA
<1
>2
Varies¶

Hepcidin
Low
Low
Very low
Normal–high
High
Normal–high
Varies¶

Zinc protoporphyrin**
Normal
High
High
High
High
High
Varies¶

Reticulocyte hemoglobin content — pg††
<25
<29
Low
Low
Low
Low
31.2±1.6

Perl’s staining of bone marrow for iron
Negative
Variable
Negative
Positive
Strongly positive
Positive
Positive

*  The value for transferrin saturation in the diagnosis of iron-deficiency anemia is from Beutler and Waalen.51
†  The value for ferritin in the diagnosis of iron-deficiency anemia has a sensitivity of 92% and a specificity of 83% according to Goodnough et al.4
‡  The value for ferritin in the anemia of chronic disease and the combined value for the anemia of chronic disease and iron deficiency are from Weiss and Goodnough.3
§ 
 The value for the soluble transferrin receptor (sTFR), which is shed by the erythroblast membrane in serum, may be useful in the assessment of iron-deficiency anemia, but the meth-
ods used to measure sTFR have been not standardized.3
¶  Normal values vary according to the method of measurement used.
‖ 
 The sTFR/log ferritin index has been proposed to distinguish iron-deficiency anemia in the anemia of chronic disease from the anemia of chronic disease alone.3
**  The values for zinc protoporphyrin are used only in screening for or monitoring iron-deficiency anemia..9
††  Reduction of reticulocyte hemoglobin content is an early sign of functional iron deficiency.52

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1839

might modify the gut microbiota, increasing the 
concentration of intestinal pathogens.59

The benefit of treating iron deficiency before 
the development of anemia remains uncertain. A 
few small studies show that the administration 
of intravenous iron improves fatigue in women 
without anemia whose ferritin levels are in the 
iron-deficient range.60 Some studies have also 
suggested that oral iron supplementation bene-
fits physical performance in women of repro-
ductive age,61 but such studies have included a 
limited number of participants and are strik-
ingly heterogeneous.
Patients with severe iron-deficiency anemia 
that causes cardiovascular symptoms, such as 
heart failure or angina, should receive red-cell 
transfusions. This approach rapidly corrects not 
only hypoxia but also iron deficiency, since one 
unit of packed red cells provides approximately 
200 mg of iron.

Oral Iron Therapy
The administration of oral iron is a convenient, 
inexpensive, and effective means of treating 
stable patients. Among the myriad preparations 
on the market, iron sulfate is the most frequent-
ly used; gluconate and fumarate are also effec-
tive iron salts. The recommended daily dose for 
adults with iron deficiency is 100 to 200 mg of 
elementary iron and that for children is 3 to 6 
mg per kilogram of body weight of a liquid 
preparation; for both groups the supplement 
should be administered in divided doses without 
food. The addition of vitamin C may improve 
absorption. The low hepcidin levels in patients 
with iron-deficiency anemia ensure effective 
iron absorption and the rapid recovery of hemo-
globin levels; however, 3 to 6 months of treat-
ment are required for the repletion of iron stores 
and the normalization of serum ferritin levels. 
Long-term use of oral iron is limited by side ef-
fects, including nausea, vomiting, constipation, 
and metallic taste; these side effects are frequent 
and, although not severe, are often worrisome to 
patients. Although oral iron may cause dark 
stools, it does not produce false positive results 
on tests for occult blood. If treatment with oral 
iron fails, the reasons may include premature 
termination of treatment, lack of compliance 
with the regimen or discontinuation by the pa-
tient, or a truly refractory response to treatment. 
In the latter case, other, specific treatments,

such as the eradication of infection with H. py-
lori or the introduction of a gluten-free diet in 
patients with celiac disease, may restore the ca-
pacity for iron absorption and eliminate the 
need for supplementation in some patients.29 
There are no known markers that can be used to 
predict which patients will or will not have a 
response to oral iron therapy. The oral iron chal-
lenge test (in which 60 mg of oral iron is admin-
istered and serum iron levels are measured 1 to 
2 hours afterward) is rarely used since it has not 
been extensively validated. A pilot study showed 
that measurement of serum hepcidin levels 
could help to identify patients in whom a re-
sponse to oral iron is probable (those with low 
hepcidin levels) and those in whom it is not 
probable (those with normal or elevated hepci-
din levels).62 However, hepcidin tests are not 
routinely available for clinical use. Assessment 
of an early response to oral iron might also be 
useful in the treatment of iron-deficiency ane-
mia in patients with anemia of chronic disease. 
One study in patients with rheumatologic dis-

Iron intolerance or with low iron levels that are refractory to treatment (e.g.,  
after gastrectomy or duodenal bypass, with Helicobacter pylori infection,  
or with celiac disease, atrophic gastritis, inflammatory bowel disease, or  
genetically induced IRIDA*)

Need for quick recovery (e.g., with severe iron deficiency in the second or third 
trimester of pregnancy or with chronic bleeding that is not manageable 
with oral iron, as may occur in patients with congenital coagulation  
disorders)

Substitution for blood transfusions when not accepted by patient for religious 
reasons

Use of erythropoiesis-stimulating agents in chronic kidney disease

Anemia of chronic kidney disease (without treatment of erythropoiesis-stimu-
lating agents)

Persistent anemia after use of erythropoiesis-stimulating agents in patients 
with cancer who are receiving chemotherapy

Anemia of chronic disease unresponsive to treatment with erythropoiesis-
stimulating agents alone

Potential indication with insufficient supporting data

Transfusion-sparing strategy in surgical patients

*  Celiac disease or H. pylori infection should be considered if the anemia re-
mains refractory to treatment. IRIDA denotes iron-refractory iron-deficiency 
anemia.

Table 3. Indications for Parenteral Iron Therapy.

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1840

ease and iron-deficiency anemia showed that a 
change in the hemoglobin content of reticulo-
cytes (and in serum levels of iron and transferrin 
saturation) may predict the response to the admin-
istration of oral iron after 1 week of therapy.63

Parenteral Iron Therapy
The possibility of hypersensitivity reactions (in-
cluding anaphylaxis) to high-molecular-weight 
iron dextran has traditionally limited the indica-
tions for the intravenous administration of iron. 
Newly approved, safer iron formulations are 
modifying this clinical practice (Table 3). Be-
cause the use of intravenous iron circumvents 
the problem of iron absorption, it is more effec-
tive and increases hemoglobin levels more quick-
ly than oral iron.54,64,65 Another advantage is that 
in some patients the total dose required (up to 
1000 mg) can be provided in a single infusion 
(Table 4). The dose needed is calculated with 
this formula: body weight in kilograms × 2.3 × 
hemoglobin deficiency (target hemoglobin level 
− patient hemoglobin level) + 500 to 1000 mg iron 
for the repletion of iron stores. The cost of par-
enteral iron therapy is high, but the number of 
hospital or clinic visits that are required is sig-
nificantly decreased.67

Patients with malabsorption and genetic 
IRIDA38,39 may require intravenous iron. Intrave-
nous administration is also preferred when a 
rapid increase in hemoglobin level is required or 
when iron-deficiency anemia caused by chronic 
blood loss cannot be controlled with the use of 
oral iron, as is the case in patients with heredi-
tary hemorrhagic telangiectasia. Active inflam-

matory bowel disease is an emerging indication 
for the use of intravenous iron (Table 3); oral 
iron is not only ineffective but may also increase 
local inflammation.68

Intravenous iron is essential in the manage-
ment of anemia in patients with chronic kidney 
disease who are receiving dialysis and treatment 
with erythropoiesis-stimulating agents. The ad-
dition of iron supplementation may eliminate or 
delay the need for these agents in some patients 
with chronic kidney disease who are not receiv-
ing dialysis.6,69 Erythropoiesis-stimulating agents 
are also used in selected patients with low-risk 
myelodysplastic syndrome and in patients with 
cancer who are receiving chemotherapy: in these 
circumstances, iron supplementation is usually 
limited to patients with concomitant iron defi-
ciency or to those in whom there is no response 
to erythropoiesis-stimulating agents; intrave-
nous iron is preferred when high hepcidin levels 
create a condition that is refractory to supple-
mentation with oral iron.6 The way in which iron 
enhances the effect of erythropoiesis-stimulat-
ing agents is unclear. One hypothesis suggests 
that increased iron in macrophages leads to the 
overexpression of ferroportin by means of the 
iron-responsive element–iron-regulatory protein 
system, which enhances the mobilization of iron 
for use in erythropoiesis.4 Intravenous iron 
should be avoided in the first trimester of preg-
nancy because of the lack of data on safety70; it 
has an acceptable side-effect profile when used 
later in pregnancy.71

Studies of the use of parenteral iron therapy 
for conditions other than those mentioned are

Ferric gluconate (Ferlecit)
125 mg/10–60 min
250 mg/60 min

Iron sucrose (Venofer)
100–400 mg/2–90 min
300 mg/2 hr

Low-molecular-weight iron dextran 
(INFeD)†
100 mg/2 min
1000 mg/1–4 hr)

Ferumoxytol (Feraheme)†
510 mg/>1 min
510–1020 mg/15–60 min

Ferric carboxymaltose (Ferinject)†
750–1000 mg/15–30 min
750–1000 mg/15–30 min

Iron isomaltoside (Monofer)†‡
20 mg/kg of body weight/15 min
20 mg/kg of body weight/15 min

*  Data are adapted from Powers and Buchanan13 and Auerbach and Ballard66
†  Drugs that can be administered as a total dose in a single infusion.
‡  Iron isomaltoside is licensed for use only in Europe.

Table 4. Iron Preparations for Intravenous Use.*

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n engl j med 372;19 nejm.org May 7, 2015
1841

either limited or not controlled. A multicenter 
European trial of patients with iron deficiency 
and chronic heart failure showed that the use of 
intravenous iron supplementation led to im-
provements in physical performance, New York 
Heart Association functional class,50 and quality 
of life independently from the correction of ane-
mia72; more recently, 1 year of treatment was 
associated with a reduced risk of hospitaliza-
tion.73 However, since these results were based 
largely on subjective evaluation, larger and lon-
ger-term studies are required to assess the real 
benefit of administering iron to patients with 
heart failure.
The transient side effects of intravenous iron 
supplementation include nausea, vomiting, pru-
ritus, headache, and flushing; myalgia, arthral-
gia, and back and chest pain usually resolve 
within 48 hours, even after total dose adminis-
tration.74 Hypersensitivity reactions are rare,66,74 
as are severe or life-threatening reactions75; the 
pathophysiological features of these reactions 
are uncertain and might be exacerbated by re-
leased free iron,70,76 a phenomenon that does not 
occur with currently used formulations. Predis-
posing conditions are rapid infusions, a history

of atopy, and drug allergy. Practical recommen-
dations for minimizing risk70 include a slow in-
fusion rate, careful patient observation, and ad-
ministration by trained health care personnel in 
an environment with access to resuscitation fa-
cilities.75 The test dose may provide false reas-
surance; premedication with antihistamine is no 
longer advised because it may cause hypotension 
and tachycardia.70,75,76

Clinical trials are reassuring with regard to 
the efficacy and side-effect profile of intrave-
nous iron. Some concern persists with regard to 
the long-term biologic effects of iron and its 
effects on the generation of oxygen radicals, 
patient susceptibility to infections,54,66 and the 
potential such treatment would have to worsen 
conditions such as type 2 diabetes and other 
chronic metabolic disorders.77 Well-designed, 
randomized, controlled trials are needed to ver-
ify the long-term effects of intravenous iron 
supplementation.78 In the interim, intravenous 
iron should be used only when the benefits out-
weigh the risks.
No potential conflict of interest relevant to this article was 
reported.
Disclosure forms provided by the author are available with the 
full text of this article at NEJM.org.

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