Iron Deficiency Anaemia

Iron deficiency
anaemia
The right clinical information, right where it's needed
Last updated: Mar 05, 2020

Table of Contents
Summary 3
Basics 4
Definition 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Classification 5
Prevention 6
Primary prevention 6
Screening 7
Diagnosis 8
Case history 8
Step-by-step diagnostic approach 8
Risk factors 10
History & examination factors 12
Diagnostic tests 14
Differential diagnosis 20
Diagnostic criteria 22
Treatment 23
Step-by-step treatment approach 23
Treatment details overview 25
Treatment options 26
Emerging 32
Follow up 33
Recommendations 33
Complications 34
Prognosis 35
Guidelines 36
Diagnostic guidelines 36
Treatment guidelines 37
Evidence scores 39
References 40
Images 52
Disclaimer 53
Summary
◊ Iron deficiency anaemia (IDA) is the most common form of anaemia. Causes include decreased iron
intake, increased iron loss, and increased iron requirements.
◊ Clinical history, presentation, and findings include fatigue, pallor, dyspnoea on exertion, and pica.
◊ Blood tests reveal microcytic, hypochromic anaemia; low reticulocyte count.
◊ Other laboratory findings include low serum iron, increased total iron-binding capacity (TIBC), less
than 16% transferrin saturation, and low serum ferritin.
◊ Diagnosis of IDA requires investigation of the underlying cause.
◊ Treatment includes oral or intravenous iron replacement.

Iron deficiency anaemia Basics
Definition
The WHO defines anaemia as haemoglobin <130 g/L (13 g/dL) in men aged ≥15 years, <120 g/L (12 g/
dL) in non-pregnant women aged ≥15 years, and <110 g/L (11 g/dL) in pregnant women.[1] Iron deficiency
BASICS
anaemia (IDA) is the most common type of anaemia.[2] [3] Causes include decreased iron intake, increased
iron loss, and increased iron requirements. The cause is unknown in some cases.
Epidemiology
The global prevalence of anaemia is reported to be approximately 33%, and iron deficiency is the most
common cause.[2] [3]
The prevalence of IDA varies widely across different regions of the world, with the lowest prevalence in
higher income regions (e.g., North America and western Europe) and highest prevalence in lower income
regions (e.g., southern Asia and Carribean).[3] [5] [6] [7]
IDA is more common in young children (e.g., due to increased iron requirements during growth, and
inadequate dietary iron intake) and premenopausal women (e.g., due to increased iron loss through
menstrual bleeding or pregnancy).[6] [8] [9] [10] In the US, the prevalence of IDA is reported to be 3% in
infants aged 1 to 2 years; 3% to 5% in non-pregnant women aged 16 to 49 years; 2% in non-pregnant
women aged 50 to 69 years; and <1% in men aged 16 to 69 years (based on National Health and Nutrition
Examination Survey [NHANES] data from 1988 to 1994).[6] [8] In pregnant women aged 12 to 49 years, the
prevalence of IDA is reported to be 2.6% (based on NHANES data from 1999 and 2010).[9] Prevalence of
IDA in the first, second, and third trimesters is reported to be 5.3%, 12.7%, and 27.5%, respectively.[8] [9]
In non-pregnant women aged 15 to 49 years, the prevalence of IDA is reported to be 11.8% in non-Hispanic
black people, 8.5% in Mexican people, and 3% in non-Hispanic white people (based on NHANES data from
2007 to 2010).[9]
In the UK, an estimated 3% of men and 8% of women have IDA.[11]
Aetiology
IDA has many causes and is not an end diagnosis in and of itself. Diagnosis of IDA should prompt further
investigation to determine the cause, and to correct if possible.
Causes of IDA include:[4] [5]
• Decreased iron intake because of inadequate diet or impaired absorption (e.g., due to achlorhydria,
gastric surgery, coeliac disease, and pica)
• Increased iron loss because of menstrual bleeding (menorrhagia), gastrointestinal bleeding,
haemorrhoids, salicylate ingestion, peptic ulcer disease, hiatal hernia, diverticulosis, neoplasm,
ulcerative colitis, hookworm, milk allergy in infants, Meckel's diverticulum, schistosomiasis, trichuriasis,
blood donation, haemoglobinuria, self-induced bleeding, idiopathic pulmonary haemosiderosis,
Goodpasture's syndrome, hereditary haemorrhagic telangiectasia, angiodysplasia, disorders of
haemostasis, chronic renal failure and haemodialysis, or runner's anaemia
• Increased iron requirements of young children (e.g., due to growth, and inadequate dietary iron intake),
pregnancy, or lactation
• Unknown cause.
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Iron deficiency anaemia Basics
Blood loss is the principal cause of IDA. Rarely, in specific disorders (e.g., idiopathic pulmonary
haemosiderosis or paroxysmal nocturnal haemoglobinuria), the iron is deposited in tissues where it is
unavailable for haemoglobin production; however, total body iron stores may not be decreased.[12]
BASICS
Pathophysiology
Iron is required for the formation of haemoglobin, myoglobin, and haem enzymes (cytochromes), and is
therefore essential for red blood cell (RBC) production and cellular processes (e.g., cell metabolism, DNA
replication/repair, and cell cycle regulation).[13]
The body does not have a regulatory pathway for iron excretion.[14] Physiological iron loss occurs through
menstrual bleeding, sweating, skin desquamation, and urinary/faecal excretion.[14] Men and post-
menopausal women lose approximately 1 mg of iron daily, and menstruating women lose approximately 2
mg of iron daily.[15] Pregnancy results in a net loss of approximately 580 mg of iron during the gestation
period due to expansion of maternal RBC mass and growth of the fetus and placenta, with the highest loss
occurring in the third trimester.[9] [16] [17]
The body replenishes iron stores and maintains iron homeostasis by recycling iron from destroyed or
senescent RBCs, and regulating dietary iron intake and absorption.[8] Dietary iron is absorbed mostly in the
duodenum and jejunum, where it is transported by transferrin and stored in either ferritin or haemosiderin
forms.[18]
If iron stores are depleted because more iron is lost or used than can be absorbed, then haemoglobin
formation and RBC production are impaired. This results in IDA, which is characterised by hypochromic and
microcytic RBCs. Symptoms of IDA, such as fatigue, low energy level, and dyspnoea on exertion, occur due
to impaired RBC production and decreased oxygen-carrying capacity.[13]
Classification
Iron deficiency and related disorders[4]
There are four major categories in the causes of iron deficiency leading to IDA:
1. Decreased iron intake because of inadequate diet or impaired absorption

2. Increased iron loss because of gastrointestinal bleeding, menorrhagia, blood donation,
haemoglobinuria, self-induced bleeding, idiopathic pulmonary haemosiderosis, Goodpasture's
syndrome, hereditary haemorrhagic telangiectasia, angiodysplasia, disorders of haemostasis, chronic
renal failure and haemodialysis, or runner's anaemia
3. Increased iron requirements because of infancy, pregnancy, or lactation
4. Unknown cause.
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Mar 05, 2020.
5
Iron deficiency anaemia Prevention
Primary prevention
Infants and children
The WHO recommends delayed umbilical cord clamping to improve iron status and health outcomes in
infants.[39] Delayed cord clamping has been shown to reduce the risk of anaemia in infants at high risk for
IDA, compared with early clamping.[40]
The WHO also recommends routine iron supplementation in infants and young children living in areas where
anaemia is highly prevalent.[41]
Systematic reviews report that use of iron-fortified foods (including micronutrient fortification) and iron
supplementation in infants and primary school children (including those in low-income or middle-income
countries) can improve haematological outcomes and reduce the risk of iron deficiency and anaemia.[42] [43]
[44] [45] [46]
Long-term use of enteral iron supplementation (≥8 weeks) in preterm and low birthweight infants was
associated with reduced risk of iron deficiency and anaemia in one review.[47] Increased mean corpuscular
volume and improved cognitive outcomes have been reported in healthy exclusively breastfed infants
receiving daily iron supplementation, but there was no effect on IDA and it was associated with slower
PREVENTION
growth.[48]
Malaria-endemic regions
There are reports that routine iron supplementation in preschool children in malaria-endemic areas
may increase the risk of malaria and death.[5] [49] However, a Cochrane review reported that iron
supplementation in malaria-endemic areas with appropriate malaria prevention or management services
does not increase the clinical risk of malaria.[50] If malaria is prevalent, then iron supplementation should be
given concurrently with public health measures to prevent, diagnose, and treat malaria.[41] [51]
The effects of iron on malaria are still unclear.[52]
Women of reproductive age
The WHO recommends oral iron supplementation to prevent anaemia in:[53] [54] [55]
• Pregnant women living in areas where anaemia in pregnancy is highly prevalent

• Menstruating women and girls living in areas where anaemia is highly prevalent
• Postpartum women living in areas where gestational anaemia is a public health concern (iron
supplementation should be given with or without folic acid for 6 to 12 weeks following delivery).
The Centers for Disease Control and Prevention (CDC) recommends universal iron supplementation
during pregnancy to meet increased iron demands.[8] However, the US Preventive Services Task Force
(USPSTF) and the British Society for Haematology found insufficient evidence to recommend routine iron
supplementation in pregnant women.[56] [57]
Systematic reviews report that use of daily oral iron supplementation during menstruation or pregnancy can
improve haematological outcomes and reduce the risk of iron deficiency and anaemia.[58] [59] [60] [61]
[62] Intermittent iron supplementation during menstruation or pregnancy has similar efficacy to daily iron
supplementation, although intermittent supplementation during pregnancy is more likely to result in mild
anaemia near-term.[63] [64]
A Cochrane review reported no difference in maternal outcomes (including maternal anaemia in the third
trimester) with iron-containing multiple-micronutrient (MMN) supplementation during pregnancy compared
with iron supplementation (with or without folic acid).[65] Use of MMN supplementation may be beneficial in
low- to middle-income countries where micronutrient deficiencies are common in women of reproductive age.
In low-income postpartum women, iron supplementation has been shown to reduce the risk of anaemia.[66]
Iron deficiency anaemia Prevention
Screening
Centers for Disease Control and Prevention (CDC)
The CDC recommends periodic screening for anaemia with haemoglobin checks among high-risk
populations of infants, preschool children, pregnant women, and women of childbearing age.[8]
US Preventive Services Task Force (USPSTF)

The USPSTF has concluded that there is insufficient evidence to recommend routine screening for IDA in
pregnant women and in children aged 6 to 24 months.[56] [90] [91]
American Academy of Family Physicians (AAFP)

The AAFP concludes that there is insufficient evidence to recommend routine screening for IDA in pregnant
women and in children aged 6 to 24 months.[92]
PREVENTION
7
Iron deficiency anaemia Diagnosis
Case history
Case history #1
A 25-year-old woman presents with a history of fatigue, ice craving, and dyspnoea upon exertion. She has
three children. She did not tolerate antenatal vitamins during pregnancy, because of nausea. Examination
reveals pallor and spooning of her nails. Vital signs are normal. There is no lymphadenopathy or
hepatosplenomegaly.
Case history #2
A 68-year-old man presents with fatigue and dark stools. On examination his vital signs are normal, but he
is pale and has a rectal mass. Biopsy of the rectal mass reveals adenocarcinoma.
Step-by-step diagnostic approach

Anaemia should be considered in patients presenting with fatigue, low energy level, pallor, or dyspnoea on
exertion, as well as in children with growth impairment. Universal risk factors include pregnancy, vegetarian/
vegan diet, menorrhagia, hookworm, haemodialysis, coeliac disease, gastrectomy/achlorhydria, and non-
steroidal anti-inflammatory drug use.
Clinical evaluation
Key factors in the history specific to IDA include unusual cravings for ice or non-food items (i.e., pica)
and restless legs syndrome. Physical examination findings include glossitis, angular stomatitis, and nail
changes (e.g., thinning, flattening, spooning). Non-specific findings on history and physical examination
include dyspnoea, fatigue, pallor, dysphagia, exercise intolerance, impaired muscular performance,
growth impairment, gastric difficulties, hair loss, and cognitive or behavioural issues.
DIAGNOSIS
Initial laboratory evaluation with full blood count (FBC) and

peripheral smear
Initial laboratory testing should include an FBC (including haemoglobin and haematocrit, platelet count,
mean corpuscular volume [MCV], mean corpuscular haemoglobin [MCH], mean corpuscular haemoglobin
concentration [MCHC], red cell distribution width) with peripheral smear, reticulocyte count, and an iron
profile.
The blood count and smear will show a microcytic (low MCV), hypochromic (increased central pallor)
anaemia.
[Fig-1]
A microcytic hypochromic anaemia can also be seen in thalassaemia and other causes of anaemia;
therefore, an iron profile evaluation is required to identify iron deficiency as the cause of anaemia. A
reticulocyte count is essential to the work-up of all anaemias. It relates the number of young red cells
being produced and released by the bone marrow. Reticulocyte count is low in IDA.
Iron profile evaluation
The following iron profile is consistent with IDA:[12]
• Low serum iron

• Increased total iron-binding capacity (TIBC)
• Transferrin saturation less than 16%
• Low serum ferritin (less than 12 nanograms/mL is generally considered diagnostic of IDA, but
thresholds vary between guidelines).[67]
Patients with this iron profile do not require further iron tests.
Comments on laboratory evaluation

Many of these tests have variability and can be affected by other disorders. For example, ferritin, an acute
phase reactant, can be increased in patients with infection or chronic disease (e.g., cancer, autoimmune
disorders), which may complicate diagnosis. The transferrin receptor to ferritin index can help diagnose
IDA in these patients.[68] [69] Transferrin receptor is increased in iron deficiency and has a high sensitivity
and specificity for IDA.[68] [69] Bone marrow biopsy is the most sensitive and specific test for IDA, but is
not necessary in most cases and is not completely free of error.[4] [12] It is usually reserved for patients
with unclear serum studies in order to differentiate IDA from anaemia of chronic disease.
Follow-up clinical evaluation

The underlying cause of IDA must always be evaluated.
• Coeliac serology is recommended at initial presentation to evaluate for coeliac disease.[70] If

coeliac serology is positive or coeliac disease is suspected, it should be confirmed with small-bowel
biopsy.[70]
• Urinalysis is done routinely in all patients to evaluate blood loss from the renal tract.
• Testing for Helicobacter pylori infection should be carried out in all patients at initial presentation.
A positive test (i.e., presence of IgG antibodies or faecal antigen associated with H pylori ) should
be confirmed with a urease breath test or endoscopy with biopsy.[71]
DIAGNOSIS
• Testing for autoimmune gastritis should be carried out if autoimmune gastritis is suspected.
Patients with a positive test (i.e., presence of antiparietal cell or intrinsic factor antibodies, and
elevated gastrin) should be referred for endoscopic evaluation.[71]
• If the patient has any upper or lower gastrointestinal (GI) symptoms, such as nausea, dyspepsia,
or change in bowel habits, an upper GI endoscopy (gastroscopy) or lower GI endoscopy
(colonoscopy) is indicated as an initial evaluation depending on the symptoms. If the patient is
asymptomatic, both upper and lower GI endoscopy are indicated.
• GI examination is important if there is no overt blood loss or obvious cause. This can include
upper GI endoscopy with small-bowel biopsy, lower GI endoscopy, or barium enema to exclude
GI malignancies. All men (without history of obvious blood loss from an area other than the GI
tract), and all women who are post-menopausal, aged >50 years, or have a significant colon cancer
history in the family, should be evaluated with upper and lower GI endoscopy.[70]
• A rectal examination is important and can be done at the same time as lower GI endoscopy. The
presence of haemorrhoids as an overt site of bleeding does not preclude further GI examination,
which should be performed to look for other proximal lesions (e.g., a neoplasm) in the GI tract.[72]
• Double contrast barium enema and sigmoidoscopy can be done if colonoscopy is not available or
suitable for the patient.[70]
9
• Faecal occult blood tests are generally not useful in evaluation of IDA.[70] If a patient has
already been shown to have iron deficiency, a site for potential bleeding must be sought through
endoscopy. A faecal occult blood test may, however, be useful in frail patients to screen for GI
bleeding to avoid unnecessary invasive testing (e.g., endoscopy).[73]
• Small-bowel biopsy is advised during upper GI endoscopy (if done), regardless of coeliac serology
result.[70] However, it may not be recommended in all patients. For example, if a large bleeding
source on colonoscopy is found, then small-bowel biopsy is likely to be of less value. Its use should
be determined by the gastroenterologist.
• IDA in premenopausal women is not investigated further with GI endoscopy unless the patient is
>50 years old; has GI symptoms or a strong family history; or has not responded to iron therapy
and resolution of possible other causes of iron loss such as menorrhagia, inadequate intake, and
blood donation.[70] Referral to a gynaecologist may be required for evaluation of vaginal causes of
bleeding.
Emerging tests
Emerging tests include urinary hepcidin, the use of which is still being evaluated in research settings;
however, initial studies show it may be able to differentiate between IDA and anaemia of chronic
disease.[74] Percentage of hypochromic erythrocytes, such as decreased MCH, is a late finding in IDA
and its manual calculation can be time consuming. In contrast, the reticulocyte haemoglobin content
decreases within the first few days of IDA. This appears to have a high sensitivity but questionable
specificity and is not widely available.[75] Erythrocyte protoporphyrin is the immediate precursor
of haemoglobin and its levels increase when there is insufficient iron available for haemoglobin
production.[8]
Risk factors
Strong
pregnancy
DIAGNOSIS
• Pregnancy increases iron requirements due to expansion of maternal red blood cell mass and growth
of the fetus and placenta.[16] [17] This results in a net loss of approximately 580 mg of iron during the
gestation period, with the highest loss occurring in the third trimester.[16] [17]
• In the US, the prevalence of IDA in pregnant women aged 12 to 49 years is reported to be 2.6%
(based on National Health and Nutrition Examination Survey data from 1999 to 2010).[9] Prevalence
of iron deficiency is reported to be 5.3%, 12.7%, and 27.5% in the first, second, and third trimesters,
respectively.[9]
vegetarian and vegan diet

• In a German study, approximately 40% of vegans aged 19 to 50 years were iron deficient.[19]
• A systematic review reported lower serum iron levels in adult vegetarians compared with adult non-
vegetarians (-0.53 micromol/L [-2.97 microgram/dL]).[20]
• Dietary iron exists in two forms: haem iron and non-haem iron. Vegetarian and vegan diets contain
non-haem iron, which is not as easily absorbed as haem iron found in meat.[21]
menorrhagia
• Menstrual iron loss (approximately 2 mg daily during menstruation) is inversely related to iron status
as measured by ferritin.[15] [22] Therefore, any bleeding disorder (e.g., von Willebrand's disease) or
disease (e.g., fibroids) that can lead to menorrhagia can be considered a risk factor for IDA.
hook worm infestation

• Although hookworm is not common in the US, it can be a frequent cause of blood loss in other
countries and has been linked to iron deficiency.[23]
haemodialysis
• Patients on haemodialysis are frequently iron deficient secondary to a combination of blood loss
related to dialysis and poor oral iron absorption.[24] Furthermore, iron deficiency is a frequent cause
of erythropoietin resistance in this population. Weekly low-dose iron in haemodialysis patients
(even if iron-replete) may stabilise iron and haemoglobin levels, and allow for erythropoietin dose
reduction.[25]
coeliac disease
• IDA is reported in up to 46% of cases of subclinical coeliac disease and may be the presenting
feature.[26]
gastrectomy/achlorhydria
• Gastric acid facilitates iron absorption. Patients with achlorhydria and those who have had a
gastrectomy are at increased risk for IDA due to low or absent gastric acid production.[27]
• Long-term follow-up of patients after gastrectomy showed a high rate of iron deficiency (up to 90%),
which appears to correct with iron supplementation.[28] [29]
non-steroidal anti-inflammatory drug (NSAID) use

• NSAID use has been shown to cause stomach and duodenal ulcers (22% vs 12% in non-users), and
small intestinal ulcers (8.4% vs 0.6% in non-users), which can lead to chronic gastrointestinal bleeds
DIAGNOSIS
and IDA.[29]
Weak
black women and Mexican women
• In the US, the prevalence of IDA among non-pregnant females aged 15 to 49 years is reported to
be 11.8% in non-Hispanic black people, 8.5% in Mexican people, and 3% in non-Hispanic white
people (based on National Health and Nutrition Examination Survey data collected between 2007 and
2010).[9]
low socioeconomic status postnatal

• Postnatal IDA has been reported among women from low-income populations in the US.[30] [31]
obesity
• Risk of iron deficiency is higher in overweight and obese children and adolescents, likely due to
chronic inflammation rather than dietary factors.[32] Childhood and adolescent obesity (body mass
index above 85th percentile) carries an odds ratio of 2.0 to 2.3 for IDA.[33]
11
Helicobacter pylori infection
• Studies have found an association between H pylori and IDA.[34] [35] In one US-based study,
H pylori infection was associated with a 40% increased prevalence of iron deficiency.[35] It is
unclear how H pylori infection leads to IDA, but possible mechanisms include poor iron absorption
subsequent to acid suppression, and blood loss related to gastritis or ulcer disease.[36] IDA appears to
decrease after eradication of H pylori infection.[37] [38]
History & examination factors

Key diagnostic factors
fatigue (common)
• The relation between fatigue and anaemia is unclear.[4] Fatigue does not appear to be increased in
patients with mild-to-moderate anaemia (haemoglobin from 80 to 120 g/L [8 to 12 g/dL]) and treatment
of this range of anaemia does not necessarily lead to improvements in fatigue. However, patients with
haemoglobin below 80 g/L (8 g/dL) may have a component of fatigue that will correct with correction of
their anaemia.
dyspnoea on exertion (common)

• Dyspnoea may occur due to impaired red blood cell production and decreased oxygen-carrying
capacity.
pica (common)
• Pica is the abnormal craving or appetite for non-food substances, such as dirt, ice, paint, or clay. It has
been reported in up to 55% of patients with IDA.[76] Ingestion of some materials, such as clay, has
chelating effects, which can impair the absorption of iron. These cravings correct within 2 weeks of
iron replacement.
restless legs syndrome (common)

DIAGNOSIS
• Iron deficiency and IDA are known causes of restless legs syndrome, and treatment of the iron
deficiency often leads to alleviation of these symptoms.[77]
nail changes (common)

• Typical nail changes occur in a stepwise fashion of thinning, flattening, and then spooning of the nails
(koilonychia); however, spooning is rare. Approximately 28% of patients have some nail changes.[4]
• Chronic exposure to hot soap suds or caustic chemicals may also give rise to these nail changes.
dysphagia (uncommon)
• Approximately 7% of patients may complain of a gradual onset of swallowing difficulties with
discomfort sharply located in the area of the cricoid cartilage consistent with Plummer-Vinson
syndrome.[4] This may require invasive procedures for management.
Other diagnostic factors

impaired muscular performance (common)
• Many measures of muscular performance, such as total exercise time, maximal work load, heart rate,
and serum lactate levels after exercise, are impaired by IDA and correct with iron replacement.[4]
glossitis and angular stomatitis (common)
• Glossitis with soreness or burning of the tongue with loss or atrophy of papillae can occur.
Approximately 50% of patients may have some changes. These resolve after 1 to 2 weeks of iron
replacement therapy.[4] Patients can also have angular stomatitis with sores in the corners of the
mouth.
gastric difficulties (common)

• Gastric biopsies in patients with iron deficiency are much more likely to show gastritis (75%) than in
patients without iron deficiency (29%). Patients can also have absent or reduced acid secretion in the
stomach (achlorhydria).[4]
hair loss (common)

• Associated with iron deficiency, mostly in women.[78] [79] However, this association is controversial
because the evidence is unclear.
rectal lesion on examination (uncommon)

• Blood loss from the lower gastrointestinal tract may be caused by a rectal lesion, such as
haemorrhoids or a neoplasm.
growth impairment (uncommon)

• Iron deficiency in infancy can lead to growth impairment, which is corrected with iron replacement.[4]
cognitive and behavioural impairment (uncommon)

• Cognitive and behavioural impairment, especially attention deficits, have been noted in children with
IDA.[4] [13] These appear to correct with iron replacement. However, there remains tremendous
debate in this area.[80] [81]
heart failure (uncommon)

• High-output heart failure can be seen in patients with severe anaemia, especially with a haemoglobin
DIAGNOSIS
less than 50 g/L (5 g/dL). This can be reversed with iron replacement, and may not require specific
treatment. Caution should be used in giving transfusions in this setting because of the risk of fluid
overload.[82]
recurrent infections (uncommon)

• Iron is necessary for proper neutrophil functioning and there are some studies to suggest that
infection-fighting capacity is decreased in patients with iron deficiency. However, further study is
required before a definite connection can be made.[4]
13
Diagnostic tests
1st test to order
Test Result
haemoglobin and haematocrit WHO defines anaemia
as: haemoglobin <130 g/L
• It is reasonable to use the lower limit of normal for the individual
(13 g/dL) in men aged ≥15
laboratory.[70] A low haemoglobin or haematocrit will establish the
years; <120 g/L (12 g/dL)
presence of anaemia.
• Anaemia is a late manifestation of iron deficiency but is a requirement in non-pregnant women
aged ≥15 years; and <110
for the diagnosis of IDA. It has low specificity.
g/L (11 g/dL) in pregnant
women
platelet count normal or elevated

• Platelet count is commonly reported as part of the FBC.
• Variable sensitivity and specificity.[83]
MCV <80 fL
• This is routinely reported as part of the FBC and is calculated as
haematocrit (%) × 10/red blood cell count (× 10⁶/microL). MCV <80 fL
is considered microcytic.
• Iron deficiency is still considered a potential cause of anaemia unless
the MCV is >95 fL, because this cutoff has a sensitivity of 97.6%.[84]
• A low MCV is encountered in a number of different diseases and so
is not specific for IDA.[75]
MCH low (<27.5 picograms/red
cell)
• This is a measurement of the haemoglobin mass per cell and is
calculated from findings on the FBC as Hb (g/dL) × 10/red blood cell
count (× 10⁶/microL). A value less than 27.5 picograms/red cell is
considered low.
• Medium sensitivity and specificity.[85]
MCHC low (<295 g/L [<29.5 g/dL])
DIAGNOSIS
• This is a measurement of the haemoglobin concentration per cell

corrected for the haematocrit and is calculated from findings on the
FBC as haemoglobin (g/dL) × 100/haematocrit (%).
• Medium sensitivity and specificity.[85]
red cell distribution width (RDW) >14.6%
• The RDW is the coefficient of variation in red cell volume. Increased
RDW can be an early finding in IDA even before a change appears in
the MCV.
• An increased RDW has a sensitivity of 90% to 100% for IDA,
but a specificity of only 50% to 70% in distinguishing it from
thalassaemia.[4]
peripheral blood smear microcytic, hypochromic
pencil red cells
• The peripheral smear of IDA contains small, pale red cells with
anisopoikilocytosis (variation in size and shape) and pencil cells.
• Changes on the peripheral smear may be seen before changes in
MCV. Sensitivity and specificity varies by experience.
[Fig-1]
reticulocyte count low
Test Result
• Reticulocytes are the youngest population of red cells.
• Reticulocyte count is low in IDA because the bone marrow does not
have sufficient iron to produce red cells.
• High sensitivity, low specificity.
serum iron decreased
• The serum iron level measures the amount of metal bound to
transferrin for transport.
• Values can vary greatly between laboratories, and values from the
same individual performed at the same laboratory can vary as much
40% from day to day, partly because of diurnal variation.[4]
total iron-binding capacity (TIBC) increased
• TIBC is an indirect measure of the amount of iron that transferrin will
bind.
• Values can vary greatly between laboratories and there is great
overlap in patients with iron deficiency and normal patients.[4]
transferrin saturation <16%
• Transferrin saturation = serum iron × 100/total iron-binding capacity
(TIBC).
• Values of transferrin saturation are more reliable between
laboratories than are iron and TIBC values on their own, because
sources of error cancel each other out. Once the transferrin
saturation falls below 16%, the decreased supply of iron limits red
blood cell production.[4] Among non-pregnant women of childbearing
age, this has a sensitivity of 20% and a specificity of 93%.[8]
serum ferritin low (<12 nanograms/mL
is generally diagnostic of
• This is an indirect yet quantitative and non-invasive measure of
IDA, but thresholds vary
iron stores. Ferritin is an intracellular iron storage protein but small
between guidelines)
amounts are secreted into plasma.[4]
• A serum ferritin <45 nanograms/mL has a sensitivity of 85% and a
specificity of 92% and a likelihood ratio of 11 for the diagnosis of
IDA.[84]
DIAGNOSIS
• A level between 45 and 100 nanograms/mL has a sensitivity of 9.4%
and a specificity of 80% and a likelihood ratio of 0.5.
• A level >100 nanograms/mL effectively rules out iron deficiency with
a sensitivity of 5.5%, specificity of 29%, and likelihood ratio of 0.1.[84]
• In a paper evaluating a clinical guideline for the diagnosis and
management of IDA, it is recommended that serum ferritin level be
measured on all patients with anaemia and an MCV ≤95 fL.
• For ferritin ≤45 nanograms/mL panendoscopy of the gastrointestinal
tract recommended.
• For ferritin ≥100 nanograms/mL other causes of anaemia were
suggested.
• For ferritin values in between, empiric iron supplementation or bone
marrow biopsy were recommended. Institution of this guideline led to
an increase in the work-up for IDA and an increase in the number of
serious gastrointestinal lesions discovered.[84]
coeliac serology if positive, coeliac disease
is likely
• Coeliac serology is recommended at initial presentation to evaluate
for coeliac disease.[70]
• If coeliac serology is positive or coeliac disease is suspected, it
should be confirmed with small-bowel biopsy.[70]
15
Test Result
urinalysis blood in the urine may
indicate blood loss is
• Urinalysis is done routinely in all patients to evaluate blood loss from
from the renal tract
the renal tract.
• Renal tract malignancy is found in about 1% of patients presenting
with IDA.[70]
Helicobacter pylori testing if positive, H pylori is
likely
• Testing for H pylori infection should be carried out in all patients at
initial presentation. A positive test (i.e., presence of IgG antibodies or
faecal antigen associated with H pylori ) should be confirmed with a
urease breath test or endoscopy with biopsy.[71]
DIAGNOSIS
Other tests to consider
Test Result
urease breath test if positive, suggestive of
the presence of H pylori
• Rapid response diagnostic procedure used to identify H pylori
infection if initial H pylori testing (IgG antibodies or faecal antigen) is
positive.
autoimmune gastritis testing if positive, suggestive of
an autoimmune aetiology
• Testing for autoimmune gastritis should be carried out if autoimmune
of gastritis
gastritis is suspected. Patients with a positive test (i.e., presence of
antiparietal cell or intrinsic factor antibodies, and elevated gastrin)
should be referred for endoscopic evaluation.[71]
upper gastrointestinal (GI) endoscopy (gastroscopy) evidence of gastritis (e.g.,
salicylate ingestion),
• If the patient has any upper or lower GI symptoms, such as
angiodysplasia, peptic
nausea, dyspepsia, or change in bowel habits, an upper or lower GI
ulcer disease, hiatal
endoscopy is indicated depending on the symptoms. If the patient is
hernia, or neoplasm may
asymptomatic, both upper and lower GI endoscopy are indicated.
be found
• GI examination is important if there is no overt blood loss or obvious
cause. All men (without history of obvious blood loss from an area
other than the GI tract), and all women who are post-menopausal,
aged >50 years, or have a significant colon cancer history in the
family, should be evaluated with upper and lower GI endoscopy.[70]
small-bowel biopsy features of coeliac disease
if present
• Small-bowel biopsy is advised during upper gastrointestinal
endoscopy (if done), regardless of coeliac serology result.[70]
However, it may not be recommended in all patients. For example, if
a large bleeding source on colonoscopy is found, then small-bowel
biopsy is likely to be of less value. Its use should be determined by
the gastroenterologist.
lower gastrointestinal (GI) endoscopy (colonoscopy) haemorrhoids,
diverticulosis, ulcerative
• If the patient has any upper or lower GI symptoms, such as
colitis, neoplasm, or
DIAGNOSIS
nausea, dyspepsia, or change in bowel habits, an upper or lower GI
Meckel's diverticulum may
endoscopy is indicated depending on the symptoms. If the patient is
asymptomatic, both upper and lower GI endoscopy are indicated. be found
• GI examination is important if there is no overt blood loss or obvious
cause. All men (without history of obvious blood loss from an area
other than the GI tract), and all women who are post-menopausal,
aged >50 years, or have a significant colon cancer history in the
family, should be evaluated with upper and lower GI endoscopy.[70]
• Rectal examination is important, and can be done at the same time
as lower GI endoscopy. Blood loss from the lower GI tract may be
caused by a rectal lesion, such as haemorrhoids or a neoplasm.
• The presence of haemorrhoids as an overt site of bleeding does not
preclude further GI examination, which should be performed to look
for other proximal lesions (e.g., neoplasms) in the GI tract.[72]
double contrast barium enema and sigmoidoscopy diverticulosis, ulcerative
colitis, or neoplasm may
• Can be done if colonoscopy is not available or suitable for the
be found
patient.[70]
transferrin receptor-ferritin index high ratio of transferrin
receptor to log ferritin
• Transferrin receptors are the membrane-binding sites for circulating
transferrin-bound iron leading to uptake into the cell. The soluble
17
Test Result
transferrin receptor is a truncated form found in the serum bound
to transferrin. Transferrin receptor synthesis is stimulated by iron
deficiency.[68]
• This index has a very high sensitivity and specificity for IDA with an
area under the curve of the receiver operator curve of 1.0.[69]
• Transferrin receptor-ferritin index can help diagnose IDA in patients
with infection or chronic disease (e.g., cancer, autoimmune
disorders).
bone marrow biopsy absent iron stores
• Haemosiderin in the bone marrow can be quantitated by assessing
these golden-yellow refractile granules on an unstained bone marrow
slide or by using Prussian blue staining. This staining is graded from
0 to 6+ by an experienced pathologist.[4]
• Bone marrow biopsy is considered the most specific and sensitive
test for IDA diagnosis but is not completely free of error.[4] [12] It is
usually reserved for patients with unclear serum studies in order to
differentiate IDA from anaemia of chronic disease.
monitored trial of iron rise in haemoglobin of 20
g/L (2 g/dL) in 4 weeks with
• Oral iron supplements given at 180 to 220 mg elemental iron given
iron supplementation
per day.
• High specificity, medium sensitivity.
faecal occult blood tests may be positive, requiring
further testing (e.g.,
• Faecal occult blood tests are generally not useful in evaluation of
endoscopy)
IDA.[70] If a patient has already been shown to have iron deficiency,
a site for potential bleeding must be sought through endoscopy.
• A faecal occult blood test may, however, be useful in frail patients to
screen for gastrointestinal bleeding to avoid unnecessary invasive
testing (e.g., endoscopy).[73]
DIAGNOSIS
Emerging tests
Test Result
urinary hepcidin low
• Initial studies suggest that urinary hepcidin is able to differentiate
between IDA and anaemia of chronic disease.[74] Serum hepcidin
does not correlate with disease state.
• The usefulness of urinary hepcidin is still being evaluated in research
settings.
percentage of hypochromic erythrocytes increased percentage of
• This could be calculated manually but would be very time-intensive. It hypochromic erythrocytes
can also be calculated in selected haematology analysers, which are (>5%)
not widely available. As with decreased MCV, this is a late finding in
IDA.[75]
reticulocyte haemoglobin content low (<28 picogorams)
• Reticulocyte haemoglobin content shows the amount of available iron
for erythropoiesis in the previous 3 to 4 days, and is an early indicator
of iron status.[86]
• Reticulocyte haemoglobin content decreases within the first few days
of IDA.
• This appears to have a high sensitivity and questionable specificity
but is not widely available.[75] Patients with other causes of high
MCV or thalassaemia may have false-normal values.
erythrocyte protoporphyrin >80 mmol/mol
• Erythrocyte protoporphyrin is the immediate precursor of
haemoglobin and its levels increase when there is insufficient iron
available for haemoglobin production.[8] Zinc protoporphyrin is a
product of abnormal haem synthesis. An elevated level is found in
patients with IDA and in patients with anaemia of chronic disease.[87]
• Results can be falsely elevated with lead toxicity or high bilirubin.[75]
In children and adolescents aged 6 months to 17 years, this has an
estimated sensitivity of 42% and specificity of 61%.[8]
DIAGNOSIS
19
Differential diagnosis
Condition Differentiating signs / Differentiating tests

symptoms
Anaemia of chronic • Signs and symptoms of • FBC and peripheral smear:
disease underlying chronic disease anaemia, hypochromia,
(e.g., infection, cancer, microcytosis, anisocytosis,
autoimmune disease, kidney and poikilocytosis are less
disease). pronounced than in IDA.
• In 80% of cases, anaemia
of chronic disease
is normocytic and
normochromic. However, in
20% of cases it can present
as a microcytic, hypochromic
anaemia similar to IDA.
• Ferritin is often elevated in
patients with anaemia of
chronic disease.[74]
• Anaemia of chronic disease
has a normal transferrin
receptor assay.[74]
Disorders of globin • Patients with severe • FBC: often more severe

synthesis (thalassaemias, thalassaemia are usually microcytosis than expected
haemoglobin E, transfusion dependent from for the degree of anaemia.
haemoglobin C, unstable childhood and therefore • Haemoglobin: usually
haemoglobins) diagnosed early. Patients reduced.
with thalassaemia minor • Red cell distribution
may not be diagnosed until width: usually normal in
adulthood. thalassaemia.
• Haemoglobin • Peripheral smear: more
electrophoresis may help pronounced basophilic
distinguish these disorders stippling and target cells.
DIAGNOSIS
but can be normal. • Haemoglobin

electrophoresis: raised
haemoglobin A2 level is a
common beta-thalassaemia
trait.
Sideroblastic anaemias • Alcoholism can be a • Peripheral smear:

cause of a reversible erythrocyte dimorphism
sideroblastic anaemia. (hypochromic, microcytic
Hepatosplenomegaly is population mixed with normal
found in one third to one half population); erythrocyte
of patients with sideroblastic dimorphism is also seen in
anaemia and is not present partially treated IDA.
in IDA.[4] • Presence of the occasional
heavily stippled,
hypochromic cell.[4]
• Bone marrow biopsy: ringed
sideroblasts seen because
of accumulation of iron in the
mitochondria.

symptoms
Disorders of porphyrin • A collection of disorders • Testing for most of these
and haem synthesis characterised by defective disorders is not readily
synthesis of porphyrin and available.
haem. • Referral to a haematologist
• A positive family history may and/or research centre may
be present. Neurological be necessary.
disorders and/or
photosensitivity may be
present.
Lead intoxication • Patients may have a • Lead level and free

history of risk factors for erythrocyte protoporphyrin
lead exposure such as (FEP) or zinc protoporphyrin
occupational exposures (ZPP) can be tested. Lead
(exposure to lead paint) or level is increased. Increased
distillation of illicit (illegally FEP or ZPP can reflect
produced homemade) exposure to lead in previous
alcohol. 3 months (the typical lifespan
of a red cell).
Atransferrinaemia • Very rare disorder • Serum and bone marrow

characterised by low plasma iron levels: low as they are
iron concentration secondary in IDA, but, unlike in IDA,
to a lack of transferrin, which total iron-binding capacity
normally acts as a specific will also be low.[4]
iron transport protein.
• Transferrin can be given to
correct the disorder.[4]
Antibodies against the • Case reports exist, but very • Iron profile: increased serum
transferrin receptor rare.[88] iron concentration, normal
• Clinically, these patients serum ferritin level.
resemble patients with IDA. • FEP: dramatically
DIAGNOSIS
increased.[4]
Aluminium intoxication • Occurs primarily in • Erythrocyte aluminium levels

haemodialysis patients if increased.[4]
the public water supply is
used as a source of water for
dialysis.
• Can be avoided with the use
of deionised water and can
be reversed with the use of a
deferoxamine chelator.[4]
Copper deficiency • Patients often • Microcytic anaemia,

(hereditary have neurological increased ferritin, and no
aceruloplasminaemia) abnormalities.[89] serum ceruloplasmin.[89]
Gallium administration • History of gallium infusion. • History of gallium

• Used as diagnostic and administration.
therapeutic agent in cancer,
and disorders of calcium and
bone metabolism.
21

symptoms
• Gallium binds to transferrin
and inhibits cellular iron
uptake.
• Microcytic hypochromic
anaemia was noted in
patients treated with gallium
in a phase 2 chemotherapy
trial.[4]
Diagnostic criteria
WHO definition of anaemia
The WHO defines anaemia as:[1]
• haemoglobin <130 g/L (13 g/dL) in men aged ≥15 years

• haemoglobin <120 g/L (12g/dL) in non-pregnant women aged ≥15 years
• haemoglobin <110 g/L (11 g/dL) in pregnant women.
DIAGNOSIS
Iron deficiency anaemia Treatment
Step-by-step treatment approach

Treatment for IDA includes oral or intravenous iron replacement therapy. Blood transfusion may be
required in patients with symptoms of cardiovascular compromise (e.g., dyspnoea at rest, chest pain, or
lightheadedness).
Oral iron replacement therapy

Initial treatment is daily oral iron replacement therapy (e.g., ferrous sulfate, ferrous gluconate, ferrous
fumarate, or ferric maltol). The reticulocyte count should peak at 1 to 2 weeks and haemoglobin should
show improvement at 3 to 4 weeks (by 20 g/L [2 g/dL]) with normalisation of haemoglobin after 2 to 4
months and replacement of iron stores after 6 months.[4] 1[B]Evidence
Absorption of non-haem iron in plants and dairy requires acid for digestion. Absorption is enhanced
by ascorbate and meat, and inhibited by calcium, fibre, tea, coffee, and wine.[21] Ascorbic acid
supplementation to aid absorption of dietary iron should be considered when response to oral iron is
poor.[70]
There is evidence to suggest that oral iron supplementation administered as a single dose on alternate
days (e.g., Monday, Wednesday, and Friday) may optimise iron absorption and offer more convenient
dosing compared with daily oral iron supplementation.[95] [96] [97]
In women with twin pregnancies and IDA, doubling the dose of iron may provide benefit without causing
gastrointestinal adverse effects.[98]
Treatment failure with oral iron

Up to 10% of patients may have gastrointestinal intolerance to oral iron. Alternative options for these
patients include switching to a formulation with lower levels of elemental iron, taking a liquid formulation,
taking pills with food (although this will decrease absorption), or switching to intravenous iron.
Patients not responding to oral iron, or who are intolerant of oral iron, can be considered for intravenous
iron replacement.2[B]Evidence One study suggests transitioning from oral iron to intravenous iron if
haemoglobin response with oral iron is <10.0 g/L (<1.0 g/dL) at day 14.[99]
Compared with oral iron, the use of intravenous iron has shown superior efficacy in the treatment of IDA
related to malignancy, inflammatory bowel disease, and possibly heart failure.[100] [101] [102] [103]
[104] [105] [106] Supplemental intravenous iron is not beneficial in anaemic critically ill trauma patients;
therefore, routine intravenous iron supplementation is not recommended in these patients.[107]
Intravenous iron replacement therapy

Several intravenous iron preparations are available.
Iron dextran:
• Only available as a low-molecular-weight preparation.[108] High-molecular-weight preparations

TREATMENT
of iron dextran have been discontinued. Adverse effects include anaphylaxis, arthralgias, and
myalgias.[109] [110] In one study, use of intravenous methylprednisolone before and after total
dose infusion of iron dextran decreased the risk of arthralgias and myalgias dramatically.[110]
Patients who are intolerant of iron dextran can be considered for treatment with newer intravenous
23
iron preparations. One preparation has not been found to be more efficacious than the other.[111]
[112] [113] [114] Furthermore, the risk of adverse effects may be lower with newer intravenous iron
preparations compared with iron dextran.[115] [116] [117] [118] [119] [120]
Iron sucrose:
• Has a similar safety profile to iron dextran.[121] It appears to be safe during pregnancy, and has
been shown to be more efficacious than oral iron.[122] [123] [124] [125] In women with postnatal
anaemia, iron sucrose may provide a more rapid response than oral iron.[126]
Sodium ferric gluconate complex:
• Has a superior safety profile compared with iron dextran.[119] In one study, anaphylactic reactions
to sodium ferric gluconate complex were approximately one third as frequent compared with iron
dextran, and no deaths were reported.[127]
Ferumoxytol:
• Has a more convenient dosing schedule than iron dextran and iron sucrose. It has similar efficacy
and safety compared with iron sucrose and ferric carboxymaltose.[112] [113] [128] Ferumoxytol is
safe to use in patients with chronic kidney disease, but if haemodialysis is required, it should be
given >1 hour after haemodialysis when blood pressure has stabilised.[129]
Ferric carboxymaltose:
• Superior safety and efficacy compared with oral iron.[114] [130] It is better tolerated and more
effective than other intravenous iron preparations at treating IDA in patients with inflammatory
bowel disease.[131] Its use in systolic heart failure patients with iron deficiency may reduce
recurrent cardiovascular hospitalisations.[132] In women with postnatal anaemia, use of ferric
carboxymaltose may restore haemoglobin and ferritin levels faster than other intravenous iron
preparations.[133]
Iron isomaltoside:
• Can be given as a single infusion; therefore, dosing is more convenient than other preparations.
Superior efficacy and faster acting than iron sucrose, with a similar safety profile.[134] [135] In
one study, the likelihood of hypersensitivity reactions was 3.4 times higher with iron isomaltoside
compared with ferric carboxymaltose.[136]
Intravenous iron in pregnancy and postpartum

Intravenous iron may be considered in pregnancy during the second or third trimesters if benefits
outweigh the risks to mother and fetus, but it should be avoided in the first trimester.[57]
In women with severe postnatal anaemia, adding intravenous iron (e.g., iron sucrose) to oral iron does not
provide additional benefits compared with oral iron alone.[137]
Adverse effects of intravenous iron

TREATMENT
Use of intravenous iron is associated with anaphylaxis, which can be life threatening.[119] [138] A test
dose can be carried out, although this is not recommended in some countries as allergic reactions may
still occur in patients who have not reacted to a test dose.[139] Intravenous iron should be administered
in settings where appropriately trained staff and resuscitation facilities are available to manage
allergic reactions.[138] Patients should be closely monitored for signs of allergy during and after every
administration.[138]
Infection- and cardiovascular-related adverse events have also been reported with intravenous iron.[140]
[141]
Treatment failure with intravenous iron

Failure to respond to intravenous iron should lead to an investigation for ongoing blood loss and a
questioning of the diagnosis. The diagnosis of IDA or recurrent IDA must be followed by an evaluation to
determine the underlying cause.[142]
Patients with cardiac compromise

Patients with symptoms of cardiovascular compromise (e.g., dyspnoea at rest, chest pain, or
lightheadedness) can be given red cell transfusions, but caution should be used to avoid replacing red
cells too quickly (which may lead to volume overload).[82] Red cell transfusion provides the patient with
only approximately 250 mg of elemental iron per unit (enough to raise the haemoglobin by 1 gram) and so
further iron replacement is required even after blood transfusion. Intravenous iron replacement in patients
with heart failure and iron deficiency (with or without anaemia) has been shown to improve symptoms,
functional capacity, and quality of life.[117]
Serious hazards of transfusion include infectious disease transmission, acute and delayed transfusion
reactions, post-transfusion purpura, transfusion-associated graft-versus-host disease, and transfusion-
related acute lung injury.[143]
Transfusion is not indicated in patients with cardiac compromise who are asymptomatic at rest and on
exertion. Rest and treatment of anaemia are advised.
Treatment details overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Acute ( summary )
all patients
1st oral iron replacement
adjunct ascorbic acid
2nd intravenous iron replacement
with symptomatic cardiac plus red cell transfusion

compromise
TREATMENT
25
Treatment options
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
TREATMENT
Acute
all patients
1st oral iron replacement

Primary options
» ferrous sulfate: 2-3 mg/kg/day orally given

in 2-4 divided doses
Dose expressed as elemental iron.
OR
» ferrous gluconate: 2-3 mg/kg/day orally

given in 2-4 divided doses
OR
» ferrous fumarate: 2-3 mg/kg/day orally given

in 2-4 divided doses
OR
» ferric maltol: 30 mg twice daily

» Initial treatment is daily oral iron replacement

therapy (e.g., ferrous sulfate, ferrous gluconate,
ferrous fumarate, or ferric maltol). The
reticulocyte count should peak at 1 to 2 weeks
and haemoglobin should show improvement
at 3 to 4 weeks (by 20 g/L [2 g/dL]) with
normalisation of haemoglobin after 2 to 4 months
and replacement of iron stores after 6 months.[4]
1[B]Evidence
» Evidence suggests that oral iron

supplementation administered as a single dose
on alternate days (e.g., Monday, Wednesday,
and Friday) may optimise iron absorption and
offer more convenient dosing compared with
daily oral iron supplementation.[95] [96] [97]
» Up to 10% of patients may have

gastrointestinal intolerance to oral iron.
Alternative options for these patients include
switching to a formulation with lower elemental
iron per pill, taking a liquid formulation, taking
pills with food (although this will decrease
absorption), or switching to intravenous iron.
TREATMENT
» In women with twin pregnancies and IDA,

doubling the dose of iron may provide benefit
without causing gastrointestinal adverse
effects.[98]
27
Acute
» In women with severe postnatal anaemia,
adding intravenous iron (e.g., iron sucrose) to
oral iron does not provide additional benefits
compared with oral iron alone.[137]
adjunct ascorbic acid
Treatment recommended for SOME patients in
selected patient group
Primary options
» ascorbic acid: 500 mg orally two to three

times daily
» Absorption of non-haem iron in plants and

dairy requires acid for digestion. Absorption is
enhanced by ascorbate and meat and inhibited
by calcium, fibre, tea, coffee, and wine.[21]
» Ascorbic acid supplementation to aid

absorption of dietary iron should be considered
when response to oral iron is poor.[70] To be
taken at time of iron supplement.
2nd intravenous iron replacement
Primary options
» iron dextran: dose depends on patient's

haemoglobin values and weight; consult
specialist or product literature for guidance on
dose
OR
» sodium ferric gluconate complex: 125

mg intravenously once weekly for 8 weeks,
maximum cumulative dose 1000 mg
OR
» iron sucrose: 200 mg/dose intravenously

given over 2-5 minutes on 5 different
occasions within a 14-day period, maximum
cumulative dose 1000 mg
OR
» ferumoxytol: 510 mg intravenously as a

single dose, followed by 510 mg as a single
dose 3-8 days later
TREATMENT
OR
» ferric carboxymaltose: adults ≥50 kg: 750

mg intravenously as a single dose initially and
Acute
repeat after at least 7 days; adults <50 kg: 15
mg/kg intravenously as a single dose initially
and repeat after at least 7 days; maximum
cumulative dose 1500 mg per course
OR
» iron isomaltoside: dose depends on

patient's haemoglobin values and weight;
consult specialist for guidance on dose
» Patients not responding to oral iron or who

are intolerant of oral iron can be considered for
intravenous iron replacement.2[B]Evidence
» One study suggests transitioning from oral iron

to intravenous iron if haemoglobin response with
oral iron is <10.0 g/L (<1.0 g/dL) at day 14.[99]
» Intravenous iron has superior efficacy in

treating IDA related to malignancy, inflammatory
bowel disease, and possibly heart failure.[100]
[101] [102] [103] [104] [105] [106] Supplemental
intravenous iron is not beneficial in anaemic
critically ill trauma patients; therefore, routine
intravenous iron supplementation is not
recommended in these patients.[107]
» Intravenous iron may be considered in

pregnancy during the second or third trimesters
if benefits outweigh the risks to mother and fetus,
but it should be avoided in the first trimester.[57]
» Several intravenous iron preparations are

available (e.g., iron dextran, iron sucrose,
sodium ferric gluconate complex, ferumoxytol,
ferric carboxymaltose, and iron isomaltoside).
» Iron dextran is only available as a low-

molecular-weight preparation.[108] High-
molecular-weight preparations of iron dextran
have been discontinued. Adverse effects include
anaphylaxis, arthralgias, and myalgias.[109]
[110] In one study, use of intravenous
methylprednisolone before and after total dose
infusion of iron dextran decreased the risk of
arthralgias and myalgias dramatically.[110]
Patients who are intolerant of iron dextran
can be considered for treatment with newer
intravenous iron preparations. One preparation
has not been found to be more efficacious than
TREATMENT
the other.[111] [112] [113] [114] Furthermore, the

risk of adverse effects may be lower with newer
intravenous iron preparations compared with iron
dextran.[115] [116] [117] [118] [119] [120]
29
Acute
» Iron sucrose has a similar safety profile to low-
molecular-weight iron dextran.[121] It appears to
be safe during pregnancy, and has been shown
to be more efficacious than oral iron.[122] [123]
[124] [125] In women with postnatal anaemia,
iron sucrose may provide a more rapid response
than oral iron.[126]
» Sodium ferric gluconate complex has a

superior safety profile compared with iron
dextran.[119] In one study, anaphylactic
reactions to sodium ferric gluconate complex
were approximately one third as frequent
compared with iron dextran, and no deaths were
reported.[127]
» Ferumoxytol has a more convenient dosing

schedule than iron dextran and iron sucrose. It
has similar efficacy and safety compared with
iron sucrose and ferric carboxymaltose.[112]
[113] [128] Ferumoxytol is safe to use in patients
with chronic kidney disease, but if haemodialysis
is required, it should be given >1 hour after
haemodialysis when blood pressure has
stabilised.[129]
» Ferric carboxymaltose has superior safety and

efficacy compared with oral iron.[114] [130] It is
better tolerated and more effective than other
intravenous iron preparations at treating IDA in
patients with inflammatory bowel disease.[131]
Its use in systolic heart failure patients with iron
deficiency may reduce recurrent cardiovascular
hospitalisations.[132] In women with postnatal
anaemia, use of ferric carboxymaltose may
restore haemoglobin and ferritin levels faster
than other intravenous iron preparations.[133]
» Iron isomaltoside can be given as a single

infusion; therefore, dosing is more convenient
than other preparations. It has superior efficacy
and is faster acting than iron sucrose, but has
a similar safety profile.[134] [135] In one study,
the likelihood of hypersensitivity reactions was
3.4 times higher with iron isomaltoside compared
with ferric carboxymaltose.[136]
» Use of intravenous iron is associated with

anaphylaxis, which can be life threatening.[119]
[138] A test dose can be carried out, although
this is not recommended in some countries
as allergic reactions may still occur in patients
TREATMENT
who have not reacted to a test dose.[139]

Intravenous iron should be administered in
settings where appropriately trained staff and
resuscitation facilities are available to manage
allergic reactions.[138] Patients should be
Acute
closely monitored for signs of allergy during and
after every administration.[138]
» Infection- and cardiovascular-related adverse

events have also been reported with intravenous
iron.[140] [141]
» Failure to respond to intravenous iron should

lead to an investigation for ongoing blood
loss and a questioning of the diagnosis. The
diagnosis of IDA or recurrent IDA must be
followed by an evaluation to determine the
underlying cause.[142]
with symptomatic cardiac plus red cell transfusion
compromise
Treatment recommended for ALL patients in
selected patient group
» Patients with symptoms of cardiovascular
compromise (e.g., dyspnoea at rest, chest
pain, or lightheadedness) can be given red cell
transfusions, but caution should be used to avoid
replacing red cells too quickly to prevent volume
overload.[82]
» The use of a blood transfusion does not

obviate the need for other forms of iron
replacement, because one unit of packed red
blood cells will provide only approximately 250
mg of elemental iron and would provide only
enough iron to raise the haemoglobin by 1 gram.
» Intravenous iron replacement in patients

with heart failure and iron deficiency (with or
without anaemia) has been shown to improve
symptoms, functional capacity, and quality of
life.[117]
» Serious hazards of transfusion include

infectious disease transmission, acute and
delayed transfusion reactions, post-transfusion
purpura, transfusion-associated graft-versus-
host disease, and transfusion-related acute lung
injury.[143]
» Transfusion is not indicated in patients with

cardiac compromise who are asymptomatic
at rest and on exertion. Rest and treatment of
anaemia are advised.
TREATMENT
31
Emerging
Roxadustat
Roxadustat (an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor) stimulates erythropoiesis and
regulates iron metabolism. In a phase 3 trial of patients with chronic kidney disease not undergoing
dialysis, roxadustat resulted in a higher mean haemoglobin level compared with placebo.[144] Roxadustat
demonstrated continued efficacy in the open-label phase of the trial.[144] In a study of patients with anaemia
undergoing dialysis, roxadustat demonstrated non-inferiority to epoetin alfa in managing anaemia.[145]
TREATMENT
Iron deficiency anaemia Follow up
Recommendations
Monitoring
FOLLOW UP
The British Society of Gastroenterology recommends regular laboratory follow-up after replacement of
iron.[152] Haemoglobin concentration and red cell indices should be measured every 3 months for a year
and then yearly thereafter.
Patient instructions
Drugs and supplements that can interfere with iron absorption when given at the same time as iron
supplements include cholestyramine, colestipol, neomycin, quinolone antibiotics, tetracyclines, calcium,
magnesium, manganese, and zinc. H2-receptor antagonists impair acid secretion throughout the entire
time that the H2 blocker is active.
Iron can impair the absorption of fluoroquinolones and tetracyclines. It can also interfere with vitamin E
activity.
Absorption can also be helped by ascorbate (found in orange juice or can be taken as a supplement) and
meat, and inhibited by calcium, fibre, tea, coffee, and wine.[21]
33
Complications
Complications Timeframe Likelihood

FOLLOW UP
cognitive impairment short term low
Cognitive and behavioural impairments, especially attention deficits, have been noted in children with
IDA.[4] [13] These appear to correct with iron replacement. However, there remains tremendous debate in
this area.[44] [80] [146] [147]
Treatment revolves around correction of the iron deficiency.
impaired muscular performance short term low
Many measures of muscular performance, such as total exercise time, maximal workload, heart rate, and
serum lactate levels after exercise, are impaired by IDA and correct with iron replacement.[4]
Treatment revolves around correction of the iron deficiency.
preterm delivery short term low
Iron deficiency during the first two trimesters of pregnancy is associated with a twofold increase in preterm
delivery and a threefold increase in delivering a low-birth-weight baby.[8] In contrast, antenatal iron
supplementation results in increased infant birthweight and a lower incidence of small-for-gestational-age
births.[148]
The infants born to iron-deficient women should undergo screening for IDA themselves, and the mother's
iron stores should be replenished. Otherwise, care should be similar to that of other preterm and low-birth-
weight infants.
high-output heart failure variable low
High-output heart failure can be seen in patients with severe anaemia (e.g., haemoglobin <50 g/L [<5 g/
dL]). This can be reversed with iron replacement, and may not require specific treatment.
Caution should be used in giving transfusions in this setting, because of the risk of volume overload.[82]
Specific therapy for heart failure (e.g., beta-blockers) is not often required.
transfusion-transmit ted infectious diseases variable low
Patients who contract these infections from blood products should be treated according to standard of
care. Physicians should have a high clinical suspicion of the possibility of these infections in patients who
have required blood transfusions.
The risk of a transfusion-transmitted infectious disease from a standard unit of fresh frozen plasma is the
same as for a unit of red cells.
Declining rates of post-transfusion infection in developed countries reflect the relative safety of the blood
supply.[149] [150]
developmental delay variable low
Complications Timeframe Likelihood

Iron deficiency in childhood can be associated with developmental delay, which may not fully correct after
correction of the iron deficiency.[151]
FOLLOW UP
Prognosis
Patient outlook
This depends upon the underlying cause of the IDA. Uncomplicated IDA secondary to multiple pregnancies
has a very good prognosis with relatively simple treatment. However, if the IDA is secondary to a
gastrointestinal cancer, prognosis is dependent upon tumour staging. Once the haemoglobin is corrected, it
takes an additional 6 months or so of iron replacement therapy to restore iron stores.
35
Iron deficiency anaemia Guidelines
Diagnostic guidelines
Europe
UK guidelines on the management of iron deficiency in pregnancy

Published by: British Society for Haematology Last published: 2019
Diagnosis and treatment of iron-deficiency anaemia in pregnancy and

postpartum
Published by: Swiss Society of Gynecology and Obstetrics Last published: 2017
Diagnosis and treatment of iron deficiency anemia during pregnancy and the
postpartum period
Published by: Iron Deficiency Anemia Working Group Last published: 2015
GUIDELINES
European consensus on the diagnosis and management of iron deficiency

and anaemia in inflammatory bowel diseases
Published by: European Crohn’s and Colitis Organisation Last published: 2015
Chronic kidney disease: managing anaemia

Published by: National Institute for Health and Care Excellence Last published: 2015
Guideline for the laboratory diagnosis of functional iron deficiency

Published by: British Committee for Standards in Haematology Last published: 2013
Guidelines for the management of iron deficiency anaemia

Published by: British Society of Gastroenterology Last published: 2011
North America
Iron deficiency - diagnosis and management

Published by: British Columbia Medical Association Last published: 2019
Iron deficiency anemia: evaluation and management

Published by: American Academy of Family Physicians Last published: 2013
KDOQI clinical practice guideline for anemia in chronic kidney disease

Published by: National Kidney Foundation Last published: 2012
Diagnosis and prevention of iron deficiency and iron-deficiency anemia in

infants and young children (0-3 years of age)
Published by: American Academy of Pediatrics Last published: 2010
Oceania
Expert recommendations for the diagnosis and treatment of iron-deficiency

anemia during pregnancy and the postpartum period in the Asia-Pacific
region
Published by: Expert panel on the treatment of IDA in pregnant and Last published: 2011
postpartum women in the Asia-Pacific region
Treatment guidelines
Europe

Published by: British Society for Haematology Last published: 2019
GUIDELINES
Diagnosis and treatment of iron-deficiency anaemia in pregnancy and
postpartum
Published by: Swiss Society of Gynecology and Obstetrics Last published: 2017
Chronic kidney disease: managing anaemia

Published by: National Institute for Health and Care Excellence Last published: 2015
Diagnosis and treatment of iron deficiency anemia during pregnancy and the
postpartum period
Published by: Iron Deficiency Anemia Working Group Last published: 2015

Published by: British Committee for Standards in Haematology Last published: 2011
Guidelines for the management of iron deficiency anaemia

Published by: British Society of Gastroenterology Last published: 2011
37
International
International consensus statement on the peri-operative management of

anaemia and iron deficiency
Published by: International consensus group Last published: 2017
Nutritional anaemias: tools for effective prevention and control

Published by: World Health Organization Last published: 2017
Daily iron supplementation in infants and children

Daily iron supplementation in adult women and adolescent girls

GUIDELINES
North America
Iron deficiency – diagnosis and management

Published by: British Columbia Medical Association Last published: 2019
Iron deficiency anemia: evaluation and management

Published by: American Academy of Family Physicians Last published: 2013
KDOQI clinical practice guideline for anemia in chronic kidney disease

Published by: National Kidney Foundation Last published: 2012
Clinical practice guidelines for assessment and management of iron

deficiency
Published by: Canadian Society of Nephrology Last published: 2008
Oceania
Expert recommendations for the diagnosis and treatment of iron-deficiency

anemia during pregnancy and the postpartum period in the Asia-Pacific
region
Published by: Expert panel on the treatment of IDA in pregnant and Last published: 2011
postpartum women in the Asia-Pacific region
Iron deficiency anaemia Evidence scores
Evidence scores
1. Efficacy of oral iron supplementation: there is medium-quality evidence that oral iron given at a dose
of 180 to 220 mg of elemental iron per day led to an average rate of haemoglobin increase of 0.25
g/100 mL/day.[93] Another randomised study found ferrous fumarate gave superior treatment response
compared with a polysaccharide iron complex containing ascorbic acid.[94]
Evidence level B: Randomized controlled trials (RCTs) of <200 participants, methodologically
flawed RCTs of >200 participants, methodologically flawed systematic reviews (SRs) or good quality
observational (cohort) studies.
2. Efficacy of intravenous iron supplementation: there is medium-quality evidence that intravenous iron
dextran results in an average rate of haemoglobin increase of 0.28 g/100 mL/day and saccharated iron
oxide results in an increase of 0.33 g/100 mL/day.[93]
Evidence level B: Randomized controlled trials (RCTs) of <200 participants, methodologically
flawed RCTs of >200 participants, methodologically flawed systematic reviews (SRs) or good quality
observational (cohort) studies.
EVIDENCE SCORES
39
Iron deficiency anaemia References
Key articles
• Gera T, Sachdev HS, Boy E. Effect of iron-fortified foods on hematologic and biological outcomes:
REFERENCES
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• Pavord S, Daru J, Prasannan N, et al. UK guidelines on the management of iron deficiency in

pregnancy. Br J Haematol. 2019 Oct 2 [Epub ahead of print]. Full text Abstract
• Mitra AK, Khoury AJ. Universal iron supplementation: a simple and effective strategy to reduce
anaemia among low-income, postpartum women. Public Health Nutr. 2012 Mar;15(3):546-53. Full text
Abstract
• Goddard AF, James MW, McIntyre AS, et al. Guidelines for the management of iron deficiency
anaemia. Gut. 2011 Oct;60(10):1309-16. Full text Abstract
• US Preventive Services Task Force. Iron deficiency anemia in young children: screening. Sep 2015
[internet publication]. Full text
• Cantor AG, Bougatsos C, Dana T, et al. Routine iron supplementation and screening for iron deficiency
anemia in pregnancy: a systematic review for the US Preventive Services Task Force. Ann Intern Med.
2015 Apr 21;162(8):566-76. Full text Abstract
• Pritchard JA. Hemoglobin regeneration in severe iron-deficiency anemia. Response to orally and
parenterally administered iron preparations. JAMA. 1966;195:717-720. Abstract
• Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet. 2007 May
5;369(9572):1502-4. Abstract
• Breymann C, Honegger C, Hösli I, et al. Diagnosis and treatment of iron-deficiency anaemia in

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J Heart Fail. 2018 Jan;20(1):125-33. Full text Abstract
• Goddard AF, James MW, McIntyre AS, et al. Guidelines for the management of iron deficiency
anaemia. Gut. 2011;60:1309-1316. Full text Abstract
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51
Iron deficiency anaemia Images
Images
IMAGES
Figure 1: Peripheral blood smear demonstrating some changes often seen with iron deficiency anaemia.
Note that many of the red cells are microcytic (compare size of red cell with the lymphocyte nucleus) and
hypochromic (wide central pallor). There are some pencil forms
From personal collection of Dr Rebecca Fischer Connor
Iron deficiency anaemia Disclaimer
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53
Contributors:
// Authors:
Atul Mehta, MD
Consultant Haematologist
Lysosomal Storage Disorders Unit, Department of Haematology, Royal Free Hospital, London, UK
DISCLOSURES: AM declares that he has no competing interests.
// Acknowledgements:
Dr Atul Mehta would like to gratefully acknowledge Dr Martina Murphy, Dr Marc Zumberg, and Dr Rebecca
Fischer Connor, previous contributors to this topic.
DISCLOSURES: MZ declares that he is medical director for NCF Diagnostics and DNA Technologies, and a
consultant for Alexion Pharmaceuticals. MM and RFC declare that they have no competing interests.
// Peer Reviewers:
Carlos Aravena, MD
Internal Medicine Instructor
Member of Evidence Based Medicine Unit, Catholic University of Chile, Santiago, Chile
DISCLOSURES: CA declares that he has no competing interests.
Jim Murray, MBBS

Consultant Haematologist
Clinical Haematology, University Hospital Birmingham NHS Trust, Birmingham, UK
DISCLOSURES: JM declares that he has no competing interests.
Ajay Kumar, MD, FACP

Medical Director
Blood Management, Cleveland Clinic, Cleveland, OH
DISCLOSURES: AK has received a fee for speaking about perioperative blood management from Ortho-
Biotech, and has also received reimbursement from medscape.com for the education webcast of the same
presentation.

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Iron deficiency

The right clinical information, right where it's needed

Last updated: Mar 05, 2020

◊ Blood tests reveal microcytic, hypochromic anaemia; low reticulocyte count.

◊ Diagnosis of IDA requires investigation of the underlying cause.

◊ Treatment includes oral or intravenous iron replacement.

In the UK, an estimated 3% of men and 8% of women have IDA.[11]

Causes of IDA include:[4] [5]

1. Decreased iron intake because of inadequate diet or impaired absorption

The effects of iron on malaria are still unclear.[52]

Women of reproductive age

• Pregnant women living in areas where anaemia in pregnancy is highly prevalent

US Preventive Services Task Force (USPSTF)

American Academy of Family Physicians (AAFP)

Step-by-step diagnostic approach

Initial laboratory evaluation with full blood count (FBC) and

• Low serum iron

Comments on laboratory evaluation

Follow-up clinical evaluation

• Coeliac serology is recommended at initial presentation to evaluate for coeliac disease.[70] If

vegetarian and vegan diet

hook worm infestation

non-steroidal anti-inflammatory drug (NSAID) use

low socioeconomic status postnatal

History & examination factors

dyspnoea on exertion (common)

restless legs syndrome (common)

nail changes (common)

Other diagnostic factors

gastric difficulties (common)

hair loss (common)

rectal lesion on examination (uncommon)

growth impairment (uncommon)

cognitive and behavioural impairment (uncommon)

heart failure (uncommon)

recurrent infections (uncommon)

platelet count normal or elevated

• This is a measurement of the haemoglobin concentration per cell

Other tests to consider

Condition Differentiating signs / Differentiating tests

Disorders of globin • Patients with severe • FBC: often more severe

but can be normal. • Haemoglobin

Sideroblastic anaemias • Alcoholism can be a • Peripheral smear:

Condition Differentiating signs / Differentiating tests

Lead intoxication • Patients may have a • Lead level and free

Atransferrinaemia • Very rare disorder • Serum and bone marrow

Aluminium intoxication • Occurs primarily in • Erythrocyte aluminium levels

Copper deficiency • Patients often • Microcytic anaemia,

Gallium administration • History of gallium infusion. • History of gallium

Condition Differentiating signs / Differentiating tests

• haemoglobin <130 g/L (13 g/dL) in men aged ≥15 years

Step-by-step treatment approach

Oral iron replacement therapy

Treatment failure with oral iron

Intravenous iron replacement therapy

• Only available as a low-molecular-weight preparation.[108] High-molecular-weight preparations

Intravenous iron in pregnancy and postpartum

Adverse effects of intravenous iron

Treatment failure with intravenous iron

Patients with cardiac compromise

Treatment details overview

1st oral iron replacement

adjunct ascorbic acid