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Nutrition and metabolism

Iron deficiency anaemia: pathophysiology,

assessment, practical management
Aditi Kumar ‍ ‍,1 Esha Sharma,2 Alexandra Marley,1 Mark A Samaan,2
Matthew James Brookes ‍ ‍1,3

To cite: Kumar A, Sharma E, ABSTRACT malabsorption, nausea, weight loss and

Marley A, et al. Iron deficiency The WHO has recognised iron deficiency anaemia (IDA) abdominal pain. Central hypoxia can cause
anaemia: pathophysiology, as the most common nutritional deficiency in the world,
assessment, practical
headaches, vertigo and lethargy as well as
with 30% of the population being affected with this cognitive impairment with several studies
management. BMJ Open Gastro
condition. Although the most common causes of IDA are showing an improvement in cognitive func-
2022;9:e000759. doi:10.1136/
gastrointestinal bleeding and menstruation in women,
bmjgast-2021-000759 tions once anaemia has normalised.6–9 It
decreased dietary iron and decreased iron absorption are
is well known that IDA significantly affects
also culpable causes. Patients with IDA should be treated
Received 16 November 2021
with the aim of replenishing iron stores and returning the quality of life (QoL)9 with recent evidence
Accepted 20 December 2021
haemoglobin to a normal level. This has shown to improve demonstrating that treating IDA improves
quality of life, morbidity, prognosis in chronic disease and QoL, regardless of the underlying cause for
outcomes in pregnancy. Iron deficiency occurs in many anaemia.8 10

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chronic inflammatory conditions, including congestive In this review, we will discuss the patho-
cardiac failure, chronic kidney disease and inflammatory physiology, diagnosis, treatment and compli-
bowel disease. This article will provide an updated cations in the management of IDA. The
overview on diagnosis and management of IDA in patients investigative criteria for IDA are beyond the
with chronic conditions, preoperative and in pregnancy. scope of this article and have been compre-
We will discuss the benefits and limitations of oral versus
hensively outlined in the recent British
intravenous iron replacement in each cohort, with an
Society of Gastroenterology guidelines.11
overview on cost analysis between the different iron
formulations currently on the market.
Pathophysiology
Iron is an essential element and is controlled
primarily by dietary intake, intestinal absorp-
tion and iron recycling.12 Dietary iron can be
INTRODUCTION found in two forms: haem and non-­haem iron.
The WHO has recognised iron deficiency Haem iron is easily absorbable and arises from
anaemia (IDA) as the most common nutri- haemoglobin (Hb) and myoglobin in the
tional deficiency in the world, with 30% of form of animal meat, poultry and fish. Non-­
the population being affected with this condi- haem iron is mostly found in plant food but
tion.1 While IDA is more prevalent in children is not as easily absorbable. Compounds such
© Author(s) (or their
and women, adult men are also susceptible as phytate, oxalate, polyphenols and tannin,
employer(s)) 2022. Re-­use depending on their socioeconomic status which are found in plants, diminish the
permitted under CC BY-­NC. No and health conditions.2 Although the most uptake of non-­haem iron, as do some drugs,
commercial re-­use. See rights common causes of IDA are gastrointestinal
and permissions. Published such as proton pump inhibitors.13 14 Ascorbic
by BMJ.
(GI) bleeding and menstruation in women, acid, citrate and gastric acid, conversely,
1
Department of
decreased dietary iron intake and absorption facilitate iron absorption.15 In a healthy diet,
Gastroenterology, The Royal are also culpable causes.3 approximately 5–15 mg of elemental iron
Wolverhampton NHS Trust, Iron is required for various cellular func- and 1–5 mg of haem iron are ingested daily
Wolverhampton, UK tions, including but not limited to enzymatic although only 1–2 mg is ultimately absorbed
2
Inflammatory Bowel Disease processes, DNA synthesis, oxygen transport
Unit, Guys and St Thomas' NHS into the intestine, predominantly in the
Foundation Trust, London, UK
and mitochondrial energy generation.4 5 As duodenum and proximal jejunum.16 Please
3
Research Institue, Faculty such, the symptoms of IDA can vary over a see figure 1 for details on the iron absorption
of Science and Engineering, wide range. Shortness of breath, fatigue, pathways.
University of Wolverhampton, palpitations, tachycardia and angina can
Wolverhampton, UK result from reduced blood oxygen levels. Assessment and diagnosis
Correspondence to This resultant hypoxemia can subsequently The WHO defines anaemia as blood Hb
Dr Aditi Kumar; cause a compensatory decrease in intestinal level below 130 g/L in men and 120 g/L in
​aditikumar@​nhs.​net blood flow, leading to motility disorder, women.1 In isolated iron deficiency, serum

Kumar A, et al. BMJ Open Gastro 2022;9:e000759. doi:10.1136/bmjgast-2021-000759 1

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Open access

Table 1 Diagnostic criteria for iron deficiency anaemia

Serum markers Diagnosis for IDA
Haemoglobin <130 g/L males
<120 g/L females
<110 g/L in pregnancy
Ferritin* <30 ug/L if no inflammation
<100 ug/L if inflammation
Transferrin† Raised
Total iron binding capacity Raised
Iron Reduced
Transferrin saturations <20%
Mean corpuscular volume Low

Figure 1 The two different iron absorption pathways. Non-­

haem absorption pathway (left): insoluble ferric iron (Fe3+) is
*Is an positive acute phase protein and can be raised in
reduced to absorbable ferrous iron (Fe2+), which is carried out inflammatory conditions.
by the enzyme duodenal cytochrome B (DcytB). The divalent †Is a negative acute phase protein and can be normal or reduced
metal transporter 1 (DMT1) imports Fe2+ across the apical in inflammatory conditions.
surface and into the cell, which can then be either stored as IBD, inflammatory bowel disease.
ferritin or exported into circulation through ferroportin. Prior
to exiting the enterocyte, Fe2+ must be oxidised back to Fe3+
by hephaestin or ceruloplasmin. Haem absorption pathway This has been shown to improve QoL, morbidity, prog-
nosis in chronic disease and outcomes in pregnancy.22

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(right): the haem carrier protein (HCP1) transports haem
iron directly into the enterocyte. Once inside the enterocyte, Iron replenishment can occur via three routes: oral
haem iron can either be released into plasma via the haem iron, parenteral oral and transfusion of packed red cells.
exporter FLVCR1 or be converted back into Fe2+ via the haem Each route has its benefits and limitations, which will be
oxidase (HO) enzyme. The ferroportin receptor then releases discussed below in greater detail.
Fe2+ into the plasma. Hepcidin, a hepatic peptide hormone,
controls ferroportin, the sole iron exporter, by promoting Conventional oral iron formulations
its endocytosis. Hepcidin production and circulation are The British Society of Gastroenterology recommends
regulated by plasma iron concentration and iron stores. ferrous preparations, specifically ferrous sulphate, as
Hepcidin is increased in the presence of inflammation,
first-­
line therapy for iron replenishment as they are
which then promotes the degradation of ferroportin and
cheap, have good bioavailability, available in multiple
subsequently impairs the exportation of cellular iron into
plasma. Figure taken with permission from Kumar and preparations and have been shown to replenish iron
Brookes.84 stores and correct anaemia effectively.11 However, there
are also many limitations to their use, with the most
ferritin (the storage molecule for iron) should be less common being the frequency and severity of side effects.
than 30 ug/L.17 However, ferritin is an acute phase protein A systematic review demonstrated that GI side effects
and can be increased in the presence of inflammation.18 were the most problematic with constipation being the
Thus, if there is evidence of concomitant inflammation, most frequent complaint, followed by nausea and diar-
such as elevated C reactive protein, ferritin less than rhoea.23 This will have a resultant effect on patient adher-
100 ug/L is indicative of IDA.19 Transferrin, the iron ence, likely leading to cessation and, thus, inadequate
transporter, is generally elevated; however, it is a nega- treatment.24
tive acute phase protein and, therefore, can be normal The appropriate dosing of ferrous iron preparations is
or reduced in chronic inflammatory states.20 Serum iron also a contentious issue between clinicians. To adequately
and transferrin saturations (TSAT) will be reduced with replenish iron stores, therapeutic treatment of IDA was
TSAT less than 20% required for the diagnosis of IDA.17 initially felt to require 200 mg of iron sulphate 2–3 times
See table 1 for the breakdown of diagnostic criteria for per day in order to raise Hb by 20 g/L over a 4-­week period,
IDA. It is crucial to note that iron deficiency should not with treatment continuing for 3 months.25 However, the
be excluded in the presence of a normal Hb as a signif- daily doses of elemental iron should not be greater than
icant amount of iron must be lost before the Hb levels 100 mg/day26 as the body can only absorb 10–20 mg of
begin to decline. Thus, a low mean corpuscular Hb with iron per day.26 It should be noted that 200 mg of ferrous
a normal Hb or an increase in red cell distribution width sulphate is equivalent to 65 mg of elemental iron.27
signifies mild iron deficiency without anaemia.21 A recent study compared oral iron dosing regimens
in women with mild anaemia with divided daily, once
Management daily and alternate-­day dosing. The results demonstrated
Patients with IDA should be treated with the aim of replen- superiority with alternate-­day dosing, with 33% greater
ishing iron stores and returning the Hb to a normal level. fractional iron absorption over 14 doses.28 In addition,

2 Kumar A, et al. BMJ Open Gastro 2022;9:e000759. doi:10.1136/bmjgast-2021-000759

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Open access

a randomised trial of elderly patients with IDA received can be transported to the intestinal mucosa where it
15 mg, 50 mg or 150 mg of elemental iron per day. After is absorbed without free iron interacting with the gut
2 months, the mean increase in Hb was the same in all wall.39 40 This unique structure protects iron from the
groups (1.4 g/dL); however, adverse effects were signifi- acidic environment in the stomach, increases intestinal
cantly greater with higher doses.29 It is, therefore, an epithelial absorption and ensures high bioavailability
evolving view that a single daily dose (40–60 mg) or a while reducing the risk for potential adverse GI effects.39
slightly higher alternate-­ day dose (80–100 mg) is the Despite lower doses of elemental iron, this newer oral
preferred dosing regimen in order to reduce the side iron preparation (30–60 mg/day) has also shown greater
effects and optimise the proportion of elemental iron efficacy in increasing Hb and ferritin concentrations
absorbed.28–30 compared with ferrous sulphate (105–210 mg/day), with
Sodium feredetate is a water-­soluble EDTA compound a mean Hb increase in 2.7 g/dL and 1.4 g/dL, respec-
with higher bioavailability than the ferrous iron salt prepa- tively, over a 12-­week course of treatment.39
rations. In the UK, it is available as a liquid preparation Recent studies have demonstrated sucrosomial iron
(Sytron); however, it is also available in tablet form (Ecofer, to be non-­inferior to parenteral iron in patients with
not currently licensed in the UK) often in combination anaemia secondary to coeliac disease, cancer, bariatric
with B12 and folate.31 In a study looking at treatment of surgery and chronic kidney disease (CKD).41–43 In a
IDA in pregnant women, sodium feredetate increased study looking at patients with IDA as a result of benign
Hb by 1.28 g/dL after 1 month of treatment and 2.11 g/ GI or gynaecological bleeding who had previously not
dL after 2 months of treatment. This was in comparison responded to or not tolerated ferrous sulphate were
to the group of women who received ferrous sulphate, randomised to receive a high dose of either sucrosomial
where the mean Hb rose by 1 g/dL after 1 month and iron or intravenous ferrous gluconate. Results demon-
1.58 g/dL after 2 months. As well as a significantly greater strated that patients were comparable at baseline and
increase in Hb, there were significantly fewer side effects rise in Hb was not significantly different between the two

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seen with sodium feredetate than ferrous sulphate.32 groups, with the number of weeks required to achieve an
This study also highlighted the improved bioavailability Hb target value of 12 g/dL was four in the sucrosomial
of sodium feredetate as this cohort was given one 231 mg iron group and 3.5 in the ferrous gluconate group.44
tablet once per day for 2 months (equivalent to 33 mg
of elemental iron) compared with the ferrous sulphate Intravenous iron
cohort who were given 200 mg tablets two times per day An alternative to oral iron supplementation is parenteral
for 2 months (equivalent to 60 mg of elemental iron). administration. Intravenous iron is the preferred route
of administration in some patients and is increasingly
Novel oral iron formulations favoured due to its rapid correction of Hb, fewer side
Ferric maltol, a novel preparation, is a non-­salt oral iron effects and improved safety profile. The primary advan-
formulation composed of stable ferric iron complexed tage of intravenous iron is that it bypasses the GI tract
with a sugar derivative, tri-­maltol. It is licenced in the absorption, thereby avoiding further mucosal aggrava-
European Union and the USA and sold under the tion and inflammation and producing less side effects.45
brand names Feraccru and Accrufer, respectively. When Clinicians also do not have to worry about patient’s
absorbed, the maltol ligand remains complexed to iron, adherence to medication.
which reduces the formation of free iron and facilitates There are a variety of intravenous iron preparations
iron transport across the enterocyte.33 This subsequently with selection of the agent dependent on multiple factors
increases the bioavailability of iron such that lower doses including cost considerations, patient and physician pref-
of elemental iron are required to treat IDA compared erence and product availability. It is important to note
with the ferrous iron preparations.34 Furthermore, ferric that clinical studies of the various formulations follow
maltol has been shown to have less of an effect on the different protocols, and as of yet, there are no large head-­
gut microbiome.35 Studies on the use of ferric maltol to-­head trials between these formulations comparing effi-
has been limited to patients with inflammatory bowel cacy and safety profile.
disease (IBD), with results demonstrating improvement Older intravenous iron preparations such as high-­
in Hb levels beyond 12 weeks with sustained normal Hb molecular weight dextran iron (Dexferrum) have been
levels up to 64 weeks when compared with placebo.36 37 discontinued due to their unfavourable safety profiles
When compared with intravenous ferric carboxymaltose, with relatively high incidence of anaphylaxis.46 The lower
however, ferric maltol was shown to be inferior and did molecular weight dextran compounds such as Cosmofer
not meet the primary endpoint of increasing Hb by 2 g/L are, however, still in use and have been shown to be
or Hb normalisation by 12 weeks (85% vs 68%, respec- effective with a much lower incidence of anaphylactoid
tively).38 reactions.47 While there has not been a study comparing
Finally, sucrosomial iron is an innovative oral iron-­ the different preparations, a meta-­ analysis looking at
containing carrier, in which ferric pyrophosphate is the overall rate of anaphylaxis with intravenous dextran
within a phospholipid bilayer membrane forming the was 0.61%,48 which is significantly greater than with the
‘sucrosome’, creating a gastroresistant complex, which newer non-­dextran intravenous preparations.49

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Open access

Ferric derisomaltose (Monofer) is an alternative intra- iron stores, particularly if the cause for their anaemia is
venous iron preparation, which is often preferred to chronic and not easily treatable, for example, advanced
Cosmofer due to its shorter infusion time, thereby opti- malignancy or haematological disease.
mising the use of medical infusion units and nursing time Clinicians are rightly reluctant to transfuse patients
as these drugs are often given as day-­case procedures. unnecessarily as it is associated with not insignificant
Monofer is also preferred by some as it can be given as risks. These include an increased mortality with liberal
one infusion rather than two infusions. Ferric carboxy- blood transfusion in the setting of upper GI bleeding.52
maltol (Ferinject) is a preparation widely used in the UK. There is also increased incidence of transfusion-­related
It can be safely administered at a single dose of 1000 mg reactions. This includes the risk of Transfusion Related
within 15 min; however, two infusions may be required in Acute Lung Injury, which is one of the most serious reac-
some patients, depending on their weight and Hb levels. tions, the incidence of which is approximately 1 in 5000
Finally, iron sucrose (Venofer) is given by a slow injec- transfusions.53 Furthermore, there remains a small risk
tion of 100–200 mg 2–3 times a week.50 It has been shown for transmitting infections, both viral and bacterial.54–56
to be effective, although a comparison study showed
Ferinject to be superior. In this study, Ferinject was asso- Considerations in management
ciated with a higher rate of achieving a 2 g/dL increase Comorbidities
in Hb concentration in comparison to iron sucrose by
IDA occurs in many chronic inflammatory conditions,
a relative risk of 1.65.51 While Venofer has been exten-
including congestive cardiac failure (CCF), CKD and
sively studied, the major drawback in its use is the need
IBD (table 2). To complicate matters, symptoms such as
for multiple infusions, which can not only be less accept-
fatigue are commonly seen in these conditions, which
able to patients but also made difficult for overstretched
can mimic and be confused with symptoms of IDA.
healthcare services.
Consequently, the management of IDA can often be over-
looked. Untreated IDA can have greater consequences in

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Red blood cell transfusion
It is advised that transfusions should be reserved for these conditions causing an exacerbation of the under-
patients with severe anaemia, haemodynamically unstable lying disease.6
and/or have associated comorbid conditions.26 However,
while severe anaemia is defined as Hb <70 g/dL, many Congestive cardiac failure
of these patients may be haemodynamically stable and In CCF, IDA is one of the most prevalent comorbid condi-
rather have chronic anaemia, remaining asymptomatic. tions57 and can be a result of multiple factors including
Although a unit of blood contains approximately 200 mg reduced appetite, increased GI blood losses as a result of
of iron,22 these patients are very likely to require further antiplatelet or anticoagulant medication and decreased
iron supplementation to adequately replenish their GI absorption due to oedema.58

Table 2 A list of common conditions and patient groups who have an increased risk of developing iron deficiency anaemia
Cause of iron deficiency Recommended route of iron
Background anaemia Cause of blood loss replacement
Congestive cardiac ailure Poor nutrition Antiplatelet and/or anticoagulant Intravenous
Decreased GI absorption use
Chronic kidney disease Dialysis and frequent blood Intravenous
sampling
Inflammatory bowel disease Chronically inflamed and ulcerated Intravenous
bowel
Elderly Medications (antiplatelet, Oral
anticoagulant, anti-­inflammatories,
anti-­depressants)
Malignancy Poor nutrition Bleeding tumour Intravenous
Loss of healthy blood cells
Damage to the bone
marrow
Surgery Dependent on cause for Excessive bleeding either pre and/ Intravenous or oral
surgery requirement or post-­operatively
Pregnancy Poor nutrition – Intravenous or oral
Increased iron demands to
mother and fetus
The cause for iron deficiency anaemia, including causes for increased blood loss, and the recommended route of iron replacement are listed.

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Open access

The median dose of iron needed to replete iron suffi- that may be needed in the future for critical vascular
ciently in patients with CCF with IDA is 1000 mg.59 If access.65 Furthermore, there are concerns regarding
patients were given ferrous sulphate, the first-­line oral potential side effects with intravenous iron including
preparation, the bioavailability is only 10% at best,60 anaphylaxis, hypersensitivity, susceptibility to infections
and, thus, patients would need a minimum of 50 days and cardiovascular events, hypophosphataemia and
at a dose of 200 mg/day to correct the iron deficit. Real- iron overload.66 While human erythropoietin (EPO)
istically, considering missed doses or non-­adherence, it and EPO-­stimulating agents (ESA) have been in use for
can take up to 6 months to adequately replenish iron decades, they are associated with worsening hyperten-
stores.58 Thus, intravenous iron should be considered sion, seizures and dialysis access clotting.67 68 Moreover,
first line for the treatment of iron deficiency in CCF.6 ESA has not shown to reduce adverse outcomes associ-
The Ferinject Assessment in Patients with Iron Defi- ated with anaemia, including mortality rate, hospitalisa-
ciency and Heart Failure (FAIR-­HF) and Ferric Carboxy- tions and progression of kidney disease.69
maltose Evaluation on Performance in Patients with Iron
Deficiency in Combination with Chronic Heart Failure Inflammatory bowel disease
(CONFIRM-­HF) trials demonstrated the benefit of ferric IDA has been acknowledged as one of the most
carboxymaltose compared with placebo in correcting common extra intestinal manifestations of IBD.20
IDA by improving exercise capacity, cardiac function,
Impaired GI iron absorption is caused by chronically
symptom severity and QoL.61
inflamed bowel, chronic blood losses, bowel resection
Chronic kidney disease and malnutrition.6 Improvement in iron status through
The causes of IDA in CKD are similar to those in CCF, treatment with intravenous iron has led to significant
namely, reduced GI iron absorption, poor nutrition improvement in QoL in patients with IBD.10 Adverse
and blood loss caused by dialysis and frequent blood effects from oral iron are well recognised but have
greater consequences in patients with IBD. Absorp-

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sampling. A recent meta-­analysis and systematic review
demonstrated intravenous iron to be more effective than tion from the GI tract is limited (on average 10%–20%
oral iron in treating IDA in CKD, regardless of require- of ingested amount) and unabsorbed iron is exposed
ment for dialysis.6 62 The Kidney Disease: Improving to the ulcerated intestinal surface, which can cause
Global Outcomes clinical practice guidelines also further mucosal damage as well as changes to gut
recommend intravenous iron as first-­line treatment for microbiota,70 although it is not yet established whether
patients with stage 5 CKD.63 However, ferric citrate might oral iron exacerbates IBD inflammation beyond animal
be an alternative oral preparation with a recent trial of models. The European Crohn’s and Colitis Organisa-
203 patients given 1 g three times per day showing fewer tion (ECCO) guidelines advise the use of intravenous
hospitalisation rates and lower incidence of death, dial- iron as first-­line therapy in patients with active disease,
ysis or transplantation.64 Despite the evidence provided severe anaemia (Hb <100 g/L), if previously intolerant
for intravenous preparations, oral iron remains first-­line to oral iron and for patients in need of concomitant
therapy for many clinicians and patients as it is readily treatment with EPO.26 However, there is a place for
available, inexpensive and avoids the need for intra- both oral and intravenous iron in patients with IBD,
venous access, which can cause injury to blood vessels which is further outlined in figure 2.

Figure 2 Iron deficiency treatment pathway in patients with IBD patients as followed by the South East London Clinical
Commissioning Group.85 Hb, haemoglobin; IBD, inflammatory bowel disease.

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Open access

Malignancy Pregnancy
IDA is associated with multiple types of cancer, including Anaemia in pregnancy is defined as Hb <110 g/L with
GI (colorectal, pancreatic, oesophageal, gastric), lung, ferritin levels <100 μg/L.11 The total iron loss in preg-
genitourinary (cervical, prostate, testicular), breast and nancy approximately 1000 mg, and, thus, the recom-
haemotological (lymphoma, leukaemia, myeloma).71 mended daily dietary allowance for iron in pregnancy
In cancer patients, iron deficiency is associated with is 27 mg compared with 8 mg in the adult non-­pregnant
fatigue and weakness irrespective of the presence of population.76 The usual recommended dose of elemental
anaemia.66 Iron deficiency can occur frequently by iron is 80 mg, which is equivalent to 250 mg of oral
means of chemotherapy-­induced anaemia and anaemia iron sulphate tablets.76 Intermittent oral iron has been
of chronic disease.66 Blood transfusions, ESA therapy and reported to be effective as daily iron dosing in raising Hb
intravenous iron are the potential treatment options for levels and is associated with a lower incidence of adverse
IDA in patients with cancer. The aim is to improve QoL effects.77 However, a meta-­ analysis has demonstrated
and reduce reliance on blood transfusions that are often intravenous iron sucrose improved Hb (mean difference
associated with further multiorgan complications. Bene- 7.17 g/L) and serum ferritin levels (mean difference
ficial effects of ESAs are limited and both the European 49.66 ug/L) while ferric carboxymaltose improved Hb
medicines agency and Food and Drug Administration levels (mean difference 8.52 g/L), compared with oral
have recommended restricting their use to patients with ferrous sulphate.78 Furthermore, side effects were less
symptomatic anaemia and those undergoing specific common with the parenteral formulations, but included
chemotherapy.72 A consensus of cancer experts suggest local pain, skin irritation and rarely allergic reactions.
intravenous iron should be used over oral iron supple-
mentation due to reduced efficacy and poor tolerance Adverse effects
and adherence in the latter.72 This is corroborated by a As previously discussed, the common adverse effects of
meta-­analysis of 11 randomised studies, where intrave- oral iron are well known among healthcare professionals

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nous iron had an improved haematopoietic response in and patients. The potential adverse effects of intravenous
chemotherapy-­induced anaemia with no safety concerns iron have more recently been publicised as they become
and an overall reduction in blood transfusion require- further researched and understood. The rare adverse
ment, compared with oral iron.73 effect of hypersensitivity reactions has been known for
some time and have dictated specialised protocols and
Elderly population training for healthcare professionals routinely adminis-
tering intravenous iron.
Another high-­risk population are the elderly where prev-
Hypophosphataemia is an increasingly recognised
alence of iron deficiency increases rapidly with age due
adverse effect of intravenous iron. The risk of persistent
to reduce oral intake, poor absorption and excess loss.74
hypophosphataemia and osteomalacia is possibly higher
A meta-­ analysis of trial data shows treatment of iron
with ferric carboxymaltose than with the other intra-
deficiency with both oral and intravenous iron reduces
venous iron preparations. A key mechanism is the
blood transfusion requirements and increases Hb levels
carbohydrate moieties in ferric carboxymaltose inhibit
but does not significantly impact mortality68 Oral supple-
degradation of fibroblast growth factor 23, resulting in
mentation is recommended for treatment of IDA in this
greater renal loss of phosphate.79 Phosphate replacement
population, and lower doses of oral iron may be effective
is an ineffective management strategy due to this mech-
and better tolerated among elderly patients. For those
anism as any phosphate replaced is lost through greater
whose oral treatment has been unsuccessful, intravenous
renal wasting.80 Although the clinical significance is not
treatment should be considered to avoid adverse effects
yet fully understood, it is expected to have more of an
and effectively treat anaemia. However, potential adapta- effect on those patients requiring higher doses, repeat
tions of oral therapy should also be considered such as courses and are at a higher risk of electrolyte imbalances
liquid formulations or reducing dose frequency.74 due to malnutrition.79
A less commonly recognised adverse effect is that of
IDA in surgery extravasation of intravenous iron that can cause long-­
There is a growing field of evidence to focus on the lasting tattoo-­like skin discolouration preceded by skin
impact of iron deficiency on morbidity and mortality in irritation and pain at the injection site. Though this
the perioperative period. Recently published national adverse effect is considered to be rare (occurring at a
guidance recommends that IDA should be identified and rate of approximately 1.6%), the skin staining can last
treated pre and postoperatively,75 whether that be via oral for several months after the initial infusion despite
or intravenous iron supplementation. Intravenous iron is pharmacological interventions to resolve the reac-
recommended for those who are unable to tolerate oral tion.81 82 Though the extravasation of intravenous iron
iron, those with functional iron deficiency and those with is not expected to cause harm, the long-­lasting effects of
surgical procedures close to the time the IDA was diag- the skin stain can have negative psychological and social
nosed.75 Further research is necessary to assess the impact impact on patients, so awareness of this phenomenon
of the timing of iron replacement prior to surgery. among healthcare professionals is imperative. Patients

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Open access

Table 3 Cost analysis per drug

Time treatment course
Drug (brand) Form provided in (weeks) Infusion time Administration visits Cost (£)
Ferrous sulphate* Tablet 12 – – 2.43
Ferrous gluconate* Tablet 12 – – 3.27
Ferrous fumarate* Tablet 12 – – 2.47
Sodium feredate (Sytron)** Liquid 12 – – 29.90
Ferric maltol (Ferracru)† Capsule 12 – – 142.80
Ferric carboxymaltose Injection 2 30 2 308.46
(Ferinject)‡
Ferric derisomaltose Injection 2 30 2 339.00
(Monofer)‡
Iron sucrose (Venofer)§ Injection 3 30 8 768.00
Iron dextran (Cosmofer)§ Injection 1 240 1 119.55
National Health Service (NHS) indicative price as per British National Formulary (BNF).
*Cost based on one one tablet or 10 mL per day.
†Cost based on two capsules per day.
‡Based on 70 kg patient, with Hb <10 according to each summary of product characteristics.
§Based on 70 kg patient with Hb of 90 g/L.
Hb, haemoglobin.

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should be informed of this potential adverse effect prior treatment, then ferric maltol may offer an alternative
to administration of intravenous iron. choice with less potential adverse effects, although direct
comparisons of this drug with other iron formulations
Cost implications still need to be studied.
It is important to consider both the cost of the impact
of iron deficiency to the healthcare system and the cost Looking to the future: service development and redesign
of the individual treatments when assessing the overall IDA is the most common nutritional disorder globally
cost of IDA management (table 3). Oral treatment with and is associated with multiple comorbid states with
standard ferric salts is by far the lowest cost option with severe implications in QoL. Despite national guidance
convenient administration and low drug cost (a 12-­week on managing IDA, there is still wide variability in current
course is approximately £2). Conversely, intravenous iron practices, not just between National Health Service trusts
preparations can cost approximately £1400 per patient but also between clinicians and departments. Choosing
infusion when based on the highest iron requirement between intravenous and oral iron therapies is dependent
and including costs to the healthcare system for patient on many factors, including the therapy goal, response to
day-­case admission. However, the most significant cost prior therapy, patient preference, cost and ease of access
to the healthcare system is that of untreated IDA, which to an infusion centre. A standardised pathway steered
can result in emergency hospitalisation and multiple by evidence-­ based medicine can reduce this variance
blood transfusions, approximately £1700 per admission in care, while simultaneously supporting cost-­ effective
on average. Brookes et al reviewed management of IDA anaemia management across and between the new inte-
in England between 2012 and 2018 and identified that grated care systems.
£42.4 million was spent on emergency hospital admis- Twitter Aditi Kumar @dr_dee_kumar
sions. In comparison, £46 million was spent on day case
admissions, although four times as many patients were Contributors AK, AM and ES wrote the manuscript. MAS and MJB provided critical
treated in the outpatient setting.83 Though intravenous revisions of the manuscript. All authors have read and agreed to the published
version of the manuscript.
iron administration can seem more expensive than oral
Funding The authors have not declared a specific grant for this research from any
treatment, these findings strongly suggest that there is a
funding agency in the public, commercial or not-­for-­profit sectors.
need for a national strategy for standardising and stream-
Competing interests ES served as a speaker and/or an advisory board member
lining elective intravenous iron administration to prevent for Takeda, Janssen and Pharmacosmos. MAS served as a speaker, a consultant
more costly emergency admissions. For those who have and/or an advisory board member for Abbvie, Bristol Myers Squibb, Sandoz,
not tolerated standard oral supplementation, ferric Janssen, Takeda, MSD, Falk and Samsung Bioepis. MJB has received funding from
maltol may offer a more suitable alternative than intrave- Vifor International and Tillotts Pharma in the form of grants for research work and
travel expenses, outside of the submitted work.
nous iron. The cost of ferric maltol is significantly more
than the standard oral iron (approximately £170 for a Patient consent for publication Not applicable.
12-­week course) but much less than intravenous iron. Ethics approval This study does not involve human participants.
If oral intolerance is the drive for choosing intravenous Provenance and peer review Commissioned; externally peer reviewed.

Kumar A, et al. BMJ Open Gastro 2022;9:e000759. doi:10.1136/bmjgast-2021-000759 7

 BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2021-000759 on 7 January 2022. Downloaded from http://bmjopengastro.bmj.com/ on September 15, 2023 at Sri Lanka:BMJ-PG
Open access

Data availability statement No data are available. in adults: a systematic review and meta-­analysis. PLoS One
2015;10:e0117383.
Open access This is an open access article distributed in accordance with the 24 Pasricha S-­R, Tye-­Din J, Muckenthaler MU, et al. Iron deficiency.
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which Lancet 2021;397:233–48.
permits others to distribute, remix, adapt, build upon this work non-­commercially, 25 Summary of product characteristics (SMPC): ferrous sulfate tablets
and license their derivative works on different terms, provided the original work is 200mg, 2020. Available: https://www.medicines.org.uk/emc/product/​
properly cited, appropriate credit is given, any changes made indicated, and the 4231/smpc#gref
use is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. 26 Dignass AU, Gasche C, Bettenworth D, et al. European consensus
on the diagnosis and management of iron deficiency and anaemia in
ORCID iDs inflammatory bowel diseases. J Crohns Colitis 2015;9:211–22.
Aditi Kumar http://orcid.org/0000-0003-1026-3173 27 compendium, E.m. Summary of product characteristics (SMPC):
ferrous sulfate tablets 200mg. Available: https://www.medicines.org.​
Matthew James Brookes http://orcid.org/0000-0002-8782-0292
uk/emc/product/4231/smpc#gref
28 Stoffel NU, Zeder C, Brittenham GM, et al. Iron absorption from
supplements is greater with alternate day than with consecutive
day dosing in iron-­deficient anemic women. Haematologica
2020;105:1232–9.
29 Rimon E, Kagansky N, Kagansky M, et al. Are we giving too much
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