Iron deficiency is the commonest cause of anaemia worldwide
and is frequently seen in general practice.
The anaemia of iron
deficiency is caused by defective synthesis of haemoglobin,
resulting in red cells that are smaller than normal (microcytic)
and contain reduced amounts of haemoglobin (hypochromic).
Iron metabolism
Iron has a pivotal role in many metabolic processes, and the
average adult contains 3-5 g of iron, of which two thirds is in
the oxygen-carrying molecule haemoglobin.
A normal Western diet provides about 15 mg of iron daily,
of which 5-10% is absorbed (~1 mg), principally in the
duodenum and upper jejunum, where the acidic conditions
help the absorption of iron in the ferrous form.
Absorption is
helped by the presence of other reducing substances, such as
hydrochloric acid and ascorbic acid.
The body has the capacity
to increase its iron absorption in the face of increased
demand for example, in pregnancy, lactation, growth spurts,
and iron deficiency.
Once absorbed from the bowel, iron is transported across
the mucosal cell to the blood, where it is carried by the protein
transferrin to developing red cells in the bone marrow.
Iron
stores comprise ferritin, a labile and readily accessible source of
iron, and haemosiderin, an insoluble form found
predominantly in macrophages.
About 1 mg of iron a day is shed from the body in urine,
faeces, sweat, and cells shed from the skin and gastrointestinal
tract.
Menstrual losses of an additional 20 mg a month and the
increased requirements of pregnancy (500-1000 mg) contribute
to the higher incidence of iron deficiency in women of
reproductive age.
Clinical features of iron deficiency
The symptoms accompanying iron deficiency depend on how
rapidly the anaemia develops.
In cases of chronic, slow blood
loss, the body adapts to the increasing anaemia, and patients
can often tolerate extremely low concentrations of
haemoglobin for example, <70 g/l with remarkably few
symptoms.
Most patients complain of increasing lethargy and
dyspnoea.
More unusual symptoms are headaches, tinnitus, and
taste disturbance.
On examination, several skin, nail, and other epithelial
changes may be seen in chronic iron deficiency.
Atrophy of the
skin occurs in about a third of patients, and (rarely nowadays)
nail changes such as koilonychia (spoon shaped nails) may
result in brittle, flattened nails.
Patients may also complain of
angular stomatitis, in which painful cracks appear at the angle
of the mouth, sometimes accompanied by glossitis.
Although
uncommon, oesophageal and pharyngeal webs can be a feature
of iron deficiency anaemia (consider this in middle aged
women presenting with dysphagia).
These changes are believed
to be due to a reduction in the iron-containing enzymes in the
epithelium and gastrointestinal tract.
Tachycardia and cardiac failure may occur with severe
anaemia irrespective of cause, and in such cases prompt
remedial action should be taken.
When iron deficiency is confirmed a full clinical history
including leading questions on possible gastrointestinal blood
loss or malabsorption (as in, for example, coeliac disease)
should be obtained.
Menstrual losses should be assessed, and
the importance of dietary factors and regular blood donation
should not be overlooked.
Diet alone is seldom the sole cause for iron deficiency
anaemia in Britain except when it prevents an adequate
response to a physiological challenge as in pregnancy, for
example.
Laboratory investigations
A full blood count and film should be taken.
These will
confirm the anaemia; recognising the indices of iron deficiency
is usually straightforward (reduced haemoglobin
concentration, reduced mean cell volume, reduced mean cell
haemoglobin, reduced mean cell haemoglobin concentration).
Some modern analysers will determine the percentage of
hypochromic red cells, which may be high before the anaemia
develops (it is worth noting that a reduction in haemoglobin
concentration is a late feature of iron deficiency).
The blood
film shows microcytic hypochromic red cells.
Hypochromic
anaemia occurs in other disorders, such as anaemia of chronic
disorders and sideroblastic anaemias and in globin synthesis
disorders, such as thalassaemia.
To help to differentiate the
type, further haematinic assays may be necessary.
Difficulties in
diagnosis arise when more than one type of anaemia is
present for example, iron deficiency and folate deficiency in
malabsorption, in a population where thalassaemia is present,
or in pregnancy, when the interpretation of red cell indices
may be difficult.
Haematinic assays will demonstrate reduced serum ferritin
concentration in straightforward iron deficiency.
As an acute
phase protein, however, the serum ferritin concentration may
be normal or even raised in inflammatory or malignant disease.
A prime example of this is found in rheumatoid disease, in
which active disease may result in a spuriously raised serum
ferritin concentration masking an underlying iron deficiency
caused by gastrointestinal bleeding after non-steroidal analgesic
treatment.
There may also be confusion in liver disease as the
liver contains stores of ferritin that are released after
hepatocellular damage, leading to raised serum ferritin
concentrations.
In cases where ferritin estimation is likely to be
misleading, the soluble transferrin receptor (sTfR) assay may aid
the diagnosis.
Transferrin receptors are found on the surface of
red cells in greater numbers in iron deficiency; a proportion of
receptors are shed into the plasma and can be measured using
commercial kits.
Unlike the serum ferritin, the sTfR does not
rise in inflammatory disorders, and hence can help differentiate
between anaemia due to inflammation from iron deficiency.
Diagnostic bone marrow sampling is seldom performed in
simple iron deficiency, but if the diagnosis is in doubt a marrow
aspirate may be carried out to demonstrate absent bone
marrow stores.
When iron deficiency has been diagnosed, the underlying
cause should be investigated and treated.
Often the history will
indicate the likely source of bleeding for example, menstrual
blood loss or gastrointestinal bleeding.
If there is no obvious
cause, further investigation generally depends on the age and
sex of the patient.
In male patients and postmenopausal
women possible gastrointestinal blood loss is investigated by
visualisation of the gastrointestinal tract (endoscopic or barium
studies).
Faecal occult bloods are of no value in the
investigation of iron deficiency.
Management
Effective management of iron deficiency relies on (a) the
appropriate management of the underlying cause (for
example, gastrointestinal or menstrual blood loss) and (b) iron
replacement therapy.
Oral iron replacement therapy with gradual replenishment
of iron stores and restoration of haemoglobin is the preferred
treatment.
Oral ferrous salts are the treatment of choice (ferric
salts are less well absorbed) and usually take the form of
ferrous sulphate 200 mg three times daily (providing
65mgX3=195 mg elemental iron/day).
Alternative preparations include ferrous gluconate and ferrous fumarate.
All three compounds, however, are associated with a high
incidence of side effects, including nausea, constipation, and
diarrhoea.
These side effects may be reduced by taking the
tablets after meals, but even milder symptoms account for poor
compliance with oral iron supplementation.
Modified release
preparations have been developed to reduce side effects but in
practice prove expensive and often release the iron beyond the
sites of optimal absorption.
Effective iron replacement therapy should result in a rise in
haemoglobin concentration of around 1 g/l per day (about
20 g/l every three weeks), but this varies from patient to
patient.
Once the haemoglobin concentration is within the
normal range, iron replacement should continue for three
months to replenish the iron stores.
Failure to respond to oral iron
therapy
The main reason for failure to respond to oral iron therapy is
poor compliance.
However, if the losses (for example,
bleeding) exceed the amount of iron absorbed daily, the
haemoglobin concentration will not rise as expected; this will
also be the case in combined deficiency states.
The presence of underlying inflammation or malignancy
may also lead to a poor response to therapy.
Finally, an
incorrect diagnosis of iron deficiency anaemia should be
considered in patients who fail to respond adequately to iron
replacement therapy.
Intravenous and intramuscular iron preparations
Parenteral iron may be used when the patient cannot tolerate
oral supplements for example, when patients have severe
gastrointestinal side effects or if the losses exceed the daily
amount that can be absorbed orally.
Iron sorbitol injection is a complex of iron, sorbitol and
citric acid.
Treatment consists of a course of deep
intramuscular injections.
The dosage varies from patient to
patient and depends on (a) the initial haemoglobin
concentration and (b) body weight.
Generally, 10-20 deep
intramuscular injections are given over two to three weeks.
Apart from being painful, the injections also lead to skin
staining at the site of injection and arthralgia, and are best
avoided.
An intravenous preparation is available (Venofer®) for
use in selected cases, and under strict medical supervision,
for example, on haematology day unit (risk of anaphylaxis or
other reactions).
Alternative treatments
Blood transfusion is not indicated unless the patient has
decompensated due to a drop in haemoglobin concentration
and needs a more rapid rise in haemoglobin for example, in
cases of worsening angina or severe coexisting pulmonary disease.
In cases of iron deficiency with serious ongoing acute
bleeding, blood transfusion may be required.
Prevention
When absorption from the diet is likely to be matched or
exceeded by losses, extra sources of iron should be
considered for example, prophylactic iron supplements in
pregnancy or after gastrectomy or encouragement of breast
feeding or use of formula milk during the first year of life
(rather than cows’ milk, which is a poor source of iron).
