CLINICAL SCIENCES
r
Iron, vitamin B12 and
folate
Rachel Moll
Bernard Davis
Abstract
Iron, vitamin B12 and folate are required for essential metabolic func-
tions. Deficiency states of these nutrients, either singly or in combina-
tion, are common clinical conditions. Clinically, they present with not
only disordered haematopoiesis, but also widespread effects in
other organs that can precede the appearance of haematological ab-
normalities. Investigation of suspected iron, vitamin B12 or folate defi-
ciency should first be directed at establishing that the deficiency state
exists, but this can be challenging because of the limitations of avail-
able biomarkers for evaluating tissue status. A careful assessment of
clinical symptoms and signs is indispensable to guide appropriate
requesting and interpretation of relevant laboratory tests. Every effort
should be made to determine the cause of the nutritional deficiency
and to treat it where possible. Correcting the deficiency with supple-
ments is usually straightforward, provided adherence to treatment is
ensured. Blood transfusion should be avoided unless symptoms
te r
dictate otherwise.
Keywords Anaemia; deficiency; folate; iron; vitamin B12
as
Iron
In humans, iron is an essential functional component of many
proteins that participate in vital metabolic functions such as
oxygen transport, oxidative energy production, mitochondrial
nM
respiration, inactivation of harmful oxygen radicals and DNA
synthesis.
Iron absorption and plasma transport
In health, iron is maintained at stable concentrations in plasma
and tissues primarily by tight regulation of dietary iron absorp-
tion and conservation of body iron stores. This systemic iron
homeostasis, briefly described below, is controlled by a variety of
di
proteins; the key regulator of these is hepcidin, a hormone pro-
duced by hepatocytes.1
The average body iron content in health is around 40 mg/kg
body weight for women and 50 mg/kg for men. Approximately
30 mg/kg of iron is present within red cells as haemoglobin, with
4 mg/kg as myoglobin in muscle tissue and 2 mg/kg as iron-
a te
Rachel Moll MRCP is a Specialist Registrar in Haematology at the
Whittington Hospital, London, UK. Competing interests: none
declared.
Bernard Davis MD FRCP FRCPath is Consultant Haematologist at the
re
Whittington Hospital and Honorary Clinical Senior Lecturer at
University College London Medical School, UK. Competing interests:
none declared.
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i to
Key points
C Iron, folate and vitamin B12 deficiencies are common clinical
problems with important health consequences
Ed
C Diagnosis of each deficiency state is best achieved by careful
evaluation of clinical features and appropriate laboratory tests
C Serious morbidity from these deficiencies can occur before
anaemia has developed; therefore treatment should be insti-
tuted early
F
C Nutritional replacement should be given for a sufficiently long
period to replenish tissue stores and can be needed indefi-
nitely depending on the aetiology
PD
C The underlying cause of each nutritional deficiency should be
assiduously determined and treated wherever possible
containing enzymes in cells. The remainder is held in reserve
as storage iron in the form of ferritin or haemosiderin predomi-
nantly in the liver, spleen and bone marrow. In absolute terms,
the quantity of storage iron is usually 0e2 g, the actual amount
present at any one time depending on the balance between di-
etary intake and physiological requirements. In normal circum-
stances, ferritin predominates as the principal form of tissue iron
in the liver and spleen.
An average diet in developed countries contains 10e15 mg/
day of iron, of which only 5e10% is absorbed. Iron in the form of
either haem iron or inorganic iron is absorbed mainly in the
duodenum and proximal jejunum through enterocytes that are
highly specialized for iron absorption and transport. Haem iron,
which accounts for 50% of the iron in meat, is more readily
absorbed than non-haem iron.
Once in the plasma, iron circulates bound to transferrin,
which transports most of the iron to the bone marrow for the
synthesis of haemoglobin in red cells. At the end of their lifespan,
red cells are phagocytosed in macrophages of the reticuloendo-
thelial system, where iron is released from haemoglobin and
either stored as ferritin or exported back to the plasma as
required for erythropoiesis. This recycled iron accounts for most
of the iron in the plasma compartment; only 5% of plasma iron is
derived from dietary iron absorption. Transferrin-bound plasma
iron turns over every 3e4 hours and acts as the physiological
transit pool through which iron is delivered to every cell in the
body, including the erythropoietic marrow.
Clinical features of iron deficiency
Iron deficiency is the most common cause of anaemia world-
wide. Anaemia is a late consequence of iron deficiency, as the
recycling of iron from senescent red cells continues to support
erythropoiesis for some time after depletion of tissue iron stores.
Other clinical features of tissue deficiency include fatigue,
angular stomatitis, painful glossitis, oesophageal webs causing
dysphagia (PlummereVinson syndrome), pica and restless leg
syndrome, which is particularly prevalent in pregnancy. Iron
1 Ó 2017 Published by Elsevier Ltd.
 CLINICAL SCIENCES
deficiency in infancy can lead to long-term cognitive impairment
and behavioural problems that persist long after treatment.
Causes of iron deficiency

Reduced dietary intake e diets lacking in red meat and
green vegetables. This is rarely the sole cause.

Reduced absorption e causes including coeliac disease,
gastrectomy and gastric bypass surgery.

Chronic blood loss e with menorrhagia and gastrointestinal
blood loss as particularly common causes. Malignancy
should be excluded in older patients and those with ‘red flag’
features in the history. Hookworm is the most common
cause worldwide. Intravascular haemolysis (e.g. paroxysmal
nocturnal haemoglobinuria) may be responsible for iron loss
leading to iron deficiency in the absence of bleeding.

Increased physiological demands e where iron stores
and intake are not sufficient to cope with increased re-
quirements, for example pregnancy, prematurity and the
adolescent growth spurt.
Investigation of iron deficiency
Haematological tests:

Full blood count e low mean corpuscular volume and
increased red cell distribution width are common findings.
Anaemia is a late development and may not be present in
established iron deficiency. Thrombocytosis is common,
te r
even in the absence of active bleeding.

Blood film e morphological changes (microcytosis, hypo-
chromia, target cells, pencil cells, etc.) develop before
anaemia.
as
Tests to confirm iron deficiency:

Serum iron, total iron binding capacity (TIBC), serum
ferritin and transferrin saturation e typically, serum iron,
serum ferritin and transferrin saturation are low, while
TIBC is raised. However, this pattern can be confounded
nM
by factors such as inflammatory states and acute illness,
which can complicate their interpretation.

Perl’s Prussian blue stain for iron in bone marrow aspirate
or trephine biopsy e this gives an indication of tissue
stores; it is very reliable but is invasive and rarely required.

Serum soluble transferrin receptor e values rise in iron defi-
ciency and can help differentiate iron deficiency from anaemia
of chronic disease, but the test is not widely available.
di
Establishing the underlying cause of iron deficiency: iron defi-
ciency can be a presenting feature of serious disease; therefore its
underlying cause must be found and treated. Providing there are no
other suspicious features and response to treatment is monitored, a
history of menorrhagia and/or pregnancy may be acceptable as the
a te
cause without extensive further investigation before treatment is
started. In all other cases, the cause should be assiduously investi-
gated, particularly to exclude or identify gastrointestinal malignancy.
Gastrointestinal tract investigations include:

endoscopy e in individuals with gastrointestinal symptoms or
in asymptomatic individuals with unexplained iron deficiency

capsule endoscopy e may be required to exclude occult
re
bleeding in areas of the small bowel that are inaccessible to
gastroscopy and colonoscopy
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coeliac disease investigation e anti-tissue trans-
i to
glutaminase and/or duodenal biopsy

other relevant gastrointestinal investigations for
malabsorption

stool for ova, cysts and parasites e a positive travel history
can be relevant.
Ed
Gynaecological investigations may be required to investigate
abnormal vaginal bleeding, and the urinary tract should be
investigated if there is a history of haematuria.
In a small proportion of patients, extensive tests do not un-
cover the cause of the deficiency. In such situations and if a
sinister cause has been excluded, iron replacement should be
administered to improve symptoms.
F
Treatment
The most cost-effective treatment is oral iron supplementation,
PD
most commonly with ferrous sulphate. The recommended ther-
apeutic dose is 200 mg three times daily. It is generally well
tolerated and corrects anaemia and restores tissue stores if given
for several (e.g. 4e6) months. Oral iron can cause gastrointes-
tinal adverse effects, notably abdominal bloating and con-
stipation, but diarrhoea can also occur. For patients who
experience adverse effects from ferrous sulphate, equally effec-
tive alternative preparations including liquid formulations of
iron can be trialled. A poor response to oral iron supplementa-
tion can be the result of poor adherence to therapy, malab-
sorption, misdiagnosis (e.g. thalassaemia trait) or uncontrolled
blood loss.
Iron replacement can be given parenterally by intravenous
infusion where oral iron cannot be tolerated or is ineffective and
in malabsorptive conditions. The main advantage of intravenous
iron is that iron can be rapidly replaced; however, the rate of
haemoglobin increase is identical for intravenous iron and oral
iron. The main risk of intravenous iron is anaphylaxis, which is
rare. Blood transfusion is not usually required for iron deficiency
anaemia unless the patient is severely symptomatic.
Iron deficiency can complicate a number of chronic disorders,
for example chronic kidney disease. It frequently occurs in heart
failure, where replacement of iron is associated with an
improvement in cardiac function and symptoms.
Vitamin B12
Vitamin B12 (cobalamin) is a cobalt-containing vitamin that is
synthesized by microorganisms and exists in different chemical
forms in foods of animal origin, including milk, cheese and eggs,
as well as artificially fortified foods.
In humans, vitamin B12 has two important metabolic
functions:

As methylcobalamin, it acts as a co-enzyme in the methyl-
ation of homocysteine to methionine in the cytosol. This
reaction is an important first step in the conversion of folate
to metabolically active forms that are required as co-
enzymes for the synthesis of thymidine for DNA. Thus in
B12 deficiency, the active forms of folate cannot be formed
and DNA synthesis fails, resulting in megaloblastic anaemia.

As 50 -deoxyadenosyl cobalamin, B12 acts as a co-enzyme in
the conversion of l-methylmalonyl co-enzyme A to succi-
nyl co-enzyme A in mitochondria.
2 Ó 2017 Published by Elsevier Ltd.
 CLINICAL SCIENCES
Vitamin B12 deficiency (quantitative or functional) therefore
leads to an accumulation of homocysteine and methylmalonic
acid (MMA) in plasma.
Vitamin B12 absorption and plasma transport
The average diet in developed countries contains about 5e30
microgram/day of vitamin B12, and daily requirements and los-
ses are 1e4 micrograms. Usual body stores of 3e4 mg (mainly in
the liver and kidney) are sufficient for about 3 years; thus, a
deficiency state is slow to develop.
The absorption, transport and cellular uptake of vitamin B12
are mediated by three carrier proteins: haptocorrin (formerly
transcobalamin I), gastric intrinsic factor (IF) and trans-
cobalamin (formerly transcobalamin II). Haptocorrin has the
greatest affinity for B12 but the least specificity, whereas IF has
the highest specificity and lowest affinity.
After its liberation from ingested food in the acidic gastric
environment, vitamin B12 binds to haptocorrin in the stomach.
On reaching the duodenum, haptocorrin is digested by pancreatic
proteases, allowing B12 to bind to IF, a glycoprotein secreted by
gastric parietal cells. Vitamin B12 absorption takes place in the
distal ileum by receptor-mediated endocytosis, through the
agency of a highly specialized receptor complex.2
The B12eIF complex dissociates within the ileal enterocytes,
and vitamin B12 emerges in the circulation. In plasma, B12 is bound
to haptocorrin (70e90%) and transcobalamin (10e30%).2
te r
Transcobalamin-bound vitamin B12 (holotranscobalamin) is the
biologically available fraction that is taken up into all cells
including marrow cells; in contrast, haptocorrin-bound B12 is not
available to cells outside the liver.
Vitamin B12 is secreted in bile and undergoes enterohepatic
as
circulation, a process that depends on IF. This process, together
with the renal reabsorption of the vitamin, can help to explain
why vegans can have low tissue stores without developing
clinical symptoms of deficiency.2
nM
Clinical features of vitamin B12 deficiency
It is important to distinguish clinical deficiency from subclinical
deficiency because there are major differences between these two
deficiency states.
Clinical cobalamin deficiency occurs in less than 0.1% of
adults and 1e2% of elderly individuals. It is a serious disease
that requires medical intervention.3 It is caused by severe
malabsorption due to IF failure or ileal malabsorption in more
than 95% of cases. Clinical symptoms are usually present and
di
progressive, and homocysteine and MMA concentrations are
usually markedly elevated.
Clinical deficiency of cobalamin presents with a number of
disorders including:

megaloblastic anaemia, due to disruption of DNA synthesis
a te
and repair that results in ineffective erythropoiesis; how-
ever, it should be noted that 19e24% of clinically deficient
patients are not anaemic3

neuropsychiatric manifestations, which are serious and
can occur in the absence of anaemia. They include pe-
ripheral and autonomic neuropathy, subacute combined
degeneration of the spinal cord, optic atrophy, mood and
re
behaviour changes, psychosis, and cognitive problems
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r
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including dementia; the exact underlying mechanism of
the neurological effects is not known

atrophic glossitis

infertility and recurrent spontaneous abortions.
Most identified cases of vitamin B12 deficiency fall into the
category of subclinical cobalamin deficiency (SCCD). This con-
Ed
dition is distinguished from clinical deficiency by the absence of
clinical symptoms or haematological abnormalities, and mild or
minimal changes in MMA or homocysteine concentrations.3 The
cause is usually unknown, but food-bound cobalamin deficiency
(see below) is a factor in up to 50% of cases; severe malab-
sorption is rare because IF secretion is normal. As a result, the
clinical course of SCCD is static, and progression to clinical
F
deficiency is rare. The need for treatment of SCCD is unclear
because its natural history is unknown.
PD
Causes of vitamin B12 deficiency

Inadequate dietary intake e vegan or vegetarian diets are
the main cause in younger adults. Pregnant and lactating
women on such diets are at high risk because of increased
metabolic demands.

Acquired disorders of B12 absorption:
 food-bound cobalamin malabsorption (FBCM) e the
most common cause of vitamin B12 deficiency in older
people.3 It is caused by impaired ability to release
vitamin B12 from food; IF secretion is intact and clinical
manifestations are rare. FBCM can be caused by condi-
tions resulting in gastric dysfunction or reduced gastric
acid secretion such as gastric resection, treatment with
proton pump inhibitors and persistent infection with
Helicobacter pylori
 pernicious anaemia
 ileal resection
 gastrectomy
 Crohn’s disease
 chronic pancreatitis: impaired degradation of haptocorrin-
bound B12 in the duodenum because of reduced pancreatic
enzyme secretion, preventing IF binding to vitamin B12
 HIV infection
 coeliac disease
 metformin and the oral contraceptive pill; the underlying
mechanisms are not yet established
 parasite infestation: Diphyllobothrium latum and Taenia.

Inherited disorders of B12 absorption:
 ImerslundeGr€asbeck syndrome
 hereditary IF deficiency
 transcobalamin deficiency.
Investigation of B12 deficiency
Haematological tests:

Full blood count e the characteristic finding is a macro-
cytic anaemia; however, macrocytosis and anaemia can be
absent in clinically deficient patients.3 Leucopenia and
thrombocytopenia can also occur.

Blood film e hypersegmented neutrophils, oval macrocytes.

Bone marrow examination e characteristic changes
including megaloblasts, giant metamyelocytes, nuclear
ecytoplasmic asynchrony, but rarely required.
3 Ó 2017 Published by Elsevier Ltd.
 CLINICAL SCIENCES
Tests to confirm vitamin B12 deficiency: there is no gold stan-
dard test; the limitations of current tests should be taken into
account when interpreting the results.4
Serum vitamin B12 is routinely used as the primary initial
test. It measures total serum vitamin B12, most of which is
haptocorrin-bound and thus not reflective of cellular vitamin
B12 status. Functional vitamin B12 deficiency can therefore be
present even when serum B12 concentrations are normal. It has
a sensitivity of over 95% in individuals with clinical B12 defi-
ciency.3 Falsely low results can occur in pregnancy and folate
deficiency.
Supplementary biochemical tests can be required to investi-
gate cobalamin status where there is a clinical suspicion of
deficiency with unclear serum B12 results:

plasma homocysteine e elevated homocysteine concen-
trations occur in both vitamin B12 and folate deficiency;
therefore it is of limited value as a stand-alone test

plasma MMA e concentrations are elevated in B12 defi-
ciency. It is a more specific marker of B12 deficiency than
plasma homocysteine, but concentrations are elevated in
renal impairment

serum holotranscobalamin e this has been successfully
used as a marker of bioactive vitamin B12; however, its
utility as a first-line test awaits further investigation.
Tests to establish cause of B12 deficiency:
te r

Anti-IF antibody e positive anti-IF antibody has a high
predictive value for pernicious anaemia. However, the test
has a low sensitivity so a negative result does not exclude
pernicious anaemia.4

There are no reliable tests for B12 malabsorption since the
as
Schilling test became unavailable over a decade ago. An
absorption test that measures the rise in serum holo-
transcobalamin after fixed oral doses of cobalamin is not
widely available, and there is limited information of its
performance in clinical settings.3
nM

Coeliac screening.
Other tests:

Folate status should be measured in suspected vitamin B12
deficiency in view of the interrelationship between the
metabolism of the two vitamins.

Iron status should also be checked because iron deficiency
can coexist in up to 20% of individuals with pernicious
di
anaemia.

Unconjugated bilirubin and lactate dehydrogenase can be
elevated as a result of ineffective erythropoiesis.
Treatment of vitamin B12 deficiency
Neurological complications can develop in the absence of
a te
anaemia, so it is imperative to commence treatment as soon as
the diagnosis is made.
Current standard clinical practice for the treatment of clinical
vitamin B12 deficiency in the UK is intramuscular replacement
with hydroxocobalamin 1 mg administered three times per week
for 2 weeks, or on alternate days for patients with neurological
involvement until there is no further improvement. Thereafter, it
re
is given 3-monthly for life in cases of B12 malabsorption resulting
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from failure of IF or its uptake by ileal cells (or 2-monthly for
those with neurological involvement).4
Blood transfusion should be avoided unless symptoms or
cardiovascular risks dictate otherwise. Vitamin B12 replacement
can cause depletion of iron and/or folate stores as red cell syn-
thesis increases; therefore a short period of iron and folate sup-
Ed
plementation may be required. Transient hypokalaemia can
occur during treatment in severely anaemic patients. Folic acid
must not be initiated before vitamin B12 as this can cause or
aggravate neurological complications.
The benefits of treating subclinical deficiency are unknown
because of a lack of good quality clinical trial data. A short course
of oral cyanocobalamin (50 micrograms for 4 weeks) with strict
F
instructions that the patient seek immediate medical attention if
neurological symptoms develop has been suggested, but the
strength of recommendation is weak and quality of evidence is
PD
low.4
Folate
Folate is the generic term for a family of water-soluble com-
pounds in the B vitamin family.
Folate co-enzymes play a crucial role in one carbon meta-
bolism, principally as acceptors and donors of one-carbon units.
Through this role, folate co-enzymes mediate two major inter-
related metabolic cycles: the DNA cycle (synthesis of thymidylate
and purines) and the methylation cycle (remethylation of ho-
mocysteine to methionine). Methionine is the immediate pre-
cursor of S-adenosyl methionine, which functions as the
universal donor in many transmethylation reactions, including
the methylation of DNA, histones and other proteins. Thus, folate
deficiency has severe metabolic and clinical consequences.
Folate absorption and transport
Dietary folate is found in highest concentrations in liver and leafy
green vegetables. Fortified foods provide a good additional di-
etary source in countries with folic acid food fortification prac-
tices.5 The daily adult requirement is 50 micrograms; body stores
amount to about 10e20 mg, which is sufficient for 2e3 months.
Thus, unlike vitamin B12 deficiency, folate deficiency can occur
rapidly. Moreover, in contrast to vitamin B12 which is resistant to
heat, folate is heat-labile and is destroyed when food is cooked at
high temperatures.
Dietary folate occurs in the form of polyglutamates, which are
converted to monoglutamates by enzymatic hydrolysis in the
intestinal brush border before their absorption. Folate absorption
occurs by both carrier-mediated and passive mechanisms,
mainly in the duodenum and jejunum, where dietary poly-
glutamates are hydrolysed and then reduced and methylated in
the enterocyte. Folate enters the portal circulation as methylte-
trahydrofolate, which is the predominant form in the plasma.
The principal transporter of folate in plasma is the reduced folate
carrier, which delivers folate from the systemic circulation to the
cells and tissues. Within body cells, methyltetrahydrofolate is
converted to a metabolically active form (tetrahydrofolate) in a
reaction that requires vitamin B12 as a co-enzyme. Tetrahy-
drofolate is then converted to other forms that also have co-
enzyme activity.
4 Ó 2017 Published by Elsevier Ltd.
 CLINICAL SCIENCES

r

Red cell folate e reflects folate in the preceding 120 days

i to
Causes of folate deficiency

Inadequate dietary intake e with old age, alcohol abuse (lifespan of the red cells) and also correlates well with
and poverty as risk factors hepatic stores (i.e. tissue status)

Increased requirements:
Plasma homocysteine e concentrations are elevated in
 pregnancy and lactation folate deficiency, but this finding is also observed in
 rapid growth in adolescence vitamin B12 deficiency and renal impairment.

 conditions of increased cell turnover (neoplastic dis-
eases, inflammatory diseases, haemolytic anaemias)
 patients undergoing renal dialysis

Malabsorption:
 extensive inflammatory bowel disease (e.g. Crohn’s)
 coeliac disease
 alcohol abuse
Ed
Tests to determine the cause of folate deficiency: the cause of
folate deficiency should be investigated, including a coeliac
screen and other tests of malabsorption where appropriate.
Treatment of folate deficiency
Folic acid tablets 5 mg daily given for about 3e4 months corrects

F
 tropical sprue the deficiency. Dietetic advice should be given if there is dietary

Antifolate drugs: deficiency. Prophylactic folic acid 400 micrograms daily given to
 anticonvulsants such as phenytoin women who are pregnant or planning pregnancy significantly
A

PD
 methotrexate reduces the risk of fetal neural tube defects.
 sulfasalazine
 metformin.
KEY REFERENCES
1 Ganz T, Nemeth E. Iron homeostasis in host defence and inflam-
Clinical features of folate deficiency
mation. Nat Rev Immunol 2015; 15: 500e10.
The effects of low folate mirror those of vitamin B12 deficiency,
2 Kozyraki R, Cases O. Vitamin B12 absorption: mammalian physiology
but peripheral neuropathy and subacute combined degenera-
and acquired and inherited disorders. Biochimie 2013; 95: 1002e7.
tion of the cord are less prevalent in folate deficiency.
3 Carmel R. Diagnosis and management of clinical and subclinical
Folate deficiency is strongly linked to the development of
neural tube defects in fetuses, the risk of which can be sub-
te r cobalamin deficiencies: why controversies persist in the age of
sensitive metabolic testing. Biochimie 2013; 95: 1047e55.
stantially reduced by pre-conception/early pregnancy folate
4 Devalia V, Hamilton MS, Molloy AM, British Committee for Standards
supplementation.
in Haematology. Guidelines for the diagnosis and treatment of
Investigation of folate deficiency cobalamin and folate disorders. Br J Haematol 2014; 166: 496e513.
Haematological tests: The haematological tests and findings are 5 Bailey LB, Stover PJ, McNulty H, et al. Biomarkers of nutrition for
as
identical to those for vitamin B12 deficiency. development e folate review. J Nutr 2015; 145: 1636Se80S.

Tests to confirm folate deficiency:

Serum folate e reflects recent intake so may not identify
tissue deficiency if folic acid has recently been ingested
nM

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.
di

Question 1 What is the most likely cause of this blood picture?

A. Combined effect of iron deficiency and hydroxycarbamide
A 55-year-old woman presented with a 3-month history of upper
B. Bone marrow suppression from hydroxycarbamide
abdominal pain after meals. She was taking long-term hydrox-
C. Concurrent iron and vitamin B12 deficiency
ycarbamide and aspirin for essential thrombocythaemia.
D. Increased reticulocyte count associated with drug-induced
a te

haemolysis
Investigations
E. End-stage aplastic anaemia

Haemoglobin 106 g/litre (115e165) (had been 117 g/litre 6
weeks previously)

Mean corpuscular volume 88.9 fl (80e96) Question 2

White cell count 5.6  109/litre (4.0e11.0)
A 20-year-old man presented to the emergency department with

Platelets 262  109/litre (150e400)
a 2-week history of weakness, dizziness and paraesthesia. He
re

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 CLINICAL SCIENCES

had been living rough for 4 years with a very poor diet consisting
mostly of potato crisps.
On clinical examination, his body mass index was 17 kg/m2, and
there was angular stomatitis, atrophic glossitis and mouth ulcers.
Investigations
r
i to
She was teetotal and not taking any regular medicines. On direct
questioning, she had a 2-month history of ‘pins and needles’ in
her feet.
On clinical examination, there was reduced vibration sense and
proprioception in her legs, exaggerated knee jerks and bilateral
extensor responses.

Haemoglobin 55 g/litre (130e180)

Mean corpuscular volume 111 fl (80e96)

White cell count 1.2  109/litre (4.0e11.0)

Neutrophil count 0.19  109/litre (1.5e7.0)

Platelets 11  109/litre (150e400)

Serum vitamin B12 below limit of quantitation

Serum folate 0.6 microgram/litre (2.0e11.0)
Ed
Investigations

Haemoglobin 120 g/litre (115e165)

Mean corpuscular volume 106 fl (80e96)

White cell count 5.0  109/litre (4.0e11.0)

Platelets 160  109/litre (150e400)

Blood film showing hypersegmented neutrophils

F

Serum ferritin 600 microgram/litre (15e300)
Vitamin B12 190 ng/litre (160e760)

Serum iron <3 micromol/litre (12e30)
Serum folate 4.0 microgram/litre (2.0e11.0)

Total iron binding capacity 39 micromol/litre (45e75)
Thyroid and liver function tests normal

What is the single most important next step?
A. Give folic acid
B. Give vitamin B12 injections
C. Transfuse 2 units of platelets
D. Transfuse 2 units of red cells
E. Give ferrous sulphate
PD
What is the single most appropriate next investigation?
A. Check the methylmalonic acid concentration
B. Check the red cell folate concentration
C. Perform a bone marrow examination
D. Perform nerve conduction studies
te r E. Perform a vitamin B12 absorption test

Question 3
A 44-year-old woman complained of a 3-month history of tired-
ness. She was referred with an abnormality of her blood count.
as
nM
di
a te
re

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