Symptoms and signs

Gastroenterology and
anaemia

bowel disease on subsequent investigation. In others, anaemia

will be the only abnormal finding and categorization on the basis
of red cell morphology is used as a guide to the likely cause and
subsequent investigations. This article will discuss the approach
to investigation and management of anaemia in this group of
patients particularly in relation to GI disease. The clinical features associated with anaemia are not discussed.

Anne Ballinger

Microcytic anaemia and iron deficiency anaemia

Definition of iron deficiency
The World Health Organization defines anaemia as a haemoglobin level below 13 g/dl in men and below 12 g/dl in non-pregnant
women over the age of 15 years, and below 11 g/dl in pregnant
women.1 Iron deficiency is usually indicated by reduced mean
cell haemoglobin (MCH: hypochromia) and reduced mean cell
volume (MCV: microcytosis). The blood film also shows poikilocytosis (variation in shape) and anisocytosis (variation in size).
Other causes of microcytic hypochromic anaemia are thalass
aemia, anaemia of chronic disease and sideroblastic anaemia,
but in these disorders iron stores are normal or increased.
Serum ferritin is an excellent indicator of iron stores in other
wise healthy adults. Virtually all patients with a serum ferritin
level of less than 15 ng/ml are iron deficient. However, ferritin
is an acute-phase reactant and patients with iron deficiency who
also have infectious or inflammatory disease may have ferritin
levels within the normal range. In this situation, ferritin levels
of less than 50 ng/ml usually indicate iron deficiency. In iron
deficiency anaemia the serum iron (SI) is low and the level of
transferrin measured as total iron binding capacity (TIBC) is elevated, resulting in a reduced transferrin saturation (SI/TIBC
100%) of less than 20%. In general, transferrin saturation is less
sensitive and specific than serum ferritin for the assessment of
iron deficiency. Circulating transferrin receptor concentration is
proportional to erythropoietic activity and inversely proportional
to tissue iron availability. However, an increased serum level
is not specific for iron deficiency. Bone marrow sampling and
assessment of iron stores is rarely necessary in the assessment of
suspected iron deficiency.

Abstract
Anaemia is a common reason for referral to a gastroenterologist. Iron
deficiency anaemia is characterized by a microcytic hypochromic blood
picture with a low serum ferritin concentration. All patients with iron
deficiency, irrespective of age, should be screened for coeliac disease
by appropriate serology. Men, post-menopausal women, women over
50 years of age and younger women with gastrointestinal (GI) symptoms,
or a strong family history of colon cancer, should have investigation of
the upper and lower GI tract unless there is an overt source of non-GI
blood loss. About 1015% of patients will have gastric or colon cancer.
Further investigation is not indicated in those patients with normal tests
unless their haemoglobin cannot be maintained with oral iron treatment.
Macrocytic anaemia due to vitamin B12 or folate deficiency can usually be diagnosed on the basis of the typical blood picture (anaemia,
macrocytosis, hypersegmented neutrophils) and demonstrating reduced
serum concentrations of folate or vitamin B12. Further confirmatory
tests are not usually indicated. Vitamin B12 deficiency is often due to
malabsorption and the cause is often apparent after taking a careful
dietary and medical history. Pernicious anaemia is more common in older
women and the diagnosis made by finding specific blocking and binding antibodies against intrinsic factor and antibodies against parietal
cells. Malabsorption of vitamin B12 is usually treated with intramuscular
injection of hydroxocobalamin. Folate deficiency is usually due to dietary
deficiency and increased demands and less commonly as a result of
intestinal malabsorption.

Keywords cancer; coeliac disease; iron deficiency; pernicious anaemia

Causes of iron deficiency

Iron deficiency anaemia is present in 12% of adults in the developed world and more commonly in adolescent girls and woman
of childbearing age (25%).2,3 Iron deficiency without anaemia
is more common and indicates that iron stores are depleted but
sufficient to maintain a normal level of haemoglobin. The major
cause of iron deficiency in developed countries is blood loss, usually from the uterus in pre-menopausal women or GI tract in men
and post-menopausal women (Table 1). Worldwide, about 30%
of the population are anaemic and approximately half of these
cases can be attributed to iron deficiency. Helminth infections,
in particular hookworm, can cause GI blood loss and are a common cause of iron deficiency anaemia (IDA) in the developing
world. Adult hookworms attach themselves to the mucosa of
the duodenum and upper jejunum where they cause ulceration
and promote blood loss by secretion of an anticoagulant. The
poor quality of the diet contributes to the high prevalence of iron
deficiency in developing countries. Malabsorption of dietary iron
occurs in diseases associated with generalized malabsorption

Anaemia, particularly iron deficiency, is often referred for investigation and management under the care of the gastroenterology
team. Anaemia together with diarrhoea, abnormal liver biochemistry, gastrointestinal (GI) bleeding and abdominal pain
are the commonest reasons for referral of in-patients to a gast
roenterologist. In some patients, abnormal symptoms and signs
will dominate the clinical picture and guide investigation, e.g.
the patient with bloody diarrhoea, raised erythrocyte sedimentation rate (ESR) and anaemia who is found to have inflammatory

Anne Ballinger MD FRCP is a Consultant Gastroenterologist and General

Physician at the Homerton University Hospital NHS Foundation Trust,
London, UK. She qualified from University College London and trained
in gastroenterology in London. Her clinical and research interests
include inflammatory bowel disease and gastrointestinal cancer.
Competing interests: none declared.

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Symptoms and signs

regnancy and breast-feeding. Current guidelines recommend

p
that GI investigation, other than coeliac serology, in this group
of patients is unnecessary as the yield will be extremely low.
The exception is patients who are at increased risk for GI malignancy based on age, symptoms or family history (Table 2).9
Pre-menopausal women with iron deficiency anaemia and who
are not menstruating (e.g. due to hysterectomy) should be fully
investigated as described below.
Iron deficiency is common after partial or total gastrectomy.
The risk of carcinoma in the gastric remnant is increased compared with the unoperated stomach. However, comparative
studies have shown similar upper GI and colonic pathology in
post-gastrectomy and non-operated iron-deficient patients.11
Therefore, endoscopic investigation of iron deficiency should not
differ in post-gastrectomy patients.

Causes of iron deficiency

Occult gastrointestinal blood loss
Aspirin/NSAID ingestion
Colon cancer
Gastric cancer
Gastric ulceration
Gastrointestinal vascular abnormality (e.g. hereditary
haemorrhagic telangiectasia)
Oesophagitis
Oesophageal carcinoma
Small bowel tumour
Hookworm infection
Decreased iron absorption
Coeliac disease
Gastrectomy
Autoimmune gastritis
H. pylori infection
Gut resection

Investigation of patients with iron deficiency anaemia

Both upper GI endoscopy and colonoscopy should be performed
in all post-menopausal women and all male patients with iron
deficiency anaemia unless the history and examination has suggested a significant non-GI cause, or symptoms and signs localize
pathology to the upper or lower intestine. Colonoscopy is usually
preferred over double-contrast barium enema as biopsies can
be taken if necessary and vascular lesions are visualized. However, barium enema is an acceptable alternative if facilities or
expertise for complete colonosocopy are not available; but note,
audit data suggest that this will miss up to 10% of colon cancers.
About 10% of patients will be found to have colon cancer and
thus iron deficiency anaemia is an indication for urgent referral
(within two weeks) and investigation in this group of patients.12
Distal duodenal biopsies for histology are taken in patients with
positive coeliac serology, or if serology is not checked prior to
endoscopy. Prospective studies have found concurrent upper

Non-gastrointestinal blood loss

Menstruation
Multiple blood donations
Haematuria
Other causes
Increased demands such as pregnancy and lactation
Intravascular haemolysis with iron loss in the urine (rare)
Pulmonary haemosiderosis (rare)
Table 1

(most frequently from coeliac disease in the UK) or achlorhydria due to gastrectomy, autoimmune atrophic gastritis or Helicobacter pylori infection. Iron deficiency is common in patients with
inflammatory bowel disease due to GI blood loss and impaired
iron absorption (in Crohns disease). However, there are usually other symptoms (e.g. diarrhoea and abdominal pain) which
point to the diagnosis, and investigation is targeted appropriately. In contrast, most patients presenting with iron deficiency
have no localizing symptoms or signs and both upper and lower
GI investigations are indicated.

Indications for gastrointestinal investigation in

pre-menopausal women with iron deficiency
anaemia
Upper GI endoscopy
Age >50 years
Dyspepsia (onset within last year)
Dysphagia
Epigastric mass
Persistent vomiting

Which patients with iron deficiency anaemia need investigation?

In most patients with iron deficiency anaemia the history and
examination do not reveal an obvious cause. All patients, including
pre-menopausal women, should be screened for coeliac disease at
presentation by appropriate serology (anti-endomysial antibody or
anti-tissue transglutaminase antibody). Recent studies have shown
that the prevalence of coeliac disease in European populations is
approximately 1 in 100 and most cases are undiagnosed.49 Pros
pective studies have shown that the prevalence of coeliac disease
in patients presenting with iron deficiency anaemia is almost threefold higher than the general population and many do not have the
classical symptoms of diarrhoea and weight loss.10
Iron deficiency in pre-menopausal women is likely to be
due to menstrual blood loss and increased demands during

MEDICINE 35:3

Colonoscopy
Age >50 years
Palpable, right-sided, abdominal mass
Rectal mass
Change in bowel habit towards looser or more frequent stools
Rectal bleeding
Persistent IDA following iron supplementation and correction
of potential causes
Strong family history of colorectal cancer
one affected first-degree relative <45 years
two affected first-degree relatives
Table 2

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Symptoms and signs

GI disease and colon cancer in patients with IDA, and thus the
presence of pathology in the upper GI tract (e.g. oesophagitis or
peptic ulceration) should not preclude investigation of the colon.
Only the presence of gastric cancer or coeliac disease should be
accepted as the cause for iron deficiency anaemia without further
investigation of the lower GI tract. Helicobacter pylori infection
impairs intestinal iron uptake and increases blood loss in the
presence of gastritis and may by associated with iron deficiency
in infected patients.13 Eradication of H. pylori in patients with
iron deficiency anaemia and H. pylori-associated gastritis has
been associated with correction of anaemia.14 Thus, in patients
who have an otherwise normal endoscopic investigation, current guidelines recommend testing for H. pylori (usually by a
CLO [rapid urease] test on an antral biopsy) and eradicating if
present.9

is usually necessary only if the haemoglobin cannot be maintained in this way.

Macrocytic anaemia
Causes of vitamin B12 deficiency
Vitamin B12 deficiency is estimated to affect 1015% of individuals over the age of 60 years. Absorption requires normal function
of the stomach, pancreas and small intestine. Animal products
(meat and dairy products) provide the only source of vitamin
B12 (cobalamin) for humans. Total body stores are 1000-fold the
average daily requirement for an adult (2 g) and so are sufficient for some years after absorption of vitamin B12 ceases. After
ingestion, cobalamin is liberated from food proteins by gastric
acid and pepsin and then binds to a vitamin B12-binding protein (R binder) present in saliva and gastric juice. Cobalamin
bound to R binders is not absorbed but in the alkaline environment of the duodenum, pancreatic proteases degrade R binders,
leaving cobalamin available to bind to gastric-derived intrinsic
factor. This complex binds to a specific ileal receptor, cubilin,
and is absorbed in an energy-dependent process. Vitamin B12 is
transported from the enterocytes to the bone marrow and other
tissues by the glycoprotein, transcobalamin II. Vitamin B12 deficiency is due to a defect in one or more of these steps in the
absorption and transport pathway (Table 3).

Further investigation of iron deficiency anaemia

Upper and lower GI endoscopy with appropriate biopsies (small
bowel for coeliac disease and CLO test for H. pylori infection)
frequently reveals at least one lesion potentially responsible for
blood loss in IDA patients. After conventional investigation,
the source of bleeding remains unidentified in approximately
10% of patients. The yield from subsequent radiographic
examination of the small bowel is low in this group and not
recommended unless there is clinical evidence for small bowel
disease, e.g abdominal pain suggestive of Crohns disease.12,15
Follow-up studies have shown that the prognosis of iron deficiency after negative endoscopic examination is favourable. Iron
deficiency resolves with iron supplementation in most patients
and does not recur on follow-up.16 Subsequent GI investigation
is reserved for those patients whose anaemia is refractory to
iron replacement (see below) and in whom NSAIDs have been
stopped. In this situation enteroscopy allows direct visualization
of the small bowel mucosa to a distance of 80120 cm beyond
the ligament of Treitz and is able to detect vascular lesions
not seen on small bowel barium follow-through examination.
Video capsule endoscopy examines the entire small intestine
and has a higher diagnostic yield than enteroscopy in this
group of patients.

Causes of vitamin B12 deficiency

Dietary
Low dietary intake
Strict vegan
Gastric abnormalities
Gastrectomy
Pernicious anaemia
Atrophic gastritis
Pancreatic abnormalities
Chronic pancreatitis
Pancreatectomy

Treatment of iron deficiency

Iron is best absorbed from the duodenum and proximal jejunum in the ferrous form (Fe2+) in a mildly acidic environment.
The cheapest and simplest method of treating iron deficiency
is ferrous sulphate tablets of which each 200 mg tablet contains 65 mg of elemental iron. Lower doses may be better tolerated and equally efficacious as the two to three tablets daily
recommended in the British National Formulary. Ascorbic acid
(250 mg) taken at the time of iron administration may enhance
iron absorption. Side effects of iron treatment (diarrhoea, constipation, nausea, abdominal discomfort) are thought to be related
to the content of elemental iron. Preparations with a lower elemental iron content, e.g. ferrous gluconate (35 mg elemental
iron in a 300 mg tablet) may be useful for patients with troublesome side effects. Parenteral iron therapy is reserved for the
rare patient who cannot tolerate oral iron in the doses necessary
to maintain haemoglobin. Iron treatment is continued until the
haemoglobin and red cell indices normalize and a further course
given if the haemoglobin falls. Further investigation (see above)

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Small bowel disease

Ileal disease e.g. coeliac or Crohns disease
Terminal ileal resection or bypass
Bacterial overgrowth
Fish tapeworm (Diphyllobothrium latum)
Inherited disorders
Transcobalamin II deficiency
Intrinsic factor deficiency
Cubilin deficiency
Medication
Metformin (mechanism uncertain)
Proton pump inhibitors (inhibits gastric acid secretion)
H2 receptor antagonists (inhibits gastric acid secretion)
Nitrous oxide (inactivates cobalamin)
Table 3

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Symptoms and signs

Diagnosis of vitamin B12 deficiency

Normal serum concentrations of vitamin B12 have been reported
in patients with overt B12 deficiency and in whom the clinical and
haematological picture was strongly suggestive and prompted
further investigation.17 This is in part related to the difficulty
in selection of a cut-off point for the reference range and also
false-normal results where the serum levels are well within the
reference range. Measurement of serum metabolites may facilitate identification of such patients by demonstrating biochemical features of B12 deficiency (raised serum homocysteine and
methylmalonic acid).

Causes of folate deficiency

Poor intake
Anorexia
Alcohol excess (also causes impaired utilization)
Old age
Poor dietary intake
Malabsorption
Small bowel disease or resection
Increased requirements
Pregnancy
Breast-feeding
Haemolytic anaemia
Exfoliative skin disease
Renal dialysis

Investigation of patients with vitamin B12 deficiency

Testing for antibodies to intrinsic factor and parietal cells and
serology for coeliac disease are usually the initial investigations
in patients in whom the cause of vitamin B12 deficiency is not
clear from a careful dietary and clinical history. Low vitamin B12
is common in coeliac disease without concurrent pernicious anaemia and may be a presenting manifestation.18 Pernicious anaemia
is a common cause of vitamin B12 deficiency and occurs in 24%
of people over the age of 60 years. It is an autoimmune condition
that is associated with gastric atrophy and loss of intrinsic factor
production by gastric parietal cells. Antiparietal cell antibodies
occur in 90% of patients with pernicious anaemia but also occur
in healthy adults and are not specific for the diagnosis. Binding and blocking antibodies to intrinsic factor are found in 50%
of patients with pernicious anaemia and provide a highly specific but insensitive test for pernicious anaemia. Autoantibodies
directed against parietal cells are associated with a chronic atrophic gastritis and a reduction in intrinsic factor production. However, upper GI endoscopy and gastric biopsy for histology is not
usually necessary to make the diagnosis. The chronic gastritis in
pernicious anaemia is, however, associated with an increased
risk of intestinal-type gastric cancer and endoscopy should be
performed if there are gastric symptoms. Mild and usually subclinical B12 deficiency occurs with increased frequency in the
elderly (approximately 10% of people >75 years).19 In most of
these patients intake of vitamin B12 is adequate and they do not
have pernicious anaemia. There is an inability to release vitamin
B12 from dietary proteins and many factors contribute, including
gastric atrophy and achlorhydria related to H. pylori infection.
Radioactive B12 is not available in the UK and the Schilling test is
no longer used in the assessment of vitamin B12 deficiency. The
clinical history and simple blood tests will usually diagnose the
cause of vitamin B12 deficiency.

Drugs
Trimethoprim
Phenytoin
Sodium valproate
Methotrexate
Table 4

necessary if serum folate is not thought to be reliable, e.g. borderline serum values, combined folate and vitamin B12 deficiency or
recent anorexia. Folic acid deficiency because of poor nutrition
or increased demands is treated with folic acid 5 mg daily.

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Treatment of vitamin B12 deficiency

Vitamin B12 deficiency due to malabsorption is usually treated
with intramuscular injection of hydroxocobalamin 1 mg three
times a week for two weeks and then three-monthly for life. Daily
dosing is given initially if there is neurological involvement.
Folate deficiency
Folate occurs in animal products and leafy vegetables but is easily destroyed by heat during cooking. The main cause of deficiency is poor intake and malabsorption of folate is usually not
the only cause (Table 4). Measurement of serum folate reflects
short-term folate balance but is usually a reliable measure of tissue folate stores. Measurement of red cell folate is usually only

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Symptoms and signs

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