Sheet 2 Iron deficiency Pathway

All patients:
commence iron
therapy

If Hb <50g/L
or very
symptomaticconsider
admission

Hb < 120g/L women

Hb < 130g/L men
WITH MCV <80fl and ferritin <15g/L
OR MCV Normal (80-100fl) AND
Ferritin 15-50g/L
+ Transferrin saturation 20%

Careful history/
examination
including assessment
of family history

Yes

Coeliac Screen (TTG)

Dyspepsia/Colorectal Guidelines
Consider urgent referral if:
Weight loss
Progressive dyspepsia
Mass in abdomen
PR bleed
Change in bowel habit >6/52
Age >60

GI symptoms

Referral to gynaecology,
haematology,
urology
etc as appropriate
No

Yes

Exclude obvious causes:

i.e. Menorrhagia / haematuria
By history and urine dipstick
Dietary and drug history
No
Check
haemoglobinopathy
screen
If abnormal, see sheet 6)

Urgent
referral
HSC205

Page 1 of 2

Coeliac Screen
(TTG)

Positive

Negative

Male

Female

Menstruating

Nonmenstruating or
minimal periods

OGD with
duodenal
biopsy

Strong family
history of colorectal ca
Iron replacement
for 3/12 & correct
potential causes of
losses then reassess

Inadequate
response

HSC205
OGD + Duodenal
Bx
Colonoscopy

Consider
colonoscopy if:
Aged >50 yrs or
family history of
colorectal cancer
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Sheet 2 Iron deficiency Pathway

2-5% of population have Iron deficiency anaemia (IDA), but this makes up
4-13% of referrals to gastroenterology. The commonest gastrointestinal
causes are colorectal and gastric carcinoma and coeliac disease
Investigation
Do a urine dipstick, 1% of IDA with have renal malignancy.
Consider aspirin / NSAIDs as cause but investigate all IDA.
A significant family history for colon ca is two 1st degree relatives or
one if <40yrs.
Consider OGD as first investigation as will exclude colonoscopy in gastric
ca and coeliac and avoids bowel prep. Consider colonoscopy if: aged >50
yrs or family history of colorectal ca even in patients with confirmed
coeliac disease.
Treatment
Patients with established iron deficiency anaemia should be given
100- 200mg elemental iron daily. This can be achieved with oral ferrous
sulphate 200mg bd
Patients should be advised on correct administration to optimise
absorption, including the use of ascorbic acid 500mg daily, taking on
empty stomach, avoiding other medications or antacids at same time.
All patients should be counselled regarding diet including details of iron
rich food sources and factors that may inhibit or promote iron
absorption. This should be consolidated by the provision of an
information leaflet in the appropriate language.
Link to iron in your diet leaflet: http://hospital.blood.co.uk/library/
pdf/2011_Iron_English.pdf
For nausea and epigastric discomfort, preparations with lower iron
content should be tried. Slow release and enteric coated forms should
be avoided

Page 2 of 2

If not responsive to oral iron, consider non-compliance as a cause.

Once Hb is in the normal range, supplementation should continue for
three months.
Parenteral iron should be considered for patients with confirmed iron
deficiency who fail to respond to or are intolerant of oral iron. Parenteral
iron is currently administered intravenously in a hospital setting
Consider first line if: History of oral iron intolerance or poor compliance
Impaired gastrointestinal absorption
Haemodialysis
Major surgery must take place in < 3 weeks
Blood transfusion should be reserved for those with risk of further
bleeding, imminent cardiac
compromise or symptoms requiring immediate attention. Iron treatment
should follow transfusion to replenish stores
Iron salt
Ferrous fumerate
Ferrous gluconate
Ferrous sulphate
Ferrous sulphate, dried

Amount
200mg
300mg
300mg
200mg

Contents of ferrous iron

65mg
35mg
60mg
65mg

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Sheet 3 B12 deficiency

Anaemia or clinical suspicion
check B12

B12
200ng/L

B12
<200ng/L

BUT strong clinical suspicion

(e.g.: macrocytic anaemia/
neuropsychiatric symptoms/
glossitis)

Check Intrinsic
factor Antibodies
(specificity 95%
sensitivity 50%)

If 150-200 and no Symptoms

or anaemia recheck in 2/12
If <150ng/L or symptomatic
(eg: neuropsychiatric symptoms
/ glossitis

Positive

Referral to gastro if:

malabsorption not pernicious anaemia
Or Pernicious anaemia with IDA/ folate def
Or GI symptoms (URGENT if ?Gastric Ca)

Check FBC/ retics after 10/7

of Treatment
If no improvement check folate / ferritin
Check FBC/ retics again at 8/52
Page 1 of 2

Causes of vitamin B12 deficiency

Pernicious anaemia
Gastric causes
Gastrectomy
Gastric resection
Inadequate dietary intake of B12 eg: vegan diet
Intestinal causes
Malabsorption
Ileal resection
Crohns disease
Medications
eg: colchicine, metformin, anticonvulsants
long term use of PPIs and H2blockers
Food based malabsorption associated with gastric
atrophy either age related or associated with long
term PPI use likely cause for 30-50% of cases
with sub clinical B12 deficiency.

Referral to
dietician if poor diet

Initial Treatment
If neurological symptoms:
IM hydroxocobalamin
1000mcg every 2nd day until no
improvement
If no neurological symptoms:
IM hydroxocobalamin
1000mcg x3/week for 2 weeks

If history suggests malabsorption

Consider coeliac disease (check TTG)

See below for maintenance

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Sheet 3 B12 deficiency

Investigation
Pregnant women with low B12
Serum B12 levels of 150 to 200 ng/l in pregnancy may be physiological
and other biochemical tests to determine tissue deficiency are unproven.
Check anti-intrinsic factor antibodies and treat as pernicious anaemia if
positive. If negative, in order to limit extensive investigation with
resultant anxiety, three injections of hydroxocobalamin are suggested to
cover the pregnancy, and serum B12 levels checked two months
post-partum to ensure resolution to normal levels

Treatment
For patients with neurological symptoms
Initial treatment:
Intramuscular (IM) injections of hydroxocobalamin 1000mcg every
second day until no further improvement
Maintenance:
IM injections of hydroxocobalamin 1000mcg every 2 months for life
Oral cobalamin is not currently recommended for those with
neurological symptoms.

Patients on oral contraceptive or hormone replacement therapy

These therapies can result in a low B12 level that does not require further investigation and
treatment unless a string clinical suspicion of B12 deficiency

For patients without neurological symptoms

Initial treatment:
Intramuscular (IM) injections of hydroxocobalamin
1000mcg on x 3/week for 2 weeks
Maintenance:
Long-term treatment where the underlying cause is not dietary:
IM injections of hydroxocobalamin every 3 months for life
Long-term treatment where the underlying cause is dietary:
Advise either: oral cyanocobalamin tablets 50150micrograms daily
between meals (in adults); or
Twice-yearly hydroxocobalamin 1000mcg injection - may be preferable
in the elderly who are more likely to have malabsorption
In vegans, this treatment may need to be life-long
In non-vegans treatment can be stopped once vitamin B12 levels have
been corrected and diet has improved but monitor B12 levels 6
monthly
Advise consumption of foods rich in vitamin B12, eg: foods fortified
with vitamin B12 - some soy products, and some breakfast cereals and
breads, meat, eggs, and dairy products
Further monitoring is generally considered unnecessary exceptions to this are:
Suspected lack of compliance with treatment
Recurrence of anaemia

Patients with type 2 diabetes on long term Metformin (longer than

12 months)
These patients should have serum B12 monitored at 6 monthly intervals.
If serum B12 levels fall,
patients should have tests for anti-intrinsic factor antibody. If positive,
they should have lifelong
treatment with replacement hydroxocobalamin. If negative, the reduced
level may be purely as a
result of metformin. Treatment with three injections of hydroxocobalamin with subsequent
monitoring of serum B12 at 6 monthly intervals is suggested.

Page 2 of 2

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Sheet 4 Folate deficiency

Causes of folate deficiency
Low serum folate <3 g/L
or 3-4.5g/L with symptoms

Ensure Vitamin B12 is normal

prior to commencing
treatment with folate

Dietary deficiency eg: alcoholism,

dietary fads
Malabsorption eg: coeliac disease
Excessive requirements
Physiological
Malignancy
Haemolytic anaemia
Medication
Cholestyramine, sulfasalazine,
methotrexate

Consider Coeliac disease

(check TTG)

Treatment
Dietary advice
Folic acid 5mg daily for 4 months
Longer if underlying
cause is persistent

Follow up
FBC/retics in 10 days
to ensure normalising

Consider referral

Haematology
If suspect haematological
malignancy or other
blood disorder
Cause Unclear

Page 1 of 2

Gastro
Malabsorption
Coeliac

Dietician
If cause is poor diet

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Sheet 4 folate deficiency

Folate deficiency
Treatment
Give information on improving diet with natural sources of folate, eg:
broccoli
brussel sprouts
asparagus
peas
chickpeas
brown rice
Offer daily oral folic acid:
Treatment for 4 months is usually sufficient to replenish body stores if
inadequate dietary intake is the cause treatment may be required for
longer if the underlying cause is persistent

Page 2 of 2

Follow up
FBC and reticulocyte count should be performed:
After 10 days to check response to treatment: there should be a rise
in the haemoglobin level and an increase in the reticulocyte count to
above normal range
After 8 weeks to confirm normal blood count
On completion of treatment to confirm response

NB: If haemoglobin (Hb) initially responds and then stops, check ferritin
to see if a secondary iron deficiency has occurred.
Further monitoring is generally considered unnecessary exceptions to this are:

Suspected lack of compliance with treatment

Recurrence of anaemia

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Sheet 5 Renal Anaemia

Consider investigating and treating anaemia if:
Hb 110 g/L
Symptoms attributable to anaemia develop

Serum ferritin >100g/L

No

Iron replete
(serum ferritin > 100 g/L
and functional iron deficiency excluded,
Hb <110 g/L refer to local Nephrologist,
patient may require erythropoiesis stimulating
agents (ESA)

Yes

?functional iron deficiency

Ferritin>100g/L
and <800g/L
Transferrin saturation <20%

No

Consider
other causes for
anaemia (see
Sheet 1)
If anaemia continues

Yes
Optimise iron stores
Oral iron If intolerant of oral iron
or poor response, consider IV iron
(via Nephrology clinic referral)

Iron deficient
Iron deficiency pathway
Sheet 2

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Sheet 6 Haemoglobinopathies
Inherited disorders of haemoglobin (haemoglobinopathy) should be
considered in all individuals with microcytic anaemia, particularly if there
is no evidence of iron deficiency or red cell changes persist after adequate
iron replacement. . Although these conditions are more frequently
associated with individuals of non northern European origin, they may
be found in all ethnic groups.
Conditions most frequently associated with microcytic hypochromic indices
include:
1. Alpha thalassaemia
2. Beta thalassaemia
3. Delta beta thalassaemia
4. Haemoglobin E
5. Other haemoglobin variants
Carriers for these haemoglobinopathies are asymptomatic.
Milder carriers may have a normal haemoglobin with minimal reduction
in MCV and MCH while other carriers will have mild anaemia with more
marked reduction in MCV and MCH. Carriers for haemoglobinopathy do
not need haematology follow up however, individuals with more severe
anaemia (> 20g/l below lower limit of normal) or those with symptoms
or splenomegaly should be referred for a haematological review.
It is important to recognize carrier states for these haemoglobinopathies
as they do not require iron treatment and the information may be
important for genetic counseling for themselves or other members of their
family. Women who have had pregnancies in recent years or partners of
women with significant carrier states may have been screened as part of
the national antenatal screening programme and may be aware of their
haemoglobinopathy results. It is also useful to refer back to historical
esults, for Hb, MCV and MCH, if available, as these remain relatively
constant throughout adult life for a given individual; any significant
deviation indicates an additional cause for anaemia.
Page 1 of 2

Further information for health professionals and information for carriers

may be found on the following websites and these contain useful genetic
counselling information for those contemplating pregnancy.
http://www.chime.ucl.ac.uk/APoGI/data/html/hb/menu.htm
www.screening.nhs.uk/sickleandthal
Leaflets and further advice are also available from the
Manchester Sickle Cell/ Thalassaemia
Centre Tel: 0161 2743322
Beta thalassaemia
Carrier states for beta thalassaemia are asymptomatic and have a mild
anaemia often with marked microcytosis. Carriers should be informed for
genetic counselling purposes as homozygous beta thalassaemia produces
a clinically significant condition causing severe anaemia and a need for
regular blood transfusion. Beta thalassaemia is typically diagnosed on the
finding of a raised Hb A2 level with other phenotypic evidence suggesting
beta thalassaemia. In these cases a haemoglobinopathy card may
be issued.
Other significant haemoglobinopathies causing anaemia
This includes other types of thalassaemia and some haemoglobin variants.
In such cases further information should be sought from the Manchester
Sickle cell and thalassaemia centre.

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Sheet 6 Haemoglobinopathies
Further information on Alpha Thalassaemia
Alpha thalassaemia is caused by deletions or mutations affecting the alpha
thalassaemia gene and results in deficient production of alpha globin
chains. Alpha thalassaemia is usually suspected in a patient with a
hypochromic, microcytic blood picture (with or without anaemia) where
other causes for these findings such as beta thalassaemia or iron deficiency
have been excluded. Definitive diagnosis of alpha thalassaemia can only
be made by DNA studies. This is not usually necessary except in certain
circumstances (see below).

Issue of alpha thalassaemia reports

Possible alpha thalassaemia may be picked up on routine testing or in
the course of screening for haemoglobin disorders. In the antenatal or
pre-conceptual counselling context, the national screening algorithm will
dictate those women for whom partner screening is indicated. This will
be on the basis of blood results and that womans ethnic origin. Partner
screening is indicated if the womans MCH is < 25pg and she comes from
a high risk ethnic group. Partner testing will be arranged by the screening
midwife in the ANC.

There are 4 genes controlling alpha thalassaemia (2 on each chromosome)

and the number of defective genes will dictate the clinical features:

Outside the antenatal setting, reports may be issued as follows:

Suggestive of alpha thalassaemia This is reported when hypochromic
microcytic indices coexist but with normal ferritin levels and haemoglobin
electrophoresis.
Possible alpha thalassaemia/alpha thalassaemia can not be
excluded This will be reported when microcytic hypochromic indices are
present, Hb electrophoresis is normal but iron levels are not available or are
borderline low /unreliable. In this situation iron levels should be checked if
no result available. If iron levels are low or borderline, a short course of iron
should be given with repeat blood count after 4 weeks. If hypochromic
microcytic indices persist despite adequate iron levels then alpha
thalassaemia is likely. Iron deficiency should be investigated and
managed in the usual way.

Persons with 1 or 2 defective genes are usually asymptomatic and do not

need any further investigation or treatment. Iron treatment is not effective
and should not be given unless concomitant iron deficiency is proven.
The only indication for further testing is in the antenatal context where it is
important to distinguish those who have alpha zero (2 defective genes on
the same chromosome) from those who have
homozygous alpha + (2 defective genes on opposite chromosomes).
The former will require partner testing to establish the risk of haemoglobin
H or Barts hydrops whilst the latter requires no further action. Alpha zero
cannot be distinguished from homozygous alpha plus on blood
indices alone.
Alpha plus thalassaemia is extremely common being found in up to 30%
or persons of African origin.
It is also common in all parts of Asia, particularly in South East Asia. Alpha
zero is found in some
Mediterranean populations but its highest frequency is in individuals from
south East Asia. This forms the basis of the antenatal screening algorithm
Page 2 of 2

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Sheet 7 Anaemia of chronic disorder

Anaemia with low/normal MCV

Ferritin >50g/L
And Transferrin Saturation >20%

If Hb <50g/L or
very symptomatic
consider admission

Look for causes (see box)

Take careful history/examination
Check TFTs/Blood glucose/Calcium
And other tests as suggested by history

Refer to relevant specialist if required

IV iron if transferrin saturation

<20%

Treat underlying cause

Symptomatic affecting quality of life

Causes of Anaemia of Chronic disease

Collagen vascular and autoimmune disorders
(e.g., rheumatoid arthritis, SLE,
dermatomyositis, giant cell arteritis,
polymyalgia rheumatica, scleroderma,
inflammatory bowel disease)
Chronic infection (e.g., tuberculosis, chronic
fungal infections, hepatitis, osteomyelitis, HIV)
Acute infection (e.g., pneumonia,
pyelonephritis, endocarditis, cellulitis, and soft
tissue infections)
Chronic diseases (e.g., chronic kidney disease,
diabetes mellitus, congestive heart failure,
major recent thrombosis, chronic pulmonary
disease)
Malignancy (e.g., lymphoma, renal cell
carcinoma, multiple myeloma)
Critical illness and major trauma.

Consider referral for erythropoietin

(ensure iron stores replenished)

Page 1 of 2

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Sheet 7 Anaemia of chronic disease

Anaemia of chronic disease (ACD) is a common, if misleading, name for a
syndrome in which the anaemia is due to an inflammation-mediated
reduction in RBC production and sometimes in RBC survival
Symptoms and signs
There may be a history of an underlying autoimmune, malignant, or
infectious disorder or of recent major surgery, major trauma, or a
critical illness.
Common presenting features of such underlying disorders include fever,
anorexia, night sweats, arthralgia, myalgia, weight loss, the presence
of a mass, adenopathy, hepatomegaly, splenomegaly, decreased breath
sounds with rales, stiff neck, rash, abdominal tenderness, and tenderness
of joints, shoulder girdle, or bones.
History of bleeding is unusual and, if present, an alternative or
additional workup is required.
Initial investigations
FBC, blood film, reticulocyte count, ferritin, seru iron studies, CRP/ ESR / PV,
creatinine, LDH, and liver function tests are the tests to order first.
The ACD syndrome is defined by the following constellation laboratory
test results:
Mild to moderate anaemia that is either normocytic normochromic
or microcytic hypochromic
Otherwise normal RBC morphology
Elevated serum ferritin
Transferrin saturation <15%
Elevated CRP
Significantly elevated ESR

Page 2 of 2

Treatment approach
The treatment of choice in ACD is first and foremost treatment of the
underlying disorder.
Patients with non-severe ACD whose cause cannot be treated, or in
whom such treatment does not improve the Hb level, do not usually
require treatment for the anaemia. Simple observation suffices.
In patients with anaemia that significantly impairs their quality of life or
with comorbidities in which a non-severe anaemia imposes additional
risk (e.g., heart failure, significant pulmonary disease), and in whom the
underlying disorder is not responsive to treatment (or requires time to
respond), intravenous iron, or erythropoiesis-stimulating agents (ESAs)
to stimulate endogenous RBC production, are two possible treatment
choices.
Iron deficiency should be ruled out prior to initiating therapy. Because
ESAs often produce functional iron deficiency in iron-replete subjects,
supplementary iron therapy may be required to achieve an adequate
therapeutic response. This decision is also best made in consultation with
specialists, as the distinction between whether an initially poor response
to ESAs is due to inadequate iron supply versus ESA under-dosing is
difficult. Iron therapy should be considered if the transferrin saturation
is <20% . Intravenous iron is preferred because optimal ESA effect r
equires that transferrin saturation be raised, ideally to the 30% to 40%
range, and this cannot usually be accomplished with oral iron in ACD.
However, intravenous iron should not generally be given in patients
with active infection, as iron promotes growth of many micro-organisms.

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Sheet 8 Haematology Referrals

Red flags
Film suggestive of leukaemia. Features of spinal cord compression,
hypercalcaemia, acute renal failure. If Hb <50g/L or very symptomatic
consider admission

Admit to hospital
Admit to hospital
straight away
straight away

Urgent referral:
Suspected haematological malignancy:
lymphadenopathy persisting for six weeks or more
lymph nodes increasing in size
lymphadenopathy associated splenomegaly
hepatosplenomegaly
bone pain associated with anaemia and a raised erythrocyte sedimentation
rate (ESR) or plasma viscosity
constellation of three or more of the following:

fatigue

night sweats

weight loss

Itching

breathlessness

bruising

recurrent infections

bone pain

Referral to haematology
on HSC205 pathway

Persistent unexplained anaemia

Anaemia with abnormal blood film and / or abnormal white cell count /
platelet count
Anaemia with increased reticulocytes (>2%), jaundice (raised bilirubin)
suggestive of haemolysis
Anaemia with persistent unexplained macrocytosis (exclude liver disease,
alcohol excess, B12/folate deficiency, hypothyroidism)

Referral to
haematology

If unsure how quickly a patient needs to be seen please contact local haematologist on call
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