3. definition
• The megaloblastic anaemias are macrocytic anaemias
(raised MCV).
• There is an abnormality in the maturation of
haematopoietic cells in the bone marrow.
• In addition to abnormal red cells the white cells and
platelets may be affected.
• The two major causes are folate deficiency and vitamin B12
deficiency.
• Pernicious anaemia is a specific disease caused by
malabsorption of vitamin B12. 3
4. Epidermiology
A. Folate deficiency anaemia
• Much of the world's population has a marginal dietary
intake of folate.
• Body stores are low, and as soon as there is a decrease in
dietary intake or there is increased folate demand,
deficiency readily occurs.
4
5. B. Vitamin B12 deficiency anaemia
• Strict vegans, for example Hindus, commonly have low
vitamin B12, levels due to their dietary deficiency though
actual anaemia is rarer.
• All patients who have had a total gastrectomy and 6%
of those with a partial gastrectomy will develop vitamin
B12 deficiency anaemia.
5
6. C. Pernicious anaemia
• Pernicious anaemia (reduced vitamin B12 absorption due
to a lack of intrinsic factor) is found most commonly in
people of Northern European descent.
• In Britain the incidence is about 120 per 100 000, being
higher in Scotland than in the south of England.
• Pernicious anaemia is usually a disease of the elderly, the
average patient presenting at 60 years of age.
6
7. aetiology
A. Folate deficiency anaemia
• Fruit, green vegetables and yeast all contain
relatively large amounts of folate.
• Despite this relative abundance of folate in many
foods, dietary deficiency is common, either as the
sole cause of the folic acid deficiency anaemia or
in conjunction with increased folate utilization.
7
8. B. Vitamin B12 deficiency anaemia
• Deficiency occurs from inadequate intake or
malabsorption.
• The only dietary source of vitamin B12 (cyanocobalamin)
is from food of animal origin. It is present in meat, fish,
eggs, cheese and milk.
• Daily requirements are between 1 and 3 micrograms.
• Deficiency arises either from inadequate intake over a
prolonged period or, more commonly, in Western Europe,
from impaired absorption. 8
9. • Malabsorption occurs if the distal ileum is removed; it
may also occur with certain intestinal pathologies,
particularly stagnant loop syndrome, tropical sprue and
fish tapeworm infestation.
• Passive absorption does take place in the jejunum, but this
is very inefficient and usually accounts for less than 1% of
an oral dose.
9
10. Pathophysiology
• The common biochemical defect in all megaloblastic anaemias
is the inhibition of DNA synthesis in maturing cells.
A. Folate deficiency anaemia
• The folate found in food is mainly conjugated to polyglutamic
acid. Enzymes found in the gut convert the polyglutamate
form to monoglutamate, which is readily absorbed.
• During absorption the folate is methylated and reduced to
methyltetrahydrofolate monoglutamate.
10
12. • This travels through the plasma and is transported into cells via
a carrier specific for the tetrahydrofolate form.
• Within the cell the methyl group is removed (in a reaction
requiring vitamin B12) and the folate is reconverted back to a
polyglutamate form (Fig.)
• It has been suggested that the polyglutamate form prevents the
folate leaking out of cells.
• The folate eventually acts as a co-enzyme involved in a number
of reactions including DNA and RNA synthesis. 12
13. • DNA synthesis mainly affects cells with a rapid turnover, such as
gastrointestinal cells and precursors of red blood cells in bone
marrow, hence the sore tongue and anaemia seen in folate
deficiency.
• During DNA synthesis the folate co-enzyme is oxidized to the
dihydrofolate form, which is inactive and has to be reactivated by
the enzyme dihydrofolate reductase.
• This is the enzyme inhibited by methotrexate and to a lesser extent
by trimethoprim and pyrimethamine.
• Co-trimoxazole has been shown to increase the severity of
megaloblastic anaemia. 13
14. B. Vitamin B12deficiency
• Absorption of vitamin B12 is mainly by an active process. Enzymes in
the stomach release vitamin B12, from protein complexes.
• One molecule of vitamin B12 then combines with one molecule of a
glycoprotein called intrinsic factor.
• The intrinsic factor protects the vitamin B12 from breakdown by
micro-organisms.
• There are specific receptors in the distal ileum for the intrinsic
factor-vitamin B12 complex.
• The vitamin B12, enters the ileal cell and is then transported through
the blood attached to transport proteins. Intrinsic factor does not
appear in the blood.
14
15. • Since intrinsic factor is only produced by the gastric parietal
cells, a total gastrectomy always leads to vitamin B12
deficiency.
• Approximately 10-15% of patients who have had a partial
gastrectomy also develop deficiency.
• vitamin B12 is a co-enzyme for the removal of a methyl group
from methyltetrahydrofolate.
• Lack of vitamin B12, traps the folate as methyltetrahydrofolate,
and prevents DNA synthesis.
• The exact mechanism by which vitamin B12 deficiency causes
neuropathy is not clear but may be due to defect in the
methylation reactions needed for myelin formation.
15
16. investigations
A. Folic acid deficiency anaemia
• Many patients are symptomless initially, and the diagnosis is made following
a full blood count carried out for another reason.
• The peripheral blood reveals large oval red cells. Anisocytosis (RBC in
size unequal) and poikilocytosis (abnormally shaped RBC) are common.
• Some of the neutrophils are hypersegmented, and thrombocytopenia may
be present.
• The red cell folate concentration accurately reflects folate stores and is a
preferable parameter to the serum folate concentration, which is subject to
changes in diet and does not correlate as closely with anaemia.
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17. B. Vitamin B12 deficiency anaemia
• Following the recognition of megaloblastic anaemia from
the full blood count, one of the first investigations will be
the determination of the serum vitamin B12 level.
• Oral vitamin B12 absorption can be measured by the most
common test being the Schilling test.
• The test is based on giving a radiolabelled oral dose of
vitamin B12 and an unlabelled parenteral dose that
saturates the vitamin B12-binding proteins.
17
18. • The amount of labelled vitamin in the urine gives a measure
of absorption.
• The test can be repeated by giving the radiolabelled oral dose
with intrinsic factor.
• The absorption should now be approaching normal if the
patient has intrinsic factor deficiency but remains low if there
is ileal disease.
• Although 90% of patients with pernicious anaemia have
parietal cell antibodies, their presence is not diagnostic
because 50% of patients with gastric atrophy without
pernicious anaemia also have the antibodies present.
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19. Treatment
• It is necessary to establish whether the patient with
megaloblastic anaemia has vitamin B12 deficiency or folic
acid deficiency, or both.
A. Folate deficiency anaemia
• The normal daily requirement of folic acid is
approximately 100 micrograms a day; despite this, the
usual treatment doses given are 5-15 mg a day.
• Even in malabsorption states, because of these large doses,
sufficient folate is usually absorbed.
19
20. • Therefore parenteral folic acid treatment is not
normally required. Treatment for 4 months will
normally be sufficient to ensure that folate deficient
red cells are replaced.
• In pregnancy :
Prophylaxis with folate (350-500 micrograms
daily) is now frequently given in pregnancy, often
in combination with iron.
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21. Vitamin B12 deficiency anaemia
• The standard treatment is hydroxocobalamin 1 mg
intramuscularly repeated five times at 3 day intervals to
replenish body stores.
• This is followed by a maintenance dose, usually 1 mg
intramuscularly every 3 months.
• US texts recommend cyanocobalamin rather than
hydroxocobalamin because of the fear that some patients
appear to develop antibodies to the vitamin B12 transport
protein complex in the serum.
• In the UK, hydroxocobalamin is the treatment of choice.
21