Megaloblastic anemias are disorders characterized by defective nuclear maturation caused by impaired DNA synthesis, usually due to vitamin B12 or folate deficiencies. Vitamin B12 is produced by microorganisms and fungi and is present in animal foods. It plays an important role in DNA synthesis and the Krebs cycle. Pernicious anemia is a type of megaloblastic anemia characterized by gastric parietal cell atrophy leading to decreased intrinsic factor and gastric juices, resulting in vitamin B12 malabsorption.

1. Megaloblastic anemias
•MA are a group of disorders characterized by defective nuclear
maturation caused impaired DNA synthesis.
•This is usually due to vitamin B12 or folate deficiencies.
Vitamin B12
Sources and requirements:
•Produced by micro-organisms and fungi.
•Present in foods of animal origin (meat, liver, fish, eggs)
•The recommended dietary intake for adult is 2g/day.

2. Structure:
• The vitamin consists of small group of compounds
called cobalamin.
• Water soluble with MW 1335 daltons.
Transport and metabolism:
• Two important proteins involved in the transport of Vit
B12:
1. From diet to ileum (Intrinsic factor [IF]).
2. From ileum to tissues (Transcbalamins I, II, III [TCII]).

3. Transportation path of Vit B12
Diet Stomach
B12 IF
B12 +
IF
Ileum
B12+IF
TCII
B12 +TCII
Circulation
Bone marrow
(DNA synthesis)
Liver (storage)
Other tissues
(DNA synthesis)

4. Vit B12 plays important role in two reactions:
• Necessary in the synthesis of methionine from homocysteine.
1. In this reaction both vit B12 and folic acid are involved.
2. B12 acts as a co-enzyme (methyl cobalamin) for
methyltransferase.
Homocysteine methionine
Methyl B 12
Methyl THF
THF
• Vit B12 is important in conversion of methylmalonyl CoA to
succinyl CoA in Krebs cycle.
1. In this reaction B12 acts as co-enzyme for methylmalonyl Co A
mutase.
Methylmalonyl Co A Succinyl Co A
Adenosyl Cb
Ado B12

5. Vitamin B 12 deficiency
Due to other causes
•Nutritional (Vegans).
•Malabsorption.
•Intestinal causes (intestinal
stagnant loop syndrome).
•Congenital malabsorption with
proteinuria.
•Fish tapewarm.
Due to intrinsic factor
deficiency (Pernicious anemia)
•Congenital lack or abnormality
of intrinsic factor.
•Total or partial gastrectomy.
•Adult PA.

6. Pernicious anemia
A disease characterized By Gastric parietal atrophy
leading to decreased secretion of intrinsic factor and
other gastric juices.

7. Clinical manifestations:
•Weakness, fatigue, shortness of the breath.
Laboratory diagnosis:
•Red cell indices
Low Hb level, elevated MCV (>98fl).
•Blood film
shows macro-ovalocytes and hypersegmented
neutrophils.
Multinucleate RBCs
Howell-Jolly bodies
•Chemical testing
Low levels of serum B12.
•In case PA
Antibodies to IF are present in the serum.
Schilling test.

8. PB Morphology
Macro-ovalocytes
Howell-Jolly bodies
Hypersegmented
neutrophils Bi-nucleated RBCs

9. The Schilling test
Radioactive cobalamin (Cbl*) is taken orally; followed by
injection of a saturating dose of non-radioactive cobalamin.
The level of Cbl* is measured in the urine. In pernicious anemia
the excreted levels of Cbl* are low.
If intrinsic factor is given with the Cbl* the Cbl* levels will
correct in PA, but not in ileal malabsorption.