haematopoitic vitamins and pathogenesis of megaloblastic anaemia

1. Haematopoeitic Vitamins
& Pathogenesis of
Megaloblastic Anaemia
Dr. Tasnim Ara
MD(part-I)
Phase -A Student
Department of Biochemistry
Sir Salimullah Medical College

2. Introduction of Vitamins
Vitamins are chemically unrelated, low molecular
weight, heat stable organic compounds.
They are not structural component, no energy value
The most prominent function is to serve as co-enzymes
for enzymatic reactions.
Most of them are not synthesized by humans and must
be supplied in the diet.

3. …………

4. Haematopoeitic
Vitamins
Haemopoeisis is the process of formation of blood
cellular components .
All cellular components are derievd from haemopoitic
stem cells.
Vitamins those directly or indirectly required for
haemopoeisis known as haematopoeitic vitamins.
Haematopoeitic vitamins are
vitamin B12
Folic Acid

5. Vitamin B12 Rich Food

6. Vitamin B12
Natural forms
Produced by microorganisms
(bacteria/fungi)
Plants do not produce or contain Vit
B12 (except contamination)
Colonic bacterial production occurs
but their location is distal to the site of
absorbtion

7. Vitamin B12
Average diet contains 5 – 30 g Vit. B12 daily
The amount of Vit. B12 in the body is about 2 – 5
mg.
Most of it is in the liver.
The store is sufficient for 2-5 years in case of
impaired absorbtion.
The storage form is mainly adenosylcobalamin.

8. SOURCES
 Dietary source : Egg, Fish,Meat, Liver, Milk &
milk products .
 Endogenous source:produced by gut flora.
Recommended daily allowance
 Adult : 3 μg
 Infants & children: 1.0- 1.5 μg
 Pregnancy & lactation: 6 μg

9. Vitamin B 12 structure

10. Structure con…….
 Vit B12 consist of corrin ring with central cobalt atom
Corrin ring has four pyrrole units
 Two pyrrole units directly bound & other two are held
by methene bridges
Cobalt is held in center of corrin ring by 4 coordination
bonds with nitrogen of pyrrole groups.
The remaining coordination bonds of cobalt with
nitrogen of dimethylbenzimida zol.
 Also attached with a neucleotide & a R group

11. Cyanocobalamin
 When Cyanide is added at the R position, the
molecule is called cyanocobalamin.
It is the commercial form.
Hydroxy cobalamin
When hydroxyl group is added at the R position the
molecule is called hydroxy cobalamin.
When taken up by the cells, these groups are removed
& deoxyadenosylcobalamin is formed.

12. Cont……
Methyl cobalamin
When methyl group replaces adenosyl group it is
known as methyl cobalamin.
It is the major form seen in blood circulation as
well as cytoplasm.

13. Vitamin B12 Absorption
Vit B12 binds with intrinsic factor of
castle(secreted from gastric parietal cell)
intrinsic factor- Vit B12 complex travels through
gut & reach ileum.
The complex binds with specific receptor on the
surface of the mucosal cells of the ileum & then
enter into the cell by active process
Viet B12 enter into the blood & binds with plasma
Protein called transcobalamin І & ІІ which carries
Cobalamin to liver & various tissue.

14. Biochemical function of vitB12
Only two reactions in the body require vitamin B12 as
a cofactor:
methylmalonyl-CoA mutase, requires vitamin
B12 as a cofactor in the conversion of
methylmalonyl-CoA to succinyl-CoA.
Methylmalonyl co - A mutase
Methylmalonyl co - A succinyl co - A
5-deoxyadenosyl B12

15. 2nd Reaction

16. …
 The second reaction catalyzed by methionine
synthase
 It converts homocysteine to methionine
 This reaction results in the transfer of the methyl
group from N5-methyltetrahydrofolate to
hydroxycobalamin generating tetrahydrofolate
and methylcobalamin during the process of the
converting.

17. Function con………….
Helps in:
 synthesis of methionine
 conversion of methylmalonyl Co-A  succinyl CoA
In vitamin B12 deficiency:
 abnormal fatty acids accumulate &
 become incorporated into cell membranes, including
those of nervous system
 such nervous system involvement causes
neurological manifestations

18. Deficiency Disorders
Megaloblastic anemia
Neurological disorders
Hyperhomocysteinemia & atherosclerosis

19. Folic Acid
Pteroyl glutamic acid and similar compounds are
termed as folic acid . Also known as Vitamin B9/
Folacin/Ptery glutamic acid.
Polyglutamate is the natural form.
Tetrahydro folate are metabolic active forms.

21. Dietary sources
 Plant source e.g.Green leafy vegetables, Whole
grain cereals,Legumes, peas, Nuts.
 Animal source e.g.Egg, Meat, Fish, Liver, Milk
& Milk Products

22. Daily requirements
Infant : 50 μg
Children : 100-300 μg
Pregnancy :800 μg
Lactation :500 μg

23. Chemistry
Folic acid consists of
Pteroic acid & One or
more glutamic acid.
Pteroic acid is composed
of Pteridine & Para amino
Benzoic acid.

24. Folate absorption
Mainly jejunum.
In the form of monoglutamate
 Methyltetrahydrofolate
monoglutamate is the form it is
found in serum .

25. Two Step Reduction In
Liver
NADP2H NADP
FA FH2
Folate reductase NADP2H NADPH2
FH2 reductase
NADP
FH4(active form)

26. Folate store
. Total body folate :12 – 15 mg
Storage place : Liver 4 to 6 month
Storage form: :Methyl-FH4 polyglutamate

27. Biomedical Role Of FC
Plays key role in transfer of one-carbon atom to
substrate for synthesis of several essential
compounds
In body, folic acid is first reduced
totetrahydrofolic acid under influence of enzyme
dihydrofolate reductase
Tetrahydrofolic acids receive one-carbon fragments
from donors such as serine, glycine & histidine
These C-fragments are transferred to appropriate
intermediates to form amino acids, purines and
thymine

28. Con……
Transfer of methyl or formyl groups to other
 compounds.
eg-During the production of thymidylate for the
synthesis of DNA (methylation of deoxyuridylate)
Source of the 1-carbon moieties;
1-serine
Serine + THF glycine + N-methylene THF
2-Formiminoglutamic acid
Formiminoglutamate+FH4 glutamate+N-
formimino THF

29. Deficiency
Disorders
Megaloblastic Anaemia
Growth failure
Gastrointestinal Tract
Disturbance
Neural Tube Defects in fetus
During Pregnancy e.g. Spina
Bifida, Anencephaly.

30. ROLE OF VIT C IN
HAEMOPOIESIS
 Vit C is a strong reducing agent
It is important in reducing the ferric form of
iron to ferrous to facilate irons absorption.

31. Megaloblastic Anaemia
A subclass of macrocytic anemia
(under morphologic classification)
A subclass of anemias due to defective DNA
synthesis (pathogenetic classification)

32. Pathogenesis of
Megaloblastic Anemia
The anemia which is charactarized by the
formation of morphologically abnormal neucleated
red cell precursor called megaloblasts in the bone
marrow due to megaloblastic erythropoisis.the
changes occur due to deficiency of vitB12 or folate.
Main causes
 Vit.B12 deficiency
 Folic acid deficiency
 Others

33. Causes of vit B12 deficiency
Decreased intake
Impaired absorption
Drug
Others

34. Causes of folic acid
defiency
Decreased intake
Increased demands
Drug related folate insufficiency

35. Pathogenesis of
Megaloblastic Anamia
Lack of B12 allows folic acid to be trapped as non functional
methyl tetrahydrofolate(folate trap)
So deficiency of functional FH4 causes impairment of formation
of deoxy thymidine monophosphate(dTMP) which is needed for
DNA synthesis
As a result large proerythroblast fails to divide rapidly to make
mature RBC rather immature precursors of erythocyte(blast
cell) appear to cause megaloblastic anaemia.

36. Clinical feature of
megaloblastic anaemia
Anaemia:Macrocytic megaloblastic anaemia
Glossitis
Subacute combined degeneration of spinal cord
Peripheral neuropathy

37. Peripheral blood picture
 CBC:
Anemia 
Leukopenia 
 Thrombocytopenia

38. Bone marrow findings in
megaloblastic anemia
Hypercellular bone marrow
Megaloblastic erythropoiesis
Giant erythroblasts called megaloblasts
Increased numbers of early erythroblasts
Nuclear cytoplasmic asynchronism
Increased mytosis

39. Bloodpictures…..
Nuclear chromatin appears loose& less
mature than nuclear chromatin of normal
red cell
 Giant bands & hypersegmened
 polymorphonuclear neutrophils are
common

40. Special tests
VitB12 Folic acid
 Serun B12 assay
 Schiling Test
 Methyl melonic acid excretion
in urine
 Response to Vit B12 adminis.
 Serum folate assay
 Red cell folate assay
 Response to folate adminis

41. PERNICIOUS ANEMIA
 It is a form of megaloblastic anemia.
 CAUSES
I. Autoantibodies against gastric mucosal cell & IF
II. Distal bowel resection.
III. Achlorohydria
IV. Gastric resection & bypass
V. Middle age & elderly

42. PATHOGENESIS OF PERNICIOUS
ANEMIA
Gastric atrophy(autoimmune)
Reduce IF secretion
Failure of absorption of dietary Vit B12
Deficiency of Vit B12
Megaloblastic anemia Glossitis peripheral neuropathy

43. Pernicious anaemia
treatment
 Life long
 Cobalamine replacement.
Complication
Gastric Ca: 2 times normal population