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Haematopoitic vitamin,pathogenesis of megaloblastic anaemia by dr. Tasnim
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.
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
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.
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
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
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.
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
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
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