Haematopoitic vitamin,pathogenesis of megaloblastic anaemia by dr. Tasnim

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 .

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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. B 12 daily The amount of Vit. B 12 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 μ g Infants & children: 1.0- 1.5 μ g Pregnancy & lactation: 6 μ g

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 m olecule 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 B 12

15. 2 nd 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 B 12 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. T etrahydro folate are metabolic active forms .

20. 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

21. Daily requirements Infant : 50 μ g Children : 100-300 μ g Pregnancy :800 μ g Lactation :500 μ g

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

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

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

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

26. 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

27. 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

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

29. 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.

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

31. 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

32. Causes of vit B12 deficiency Decreased intake Impaired absor ption Drug Others

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

34. 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 .

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

36. Peripheral blood picture CBC : Anemia  Leukopenia  Thrombocytopenia

37. 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

38. Blood pictures ….. Nuclear chromatin appears loose& less mature than nuclear chromatin of normal red cell Giant bands & hypersegmened polymorphonuclear neutrophils are common

39. 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

40. PERNICIOUS ANEMIA It is a form of megaloblastic anemia. CAUSES Autoantibodies against gastric mucosal cell & IF Distal bowel resection. Achlorohydria Gastric resection & bypass Middle age & elderly

41. 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

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

43. Thank you all