Megaloblasticanemia

1. Dr Naser Tadvi

2.  Thomas edison : Pernicious anemia
 Minot & Murphy 1926: liver preparation
 Castle: Postulated intrinsic factor theory
 1941 Mitchel : Folic acid
 1943: Pteroyl monoglutamic acid
 1948: Crystalline B12

3.  Megaloblastic anemia:
 Characterized by abnormally large nucleated
red cell precursors called megaloblasts in bone
marrow
 Megaloblast eg of unbalance between cytoplasm
and nucleus due to improper and defective
synthesis of nucleoproteins
 95 % cases due to vit B12 or folic acid deficiency
leading to defective DNA synthesis

4.  DNA present in every basic cell so abnormality
effects rapidly proliferating cells.
 Peripheral blood picture: Hemoglobinized large
RBC (Macrocytes), PMN leucocytes &
hypersegmented giant platelets.
 Anemia described is hyperchromic macrocytic

8.  Vit B12 deficiency causes damage to myelin in the
peripheral nerves , spinal cord & brain
 Folate deficiency: weight loss, nervous instability
but damage to myelin is doubtful
 Other causes of macrocytic anemias: Liver disease
, myxedema, Leukemia & certain hemolytic states

9.  Cobalamins:
 Vit B12 belongs to cobalamin family i.e cobalt
containing compounds
 Cyanocobalamin: CN group attached to cobalt
 Hydroxycobalamin: OH group attached to
cobalt
Light
Cyanocobalamin Hydroxycobalamin
Cyanide
 Other cobalamins: aquocobalamin,
nitrocobalamin & methyl cobalamin

10.  Sources of Vit B12:
 Micro-organisms (Soil, water animal intestine)
 Man and animals intestinal lumen but not
absorbed 3-5 µg excreted daily in faeces
 Non veg foods:
Muscle, liver, kidney, oysters,fish, egg yolk
 The only vegetable source is pulses(legumes)
 Dairy milk in smaller amounts
 Daily requirement: 1-3 µg,
 pregnancy & lactation 3-5 µg
 Commercial source: Streptomyces Griseus

11. Pharmacokinetics:
 Absorption: Cobalamins in food are in bound form
inactive , released by cooking (heat) and by
proteolysis in stomach & intestine .
 Vit B12 is not soluble so absorption depends on
various transfer factors
 R- Factor, Intrinsic factor & Transcobolamin II

13. Metabolic functions of Vit B12

14. C: Purine biosynthesis reduced , defective DNA
 Methyl THF trapping & lack of S- adenosyl
methionine can cause this
D: Methionine DAB12 S- adenosyl methionine
 S- adenosyl methionine required for synthesis of
phospholipids & myelin ( neuronal damage)
E: Cell growth & multiplication (Poultry)
F: Role in folate uptake & storage

15.  Deficiency:
1. Addisonian pernicious anemia
2. Gastric mucosal damage
3. Malabsorption
4. Blind loop syndrome, Fish tape worm
5. Nutritional deficiency
6. Increased demand: Pregnancy and infancy

16.  Preparations & doses:
 Cyanocobalamin: Pink color injection 100
µg/mL DOC in pernicious anemia 1000 µg once
a week IM for 8 weeks then 1000 µg once a
month life long
 Hydroxy cobalamin 100, 500, 1000 µg/mL,
better retention but can induce antibody
formation not used in US. 1 mg every 2 – 3 days
5 doses , then 1 mg 3 monthly
 Methyl cobalamin 0.5 mg tab, Dose 1.5 mg
promoted for neurological defects in diabetics
and other peripheral neuropathies

17.  Uses :
1. Treatment of vit B12 Deficiency: wise to add
folic acid and iron, symptoms improvement in
2 days ( appetite increased, feels good.
Mucosal lesions heal in 1-2 weeks. Platelet
count normal in 10 days. WBC`S = 2-3 weeks .
Neurological parameters take several month.
2. Prophylaxis : 3-10 µg/ day
3. Mega dose of B12 used in neuropathic
psychiatric disorders and as general tonic to
allay fatigue , improve growth.
4. Tobacco amblyopia: OH Cobalamine
 Adverse events

18. Folic acid: (Pteroyl Monoglutamic acid)

19.  Called as folic acid as it is found in green leafy
vegetables
 Source: Green leafy vegetable , liver , yeast, kidney,
egg, meat, fish and dairy foods
 Much of it is destroyed in cooking (heat)
 Micro-organisms
 Daily requirement: adult 50-100 µg pregnancy and
lactation 500- 800 µg

20.  Absorption:
 Folic acid conjugates hydrolysed to pteroyl
monoglutamic acid by conjugases
 Conjugases are enzymes present in vegetables
and mammalian tissue, GIT mucosa & pancreas
 Pteroyl monoglutamic acid is completely
absorbed in small intestine jejunum

21.  Transport storage and fate:
 Orally given folic acid appears in 30 min as
circulation it circulates as N5 Methyl THF
 Majority is loosely bound to albumin from
where it is easily taken up by cells
 Inside the cells converted to THF by
cobalamine dependent enzyme methionne
synthetase
 Vit C protects THF from destruction
 Total folate in body = 5 to 10 mg (1/3 in liver
as methyl folate)

22.  Metabolic functions
 Folic acid DHFA THFA (Active form)
folate DHF
reductase reductase
 THFA mediates number of one Carbon tranfer
reactions
 Conversion of homocysteine to methionine
 Generation of thymidylate
 Conversion of serine to glycine
 Purine synthesis
 Histidine metabolism

24.  Deficiency :
1. Inadequate dietary intake
2. Malabsorption : coeliac disease, tropical sprue
, regional ileitus
3. Biliary fistula: no recirculation
4. Chronic alcoholism
5. Increased demand : Pregnancy , lactation
6. Drugs: Phenytoin, phenobarbitone, primidone

25.  Preparations and dose:
 Folic acid tab 5 mg ; dose = 5 to 20 mg
 Prophylaxis 0.5 mg/day
 Parenteral form available in combination only
 Folinic acid: N5 Formyl THFolinic acid
(Citrovorum factor) 3 mg/mL Inj

26.  Uses:
1. Megaloblastic anemia
2. Prophylaxis
3. Methotrexate toxicity: Folinic acid used as it is an
active no need to reduced by DHFR before it can
act, Methotrexate is DHFR inhibitor, its toxicity
not reversed by folic acid
4. Citrovorum factor rescue: Methotrexate high
dose IV then half to 2 hr later 1-3 mg folinic acid
IV to rescue normal cells
Adverse events:

27.  Short gun antianemia therapy
 Erythropoietin:
 Uses
1. Primary : Anemia of CRF due to low EPO 25-100 µg/Kg
S.C /IV Three times a week max 600 µg/Kg/week
2. Anemia in AIDS patients on T/t with zidovudine
3. Cancer chemotherapy induced anemia
4. Autologus blood transfusion
 Adverse events : ↑ clot formation in AV shunts ,
Hypertension, occasional seizures, flu like symptoms

28.  Drugs used in neutropenia:
 G- CSF , GM- CSF
 Recombinant drugs
Filgrastim, molgrastim
Uses:
1. To decrease severity and duration of neutropenia
2. Shorten duration of neutropenia in BMT, after
high dose intense chemotherapy
3. Stimulate release of harvested progenitor cells
4. Expand the number of progenitor before
harvesting
5. Persistant neutropenia in advanced HIV
6. Aplastic anemia

29.  Adverse events:
 Bone pain, fever, myalgia, lethargy, pain and
reddening at site of injection
 Hypersensitivity: Skin rashes, hypotension,
nausea, vomiting and dyspnoea
 Filgrastim: dysuria, derange liver function , mild
to moderate spleenomegaly