Megaloblastic anemia

Megaloblastic anemiaDr Naser Tadvi

Thomas edison : Pernicious anemia Minot & Murphy 1926: liver preparation Castle: Postulated intrinsic factor theory1941 Mitchel : Folic acid 1943: Pteroyl monoglutamic acid 1948: Crystalline B12

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

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

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

Cobalamins: Vit B12 belongs to cobalamin family i.e cobalt

containing compoundsCyanocobalamin: CN group attached to cobalt Hydroxycobalamin: OH group attached to

cobalt Light Cyanocobalamin

Hydroxycobalamin

Cyanide

Other cobalamins: aquocobalamin, nitrocobalamin & methyl cobalamin

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

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 factorsR- Factor, Intrinsic factor &

Transcobolamin II

Metabolic functions of Vit B12

C: Purine biosynthesis reduced , defective DNA Methyl THF trapping & lack of S- adenosyl

methionine can cause this D: Methionine DAB12 S- adenosyl

methionineS- adenosyl methionine required for

synthesis of phospholipids & myelin ( neuronal damage)

E: Cell growth & multiplication (Poultry)F: Role in folate uptake & storage

Deficiency: 1. Addisonian pernicious anemia2. Gastric mucosal damage 3. Malabsorption4. Blind loop syndrome, Fish tape worm 5. Nutritional deficiency 6. Increased demand: Pregnancy and

infancy

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

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

Folic acid: (Pteroyl Monoglutamic acid)

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-organismsDaily requirement: adult 50-100 µg

pregnancy and lactation 500- 800 µg

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

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)

Metabolic functionsFolic acid DHFA THFA

(Active form)

folate DHF reductase reductase THFA mediates number of one Carbon

tranfer reactions Conversion of homocysteine to methionineGeneration of thymidylate Conversion of serine to glycinePurine synthesisHistidine metabolism

Deficiency : 1. Inadequate dietary intake2. Malabsorption : coeliac disease, tropical

sprue , regional ileitus3. Biliary fistula: no recirculation4. Chronic alcoholism5. Increased demand : Pregnancy , lactation6. Drugs: Phenytoin, phenobarbitone,

primidone

Preparations and dose: Folic acid tab 5 mg ; dose = 5 to 20 mg Prophylaxis 0.5 mg/dayParenteral form available in

combination only Folinic acid: N5 Formyl THFolinic acid

(Citrovorum factor) 3 mg/mL Inj

Uses:1. Megaloblastic anemia2. 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:

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 anemia4. Autologus blood transfusion

Adverse events : ↑ clot formation in AV shunts , Hypertension, occasional seizures, flu like symptoms

Drugs used in neutropenia: G- CSF , GM- CSF Recombinant drugs Filgrastim, molgrastimUses: 1. To decrease severity and duration of

neutropenia2. 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

harvesting5. Persistant neutropenia in advanced HIV 6. Aplastic anemia

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