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This is due to vitamin B₁₂ and folic acid deficiency
Impairment of DNA synthesis and cell proliferation
in precursor cells of RBCs.
Cytosolic growth is not impaired ,cytosole ↑
Hence primitive RBCs become big(megaloblast)
Mature RBCs diminish(anemia),
Prone to hemolysis-hemolytic anemia.
Mammals can not synthesise vit B₁₂ .
Sources of vit B₁₂ are- fish, meat, liver, eggs, yeast &
Commercial source- from streptomyces griseus.
Insufficient dietary intake (RDA-2µg)
↓absorption or utilisation
Prolonged chemotherapy (interfers with purine
Fish tape worm infestation
• Important cause of vit B₁₂ deficiency
• Hereditary autoimmune disease in which antibodies
develop against intrinsic factor(IF)
• ABs either bind to IF or IF-B₁₂ complex and prevents
binding to IF receptors in ileum.
Availability of IF decreases in
• Post gastrectomy patients, diseases of ileum &
surgical removal of ileum.
Vit B₁₂ is a generic term for cyanocobalamin &
Only cobalt containing amino compounds known to
occur in nature.
Methylcobalamin & 5deoxoadenosyl cobalamin act
as coenzymes and are active forms of vit B₁₂ though
Absorption from GIT depends on various transfer
After liberation from food interacts with R-proteins
in stomach protect it from acid degradation.
In the duodenum the pancreatic proteases degrade
the complex to free cobalamin.
Vit B₁₂ is now absorbed on to the IF .
IF- cobalamin complex is transported across ileum
cell membrane through IF specific receptors
In enterocytes IF liberates cobalamin which is
converted to methylcobalamin
Transcobalamin II transports it to portal circulation.
Vit B₁₂ is taken up by cells by endocytosis.
Excess vit B₁₂ is stored as 5-deoxoadenosylcobalamin
Liver can store up to 4-6 mg of vit B₁₂ .
Stores can last for 5 yrs even if intake is stopped.
Cobalamins- cofactors for 2 main enzymatic process
1. Cofactor for methionine synthase –converts
homocysteine to methionine &
5-methyl tetrahydrofolate to tetrahydrofolic acid.
In vitB₁₂ deficiency
5-methyl-tertrahydrofollic acid gets trapped.
Defective DNA synthesis & ultimately megaloblastic
2. Deoxyadenosyl cobalamin activates
In vitB₁₂ deficiency
methylmalonyl coA accumulate results in faulty fatty
Incorporates in to cell membranes of CNS leads to
neurological symptoms due to inadequate myelin
Loss of motor and sensory reflexes.
Most commonly used preparations are
Given orally or deep intramuscularly never given i.v.
Hydroxycobalamin is longer acting but development
of Abs to transcobalamin II –vit B₁₂ complex made its
Methylcobalamin is used to treat neurological
deficits in vit B₁₂ deficiency.
Dose: cyanocobalamin or hydroxycobalamin 100-
1000 µg/day i.m on alternative days for 2 weeks
followed by once a month.
Methylcobalamin 1000-1500 µg/day orally.
I.M therapy brings changes in bone marrow with in
2-3 mts with improvement in neurological symptoms
Also called polyglutamate as each folic acid molecule
may have 2-8 molecules of glutamic acid.
Humans can not synthesise folic acid
Green leafy vegetables, fruits, mushrooms, liver,
meat, kidney, eggs, milk & yeast.
One of the B group vitamin.
Absorption occurs primarily in proximal jejunum.
Carboxypeptidases in jejunum hydrolyse dietary
polyglutamates to folic acid.
Dihydrofolate reductase converts folic acid to
tetrahydrofolic acid(THFA) in mucosa & methylated
Converted to THFA by methionine synthase in
About 5-20 mg is stored in liver.
Undergoes enterohepatic circulation similar to vitB₁₂.
Trace amounts are excreted in urine & faeces.
Stores last for about only 3 months.
THFA is transformed to folate cofactors – folinic acid,
10-formyl THFA, 5,10-methylene-THFA etc. donates
one carbon units in oxidation.
THFA through 1-C transfer reactions is involved in
synthesis of purines and pyrimidines which are
essential for DNA synthesis.
Malabsorption syndrome (coeliac disease or crohns
Excessive demand as in pregnancy & anemia.
Liver diseases and renal dialysis.
Drug induced- methotrexate, phenytoin,
Deficiecy leads to megaloblast anemia and
RDA of folic acid is 50 µg,
During pregnancy & lactation up to 200-300 µg/day.
Therapeutic doses are 1-5 mg/day.
Folinic acid for prophylaxis or treatment of
Folate deficiency by phenobarbitone & phenytoin.
Prophylactically during pregnancy, lactation.
Folic acid is always given with vit B₁₂ to treat
In the presence of vitB₁₂ deficiency if only folic acid is
used it will improve only anemia but worsen
neurological deficit as it does not convert
methylmalonyl CoA to succinyl CoA.
Adverse effects :rare for both vit B₁₂ &folic acid.
Cytokine produced in juxtatubular cell in kidney &
Essential for normal erythropoiesis.
Anaemia and hypoxia are sensed by kidney cells.
Induce rapid secretion of EPO→ acts on erythroid
EPO receptor is a JAK-STAT-binding receptor.
Recombinant human erythropoietin are Epoetin α, β.
Administered by i.v. or s.c. injection.
Plasma t½ of 6–10 hr, but action lasts several days.
Darbepoetin – longer acting glycosylated form of
epoetin, injected weekly.
Primary use- anaemia of chronic renal failure.
Anaemia in AIDS patients treated with zidovudine.
Cancer chemotherapy induced anaemia.
Preoperative increased blood production for
autologous transfusion during surgery.
Anemia in premature infants.
Supplemented with iron & folic acid.
Preferable for smptomatic patients with Hb ≤ 8 g/dl.
Epoetin 25–100 U/kg s.c. or i.v. 3 times a week (max.
Reduces need for transfusions
It is prudent to start with a low dose and titrate
upwards to keep haematocrit between 30–36%, and
Hb 10–11 g (max 12 g) per dl.