vitamin B12 & folic acid deficiency anemia

1. Dr.K. R. Prabhakar,
Asst.Proffessor

2. Pathophysiology
 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.

3.  Mammals can not synthesise vit B₁₂ .
 Sources of vit B₁₂ are- fish, meat, liver, eggs, yeast &
milk.
 Commercial source- from streptomyces griseus.
Deficiency causes:
 Insufficient dietary intake (RDA-2µg)
 ↓absorption or utilisation
 Prolonged chemotherapy (interfers with purine
metabolism).
 Fish tape worm infestation

4.  Pernicious anemia:
• 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.

5. Chemistry:
 Vit B₁₂ is a generic term for cyanocobalamin &
hydroxocobalamin.
 Only cobalt containing amino compounds known to
occur in nature.
 Methylcobalamin & 5deoxoadenosyl cobalamin act
as coenzymes and are active forms of vit B₁₂ though
unstable.

6. Pharmacokinetics
 Absorption from GIT depends on various transfer
mechanisms.
 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

7.  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
in hepatocytes.
 Liver can store up to 4-6 mg of vit B₁₂ .
 Stores can last for 5 yrs even if intake is stopped.

8. Metabolic functions
 Cobalamins- cofactors for 2 main enzymatic process
 1. Cofactor for methionine synthase –converts
homocysteine to methionine &
 5-methyl tetrahydrofolate to tetrahydrofolic acid.

10. In vitB₁₂ deficiency
 5-methyl-tertrahydrofollic acid gets trapped.
 Defective DNA synthesis & ultimately megaloblastic
bone marrow.
 2. Deoxyadenosyl cobalamin activates
methylmalonyl-coA mutase

11. In vitB₁₂ deficiency
 methylmalonyl coA accumulate results in faulty fatty
acid synthesis.
 Incorporates in to cell membranes of CNS leads to
neurological symptoms due to inadequate myelin
synthesis-
 Peripheral neuropathy,
 Dementia,
 Loss of motor and sensory reflexes.

12. Therapeutic uses
 Most commonly used preparations are
 cyanocobalamin
 hydroxycobalamin
 methylcobalamin
 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
use lesser.

13.  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

14.  Also called polyglutamate as each folic acid molecule
may have 2-8 molecules of glutamic acid.
 Humans can not synthesise folic acid
Dietary sources:
 Green leafy vegetables, fruits, mushrooms, liver,
meat, kidney, eggs, milk & yeast.
 One of the B group vitamin.

15. Pharmacokinetics
 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
to (5-MeTHFA)
 Converted to THFA by methionine synthase in
tissues.
 About 5-20 mg is stored in liver.

16.  Undergoes enterohepatic circulation similar to vitB₁₂.
 Trace amounts are excreted in urine & faeces.
 Stores last for about only 3 months.
Metabolic functions:
 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.

17. Deficiecy causes
 Dietary lack.
 Malabsorption syndrome (coeliac disease or crohns
disease).
 Excessive demand as in pregnancy & anemia.
 Liver diseases and renal dialysis.
 Drug induced- methotrexate, phenytoin,
phenobarbitone.
 Deficiecy leads to megaloblast anemia and
teratogenic effects.

18. Therapeutic use
 RDA of folic acid is 50 µg,
 During pregnancy & lactation up to 200-300 µg/day.
 Therapeutic doses are 1-5 mg/day.
Uses-
 Folinic acid for prophylaxis or treatment of
methotrexate toxicity.
 Folate deficiency by phenobarbitone & phenytoin.
 Prophylactically during pregnancy, lactation.

19.  Folic acid is always given with vit B₁₂ to treat
megaloblastic anemia.
 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.

20.  Cytokine produced in juxtatubular cell in kidney &
also macrophages.
 Essential for normal erythropoiesis.
 Anaemia and hypoxia are sensed by kidney cells.
 Induce rapid secretion of EPO→ acts on erythroid
marrow.
 EPO receptor is a JAK-STAT-binding receptor.

21.  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.

22. Uses
 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.

23.  Preferable for smptomatic patients with Hb ≤ 8 g/dl.
 Epoetin 25–100 U/kg s.c. or i.v. 3 times a week (max.
600 U/kg/week).
 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.

24. Thank you