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Megaloblastic Anaemia
• It is caused by impaired DNA synthesis and others by folate and vitamin B12 deficiency

• Abnormality in the haematopoietic precursors in the bone marrow - maturation of the nucleus is delayed
relative to that of the cytoplasm.

• Formation of morphologically abnormal nucleated red cell precursor called megaloblast in the bone marrow

• Anaemia described is hyperchromic macrocytic

Etiological Classification
I. VITAMIN B12 DEFICIENCY

A. Inadequate dietary intake e.g. strict vegetarians, breast-fed infants.

B. Malabsorption

1. Gastric causes: pernicious anaemia, gastrectomy, congenital lack of intrinsic factor.

2. Intestinal causes: tropical sprue, ileal resection, Crohn’s disease, intestinal blind loop syndrome, fish-tapeworm
infestation.

II. FOLATE DEFICIENCY

A. Inadequate dietary intake e.g. in alcoholics, teenagers, infants, old age, poverty.

B. Malabsorption e.g. in tropical sprue, coeliac disease, partial gastrectomy, jejunal resection, Crohn’s disease.

C. Excess demand

• 1. Physiological: pregnancy, lactation, infancy.

• 2. Pathological: malignancy, increased haematopoiesis, chronic exfoliative skin disorders, tuberculosis, and
rheumatoid arthritis.

D. Excess urinary folate loss e.g. in active liver disease, congestive heart failure

Pathophysiology
• The common feature in megaloblastosis is a defect in DNA synthesis in rapidly dividing cells.

• RNA and protein synthesis are impaired.

• Unbalanced cell growth and impaired cell division occur since nuclear maturation is arrested.

• More mature RBC precursors are destroyed in the bone marrow prior to entering the blood stream
(intramedullary hemolysis)

Vitamin B12
• Vitamin B12 or cobalamin is a complex organometallic compound having a cobalt atom situated within a
corrin ring.

• The liver is the principal storage site of vitamin B12

• Major source of loss is via bile and shedding of intestinal epithelial cells.

• A major part of the excreted vitamin B12 is reabsorbed in the ileum by the IF resulting in enterohepatic
circulation.

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Sources of Vitamin 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

Vegetable source: is pulses (legumes)

Dairy milk in smaller amounts

Daily requirement: 1-3 µg,

Pregnancy & lactation 3-5 µg

Commercial source: Streptomyces Griseus

FUNCTIONS
Vitamin B12 plays an important role in general cell metabolism

• Essential for normal haematopoiesis and for maintenance of integrity of the nervous system.

• Vitamin B12 acts as a co-enzyme

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

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Metabolic functions of Vit B12

C: Purine biosynthesis reduced , defective DNA

Methyl THF trapping & lack of S- adenosyl methionine can cause this

D: Cell growth & multiplication (Poultry)

E: Role in folate uptake & storage

B12 Deficiency Symptoms

Atrophic glossitis (shiny tongue)

Shuffling broad gait

Anemia and related sx

Vaginal atrophy

Malabsorption

Jaundice

Personality changes

Hyperhomocysteinemia

Neurologic symptoms (next slide)

Copper deficiency can cause similar neurologic

symptoms

Folate Metabolism
• BIOCHEMISTRY: Folate or folic acid, a yellow compound, is a member of water-soluble B complex vitamins -
pteroyl glutamic acid

• ABSORBTION: from the duodenum and upper jejunum

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• TISSUE STORES. The liver and red cells are the main storage sites of folate, largely as methyl THF
polyglutamate form

• Total folate in body = 5 to 10 mg (1/3 in liver as methyl folate)

• FUNCTIONS: acts as a co-enzyme for 2 important biochemical reactions

1. Thymidylate synthetase reaction. Formation of deoxy thymidylate monophosphate (dTMP) from its
precursor form, deoxy uridylate monophosphate (dUMP).

2. Methylation of homocysteine to methionine. This reaction is linked to vitamin B12 metabolism

Causes of Folate Deficiency

• Malnutrition: Destroyed by heat during cooking

• Alcoholism (decreased in 2-4 days): impairs enterohepatic cycle and inhibits absorption

• Increased requirement in hemolytic anemia, pregnancy, exfoliative skin disease

• IBD, celiac sprue

• Drugs

– Trimethoprim, Methotrexate, Primethamine (inhib DHFR)

– Phenytoin: blocks FA absorption, increases utilization (mech unknown)

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Folate deficiency symptoms

• Similar symptoms as B12 save for neurologic symptoms

• Presentation is different classically:

– Alcoholic

– Very poor dietary intake

– Older

– Depressed

– Living alone

Treatment
• Hydroxycobalamin as intramuscular injection 1000 μg for 3 weeks and oral folic acid 5 mg tablets daily for 4
months.

• Rule out B12 deficiency prior to treament as folic acid will not prevent progression of neurologic
manifestations of B12 deficiency

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