Megaloblastic Anaemia - B. Pharma 2nd Semester Pathophysiology notes pdf

Megaloblastic Anaemia


·         Megaloblastic anemia

·         Etiology of megaloblastic anemia

·         Epidemiology of megaloblastic anemia

·         Pathogenesis of megaloblastic anemia


At the end of the PDF Notes, the students will be able to

       Define  megaloblastic anemia

       Discuss  the etiology of megaloblastic anemia

       Describe  the epidemiology of megaloblastic anemia

       Explain the pathogenesis of megaloblastic anemia

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 of Megaloblastic Anaemia


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.


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 of Megaloblastic Anaemia

       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 

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 of B12

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 of B12


Ø  Cobalamins in food are in bound form inactive, released by cooking (heat) and by proteolysis in stomach & intestine.

Ø  Vit B12 is not soluble so absorption depends on  various transfer factors

       R- 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: 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



  Personality changes


  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

       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


      Trimethoprim, Methotrexate, Primethamine (inhib DHFR)

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

Folate deficiency symptoms

       Similar symptoms as B12 save for neurologic symptoms

       Presentation is different classically:


      Very poor dietary intake



      Living alone


       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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