Megaloblastic Anaemia
Content
·
Megaloblastic
anemia
·
Etiology
of megaloblastic anemia
·
Epidemiology of megaloblastic anemia
·
Pathogenesis
of megaloblastic anemia
Objectives
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
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 of
• 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)
–
– 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
Absorption:
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
—
— 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
• 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
- 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)
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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