MEGALOBLASTIC ANAEMIA

• Macrocytic anaemias are divided into megaloblastic and non

megaloblastic anaemias. Macrocytosis, as seen in megaloblastic
anaemias, is due to abnormalities in DNA metabolism resulting from a
deficiency in vitamin B12 or folate, as well as due to various drugs
such as hydroxyurea, zidovudine, cytosine arabinoside, methotrexate
azathioprine, 6-mercaptopurine, or cladribine.
• Megaloblastic anaemias are macrocytic anaemias(raised MCV)
• There is an abnormality in the maturation of hematopoetic cells in
the bone marrow. In addition to abnormal RBCs, the WBCs and
platelets may be affected.
• Megaloblastic anaemias are characterized by abnormally large
nucleated red cell precursors called megaloblasts in bone marrow.
• Anaemia described is hypochromic (low haemoglobin) macrocytic
(large size)
• Megaloblastosis results from impaired DNA synthesis in replicating
cells, which is signaled by a large immature nucleus. RNA and protein
synthesis remain unaffected, and the cytoplasm matures normally.
Megaloblastic changes can be observed microscopically in RBC and in
proliferating cells (e.g., in the cervix, skin, GI tract).24 The extent of
RBC macrocytosis is reported as MCV, calculated as s:
MCV (fL) = [Hct (percent) × 10]/ [RBC count (106 /μL]
AETIOLOGY
1) Vitamin B12 deficiency : Occurs due to
 Inadequate intake
 Malabsorption syndrome
 Inadequate utilization
 Usually occurs in people who are strict vegans and their breast fed infants, chronic alcoholics
or elderly patients with a “tea and toast” diet.
 Decreased absorption is seen in patient’s with pernicious anaemia (autoimmune disorder)
 Vitamin B12 deficiency may also result from overgrowth of bacteria in the bowel that utilizes
Vit B12
 Blind loop syndrome, Zollinger Ellison syndrome, tapeworm infestations, TB, IBD may also
contribute to vit B12 deficiency.
2) Folate deficiency
 Inadequate intake
 Decreased absorption
 Hyperutilization
 Inadequate utilization
 Folic acid deficiency is associated with poor eating habits, alcoholics, common in elderly
patients, food faddists, chronically ill patients
 Hyperutilization of folic acid may occur when the rate of cellular division is increased as
seen in pregnancy, malignancy, rheumatoid arthritis, burn patients, growth spurts seen in
adolescence and infancy
 Drugs causing folate deficiency : sulfasalazine, methotrexate, trimethoprim-
sulphamethoxazole, phenytoin.
3) Pernicious anaemia
It is an autoimmune disorder that results due to absence of an
intrinsic factor by causing destruction of the gastric parietal or atrophy
of the gastric mucosa
A deficiency in intrinsic factor limits vitamin B12 absorption,
contributing to vitamin B12 deficiency
PATHOGENESIS
1) Vitamin B12 deficiency anaemia
• Vitamin B12 is necessary for DNA synthesis, metabolic reactions
(involving folic acid), essential in maintaining integrity of the
neurologic system.
• Two active coenzyme forms : DAB12 (deoxy adenosyl cobalamin) and
methyl cobalamin
a) Reduced intake
Insufficient consumption of vitamin B12 rich foods like fish, meat
eggs, cheese and milk.
b) Reduced absorption of Vitamin B12
C) Folate trap
D) In neuropathy
2) Folate deficiency anaemia
• Folic acid is necessary for the production of nucleic acids, proteins,
amino acid, purines and thymine and hence DNA and RNA
• Chemically it is pteroyl glutamic acid consisting of pteridine, PABAand
glutamic acid.
• Folic acid gets converted to its active coenzyme active form : Tetra
hydrofolic acid
• THFA mediates a number of one carbon transfer reaction by carrying
a methyl group as an adduct.
3) Pernicious anaemia
CLINICAL PRESENTATIONS
• Features of megaloblastic anaemia
- Glossitis (sore, pale, smooth tongue)
- angular stomatitis
- altered bowel habits
- anorexia
- mild jaundice
- bilateral neuropathy
- melanin skin pigmentation
- fever
vitamin B12 deficiency (onset is slow and insidious) Folic acid deficiency anaemia

• Hyperpigmentation • Glossitis
• Pallor • Pallor
• jaundice • angular stomatitis
• vitiligo • anorexia
• paraesthesias with a loss of vibration • altered bowel habits
• muscle weakness, frequent falls • general debility
• NEUROPSYCHIATRIC : • weight loss
- peripheral neuropathy • sterility
areflexia
cognitive impairment
gait abnormalities
DIAGNOSIS
vitamin B12 deficiency
• Laboratory investigations
 MCV usually elevated > 100fl
 mild leukopenia and thrombocytopenia
 Peripheral blood smear : demonstrates macrocytosis accompanied by hyper
segmented polymorphonuclear leukocytes, oval macrocytes, anisocytosis and
poikilocytosis
 serum LDH and indirect bilirubin levels elevated
 low reticulocyte count
 low vitamin B12 level (< 150pg/ml)
 how haematocrit and haemoglobin levels
• Other tests :
 MMA (methyl malonic acid ) and homocysteine levels elevated
 Blood levels of vitamin b12 should be drawn for patient with
macrocytosis, peripheral neuropathy and dementia
 Schilling test (to diagnose pernicious anaemia)
 Antibody testing (positive intrinsic factor antibody may be present in
patient with pernicious anaemia) and serum gastrin levels.
 Bone marrow smears : hypercellular with frequent mitosis, presence
of megaloblasts, giant bands and giant metamyelocytes.
Folic acid deficiency anaemia
It is of paramount importance to rule out vitamin b12 deficiency when
folate deficiency is suspected.
• Laboratory investigations
 Low MCV, low haematocrit
 Serum folate levels decreases to less than 3 ng/ml
 Peripheral blood smears : macrocytosis associated with large oval
red cells, anisocytosis and poikilocytosis.
 Some of the neutrophils are hyper segmented, thrombocytopenia
 RBC folate levels also declines (<150 ng/ml)
PHARMACOTHERAPY

• It is necessary to establish whether the patient with megaloblastic

anaemia has vitamin b 12 or folic acid deficiency or both
• if it is not possible to delay until a definitive diagnosis is made, both
folic acid and vitamin b 12 be given
• Treatment of vitamin B12 deficiency with folic acid may lead to
resolution of haematological abnormalities but does not correct the
neuropathy, which continues to deteriorate.
1) FOLIC ACID DEFICIENCY ANAEMIA
• Non pharmacological therapy :
 Diet rich in folic acid (chicken liver, cereals, lentils, chickpea, kidney
beans, black beans, tomato juice, oranges etc)
 Limit consumption of tea or coffee immediately after meals
Medication regimen
• Folate deficiency is usually managed by replacement therapy, changed in
dietary habits or removal of precipitating factor should also be considered
• Daily requirement of vitamin B12 : 100 micrograms
• General management :
 For severe anaemia (hb < 4g/dl ), packed red cell transfusion is given
slowly (15-30 drops/minute) along with furosemide (40-80 mg)
 Before transfusion it is necessary to collect samples for B12 and folic acid
estimation
A bone marrow aspiration should also be performed before transfusion
 Specific management
• Patient diagnosed to have folic acid deficiency anaemia

counselling of dietary changes and removal of precipitating factors

Insuffecient folate replace Deficiency due to Drug induced deficiency

Stores (in most case) malabsorption (ex: anticonvulsants)

1 mg folate orally Oral folate 1-5 mg low dose folate therapy

For 4 months daily for 4 months (500 mcg daily)
NOTE : long term folic acid therapy should have their vitamin B12 levels checked at
regular intervasl (yearly)
Prophylaxis in pregnancy
• Prophylaxis with folate (300-400 microgram daily) often in
combination with iron, starting before conception and during the first
12 weeks of pregnancy.
• This prevents the first occurrence of neural tube defects
• The patient is also advised to consume folate rich food .
• patient with a history of neural tube defects should be advised to
take high dose (5 mg daily) of folic acid and again continued until
week 12
Preparations of folic acid
• FOLVITE, FOLITAB 5 mg tablets

EVALUATION OF THERAPEUTIC OUTCOMES :

• Symptomatic improvement, as evidenced by increased alertness,
appetite, and cooperation, often takes place early during the course of
treatment.
• Reticulocytosis occurs within 2 to 3 days and peaks within 5 to 8 days
after beginning therapy. Hct begins to rise within 2 weeks and should
reach normal levels within 2 months.
• The MCV initially increases because of an increase in reticulocytes, but
then gradually decreases to normal
VITAMIN B12 DEFICIENCY ANAEMIA
• GOALS OF THERAPY
 Reversal of hematologic manifestations
 Replacements of body stores
 Prevention of neurologic manifestations

• Non pharmacological therapy

 consume vitamin b 12 rich food (fortified cereals, beef liver, milk, tuna, yoghurt,
clams, oysters etc)
 Cessation of alcohol and smoking
 Avoid hot beverages immediately after meals
General management
 For severe anaemia (hb < 4g/dl ), packed red cell transfusion is given
slowly (15-30 drops/minute) along with furosemide (40-80 mg)
 Before transfusion it is necessary to collect samples for B12 and folic
acid estimation
A bone marrow aspiration should also be performed before
transfusion
 Specific management
Patient diagnosed to have megaloblastic anaemia
a)Patient with pernicious anaemia
b) If vit b12 levels are marginally
low and MMA and homocysteine
levels are elevated
• Initiate oral cobalamin at 1-2 mg
Daily for 1-2 weeks, followed by 1mg
daily for 3 months
patient with neurologic
manifestations
I.M cyanocobalamin 1000mcg
daily for 1 month and then
monthly.
Initiate 1 mg daily oral administration
after symptoms resolve
Vitamin B12 preparations
• Cyanocobalamin :- 35 microgram/5 ml liquid
• Hydroxycobalamin :- 500 microgram, 1000 microgram injection
• NEUROBION FORTE (15 microgram/tab)
• OPTINEURON (1000 microgram/3 ml inj)
• POLYBION (15 microgram/ cap)
• FESOVIT (15 microgram/cap)
Evaluation of therapeutic outcome
• The patient will experience an improvement in strength and well-being within
a few days. If glossitis is present, improvement is seen within 24 hours.
• Bone marrow becomes normoblastic after 24 hours
• Reticulocytosis is evident in 2 to 5 days and peaks around day 7. Hgb begins to
rise after the first week and the leukocyte and platelet counts normalize after
about 7 days.
• A CBC count and a serum cobalamin level is usually drawn 1 to 2 months after
the initiation of therapy and 3 to 6 months thereafter for surveillance
monitoring. Homocysteine and MMA levels should be repeated 2 to 3 months
after the initiation of replacement therapy to evaluate for normalization of
levels, although levels begin to decrease in 1 to 2 weeks.