Introduction Characterized by inhibition of DNA synthesis
during red blood cell production. When DNA synthesis is impaired,
the cell cycle cannot progress from the G2 growth stage to the
mitosis (M) stage. This leads to continuing cell growth without
division, which presents as macrocytosis. Most commonly result from
lack of folic acid or vitamin B 12
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MEGALOBLASTIC ANAEMIA [ VITAMIN B 12 DEFICIENCY ]
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Sources The best sources of Vitamin B12 include: eggs, milk,
cheese, milk products, meat, fish, shellfish and poultry. Some soy
and rice beverages as well as soy based meat substitutes are
fortified with vitamin B12. Although bacteria in the large
intestine synthesize vitamin B 12 it cannot be absorbed from this
site
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Absorption of Vitamin B 12 2 mechanism Active (75%) requires
the presence of intrinsic factor ( a glycoprotein produced by
gastric mucosa) Passive absorption occurs by diffusion and works
when pharmacological doses of vitamin B 12 are ingested Minimum
amount required for an adult is 1 to 4 g per day
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Vitamin B12 in food R-Binder B12-R-Binder complex IF-B12
complex + Freed R-Binder Intrinsic Factor (IF) Receptor-IF-B12
B12-TCII Circulation Receptor TCII IF Degradation Epithelial cell
of terminal iIeum Stomach Duodenum
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Functions of Vitamin B 12 Plays a key role in the normal
functioning of the brain and nervous system Erythropoesis Synthesis
of methionine from homocysteine Conversion of methyl malonyl CoA to
succinyl CoA
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FH4 FH2 Methylene FH4 Methyl FH4 Intestinal cell Dietary
folates Dihidrofolate Redutase Methionine Homocysteine Thymidylate
Synthase DNA Synthesis dTMPdUMP Role of Vitamin B12 and Folate in
DNA synthesis VitB12 (Methylcobalamin)
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General Morphological Features Of Megaloblastic Anemia
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PERIPHERAL BLOOD FINDINGS 1. Hemoglobin decreased 2. Hematocrit
decreased 3. RBC & Platelet count decreased/normal 4. MCV -
>100fl (normal 82-98fl) 5. MCH increased 6. MCHC Normal (3236
g/dL) 7. Reticulocytopenia- due to destruction of fragile and
abnormal megaloblastic erythroid precursor. 8. Howell-Jolly bodies
(chromosomal remnant) also present. 9. Hypersegmented Neutrophils
10. Poikilocytosis (abnormally shaped RBCs).
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PERIPHERAL SMEAR RBC: - Macro-ovalocytosis [ macrocytosis is
the earliest sign in Vit B 12 deficiency and can be detected even
before the onset of anaemia ] - In severe anaemia in addition to
macrocytosis, marked anisopoikilocytosis, basophilic stippling,
howell jolly bodies may be found
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Marked macro-ovalocytosis (MCV 134 fl) in the peripheral blood
smear of a patient with vitamin B12 deficiency.
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PERIPHERAL SMEAR WBC Normal count or reduced count
Hypersegmented neutrophils is one of the earliest sign of
megaloblastic haematopoiesis and can be detected even in the
absence of anaemia (when more than 5% of neutrophils show 5 lobes;
1% neutrophils with 6 lobes) PLATELETS: Normal or decreased (severe
anaemia) Giant platelet can occur
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MEGALOBLAST 1. Cell and nuclear size and amount of cytoplasm
(deeply basophilic royal blue) are increased 2. Nuclear chromatin
is sieve like or stippled (open) 3. Nuclear cytoplasmic
asynchrony/dissociation 4. Abnormally large precursor
(promegaloblast and early megaloblast) are increased in BM
Maturation arrest 5. Abnormal mitoses (increased)
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Causes of Vit B 12 deficiency Insufficient dietary intake (very
rare) Strict vegetarians Deficient absorption Pernicious anaemia
Total or partial gastrectomy Prolonged use of PPI or H 2 blockers
Diseases of small intestine(crohns disease,intestinal cancer,celiac
disease) Fish tapeworm infestation
Manifestations Megaloblastic Anemia A lack of energy Sore and
red tongue Muscle weakness Depression Problems with memory,
understanding and judgement
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PERNICIOUS ANEMIA CHRONIC ATROPHIC GASTRITIS -autoimmune
destruction of gastric mucosa marked loss of parietal cells which
are responsible, in part, for the secretion of intrinsic factor, a
protein essential for subsequent absorption of vitamin B12 in the
ileum. Pathological changes are infiltration by mononuclear cells
in submucosa and lamina propria of fundus and body of the stomach,
progressive loss of parietal and chief cells, and their replacement
by intestinal type mucous cells
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H. pylori and Zollinger-Ellison syndrome may also cause a form
of nonautoimmune gastritis that can lead to pernicious anemia
Patients with pernicious anaemia have increase risk of gastric
cancer
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DIAGNOSTIC FEATURES 1. Moderate to severe megaloblastic anemia
2. Leucopenia with hypersegmented neutrophils 3. Mild to moderate
thrombocytopenia 4. Mild jaundice due to ineffective erythropoiesis
and peripheral hemolysis 5. Neurologic changes 6. Low levels of
serum B 12
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7. Elevated levels of homocysteine 8. Striking reticulocytosis
after parenteral administration of vitamin B 12 9. Serum antibodies
to intrinsic factor (specific) and anti parietal cell antibodies in
serum 10. Abnormal Schilling test
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GASTRECTOMY Total gastrectomy : Secondary to Vit B 12
deficiency as it removes the site of synthesis of intrinsic factor
Prophylactic vitamin B 12 after surgery Partial gastrectomy Regular
follow up after surgery for early detection of deficiency
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INFESTATION BY FISH TAPEWORM Diphyllobothrium latum
(inadequately cooked fish) Vitamin deficiency by competing with the
host for vitamin in food Diagnosis made by demonstration of ova in
stool
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CLINICAL FEATURES Anaemia, mild jaundice and sometimes
neurological involvement Neurological involvement in the form of
Peripheral neuropathy Subacute combined degeneration of spinal cord
Cerebral changes (personality changes, dementia & psychosis)
Patients can present with only neurological abnormalities without
megaloblastic anaemia
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LABORATORY FEATURES 1. Morpholgical changes of megaloblastic
anaemia in PS and BM 2. Serum vitamin B 12 assays 3. Methylmalonic
acid (MMA) and homocysteine in serum 4. Abnormal Schilling test 5.
Intrinsic factor antibodies in serum
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MANAGEMENT OF B 12 DEFICIENCY When B 12 deficiency is suspected
a trial of B 12 is essential. Failure of response can only be
determined after careful follow-up over a period of several months,
particularly if the patient is non-anaemic. Standard therapy for
all cases of B 12 deficiency is by regular intramuscular injections
of B 12, usually in the form of hydroxycobalamin. In patients with
inadequate dietary intake supplements may be given by mouth.
Underlying conditions should be managed separately.
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After initiation of therapy, reticulocyte count begins to
increase around 3 rd day peak by 6 th or 7 th day gradually returns
to normal by end of 3 rd week Hematocrit steadily rises and
normalises in about 1-2 months Blood transfusion is indicated in
severely anaemic symptomatic patients or in patients with CCF
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NOTE: Both B 12 and folate are given to patients if B 12
deficiency has not been excluded. This is to prevent neurological
damage, e.g. subacute combined degeneration of the spinal
cord.
