Megaloblastic anaemia results from the deficiency of folic acid /vit- B12.
Deficiency of folic acid /vit- B12,the synthesis and maturation of nuclei is improper and delayed. As a result erythroblasts remain large with large finely stippled nuclei (megaloblast).
Production of red blood cells is slowed down and lessened; moreover there is increased destruction of these defective red blood cells precurssors in the marrow. (Intramedullary haemolysis)
The folate defficiency:
Folate source:
The folates are present in the liver, kidney,
muscle tissues and green fresh vegetables.
Milk is a poor source.
Cooking causes loss of 60-90% of folates.
Absorption:
Folates are absorbed mainly from duodenum and upper jejunum,to a certain extent from ileum. Folates formed
in the large gut by intestinal bacteria are not available for absorption.
Daily requirement: About 200mg
Daily Intake: 100-500mg
Absorption : 100-200mg
Transport: Free forms or weakly bound to plasma albumin
Storage: Liver , Kidney, muscle tissue.
Total amount 5-20mg, sufficient for months.
Function: Essential in the synthesis of DNA.
Causes of folate deficiency:
Nutritional deficiency:
Less intake
Increased demand
Pregnancy
Puerpurium
Haemolytic anaemia
Hyperthyroidism
Skin diseases
Impaired absorption:
Coeliac diseases
Tropical sprue
Some drugs: Manifestation of the deficiency
Anticancer drugs Glossitis
Marcaptopurines Megaloblastic anaemia
Fluorouracil
Actinomycine.
Vitamin B12 deficiency:
Source:
Present in high conc in the liver, kidney,
heart, meat, fish, eggs, milk and cheese
No vegetable source.
Effect of cooking 10-30% loss.
Also formed by large gut by normal bacterial flora. But it doesn’t come in human need as B12 is absorbed from jejunum and ileum.
Daily requirement: 2-4 mg
Daily intake avg: 5-30 mg
Absorption: 2-5 mg
Absorption:
Released from food by acid pepsin digestion combines with intrinsic factors of castle (secreted by parietal cells) and gets absorbed in the jejunum and ileum by active transport.
Transport occur through transcobalamine
I, II, III.
Vit B12 can also get absorbed by diffusion when high conc is present in gut.
Tissue stores - Liver, kidney.
Total body deposit 2-5 mg which is sufficient for 2-3 yrs.
Function:
Essential for DNA synthesis and maturation of nuclei
Causes of Vitamin B12 deficiency:
1)Nutritional deficiency (uncommon)
2)Lack of intrinsic factor of castle
(essential for complex formation and absorption of vit-B12)
-Pernicious Anaemia
-Gastrectomy (requires 3-5 yrs for manifestation of deficiency for good storage of vitB12 in the liver.)
3)Impairment in the absorption from the
Intestine (Malabsorption syndrome).
Coeliac diseases,
Tropical sprue,
Regional ilities
Resection of the intestine
Diffuse lymphoma of the intestine.
Bacterial overgrowth causing diarrhoea and interference with absorption.
Tape worm infestation-
Diphyllobothrium latum taking up vit B12 for its nutrition and causing diarrhoea and malabsorption.
Manifestation of vit B12 deficiency:
1.Glossitis
2.Megaloblastic anaemia
3.Peripheral neuropathy &
4.Sub acute combined degeneration of the spinal cord.
Megaloblast:
Cell size:
Megaloblast are larger than erythroblast, with an increase in cytoplasm and nuclear size at every stage of development.
Nucleus:
The chromatin network is more open, being arranged in a fine reticular fashion to give a stippled appearance. As the cell matures the chromatin clumps.
Dissociation of cytoplasmic and nuclear maturation.:
The maturation of the nucleus lags behind that of the cytoplasm. Haemoglobinization of the cytoplasm proceeds at a faster rate than nuclear maturation.
Mitosis are more common and are sometimes abnormal in appearance.
Mechanism of development of megaloblastic anaemia:
Lack of Vit B12 and folic acid causes slowing of DNA synthesis in developing erythroblasts with an accumulation of cells in the premitotic phase of the cell cycle. Some of these cells die within marrow as shown by the Ferro kinetic pattern of ineffective erythropoesis. When raised serum billirubin occurs, it is due to both haemolysis in the peripheral blood and premature destructions of developing megaloblasts in the marrow.
Investigations for vit B12 /folate deficiency anaemia:
Blood picture:
Increased MCV-above 125fl is almost diagnostic of vitB12/folic acid deficiency.
MCH- Increased, normal or reduced when associated with iron deficiency anaemia.
MCHC- Normal or reduced when associated with iron deficiency anaemia.
Blood film:
RBC- Marked oval macrocytes.
Usually normochromic.
Red cell may appear as macrocytic hypochromic if associated with iron deficiency anaemia.
WBC- Neutropenia with hyper-segmented neutrophil. (when more than 5% of nutrophil have 5 lobes or the film shows at least one six-lobed cell.
Hyper-segmentation is an early sign of vit B12 or folate deficiency, and is useful
in the diagnosis of megaloblastosis
with minimal or no anaemia.
Platelates:
Mild thrombocytopenia is present.
Bone marrow examinations:
Cellularity- Hpercellular
M:E ratio – Reduced
Erythropoesis :–Active. Megaloblastic changes occur at all stages of red cell development.
Granulopoesis:-Active. Large atypical granulocytes, which occur at all stages of development but particularly at the metamylocyte stage, resulting in “giant stab” forms.
Megakaryopoesis:-Megakeryocytes are usually present in normal or slightly increased numbers, but occasionally they are decreased. Some are atypical and have a deeply basophilic agranular cytoplasm or hyper segmented nucleus.
Marrow iron present in large amount and sideroblast is increased.
Special test:
Measurement of vitB12 by-
Serum Vit-B12 assay by:
Radioisotope technique or
Microbial technique.
Absorption test:
Schilling tests.
Measurement of Folic acid by-
Radioisotope technique or
Microbial technique.
Pernicious anaemia:
It is an autoimmuno chronic disorder of middle and old age and is associated with chronic gastritis and gastric atrophy which results in vitamin B12 deficiency.
This disorder may be hereditary or acquired.
Antiparietal or anti-intrinsic factor antibodies are found in the serum in 60-80% cases.
There is achlorhydria and intrinsic factors of castle is not formed.
What is Nutritional anaemia?
Anaemia which occur due to defficiency of iron, folic acid and vit B12.
This anaemia may occur individually or may occur combinely.
Anaemia in pregnancy:
In pregnancy there is haemodilution:
Plasma volume rises by 40-45%, red cell mass rises by 20-25%.
Hb starts falling from 3 months till 9 months.
True anaemia may occur due to iron or folic acid deficiency.
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