1. MACROCYTIC ANEMIAS

2. MACROCYTIC ANEMIAS
These are the anemias in which the RBC have an MCV of greater than 100fl
There are 2 groups of macrocytic anemias
Megaloblastic anemia
Non megaloblastic macrocytic anemia

3. Requirements for Red Blood Cell Production
Erythropoeitin
Proteins, required for globin synthesis
Iron
Vitamin B12 and folic acid
Vitamin B6
Vitamin C
Thyroid hormones, estrogens and androgens

4. MEGALOBLASTIC ANEMIA
These are a group of disorders in which the cause the anemia is due to deficiency of vitamin B12 and folic acid
The macrocytes in this condition is usually “oval” - hence they are also called as MACRO OVALOCYTES

5. NON MEGALOBLASTIC MACROCYTIC ANEMIAS
These are disorders in which the macrocytosis is not due to vitamin B12 or folic acid deficiency
Here the macrocytes are “ROUND”
The conditions in which such round macrocytes are seen are
Reticulocytosis
Hypothyroidism / myxedema
Myelodysplastic syndrome
Scurvy (Vit-C dif)
Sideroblastic anemia
Liver disorders

6. MEGALOBLASTIC ANEMIA
Vitamin B12 and folic acid are important nutrients required in the process of nuclear maturation
They are required during erythropoiesis (during DNA synthesis)
These anemias may be caused because of a nutritional deficiency or impaired absorption mainly.

7. MEGALOBLASTIC ANEMIA
Impaired DNA synthesis leading to defective cell maturation and cell division
Nuclear maturation delays from the cytoplasmic maturation – NUCLEAR CYTOPLASMIC ASYNCHRONY
Abnormally large erythroid precursors and red cells

8. MEGALOPLASTIC ANAEMIA.
Affect all marrow elements.
Neurologic symptoms (dorsal columns)
Ineffective erythropoiesis: High indirect bilirubin Very high LDH

9. Folic Acid: Daily requirement: Transportation:
It a vitamin which yellow in colour, water soluble, necessary for the production of the RBC, WBC and platelets.
It is not synthesized in the body.
It is found in large number of green fresh vegetables, fruits.
Daily requirement:
The human body needs about µg daily. Absorption:
It is absorbed in the Duodenum and Jejunum.
Transportation:
Weakly bound to albumin.

10. METABOLIC FUNCTION Purine synthesis
Conversion of homocysteine to methionine ( which also requires B12 )

11. FOLIC ACID DEFICIENCY INCREASED DEMAND DECREASED INTAKE
DECREASED ABSORPTION
METABOLIC INHIBITION

12. INCREASED DEMAND Pregnancy Lactation Infancy Puberty and growth period
Patients with chronic hemolytic anemias
Disseminated cancer

13. DECREASED INTAKE Elderly Lower socio economic status
Chronic alcoholics

14. DECREASED ABSORPTION
Acidic food substances in foods like legumes, beans
Drugs like phenytoin, oral contraceptives
Celiac disease which affect the gut absorption
Heat sensitive – more loss during cooking

15. METABOLIC INHIBITION

16. Vitamin B12:
This vitamin is synthesized in nature by micro-organism in the intestine of man and animals, but we can not obtain it from the bacteria in our bodies, because it is synthesizing in the large colon after the site of absorption and it is wasted in the faeces in about 5µg/day. So we obtain it from animal food such as liver, kidney, meat and dairy products as milk and cheese.

17. VITAMIN B12 Abundant in animal foods
Microorganisms are the ultimate origin of cobalamin
It is stored in liver for many years
It is efficiently reabsorbed from bile
It is resistant to cooking and boiling

18. Diary requirements:
The human body needs about 1-2 µg daily.
Absorption:
B12 is combined with glycoprotein called the intrinsic factor (IF), which is synthesized in the gastric cells. The absorption occurs in the distal ileum.
Transportation:
Transport by a protein synthesized in the liver called Transcobalamine II, which carry vitamin B12 to liver, nerves and bone marrow.

19. VITAMIN B12 DEFICIENCY INCREASED REQUIREMENT DECREASED INTAKE
IMPAIRED ABSORPTION

20. INCREASED DEMAND Pregnancy Lactation Puberty Growth period
Hyperthyroidism
Disseminated cancer

21. DECREASED INTAKE
Inadequate intake
Vegetarian diet

22. IMPAIRED ABSORPTION
INTRINSIC FACTOR DEFICIENCY due to chronic gastritis or antibodies against stomach cells.
- PERNICIOUS ANEMIA
- GASTRECTOMY
Malabsorption states
Diffuse intestinal diseases. Eg., lymphoma, systemic sclerosis
Competitive parasitic uptake – fish tapeworm
Bacterial overgrowth

23. CLINICAL FEATURES
Patients develop all general symptoms and signs of the anaemia.
Knuckle pigmentation
Angular stomatitis
Atrophic glossitis- “beefy” tongue
Neurological disorders: sever deficiency of the folic acid causes neuropathies diseases.
Deficiency during pregnancy causes neural tube defect.

24. PERIPHERAL BLOOD FINDINGS
Hemoglobin – decreased
Hematocrit – decreased
RBC count – decreased/normal
MCV - >100fl ( normal 82-98fl)
MCH –increased
MCHC – NORMAL
Reticulocytopenia.
Total WBC count – normal / low
Platelet count – normal/ low
Pancytopenia, especially if anaemia is sever.

25. PERIPHERAL SMEAR RBC: Poikilocytosis - tear drops and schistocytes
Anisocytosis - oval macrocytes
-Macro ovalocytes (macrocytic normochromic)
-well hemogloibised, thicker than normal
-inclusions like HOWELL JOLLY BODIES, basophilic stippling, Cabot rings

26. PERIPHERAL SMEAR WBC: Normal count or reduced count
Hypersegmented neutrophils (>5 lobes)
MACRO POLYMORPHO NUCLEAR CELLS (Macropolys)
PLATELETS:
Normal or decreased

31. BONE MARROW Markedly hypercellular
Myeloid : erythroid ratio decreased or reversed. (Normally, there are three myeloid precursors for each erythroid precursor resulting in a 3:1 ratio, known as the M:E (myeloid to erythroid) ratio)
Erythropoiesis : MEGALOBLASTIC

32. MEGALOBLAST Abnormally large precursor
Deeply basophilic royal blue cytoplasm
Fine chromatin with prominent nucleoli
Nuclear cytoplasmic asynchrony
Abnormal mitoses
Maturation arrest

37. BIOCHEMICAL FINDINGS
Increase in serum unconjugated bilirubin- because of ineffective erythropoiesis
Increase is LDH
Normal serum iron and ferritin

38. TESTS FOR FOLATE AND B12 DEFICIENCY
Serum folate assay
Red cell folate assay
Serum B12 assay

39. PERNICIOUS ANEMIA Scandinavian countries more prevalent
Disease of elderly – 5th to 8th decades
Genetic predisposition
Tendency to form antibodies against multiple self antigens

40. PATHOGENESIS
Immunologically mediated, autoimmune destruction of gastric mucosa
CHRONIC ATROPHIC GASTRITIS – marked loss of parietal cells
Three types of antibodies:
Type I antibody- 75% - blocks vitamin B12 and IF binding
Type II antibody – prevents binding of IF-B12 complex with ileal receptors
Type III antibody – 85-90% patients – against specific structures in the parietal cell
Associated with other autoimmune diseases like autoimmune thyroiditis

41. DIAGNOSTIC FEATURES Moderate to severe megaloblastic anemia
Leucopenia with hypersegmented neutrophils
Mild to moderate thrombocytopenia
Mild jaundice due to ineffective erythropoiesis and peripheral hemolysis
Neurologic changes
Low levels of serum B12
Elevated levels of homocysteine
Striking reticulocytosis after parenteral administration of vitamin B12
Serum antibodies to intrinsic factor