1. Megaloblastic Anaemia

2. Definition: Definition: A group of haematological disorders characterized by distinctive morphological appearance of the developing erythroid cells in the marrow. A group of haematological disorders characterized by distinctive morphological appearance of the developing erythroid cells in the marrow. Causes include: Causes include: B12 or folate deficiency ( in the vast majority ). B12 or folate deficiency ( in the vast majority ). Abnormalities of B12 and folate metabolism. Abnormalities of B12 and folate metabolism. Abnormalities of DNA synthesis. Abnormalities of DNA synthesis.

3. Causes of megaloblastic anaemia Cobalamin deficiency or abnormalities of cobalamin metabolism Folate deficiency or abnormalities of folate metabolism Therapy with antifolate drugs (methotrexate) Independent of either cobalamin or folate deficiency & refractory to cobalamin & folate therapy:

4. Some cases of AML or MDS Some cases of AML or MDS Therapy with drugs interfering with synthesis of DNA(cytosine arabinoside,hydroxyurea,6mercaptopurine,azid othymidine). Therapy with drugs interfering with synthesis of DNA(cytosine arabinoside,hydroxyurea,6mercaptopurine,azid othymidine).

5. Clinical features Clinical features General features of anaemia General features of anaemia Anorexia, diarrhea, low grade fever, mild jaundice and melanin pigmentation of the skin. Anorexia, diarrhea, low grade fever, mild jaundice and melanin pigmentation of the skin. Glossitis, angular cheilosis Glossitis, angular cheilosis Bruising from thrombocytopenia Bruising from thrombocytopenia The anaemia & leucopenia may predispose to infection The anaemia & leucopenia may predispose to infection Also cobalamin deficiency may be associated with bactericidal function of phagocytes Also cobalamin deficiency may be associated with bactericidal function of phagocytes Neurological and psychiatric manifestation: Neurological and psychiatric manifestation: B12 deficiency » » peripheral neuropathies and in severe cases SCDC( subacute combined degeneration of the cord). B12 deficiency » » peripheral neuropathies and in severe cases SCDC( subacute combined degeneration of the cord). Folate deficiency: mania, delirium frank psychosis. Folate deficiency: mania, delirium frank psychosis. Obstetric complication and fetal abnormalities particularly in folate deficiency. Obstetric complication and fetal abnormalities particularly in folate deficiency.

6. Gonad is also affected & sterility is common in patients with either deficiency. Gonad is also affected & sterility is common in patients with either deficiency. Maternal folate deficiency has been implicated as a cause of prematurity,folic acid supplement at the time of conception & in the first 12 weeks of pregnancy reduce the incidence of neural tube defects & most of the protective effect can be achieved by taking folic acid 0.4mg daily Maternal folate deficiency has been implicated as a cause of prematurity,folic acid supplement at the time of conception & in the first 12 weeks of pregnancy reduce the incidence of neural tube defects & most of the protective effect can be achieved by taking folic acid 0.4mg daily Reduced 5,10MTHFR caused by common c677t polymorphism in the MTHF gene also cause NTD and even cleft palate. Reduced 5,10MTHFR caused by common c677t polymorphism in the MTHF gene also cause NTD and even cleft palate. High serum homocystein lead to thrombotic disease,dementia and Alzheimer disease.. High serum homocystein lead to thrombotic disease,dementia and Alzheimer disease..

7. Haematological features Anemia, Increase MCV Peripheral blood: RBCs: macrocytosis, characteristically oval in shape with marked red cell distortion ( anisopoikilocytosis ). RBCs: macrocytosis, characteristically oval in shape with marked red cell distortion ( anisopoikilocytosis ). WBCs: usually reduced in number with hypersegmented neutrophiles WBCs: usually reduced in number with hypersegmented neutrophiles Pancytopenia ( usual in severe cases ). Pancytopenia ( usual in severe cases ).

8. Bone marrow changes Hypercellular BM. Hypercellular BM. Erythroid hyperplasia. Erythroid hyperplasia. Megaloblastic maturation: Megaloblastic maturation: Large erythroid cells. Predominance of early stages. Nuclear-cytoplasmic dissociation. Marked dyserythropoiesis Granulopoiesis: Giant forms(giant metamyelocytes or stab cells) Thrombopoiesis: hyperpolyploid megakaryocttes(normally mega. Contain up to 32 n.). Incseased marrow iron. Incseased marrow iron.

9. Sources and requirements Sources and requirements Foods of animal origin, plant origin foods are devoid of B12 Foods of animal origin, plant origin foods are devoid of B12 Daily requirements 1 – 3 μg. Daily requirements 1 – 3 μg. Stores ( mainly in the liver ) 2- 3 mg. Stores ( mainly in the liver ) 2- 3 mg. Stored B12 is sufficient for 3-4 years if supplies are cut off completely. Stored B12 is sufficient for 3-4 years if supplies are cut off completely.

10. Absorption of B12 Absorption of B12 Minor amounts are absorbed passively ( 1%). Minor amounts are absorbed passively ( 1%). The normal mechanism is through combination with gastric intrinsic factor ( IF ), absorption is through special receptors at the terminal ileum. The normal mechanism is through combination with gastric intrinsic factor ( IF ), absorption is through special receptors at the terminal ileum. B12 is carried to target organs by special proteins known as transcobalamins ( I, II and III ). B12 is carried to target organs by special proteins known as transcobalamins ( I, II and III ).

11. Causes of B12 deficiency Causes of B12 deficiency Dietary deficiency: Dietary deficiency: Vegetarians ( mainly Hindus ) Vegetarians ( mainly Hindus ) Infants born to B12 deficient mothers. Infants born to B12 deficient mothers. Malabsorption: Malabsorption: Nutritional vegans Nutritional vegans Malabsorption pernicious anemia Malabsorption pernicious anemia Gastric congenital IF deficiency Gastric congenital IF deficiency Functional abnormality Functional abnormality Total or partial gastrectomy Total or partial gastrectomy

12. Intestinal Intestinal stagnant loop syndrome Intestinal Intestinal stagnant loop syndrome Jujinal diverticulosis Jujinal diverticulosis Iloecaecal fistula Iloecaecal fistula Anatomical blind loop Anatomical blind loop Intestinal stricture etc. Intestinal stricture etc. Ileal resection Ileal resection Crohn ’ s disease Crohn ’ s disease Selective Malabsorptionvit Selective Malabsorptionvit Tropical sprue Tropical sprue TCII deficiency TCII deficiency Fish tape worm Fish tape worm

13. Folate Deficiency Folate Deficiency Sources and requirements: Sources and requirements: Unlike B12 folates are present in both plant and animal origin foods. Unlike B12 folates are present in both plant and animal origin foods. Daily requirements are about 100 μg Daily requirements are about 100 μg Body stores, mainly in the liver are about 10 mg. Body stores, mainly in the liver are about 10 mg. Stores are sufficient for about 4 months. Stores are sufficient for about 4 months.

14. Absorption and transport of folates. Absorption and transport of folates. Absorption is from upper intestinal tract, the exact mechanism is not known whether it is an active or facilitated diffusion. Absorption is from upper intestinal tract, the exact mechanism is not known whether it is an active or facilitated diffusion. In the plasma about 2/3 are free and 1/3 loosely attached to albumin, mostly in the form of methyl tetra hydro folate. In the plasma about 2/3 are free and 1/3 loosely attached to albumin, mostly in the form of methyl tetra hydro folate.

15. Causes of folate deficiency Causes of folate deficiency Dietary deficiency: Dietary deficiency: Neglected adult,poor, alcoholics and psychiatric patients. Neglected adult,poor, alcoholics and psychiatric patients. Infants with kwashiorkor, scurvy, prematurity,repeated infections and those fed on goat milk. Infants with kwashiorkor, scurvy, prematurity,repeated infections and those fed on goat milk.

16. Malabsorption : Malabsorption : Gluten enteropathy. Gluten enteropathy. As a congenital defect “ selective folate malabsorption “. As a congenital defect “ selective folate malabsorption “. Drugs as salazopyrine and. Drugs as salazopyrine and. Excess utilization: Excess utilization: Pregnancy.(requirement 200-300Mg & to400Mg) Pregnancy.(requirement 200-300Mg & to400Mg) Prematurity. Prematurity. Chronic haematological diseases. Chronic haematological diseases. Inflammatory diseases Inflammatory diseases Chronic dialysis & congestive heart failure. Chronic dialysis & congestive heart failure. Antifolate drugs: antiepileptic, alcohol, methotrexate, trimethoprim. Antifolate drugs: antiepileptic, alcohol, methotrexate, trimethoprim.

17. Diagnosis of megaloblastic anaemia Diagnosis of megaloblastic anaemia Typical clinical settings. Typical clinical settings. Haematological findings: Haematological findings: Macrocytic anaemia with ovalocytosis, hypersegmented. Macrocytic anaemia with ovalocytosis, hypersegmented. BM » » megaloblastic erythroid hyperplasia. BM » » megaloblastic erythroid hyperplasia.