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MEGALOBLASTIC ANEMIA ,L2. These are caused by either vitamin B12 or folic acid deficiency,or from disturbances in folic acid metabolism.This deficiency leads to the production of cells with arrested nuclear maturition but normal cytoplasmic developement:so-called nucleo-cytoplasmic asynchrony. All proliferating cells will exhibit megaloblastosis; ..Intramedullary hemolysis results in a raised bilirubin and LDH but no reticulocytosis.Iron stores are usually raised.The mature red cells are large and oval.Giant metamyelocytes appear and contain a large sausage-shape nucleus. The mature neutrophils show hypersegmentation of their nuclei with some cells containig 6 or more lobes. If severe, pancytopenia is present in the peripheral blood . 1 CLINICAL FEATURES OF B12 Defficiency; SYMPTOMS: These may include malaise, breathlessness, parasthesia, sore mouth, altered skin pigmentation , grey hair, poor memory , depression, Impotence, hallucination and visual disturbances. SIGNS: smooth tongue, angular cheilosis, vitiligo, skin pigmentation, heart failure in severe cases.Neurological signs include; p. neuropathy ; sensory disturbances,Loss ankyle reflex. Spinal cord; dorsal column loss, subacute combined degeneration of the cord,Bilateral upper motor neuron sign.cerebrum lesion ; optic atrophy ,Dementia & Ataxia.autonomic neuropathy . 2 DIAGNOSTIC FEATURES 1. Hb:often reduced,may be very low. 2. MCV:usually raised,commonly above 120fl. 3. RBC count:low 4. Reticulocyte count:low for degree of anemia. 5. Leucocyte count :low or normal. 6. Platelet count:low or normal. 7. Blood film:oval macrocytosis,poikilocytosis,red cell fragmentation,neutrophil hypersegmentation. 8. Bone marrow:increased cellularity,megaloblastic changes in erythroid series,giant metamyelocytes,dysplastic megakaryocytes,increased iron in stores,pathological non-ringed sideroblasts. 9. iron Serum:elevated. 10. Iron-binding capacity:increased saturation. 11. Serum ferritin:elevated 12. Plasma LDH: elevated,often markedly. 3 VITAMIN B12 ABSORPTION The average daily diet contains 5-30ug of vit B12 mainly in meat, fish,eggs and milk.The daily requirement of B12 is 1ug.In the stomach,gastric enzymes release vit.B12 from food and at gastric PH it binds to a carrier protein termed R protein.The gastric parietal cells produce acid and intrinsic factor.Intrinsic factor is a B12-binding protein which optimally binds B12 at PH 8.As gastric emptying occurs,pancreatic secretions raises the PH and B12 switches from R protein to intrinsic factor.The vit.B12 intrinsic factor complex binds to specific receptore in the terminal ilium and vit. B12 is actively transported by the enterocytes to the plasma..The liver stores enough B12 to supply the daily requirement for 3 years and this means that B12 deficiency takes years to become manifest even if all dietary intake stopped. 4 CAUSES OF VITAMIN B12 DEFICIENCY 1.Dietary deficiency: only vegans. 2.Gastric factors:hypoclorhydria, gastrectomy ... 3.Pernicious anemia:this is an autoimmune disorder in which the gastric mucosa is atrophic with loss of parietal cells causing intrinsic factor deficiency. Antiparietal cell a.b are present in over 90% of cases but are also prsent in20% of normal females over the age of 60 years.A positive result supports the diagnosis but not diagnostic. Antibodies to intinsic factor are found in the serum of 60% of patients and are diagnostic. 4.Small bowel factors: pancreatic insufficiency . 5 5. Motility disorders or hypogammaglobulinemia can result in bacterial overgrowth which leads to consumption of vit.B12 and it's deficiency.This can be corrected to some extent by a course of antibiotics. 6.Infestation with the fish tapeworm Diphyllobothrium latum which consumes vit.B12 can lead to vit .B12 deficiency. 7. Inflammatory disease of the terminal ilium such as Crohn's disease or ileal resection can result in vit. B12 deficiency. 8-Schilling test is used for the diagnosis of the cause of vit.B12 deficiency. 6 FOLATE ABSORPTION Folates are produced by plants and bacteria;hence leafy vegetables (spinach,lettuce,), fruits (bananas,melons) are rich sources. Animal proteins like kidney and liver are also good sources. in the upper small bowel (jejunum) absorbed there. Total body stores of folate are small and deficiency can occur in a matter of weeks.Vit B12 is essential for the metabolism of folate. 7 FOLATE DEFICIENCY Causes: 1. increased demands . a)pregnancy-induced folate deficiency;( twin pregnancies, multiparity and hyperemesis graviderum). b) cell proliferation e.g Hemolysis 2.Dietary deficiency (poor intake of vegetables) especially in the edantulous elderly or psychiatric patients. 3.Malabsorption eg. coeliac disease. 4.Drugs a)certain anticonvulsants eg . phenytoin b)contraceptive pills. c)certain cytotoxic drugs e.g .methotrexate. Serum folate is very sensitive to dietary intake ;a single meal can nomalise it in a patient with true folate deficiency. While anorexia,alcohol,and anticonvulsant therapy can reduce it in the absence of megaloblastosis. for this reason red cell folate levels are a more accurate indicator of folate stores and tissue folate deficiency. 8 DIAGNOSTIC FEATURES OF FOLIC ACID DEFICIENCY Diagnostic findings 1-Low fasting serum folate level. 2-Red cell folate level low (but may be normal if folate deficiency is very recent). 3-Macrocytic dysplastic blood picture. 4-Megaloblastic bone marrow. 9 MANAGEMENT Where a patient with severe megaloblastic anemia is very ill and treatment must be started before vit.B12 and red cell folate levels are available, always treat with B12 and folic acid. The use of folic acid alone in the presence of B12 deficiency results in worsening of neurological defects although the anemia may improve. In patients with angina or heart failure blood transfusion can be given with diuretic cover. 10 VitB12 deficiency Give vit.B12 (hydroxycobalamine)1000ug.i.m in 5 doses 23 days apart followed by maintenance therapy of 1000ug every 3 months for life.The reticulocyte count will peak by 5-10 days after therapy and may be as high as 50%.The Hb will rise by 1g/dl every week. The response of the marrow is associated with a fall of plasma potassium levels and rapid depletion of iron stores. If the initial response is not maintained and the blood film is dimorphic,The patient may need additional iron therapy. A sensory neuropathy may need 6-12 months to correct and recovery may be incomplete. 11 FOLATE DEFICIENCY Oral folic acid 5mg daily for 3 weeks , then 5mg once weekly as maintenance therapy. PROPHYLAXIS WITH FOLATE 1. In pregnancy to prevent megaloblastosis in women at risk(twin pregnancy, multiparity and hyperemesis graviderum).Folic acid supplimentation may reduce the risk of neural tube defects. 2. In chronic hematological diseases associated with reduced red cell life span(e.g autoimmune hemolytic anemia and hemoglobinopathies). 3. There is evidence that supraphysiological supplementation (400ug/day) can reduce the risk of coronary and cerebrovascular disease by reducing plasma Homocysteine levels. 12 • THANK YOU 13