Megaloblastic Anemia PDF

Megaloblastic Anemia By Dr. Teeb M. Jaafar MBCh.B / F.I.C.M.S. (Pathology/ Hematology)  Topics Definition of megaloblastic anemia (MBA). Causes. Pathogenesis. Pathology. Outlook about Cobalamine (Vit B12): dietery sources, abso...

Megaloblastic Anemia By Dr. Teeb M. Jaafar MBCh.B / F.I.C.M.S. (Pathology/ Hematology)  Topics Definition of megaloblastic anemia (MBA). Causes. Pathogenesis. Pathology. Outlook about Cobalamine (Vit B12): dietery sources, absorption, transport & causes of deficiency. Definition of pernicious anemia (PA). Diagnosis of PA. Outlook about folate: dietery sources, absorption, transport & causes of deficiency. Clinical features of MBA. Laboratory investigation (hematological findings). Diagnosis of MBA. Treatment of MBA.  Objectives Describe megaloblastic anemia. Describe pernicious anemia.  Megaloblastic anemia This is a group of anaemias in which the erythroblasts in the bone marrow show a characteristic abnormality: (maturation of the nucleus being delayed relative to that of the cytoplasm). This asynchrocy is due to defect in DNA synthesis. There is a distinctive morphological appearances of all the developing cells in bone marrow. i.e, not only RBCs but granulocyte and platelet precursors also are affected (although not as severely) and most patients present with pancytopenia (anemia, thrombocytopenia,and granulocytopenia). Causes Cobalamin (Vitamin B12) deficiency or abnormalities of metabolism. Folate deficiency or abnormalities of metabolism. Other defects of DNA synthesis due to: a. Congenital enzyme deficiencies: orotic aciduria. b. Acquired enzyme deficiencies: alcohol or treatment with hydroxyurea  Pathogenesis All conditions that give rise to megaloblastic changes share in common a reduced rate of synthesis or polymerization of the immediate precursors of DNA due to inadequate biosynthesis of thymidine because there is a failure to convert deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). The coenzyme 5,10-methylene tetrahydrofolate polyglutamate is needed for this reaction. Deficiency of folic acid cause reduction in methyle THF ( a substrate for this enzyme), Vitamin B 12 is needed to convert methyl THF, which enters the cells from plasma, to THF, from which polyglutamate forms of folate are synthesized. Availability of this co-enzyme (5,10-methylene tetrahydrofolate polyglutamate) is reduced in either deficiency.This reflect the cobalamin–folate relationship, that explains the abnormalities of folate metabolism that occur in cobalamin deficiency and also why the anemia that occurs in cobalamin deficiency will respond to folic acid in large doses. B12 needs to receive a methyl group from Folate so it can pass it on to Homocysteine to create Methionine. Less Folate means B12 doesn’t have a methyl group to pass on and Homocysteine builds up. So both deficiencies cause increased Homocysteine levels.  The key pathway for the development of the neurological symptoms which accompained megaloblastic anemia due to B12 deficiency is that B12 is a cofactor in the process that converts methylmalonyl CoA into Succinyl CoA. If there is not enough B12 this reaction is slowed and Methylmalonic Acid builds up which is toxic to neurons and leads to demyelination in the posterior and lateral columns of the spinal cord. This is called Subacute Combined Degeneration and presents with peripheral numbness/tingling, spasticity, and loss of vibration and proprioception. Unlike B12 deficiencies, Folate deficiency does not result in a buildup of Methylmalonic Acid but mild neurological symptoms may be due to accumulation of homocystin. B12 important biochemical roles in the pathogenesis if MBA: a. impaired DNA synthesis & b. neurological features Elevated levels of the substrates methylmalonic acid and homocysteine can be used to detect ‘functional’ B12 deficiency despite normal serum B12 concentrations.  Pathology There is a metabolic defects cause inadequate biosynthesis of thymidine, one of the building blocks of DNA causing abnormalities in rapidly dividing cells throughout the body as skin, fetus and BM, but the hematopoietic marrow is most severely affected,because the synthesis of RNA and cytoplasmic elements proceeds at a normal rate thus outpaces that of the nucleus, the hemopoietic precursors show nuclear-cytoplasmic asynchrony. This maturational derangement contributes to the anemia in several ways: 1. Many red cell progenitors are so defective in DNA synthesis that they undergo apoptosis in the marrow (ineffective hematopoiesis). 2. Others mature into red cells but do so after fewer cell divisions, further diminishing the output of red cells.  Cobalamin (vitamin B12) Dietary sources and requirements: Cobalamin is synthesized solely by micro-organisms. Animals obtain cobalamin from the foregut (internal production from intestinal bacteria), but the only source for humans is food of animal origin. The highest amounts are found in liver and kidney, but it is also present in shellfish, organ and muscle meats, fish, chicken and dairy products (eggs, cheese and milk) in small amounts. Vegetables, fruits and all other foods of non-animal origin are free from cobalamin unless they are contaminated by bacteria. Cooking does not destroy cobalamin. A normal western diet contains 7–30 μg of cobalamin daily. Adult daily losses, mainly in the urine and feces are about 1-2 μg (daily requirements). Body stores usually 2–3 mg and are sufficient for 2–4 years if supplies are completely cut off.  Absorption: Two mechanisms exist for cobalamin absorption: One is passive, occurring equally through the duodenum and the ileum; it is rapid but inefficient as less than 1% of an oral dose can be absorbed by this process. The other mechanism is active; it occurs through the ileum and is efficient for small oral doses of cobalamin. This is the normal mechanism by which the body acquires cobalamin and is mediated by gastric intrinsic factor (IF), binding of cobalamin to IF is favoured by an alkaline pH. Transport: Two main cobalamin transport proteins exist in human plasma; they both bind cobalamin one molecule for one molecule. Transcobalamin (TC, also called transcobalamin II), which delivers B12 to bone marrow and other tissues, the amount of B12 on TC is normally very low (100 fL ) and the macrocytes are typically oval. If iron deficiency is also present the MCV may be normal. A proportion of the neutrophils show hypersegmented nuclei (more than five nuclear lobes). Together, strongly suggest megaloblastic hemopoiesis. Reticulocyte count is low for degree of anemia. Total white cell and platelet counts may be moderately reduced, especially in severely anemic patients.  Macrocytes Hypersegmented neutrophile MBA  Bone marrow: Bone marrow is usually hypercellular. The most characteristic finding is dissociation between nuclear and cytoplasmic development in the erythroblasts, with the nucleus maintaining a primitive appearance (open, fine, lacy appearance) despite maturation and hemoglobinization of the cytoplasm. the cells are larger than normoblasts Giant and abnormally shaped metamyelocytes are characteristic. Magaloblast Giant metamyelocytes  Diagnosis of vitamin B12 or folate deficiency It is usual to assay: Serum B12. Serum folate. Red cell folate. Additional tests: 1. Homocystin 2. Methylmalonic acid  Treatment of megaloblastic anemia Most cases only need therapy with the appropriate vitamin. If large doses of folic acid are given in B12 deficiency they cause a hematological response but may aggravate the neuropathy. Folic acid should therefore not be given alone unless B12 deficiency has been excluded. In severely anemic patients who need treatment urgently it may be safer to initiate treatment with both vitamins after blood has been taken for B12 and folate assay. Response to therapy: The patient feels better after 24-48 hours of correct vitamin therapy with increased appetite and well-being. Hemoglobin should rise by 2-3 g/dL each fortnight. White cell and platelet counts become normal in 7-10 days Marrow is normoblastic in about 48 hours, although giant metamyelocytes persist for up to 12 days. Vitamin B12 versus Folate