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Megalobastic anemia – pathologic process characterized by delay in maturation of the nucleus of lod cell precuros and the continuing

development of cytoplasm  result of nuclear-cytoplasmic idssocaition is production of cells that are larger than normal  RBCs have elevated MCV  Bone marrow sample reveals giant bands, and the mature granulocytes are ofetne hypersegmented  Thought to be caused by problems with DNA synthesis  Macrocytic anemia – simply referes to large RBC Causes of megalobastic anemia  Vitamin B12 (cobalamin) and folate deficiencies are common cauess  must e differentiated from bone marrow syndromes such as as aplastic anemia, refractory anemia, and preleukemia  both hypo and hyper thryroidism cause maroctic anemia with pancytopenia  alchohoism, chornic liver or renal railure , and cigarettes can caused macrocytoxisc  high reticulocyte can cause increase in MCV because reticulocytes are large ineffective erythropoiesis: in severe mgalobsti and refactory anemaii, many developing RBcs are destroyed in boen marrow befoe released into circulation intramedullary destruction of RBS icnceases serum levels of indifect bilirubin and LDH in addition, bone marrow ins hyperceullular I. Megalolastic anemia A. Gneral features 1. Describes group of disrorders characterized by distinct morphological paterin hematopeotic cells a. Defect in DNA synthesis 2. Result is unblanaced cell growth and impaired cell division characterized by cells with immature appearing nucelaus, mature appearing cytoplasm and cell volume above normal 3. Vitamin B12 and folic acid deficicney are 2 most common cause B. Clinical presentation 1. Megaloblastic hematopoiesis tpically presents as anemia 2. Non hematologica manifestations of vitamin B12 and flic acid. Include effects on epithelial tissues (beefy red somooth tounge – vit b12 and FA deficiency) and neuropsyciatric manifestations (B12 only) a. Neuropsychiatric manifesations of vitamin B123 deficieny are thoughr to be ue to require for vitamin B12 in meyling sysntehsis i. Peripheral neuropathies ii. Dorsal column involvement iii. Optic atrophy iv. Psychiatric symptoms b. Manifestation induced by deficicency may rpesent in absence of anema C. Hematological manifestations 1. CBC and peripheral blod smear a. Morpholic appearance is the same – ethryocytes demosntarte increased MCV with anisocytosis elevated PRDW) and poikilocytosis b. PMNs may show nuclear hypersegmentation – finding 3+ PMNs with 5 loves c. Mild to moderate leukopenia and thymbocytpenia maybe present

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2. Bone marrow aspiration a. Hypercellularity with hyperplasia of all three major hematopoietic cell lines and abnormal appearance of the hematopoietic cells b. Hematopoietic cell abnormalities in bone marrow often confused with acute erthroblastic leukemia Cobalamin (B12) deficiency A. Metabolism 1. Overview a. Essential cofactor for 2 enzymatic reactions i. Conversation of methylmalonyl-CoA to succinyl CoA ii. Conversion of homocysteine to methionine (generates tetrahydrofolate withch is required for DNA synthesis b. Produced in nature ol by microorganisms – only get from diet c. Stored in its coenzyme form 2. Steps in cobalamin metabolism a. Cobalamin in ood uully nonspecifically protein bound in coenzyme form b. Peptic digestion at low pH required from relase of cobalamin from food preotiein c. Released cobalamin binds to R protein in saliva an d gasric juic d. Preascitc proteases degrade R protein and cobalamin binds tointrisinc factor (IF) e. IF-Cbl complex binds to specific embrane assosciated IF-Cbl recproters I n terminal ileum and transported into enterocyte f. In enterocyte, cobalamin is relaed and binds to transcobalamin II (TCII) TCIICbl complex transported to high affinity receprots on tissues. Compelx enters cells and Clb is released B. Etiology of cobalamin deficienc 1. Result from defects at aystep of metabolism 2. Possible cause a. Inadequare dieterary ineake b. Inadequate absorption, such as lack of gastric aid,peop, lack of IF i. Pernicious anemia- caused by autoimmune destruction of gastric parietal cells that results in severe atrophic gastritis and lack of IF production ii.