Megaloblastic anemias MA are a group of disorders
Megaloblastic anemias • MA are a group of disorders characterized by defective nuclear maturation caused impaired DNA synthesis. • This is usually due to vitamin B 12 or folate deficiencies. Vitamin B 12 Sources and requirements: • Produced by micro-organisms and fungi. • Present in foods of animal origin (meat, liver, fish, eggs) • The recommended dietary intake for adult is 2 g/day.
Structure: • The vitamin consists of small group of compounds called cobalamin. • Water soluble with MW 1335 daltons. Transport and metabolism: • Two important proteins involved in the transport of Vit B 12: 1. From diet to ileum (Intrinsic factor [IF]). 2. From ileum to tissues (Transcbalamins I, III [TCII]).
Diet B 12 Stomach B 12 + IF Ileum B 12+IF TCII Transportation path of Vit B 12 Bone marrow IF (DNA synthesis) Liver (storage) B 12 +TCII Circulation Other tissues (DNA synthesis)
Vit B 12 plays important role in two reactions: • Necessary in the synthesis of methionine from homocysteine. 1. In this reaction both vit B 12 and folic acid are involved. 2. B 12 acts as a co-enzyme (methyl cobalamin) for methyltransferase. Methyl B 12 methionine Homocysteine THF Methyl THF • Vit B 12 is important in conversion of methylmalonyl Co. A to succinyl Co. A in Krebs cycle. 1. In this reaction B 12 acts as co-enzyme for methylmalonyl Co A mutase. Methylmalonyl Co A Adenosyl Cb Ado B 12 Succinyl Co A
Vitamin B 12 deficiency Due to other causes • Nutritional (Vegans). Due to intrinsic factor deficiency (Pernicious anemia) • Malabsorption. • Congenital lack or abnormality • Intestinal causes (intestinal of intrinsic factor. stagnant loop syndrome). • Total or partial gastrectomy. • Congenital malabsorption with • Adult PA. proteinuria. • Fish tapewarm.
Pernicious anemia A disease characterized By Gastric parietal atrophy leading to decreased secretion of intrinsic factor and other gastric juices.
Clinical manifestations: • Weakness, fatigue, shortness of the breath. Laboratory diagnosis: • Red cell indices Low Hb level, elevated MCV (>98 fl). • Blood film shows macro-ovalocytes and hypersegmented neutrophils. Multinucleate RBCs Howell-Jolly bodies • Chemical testing Low levels of serum B 12. • In case PA Antibodies to IF are present in the serum. Schilling test.
PB Morphology Macro-ovalocytes Howell-Jolly bodies Hypersegmented neutrophils Bi-nucleated RBCs
The Schilling test Radioactive cobalamin (Cbl*) is taken orally; followed by injection of a saturating dose of non-radioactive cobalamin. The level of Cbl* is measured in the urine. In pernicious anemia the excreted levels of Cbl* are low. If intrinsic factor is given with the Cbl* levels will correct in PA, but not in ileal malabsorption.
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