Megaloblastic anemias MA are a group of disorders characterized by defective nuclear maturation caused impaired DNA synthesis. This is usually due to vitamin B12 or folate deficiencies. Vitamin B12 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 B12: 1.From diet to ileum (Intrinsic factor [IF]). 2.From ileum to tissues (Transcbalamins I, II, III [TCII]).

Transportation path of Vit B12 DietStomach B12IF B12 + IF Ileum B12+IF TCII B12 +TCII Circulation Bone marrow (DNA synthesis) Liver (storage) Other tissues (DNA synthesis)

Vit B12 plays important role in two reactions: Necessary in the synthesis of methionine from homocysteine. 1. In this reaction both vit B12 and folic acid are involved. 2.B12 acts as a co-enzyme (methyl cobalamin) for methyltransferase. Homocysteine methionine Methyl B 12 Methyl THF THF Vit B12 is important in conversion of methylmalonyl CoA to succinyl CoA in Krebs cycle. 1.In this reaction B12 acts as co-enzyme for methylmalonyl Co A mutase. Methylmalonyl Co A Succinyl Co A Adenosyl Cb Ado B12

Vitamin B 12 deficiency Due to other causes Nutritional (Vegans). Malabsorption. Intestinal causes (intestinal stagnant loop syndrome). Congenital malabsorption with proteinuria. Fish tapewarm. Due to intrinsic factor deficiency (Pernicious anemia) Congenital lack or abnormality of intrinsic factor. Total or partial gastrectomy. Adult PA.

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 (>98fl). Blood film shows macro-ovalocytes and hypersegmented neutrophils. Multinucleate RBCs Howell-Jolly bodies Chemical testing Low levels of serum B12. 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* the Cbl* levels will correct in PA, but not in ileal malabsorption.