Megaloblastic anaemia is characterised by an abnormal appearance of the bone marrow erythroblasts in which nuclear development is delayed and nuclear chromatin has a lacy open appearance (Fig. 12.3). There is a defect in DNA synthesis usually caused by deficiency of vitamin B12 (B12, cobalamin) or folate.
Biochemical basis
Folate is an essential coenzyme for the synthesis of thymidine monophosphate (TMP) and therefore of DNA because thymine is one of the four bases needed to form DNA. B12 is a coenzyme for methionine synthase, a reaction needed for the activation of folate. Demethylation of 5-methyl-tetrahydrofolate (methyl-THF) provides THF which acts as substrate for synthesis of intracellular folate polyglutamates which are coenzymes needed for DNA synthesis. During DNA synthesis (Fig. 11.1), folates are oxidized to the dihydrofolate form, and the enzyme dihydrofolate reductase (inhibited by methotrexate) is required to restore them to the active THF state.
B12 physiology (Fig. 11.2)
- Adult daily requirement for B12 is 1 μg (normal mixed diet contains 10–15 μg). B12 is present only in foods of animal origin: meat, fish, eggs, milk and butter; it is absent from vegetables, cereals and fruit, unless these are contaminated by microorganisms. Normal body stores of B12 are largely in the liver with an enterohepatic circulation. Stores are sufficient to last for 2–4 years.
- Dietary B12 combines with intrinsic factor (IF) secreted by gastric parietal cells (GPC). IF–B12 complex attaches to ileal receptors and B12 is absorbed.
- Absorbed B12 attaches to transcobalamin (TC) II which carries B12 in plasma to the liver, bone marrow, brain and other tissues. Most B12 in plasma is, however, attached to a second B12-binding protein, TC I, and is functionally inactive.
- Passive absorption (about 0.1% of oral B12) occurs through buccal, gastric and duodenal mucosae.
Causes of B12 deficiency (Fig. 11.2)
Inadequate diet
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