Megaloblastic Anemia

Deficiency of either folic acid or vitamin B12 results in megaloblastic anemia -the release into circulation of immature erythrocytes because of failure of the normal process of maturation in the bone marrow (Wickramasinghe, 1995, 1999). There may also be low white cell and platelet counts, as well as increased numbers of hypersegmented neutrophils. Iron deficiency may mask the megaloblastic anemia.

The cause of megaloblastosis is depressed DNA synthesis, as a result of impaired methylation of dCDP to TDP, catalyzed by thymidylate synthetase, but more or less normal synthesis of RNA. As discussed in Section 10.3.3, thymidylate synthetase uses methylene tetrahydrofolate as the methyl donor; it is obvious that folic acid deficiency will result in impaired thymidylate synthesis. It is less easy to see how vitamin B12 deficiency results in impaired thymidylate synthesis without invoking the methyl folate traphypothesis (Section The main circulating form of folic acid is methyl-tetrahydrofolate; before this can be used for other reactions in tissues, it must be demethylated to yield free folic acid. The only reaction that achieves this is the reaction of methionine synthetase (Section 10.8.1). Thus, vitamin B12 deficiency results in a functional deficiency of folate.

The megaloblastic response to vitamin B12 deficiency seems to be unique to human beings; deficient animals develop neuropathy, but have unimpaired hemopoeisis. It may be that human beings are more reliant on the de novo synthesis of TMP and less able to salvage it from DNA breakdown than other species. The normal suppression of the incorporation of [3H]thymidine into DNA by added dUMP (Section is less than 3% in the fruit bat, 23% in the rat, and 65% in humans.

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