CLINICAL CASES
387
inadequate amounts of cobalamin are absorbed (the dietary requirement is
approximately 200 ng/day) resulting in megaloblastic anemia. When the root
cause of the resultant megaloblastic anemia is absence of or inadequate
amounts of intrinsic factor the condition is called pernicious anemia. Other
conditions or choices may also eventuate in cobalamin deficiency-induced
megaloblastic anemia. This condition is also observed in vegetarians who
strictly avoid meat and meat products.
The cause of megaloblastic anemia seen in strict unsupplemented vegetarians
is attributed to the effects of cobalamin deficiency on DNA synthesis, specifi-
cally the thymidylate synthetase reaction which converts dUMP^dTMP.
Inadequate dTMP restricts DNA but not RNA synthesis leading to the appear-
ance of large erythroid cells with small nuclei containing a high ratio of RNA to
DNA. These cells are removed from the circulation, thus stimulating erythroge-
nesis and giving rise to anemia with an elevated presence of megaloblasts.
This process focuses on the role of cobalamin in folate metabolism. As
shown in Figure 42-3 cobalamin is required for the conversion of homocys-
teine into methionine. Cobalamin must first undergo methyl transfer to form
methyl cobalamin. It receives the methyl group from N5-methyltetrahydrofolate
thus regenerating tetrahydrofolate to participate in other one-carbon transfers in
purine metabolism or pyrimidine remodeling. If there is a cobalamin deficiency
then the methionine synthase reaction cannot occur, N5-methyltetrahydrofolate
accumulates and the other C-1 donor forms of tetrahydrofolate cannot be
formed. If N5,W0-methylenetetrahydrofolate, which is required for the methy-
lation of dUMP to dTMP, cannot be formed the thymidylate synthase reaction
will be slowed and dTMP levels will drop. An added complication is that the
thymidylate synthase reaction produces dihydrofolate unlike all the other C-1
pool reactions, which produce tetrahydrofolate. The dihydro-form must be
reduced to the tetrahydro-form by dihydrofolate reductase, which can be
inhibited by many drugs. Thus, in the absence of cobalamin methionine syn-
thesis from homocysteine ceases allowing the “trapping” of the folate pool as
N5-methyltetrahydrofolate, diminishing levels of N5W10-methylenetetrahydro-
folate, and impairing dTMP formation, and therefore DNA synthesis. Cells
requiring regeneration due to turnover feel the brunt of this situation early and
thus megaloblastic anemia is a result.
Figure 42-3. The role of cobalamin as a cofactor in the methylation of homo-
cysteine to methionine.
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