How to differentiate between a B12 and a folate deficiency

Despite whether or not megaloblastic anemia is caused by a deficiency of folate or vitamin B12 (cobalamin), large doses of folate will correct the anemia (1). Because this is the case, the extra folate can potentially “mask” symptoms of vitamin B12 deficiency such as from pernicious anemia.

Unfortunately, an undiagnosed chronic vitamin B12 deficiency can lead to irreversible neuropathy. The cobalamin in methyl derivative form is necessary to methylate homocysteine to methionine (2). It’s also necessary to convert methylmalonyl CoA to succinyl coA. In the absence of B12, then, leads to accumulation of both methylmalonic acid and homocysteine levels (2). As they accumulate, they lead to possible neuropathy via irreversible demyelination of nerves (3).

The mechanism by which this occurs is thought to be related to methylmalonyl CoA acting as an inhibitor of malonyl CoA’s role in biosynthesis of fatty acids, which leads to myelin sheath degeneration (3). However, because this does not explain why both homocysteine and methylmalonic acid must be elevated for demyelination, more research is needed.

Correct treatment can depend on telling the difference between a deficiency of B12 from folate. It can be achieved through an assessment of both methylmalonic acid and homocysteine blood levels (2 & 4). A clinician can determine that an elevated level of both will indicate a B12 deficiency in tissues (4). Further, if both are normal, no B12 deficiency exists; and if only homocysteine levels are elevated, then a possible folate deficiency may exist (4).


1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002
3. Pagana, K.D., Pagana, T.J. Mostby’s Manual of Diagnostic and Laboratory Tests, 3rd ed. Mosby Elsvier, 2006
4. Lab tests online. Methylmalonic acid. Available at:


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