Masking a vitamin B12 deficiency
Genetics and folate
Interactions between folate and medications

Masking a vitamin B12 deficiency

Many seniors may be at risk for vitamin B12 deficiency because of reduced absorption of food-bound vitamin B12. This may be due to hypochlorhydria associated with atrophic gastritis or reduced levels of intrinsic factor caused by pernicious anemia. Similar to a folate deficiency, a vitamin B12 deficiency is manifested as megaloblastic anemia. However, if not treated, a vitamin B12 deficiency can progress into neurological abnormalities that are serious and irreversible. The megaloblastic anemia resulting from a vitamin B12 deficiency can be resolved through indiscriminate folate supplementation - the so called "masking" effect - while the central nervous system degeneration continues undiagnosed. The masking effect is uncommon, but is of concern given the prevalence of vitamin B12 deficiency in older persons.

Older individuals are at increased risk for a vitamin B12 deficiency. In some instances, synthetic folic acid intakes exceeding upper limit recommendations may mask a vitamin B12 deficiency.

The potential masking effect of folic acid was considered when the Institute of Medicine established the Tolerable Upper Intake Level (UL) of 1,000 micrograms/day for folic acid (Food and Nutrition Board 1998a). This was a conservative estimate of the upper level of synthetic folic acid intake (from vitamin supplements or fortified foods) that is unlikely to mask a vitamin B12 deficiency. To decrease the chances of vitamin B12 deficiency, individuals over age 50 are urged to obtain their vitamin B12 from synthetic sources (e.g., vitamin supplements, fortified foods) (Food and Nutrition Board 1998b) since absorption of this form of the vitamin is not adversely affected by atrophic gastritis.

The impact of folic acid fortification of cereal grains on folate intake and the prevalence of vitamin B12 deficiency in older populations has been evaluated in select populations. Data from the New Mexico Aging Process Study indicate that mean total folate intake after fortification was 793 micrograms per day in individuals ≥ 60 years of age, and only 5 out of 320 study participants (1.6%) had folate intakes exceeding the UL of 1,000 micrograms per day from supplements alone (Sisk et al. 2004). An evaluation of > 1,500 patients at a veteran's affairs medical center compared the number of low vitamin B12 concentrations before and after folic acid fortification. Results indicate that the proportion of subnormal vitamin B12 concentrations did not change significantly following fortification (Mills et al. 2003). These limited data suggest that B12 masking may not have increased following folic acid fortification. However, larger population studies are needed to confirm these results.

Health care providers should be aware of the prevalence of vitamin B12 malabsorption in the elderly and the possibility for higher intakes of synthetic folic acid through concurrent intake of multivitamins or other folic acid containing supplements and fortified foods including fortified ready-to-eat breakfast cereals.

Genetics and folate

The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyzes the reaction converting 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a reaction necessary to convert homocysteine to methionine. Several mutations in the gene that codes for the MTHFR enzyme have been identified. One in particular, C677T, has been associated with reducing the activity of the enzyme and modulating the risk for NTDs, certain cancers, and elevated homocysteine concentrations. The prevalence of the homozygous form of the mutation (i.e., both gene alleles contain the mutation) varies based on race and ethnicity, with African-Americans having a low prevalence of ~1%; U.S. whites ~12%; and U.S. Hispanics ~21% (Botto & Yang 2000).   

Studies suggest there is a gene-diet interaction between C677T and folate status or intake. The presence of the mutation appears to slightly increase NTD risk although risk is modified (reduced) by adequate folate intake (Bailey et al. 2001). Individuals who are homozygous for the mutation have demonstrated a decreased risk (protective effect) for colorectal cancer, but only when folate status is normal (Chen et al. 1996, Ma et al. 1997). When folate status is low, the C677T mutation has been associated with elevated homocysteine concentrations (Jacques et al. 1996, Kauwell et al. 2000), which are associated with an increased risk for vascular diseases (Refsum et al. 1998). These data suggest that individuals with the C677T mutation may have increased folate requirements and may be at increased risk for disease if folate status is suboptimal.

Interactions between folate and medications

Certain medications may interfere with folate absorption, metabolism, or excretion. These include anti-seizure medications, certain antibiotics, medications used to treat rheumatoid arthritis or cancer, and certain anti-inflammatory medications. Individuals taking these medications may have a higher folate requirement.

* This list is not all inclusive.

References

Bailey L.B., Moyers, S., Gregory, J.F. (2001) Folate. In: Bowman B.A., Russell, R.M., ed. Present Knowledge in Nutrition . 8th Edition ed. Washington, DC: International Life Sciences Institute Press; 214-229.

Botto L.D., Yang, Q. (2000) 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 151(9):862-877.

Cabrera R.M., Hill, D.S., Etheredge, A.J., Finnell, R.H. (2004) Investigations into the etiology of neural tube defects. Birth Defects Res C Embryo Today. 72(4):330-344.

Chen J., Giovannucci, E., Kelsey, K., Rimm, E.B., Stampfer, M.J., Colditz, G.A., Spiegelman, D., Willett, W.C., Hunter, D.J. (1996) A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. Cancer Res. 56(21):4862-4864.

Food and Nutrition Board, Institute of Medicine. (1998a) Folate. Dietary Reference Intakes. Washington, DC: National Academy Press; 196-305.

Food and Nutrition Board, Institute of Medicine. (1998b) Vitamin B12. Dietary Reference Intakes. Washington, DC: National Academy Press; 306-356.

Jacques P.F., Bostom, A.G., Williams, R.R., Ellison, R.C., Eckfeldt, J.H., Rosenberg, I.H., Selhub, J., Rozen, R. (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 93(1):7-9.

Kauwell G.P., Wilsky, C.E., Cerda, J.J., Herrlinger-Garcia, K., Hutson, A.D., Theriaque, D.W., Boddie, A., Rampersaud, G.C., Bailey, L.B. (2000) Methylenetetrahydrofolate reductase mutation (677C-->T) negatively influences plasma homocysteine response to marginal folate intake in elderly women. Metabolism. 49(11):1440-1443.

Ma J., Stampfer, M.J., Giovannucci, E., Artigas, C., Hunter, D.J., Fuchs, C., Willett, W.C., Selhub, J., Hennekens, C.H., Rozen, R. (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions, and risk of colorectal cancer. Cancer Res. 57(6):1098-1102.

Mills J.L., Von Kohorn, I., Conley, M.R., Zeller, J.A., Cox, C., Williamson, R.E., Dufour, D.R. (2003) Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr. 77(6):1474-1477.

Refsum H., Ueland, P.M., Nygard, O., Vollset, S.E. (1998) Homocysteine and cardiovascular disease. Annu Rev Med. 49:31-62.

Sisk E.R., Lockner, D.W., Wold, R., Waters, D.L., Baumgartner, R.N. (2004) The impact of folic acid fortification of enriched grains on an elderly population: the New Mexico Aging Process Study. J Nutr Health Aging. 8(3):140-143.