CV# 812. Herbert V. EDITORIAL: Potential Harmful Effects of Folate Food Fortification without Added Cobalamin.  Harrisonνs Online:, 1999.  This is the on-line 1999 Harrisonνs Principles of Internal Medicine, 14th Edition, edited by Fauci et. al. The on-line 14th edition is updated monthly with new material, including this EDITORIAL.   

Editorial Related to Chapter 108: Megaloblastic Anemias 

EDITORIAL: Potential Harmful Effects of Folate Food Fortification without Added Cobalamin

Victor Herbert, M.D., J.D., M.A.C.P.

Why Folate Fortification?

As first suggested by Hibbard and Smithells in 1965, confirmed by many others since (Czeizel, Dudas, 1992; Herbert, 1992; Molloy et al, 1997; MRC Vitamin Study Research Group, 1991), and reviewed by Eskes in 1998, about half of neural tube defects (NTDs) in newborns could be prevented if mothers were to begin taking folic acid supplements a few months before becoming pregnant. The neural tube forms so early in pregnancy that it may be deformed before a woman knows she is pregnant. Over 2000 babies are born in the US each year with folate-preventable NTDs.

Folate-preventable NTDs (and some other birth defects) are related to a defect in the genes for 5,6,7,8-tetrahydrofolate reductase, which makes the reductase thermolabile (Eskes, 1998; Kang et al, 1992). The genetic defect is homozygous in 5 percent of Americans, and is overcome by supplying daily above-physiologic amounts of folate. The physiologic minimum amount of folate [as synthetic pteroylglutamic acid (PGA)] needed orally daily to prevent folate deficiency in healthy non-pregnant adult females is only 50 μ g (Herbert et al, 1962). PGA (an oxidized monoglutamate) is about twice as stable and well-absorbed as food folates (reduced folate polyglutamates) (Herbert, 1999; Kelley et al, 1997; Seyoum, Selhub, 1998).

Spearheaded by the Centers for Disease Control and Prevention's (CDC) Godfrey Oakley, folate (PGA) fortification of all fortified grains (breads, cereals, and pastas) to prevent NTDs became US Food and Drug Administration law in January 1998 (Food and Drug Administration, 1996; Oakley, 1997). Supplements containing 400 μ g PGA daily were (and are) also heavily promoted. PGA, the synthetic oxidized folate monoglutamate, is used because of it shelf-stability, a property which Colman and colleagues (1975) successfully used to fortify grain with PGA in a large study in South Africa more than two decades ago.
            A caveat: ingesting 400 μ g of PGA provides a little too much to be polyglutamated and reduced to natural forms in the process of absorption, resulting in absorption of some unaltered synthetic PGA, which can, in theory, act as an undesirable antifol (Kelley et al, 1997).

Why Folate Fortification Must Include Cobalamin (Vitamin B12)

If folate fortification (and supplementation) does not also include added crystalline vitamin B12, it can harm millions of elderly as well as fertile African-American females. We need fortification with B12 not only because it is cost effective, but also because current screening tests for total serum vitamin B12 have poor positive and negative predictive value, and assays for homocysteine and methionine are confounded by a number of variables (Green, 1996; Herbert, Bigaouette, 1997). As Green states, "Some clinical evidence supports the concept that measurements of holo-TCII [holotranscobalamin II, the serum B12 binding protein with B12 bound to it] levels may provide a better index of cobalamin status, but reliable commercial screening assays for holo-TCII are not yet available." (Editor's note: such commercial assays should be available in 1999.)

Fertile African-American females rarely have the gene defect of folate-preventable NTD babies, but sometimes do have a different gene defect: one for early pernicious anemia (PA), as described in fertile South African black females and fertile African-American females (Bar-Shany, Herbert, 1967; Carmel, Johnson, 1978; Institute of Medicine, 1998; Metz et al, 1961). In such women, PGA will mask the hematologic damage of their vitamin B12 deficiency, slowing the diagnosis of B12 deficiency until well after they develop the neurologic damage associated with B12 deficiency, some of it irreversible. One such woman, diagnosed at age 33 with PA (with combined systems disease), and only sporadically treated, gave birth at age 40 to a child with temporary vitamin B12 deficiency associated with transplacentally acquired antibody to intrinsic factor (Bar-Shany, Herbert, 1967).

Ever since Combe in the 1820s and Addison in the 1850s first described it, pernicious anemia (PA) has been generally recognized as being intimately associated with gastric atrophy and as a disease primarily of the elderly (Herbert, 1996a). Partly on a genetically predisposed basis and partly due to acquired gastric insults (such as iron deficiency, Helicobacter pylori infection, etc.), gastric atrophy begins in nearly all Americans sometime between ages 50 and 90. It gradually progresses, first with loss of gastric acid and pepsin, causing inability to split B12 from its peptide bonds in food; then, after a number of years, there is a loss of gastric intrinsic factor, causing inability to absorb crystalline B12 by the efficient physiologic mechanism. However, the capacity to absorb about 1 percent of any oral dose of crystalline B12 by simple mass action diffusion remains (Ellenbogen et al, 1958).

            To take care of those elderly who have lost only gastric acid and pepsin, the 1998 Dietary Reference Intake (DRI) for vitamin B12 states: "The RDA (recommended daily allowance) for adults is 2.4 μ g of B12 per day. Since 10 to 30 percent of older people [those over age 50 years] may be unable to absorb naturally occurring B12 normally, it is advisable for those older than age 50 years to meet their RDA mainly by taking foods fortified with [crystalline] B12 or a [crystalline] B12-containing supplement" (Institute of Medicine, 1998).

                 By median age 65 years, 49 percent of 171 "healthy" adults in Missouri were no longer able to absorb food B12, as manifested by low serum holotranscobalamin II (holo-TCII) levels (Flynn et al, 1997). Of this 49 percent, 60 percent had high levels of serum homocysteine associated with blood vessel toxicity. Only 100 μ g of vitamin B12 orally daily was able to reduce the hyperhomocysteinemia (Miller et al, 1999; Herbert, 1999). This was easily predictable, as PA patients absorb by mass action about 1 percent of any oral dose of crystalline vitamin B12, and only 0.1 μ g of cobalamin must be absorbed daily to sustain normality (Sullivan, Herbert, 1965).

This is why the FDA was petitioned to require the addition of 25-100 μ g vitamin B12 to all foods (and supplements) containing folate (as PGA) (Herbert, Bigaouette, 1997). Eating 25 μ g will result in absorption of about 0.25 μ g and eating 100 μ g will result in absorption of about 1 μ g. Although the MDR (minimum daily requirement) to sustain normality is only 0.1 μ g, when a multivitamin pill containing the RDA for iron, 200 mg of vitamin C, and the RDA for vitamin B12 and folate dissolves in the stomach, within 30 min (the gastric half-emptying time) the vitamin C and iron destroy about half of the vitamin B12 and about 20 percent of the folate because of "vitamin C-driven free radical generation from iron" (Herbert, 1996b; Herbert et al, 1996). Worse, the vitamin C and iron convert the B12 to anti-B12 molecules, which are absorbed with the undestroyed B12 and prevent cell uptake of the undestroyed B12.

Kuzminski and colleagues (1998) have reported that 1 mg oral B12 daily was better than 1 mg injections for treating B12 deficiency. The author believes that 0.1 mg (100 μ g) of oral vitamin B12 daily will prevent gastric atrophy-associated vitamin B12 deficiency from ever occurring in the first place. 

In summary, the following issues pertain to folate supplementation:

  1. Folate food supplementation is important for preventing folate-preventable NTDs.
  2. Folate supplementation will mask the hematologic manifestations of vitamin B12 deficiency.
  3. In populations at particular risk for vitamin B12 deficiency, such as fertile African-American women and the elderly, masking hematologic manifestations of disease may lead to neurologic presentations, only some of which are reversible.
  4. In light of these concerns, it makes sense to provide 0.1 mg of oral crystalline vitamin B12 as a supplement in persons at risk of vitamin B12 deficiency, a group that includes African-American women of child-bearing age and all others over age 50 years.
  5. The 0.1 mg of oral crystalline vitamin B12 should be taken on arising or between meals. It should not be taken as part of a multivitamin-mineral supplement containing iron and vitamin C, because when such a supplement dissolves in the stomach, the iron-vitamin C combination converts about half of the vitamin B12 to anti-B12 molecules.


…        Bar-Shany S, Herbert V: Transplacentally acquired antibody to intrinsic factor with vitamin B12 deficiency. Blood 30:777, 1967.

…        Carmel R, Johnson CS: Racial patterns in pernicious anemia: Early age at onset and increased frequency of intrinsic-factor antibody in Black Women. N Engl J Med 298:647, 1978.

…        Colman N et al: Prevention of folate deficiency by food fortification. III. Effect in pregnant subjects of varying amounts of added folic acid. Am J Clin Nutr 28:465, 1975.  

…        Czeizel AE, Dudas I: Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation. N Engl J Med 327:1832, 1992.  

…        Ellenbogen L et al: Effect of D-sorbitol on absorption of vitamin B12 by pernicious anemia patients. Proc Soc Exp Biol Med 99:257, 1958

…        Eskes TK: Open or Closed? A world of difference: A history of homocysteine research. Nutr Rev 56:236, 1998.

…        Flynn MA et al: Atherogenesis and the homocysteine-folate-cobalamin triad: Do we need standardized analysis? J Am Coll Nutr 16:258, 1997.

…        Food and Drug Administration: Food standards: Amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register 61:8781, 1996

…        Green R: Screening for vitamin B12 deficiency: Caveat emptor. Ann Intern Med 124:509, 1996.  

…        Herbert V et al: Minimal daily adult folate requirements. Arch Intern Med 110:649, 1962

…        Herbert V: Folate and neural tube defects. Nutr Today 27(6):30, 1992.

…        Herbert V: Vitamin B12, in Ziegler EE, Filer LJ (eds.): Present Knowledge in Nutrition, 7th edition, Washington D.C., International Life Sciences Institute Press, 1996a, pp 191-205

…        Herbert V: Anti-hyperhomocysteinemic supplemental folic acid and vitamin B12 are significantly destroyed in gastric juice if co-ingested with supplemental vitamin C and iron. Blood 88:492a (abstr 1957), 1996b

…        Herbert V et al: Vitamin C-driven free radical generation from iron. J Nutr 126(suppl 4):1213S, 1996 (Note: Figure 3 as printed is incorrect; see Errata in J Nutr 126:1746, 1996 and J Nutr 126:1902, 1996).

…        Herbert V, Bigaouette J: Call for endorsement of a petition of the Food and Drug Administration to always add vitamin B12 to any folate fortification or supplement. Am J Clin Nutr 65:572, 1997.

…        Herbert V: Folic acid, in Shils M, et al (eds.): Modern Nutrition in Health and Disease, 9th edition, 1999, in press.

…        Herbert V: To prevent vasculotoxicity from hyperhomocysteinemia, give children vitamin B6, give fertile females folate, and give all >50 daily oral 25 to 100 g vitamin B12. FASEB J in press, 1999.

…        Herzlich B, Herbert V: Depletion of serum holotranscobalamin II. An early sign of negative vitamin B12 balance. Lab Invest 58:332, 1988.  

…        Hibbard ED, Smithells RW: Folic acid metabolism and human embryopathy. Lancet i:1254, 1965.

…        Institute of Medicine: Pernicious anaemia-like syndromes in the non-white population of Natal. S Afr Med J 47(21):915, 1973.  

…        Institute of Medicine, Panel on Folate, other B Vitamins and Choline: Dietary reference intakes: Thiamin, riboflavin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington, D.C., National Academy Press, 1998

…        Kang SS et al: Homocysteinemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12:279, 1992.  

…        Kelly P et al: Unmetabolized folic acid in serum: Acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 65:1790, 1997.  

…        Kuzminski AM et al: Effective treatment of cobalamin deficiency with oral cobalamin. Blood 92:1191, 1998.

…        Metz J et al: Addisonian pernicious anemia in young Bantu females. Br Med J 1:178, 1961

…        Miller J et al: Oral vitamin B12 supplementation decreases homocysteine in healthy elderly people with suboptimal vitamin B12 status. FASEB J in press, 1999.

…        Molloy AM et al: Thermolabile variant of 5,10-methylene tetrahydrofolate reductase associated with low red cell folate: Implications for folate intake recommendations. Lancet 349:1591, 1997.

…        MRC Vitamin Study Research Group: Prevention of neural tube defects: Results of the Medical Research Council vitamin study. Lancet 338:131, 1991.

…        Oakley GP: Let's increase folic acid fortification and include vitamin B12. Am J Clin Nutr 65:1889, 1997.   

…        Seyoum E, Selhub J: Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action. J Nutr 128:1956, 1998

…        Sullivan LW, Herbert V: Studies on the minimum daily requirement for vitamin B12. Hematopoietic responses to 0.1 microgram of cyanocobalamin or coenzyme B12, and comparison of their relative potency. N Engl J Med 272:340, 1965.  


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