Traditionally it was thought that low vitamin B12 status was accompanied by a low serum or plasma vitamin B12. Recently this has been challenged by Lindenbaum et al.,who suggested that a proportion of people with normal vitamin B12 levels are in fact vitamin B12 deficient. They also suggested that elevation of plasma homo-cysteine and plasma MMA are more sensitive indicators of vitamin B12 status. Although plasma homo-cysteine may also be elevated because of folate or vitamin B6 deficiency, elevation of MMA apparently always occurs with poor vitamin B12 status. There may be other reasons why MMA is elevated, such as renal insufficiency, so the elevation of itself is not diagnostic. Many would feel that low or decreased plasma vitamin B12 levels should be the first indication of poor status and that this could be confirmed by an elevated MMA if this assay was available.
Evidence on which to base a recommended intake
Recommendations for nutrient intake
The Food and Nutrition Board of the National Academy of Sciences (NAS) Institute of Medicine has recently exhaustively reviewed the evidence of intake, status, and health for all age groups and during pregnancy and lactation. This review has lead to calculations of what they have called an estimated average requirement (EAR). The EAR is defined by NAS as “the daily intake value that is estimated to meet the requirement, as defined by the specific indicator of adequacy, in half of the individuals in a life-stage or gender group”. They have estimated the recommended dietary allowances to be this figure plus 2 standard deviations (SDs). Some members of the Food and Agriculture Organization of the United Nations and World Health Organization (FAO/WHO) Expert Consultation were involved in the preparation and review of the NAS recommendations and judge them to have been the best estimates based on available scientific literature. The FAO/WHO expert group felt it appropriate to adopt the same approach used by the NAS in deriving the RNIs. Therefore the RNIs suggested in
Adults
Several lines of evidence point to an adult average requirement of about 2.0 μg/day. The amount of intramuscular vitamin B12 needed to maintain remission in people with PA suggests a requirement of about 1.5 μg/day, but they would also be losing 0.3–0.5μg/day through interruption of their enterohepatic circulation, which is not typical. This might suggest a requirement of 0.7–1.0 μg/day. Because vitamin B12 is not completely absorbed from food, an adjustment of 50 percent has to be added giving a range of 1.4–2.0 μg/day. Therapeutic response to ingested food vitamin B12 suggests a minimum requirement of something less than 1.0 μg/day. Diets containing 1.8 μg/day seemed to maintain adequate status but lower intakes showed some signs of deficiency. Dietary intakes of less than 1.5 μg/day were reported to be inadequate in some subjects.
In summary, the average requirement could be said to be 2 μg/day. The variability of the requirements for vitamin B12 is accounted for by adding two SDs, that is, 2.4 μg/day as an RNI for adults, including the elderly.
Children
The Food and Nutrition Board of the NAS Institute of Medicine suggested the same intakes for adolescents with progressive reduction of intake for younger groups.
Pregnancy
The previous FAO/WHO Expert Consultation suggested that 0.1–0.2 μg/day of vitamin B12 is transferred to the foetus during the last two trimesters of pregnancy. On the basis of on foetal liver content from post-mortem samples, there is further evidence that the foetus accumulates on average 0.1–0.2 μg/day during pregnancies of women with diets which have adequate vitamin B12. It has been reported that children born to vegetarians or other women with a low vitamin B12 intake subsequently develop signs of clinical vitamin B12 deficiency such as neuropathy. Therefore, when calculating the EAR for pregnant women, 0.2 μg/day of vitamin B12 is added to the EAR for adults to result in an EAR of 2.2 μg/day and an RNI of 2.6 μg /day during pregnancy.
Infants
As with other nutrients, the principal way to determine requirements of infants is to examine the levels in milk from mothers on adequate diets. There is a wide difference in the vitamin B12 values reported in human milk because of differences in methodology. The previous FAO/WHO report used milk vitamin B12 values of normal women of about 0.4 μg/l. For an average milk production of 0.75 l/day, the vitamin B12 intake by infants would be 0.3 μg/day. Other studies have reported ranges of vitamin B12 in human milk to be 0.4–0.8 μg/L. Although daily intakes ranging from 0.02 to 0.05 μg/day have been found to prevent deficiency, these intakes are totally inadequate for long-term health. An EAR of 0.3–0.6 μg/day would result in an RNI of 0.36–0.72 μg/d. It might be prudent to use the lower figure of 0.4 μg/day for the first 6 months of pregnancy and 0.7 μg/day for last trimester.
Adults
Several lines of evidence point to an adult average requirement of about 2.0 μg/day. The amount of intramuscular vitamin B12 needed to maintain remission in people with PA suggests a requirement of about 1.5 μg/day, but they would also be losing 0.3–0.5μg/day through interruption of their enterohepatic circulation, which is not typical. This might suggest a requirement of 0.7–1.0 μg/day. Because vitamin B12 is not completely absorbed from food, an adjustment of 50 percent has to be added giving a range of 1.4–2.0 μg/day. Therapeutic response to ingested food vitamin B12 suggests a minimum requirement of something less than 1.0 μg/day. Diets containing 1.8 μg/day seemed to maintain adequate status but lower intakes showed some signs of deficiency. Dietary intakes of less than 1.5 μg/day were reported to be inadequate in some subjects.
In summary, the average requirement could be said to be 2 μg/day. The variability of the requirements for vitamin B12 is accounted for by adding two SDs, that is, 2.4 μg/day as an RNI for adults, including the elderly.
Children
The Food and Nutrition Board of the NAS Institute of Medicine suggested the same intakes for adolescents with progressive reduction of intake for younger groups.
Pregnancy
The previous FAO/WHO Expert Consultation suggested that 0.1–0.2 μg/day of vitamin B12 is transferred to the foetus during the last two trimesters of pregnancy. On the basis of on foetal liver content from post-mortem samples, there is further evidence that the foetus accumulates on average 0.1–0.2 μg/day during pregnancies of women with diets which have adequate vitamin B12. It has been reported that children born to vegetarians or other women with a low vitamin B12 intake subsequently develop signs of clinical vitamin B12 deficiency such as neuropathy. Therefore, when calculating the EAR for pregnant women, 0.2 μg/day of vitamin B12 is added to the EAR for adults to result in an EAR of 2.2 μg/day and an RNI of 2.6 μg /day during pregnancy.
Infants
As with other nutrients, the principal way to determine requirements of infants is to examine the levels in milk from mothers on adequate diets. There is a wide difference in the vitamin B12 values reported in human milk because of differences in methodology. The previous FAO/WHO report used milk vitamin B12 values of normal women of about 0.4 μg/l. For an average milk production of 0.75 l/day, the vitamin B12 intake by infants would be 0.3 μg/day. Other studies have reported ranges of vitamin B12 in human milk to be 0.4–0.8 μg/L. Although daily intakes ranging from 0.02 to 0.05 μg/day have been found to prevent deficiency, these intakes are totally inadequate for long-term health. An EAR of 0.3–0.6 μg/day would result in an RNI of 0.36–0.72 μg/d. It might be prudent to use the lower figure of 0.4 μg/day for the first 6 months of pregnancy and 0.7 μg/day for last trimester.
Upper limits
The absorption of vitamin B12 mediated by intrinsic factor is limited to 1.5–2.0 μg per meal because of the limited capacity of the receptors. In addition, between 1 percent and 3 percent
of any particular oral administration of vitamin B12 is absorbed by passive diffusion. Thus, if 1000 μg vitamin B12 (sometimes used to treat those with PA) is taken orally, the amount absorbed would be 2.0 μg by active absorption plus about 30 μg by passive diffusion. This amount has never been reported to have any side effects. Similar large amounts have been used in some preparations of nutritional supplements without apparent ill effects. However, there are no established benefits for such amounts. Such high intakes thus represent no benefit in those without malabsorption and should probably be avoided.
The absorption of vitamin B12 mediated by intrinsic factor is limited to 1.5–2.0 μg per meal because of the limited capacity of the receptors. In addition, between 1 percent and 3 percent
of any particular oral administration of vitamin B12 is absorbed by passive diffusion. Thus, if 1000 μg vitamin B12 (sometimes used to treat those with PA) is taken orally, the amount absorbed would be 2.0 μg by active absorption plus about 30 μg by passive diffusion. This amount has never been reported to have any side effects. Similar large amounts have been used in some preparations of nutritional supplements without apparent ill effects. However, there are no established benefits for such amounts. Such high intakes thus represent no benefit in those without malabsorption and should probably be avoided.
References:
Chanarin, I. 1979. The Megaloblastic Anaemia 2nd Edition. London. Blackwell Scientific Oxford.
Food and Nutrition Board, Institute of Medicine, National academy of Sciences. 1998. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6 , folate, and vitamin B12, pantothenic aid, botin, and choline. National Academy Press Washington DC, USA.
Lindenbaum, J., Savage, D.G., Stabler, S.P. & Allen, R.H. 1990. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homo-cysteine concentrations. Am. J. Hematol., 34: 99-107.
Narayanan, M.M., Dawson, D.W. & Lewis, M.J. 1991. Dietary deficiency of vitamin B12 in association with low serum cobalamin levels in non-vegetarians. Eur. J. Hematol., 47: 115-118.
FAO/WHO. 1988. Requirements of Vitamin A, Iron, Folate and Vitamin B12. Report of a joint FAO/WHO expert consultation. p. 62-73. Food and Agriculture Organization of the United Nations, Rome, Italy.
Doscherholmen, A., McMahon, J. & Ripley, D. 1978. Vitamin B12 assimilation from chicken meat. Am. J. Clin. Nutr., 31: 825-830.
Baker, S.J., Jacob, E., Rajan, K.T. & Swaminathan, S.P. 1962. Vitamin B12 deficiency in pregnancy and the puerperium. BMJ, 1: 1658-1661.
Loria A., Vaz-Pinto A., Arroyo P. & Ramirez-Mateos C., Sanchez-Medal L. 1977. Nutritional anemia. VI. Foetal hepatic storage of metabolites in the second half of pregnancy. J. Pediatr., 91: 569-573.
Vaz Pinto, A., Torras, V., Sandoval, J.F., Dillman, E., Mateos, C.R. & Cordova, M.S. 1975. Folic acid and vitamin B12 determination in foetal liver. Am. J. Clin. Nutr., 28: 1085-1086.
Specker, B.L., Black, A., Allen, L. & Morrow, F. 1990. Vitamin B12: Low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. Am. J. Clin. Nutr., 52: 1073-1076.
Collins, R.A., Harper, A.E., Schreiber, M. & Elvehjen, C.A. 1951. The folic acid and vitamin B12 content of the milk of various species. J. Nutr., 43: 313-321.
Donangelo, C.M., Trugo, N.M., Koury, J.C., Barreto, Silva M.I., Freitas, L.A., Feldheim, W. & Barth, C. 1989. Iron, zinc, folate and vitamin B12 nutritional status and milk composition of low income Brazilian mothers. Eur. J. Clin. Nutr., 43:253-266.
Dagnelie, P.C., van Staveren, W.A., Roos, A.H., Tuinstra, L.G. & Burema, J. 1992 Nutrients and contaminants in Human milk from mothers on macrobiotic and omnivorous diets. Eur. J. Clin. Nutr., 46: 355-366.
Trugo, N.M. & Sardinha, F. 1994. Cobalamin and cobalamin-binding capacity in Human milk. Nutr. Res., 14: 22-33.
Ford,C., Rendle, M., Tracy, M., Richardson,V. & Ford, H. 1996. Vitamin B12 levels in Human milk during the first nine months of lactation . Int. J. Vit. Nutr. Res., 66: 329-331.
Srikantia, S.G. & Reddy, V. (1967). Megaloblastic anaemia of infancy and vitamin B12. Br. J. Haematol., 13: 949-953.
Roberts, P.D., James, H., Petric, A., Morgan, J.O. & Hoffbrand, A.V. (1973) Vitamin B12 status in pregnancy among immigrants in Britain. BMJ, iii: 67-72.
Chanarin, I. 1979. The Megaloblastic Anaemia 2nd Edition. London. Blackwell Scientific Oxford.
Food and Nutrition Board, Institute of Medicine, National academy of Sciences. 1998. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6 , folate, and vitamin B12, pantothenic aid, botin, and choline. National Academy Press Washington DC, USA.
Lindenbaum, J., Savage, D.G., Stabler, S.P. & Allen, R.H. 1990. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homo-cysteine concentrations. Am. J. Hematol., 34: 99-107.
Narayanan, M.M., Dawson, D.W. & Lewis, M.J. 1991. Dietary deficiency of vitamin B12 in association with low serum cobalamin levels in non-vegetarians. Eur. J. Hematol., 47: 115-118.
FAO/WHO. 1988. Requirements of Vitamin A, Iron, Folate and Vitamin B12. Report of a joint FAO/WHO expert consultation. p. 62-73. Food and Agriculture Organization of the United Nations, Rome, Italy.
Doscherholmen, A., McMahon, J. & Ripley, D. 1978. Vitamin B12 assimilation from chicken meat. Am. J. Clin. Nutr., 31: 825-830.
Baker, S.J., Jacob, E., Rajan, K.T. & Swaminathan, S.P. 1962. Vitamin B12 deficiency in pregnancy and the puerperium. BMJ, 1: 1658-1661.
Loria A., Vaz-Pinto A., Arroyo P. & Ramirez-Mateos C., Sanchez-Medal L. 1977. Nutritional anemia. VI. Foetal hepatic storage of metabolites in the second half of pregnancy. J. Pediatr., 91: 569-573.
Vaz Pinto, A., Torras, V., Sandoval, J.F., Dillman, E., Mateos, C.R. & Cordova, M.S. 1975. Folic acid and vitamin B12 determination in foetal liver. Am. J. Clin. Nutr., 28: 1085-1086.
Specker, B.L., Black, A., Allen, L. & Morrow, F. 1990. Vitamin B12: Low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. Am. J. Clin. Nutr., 52: 1073-1076.
Collins, R.A., Harper, A.E., Schreiber, M. & Elvehjen, C.A. 1951. The folic acid and vitamin B12 content of the milk of various species. J. Nutr., 43: 313-321.
Donangelo, C.M., Trugo, N.M., Koury, J.C., Barreto, Silva M.I., Freitas, L.A., Feldheim, W. & Barth, C. 1989. Iron, zinc, folate and vitamin B12 nutritional status and milk composition of low income Brazilian mothers. Eur. J. Clin. Nutr., 43:253-266.
Dagnelie, P.C., van Staveren, W.A., Roos, A.H., Tuinstra, L.G. & Burema, J. 1992 Nutrients and contaminants in Human milk from mothers on macrobiotic and omnivorous diets. Eur. J. Clin. Nutr., 46: 355-366.
Trugo, N.M. & Sardinha, F. 1994. Cobalamin and cobalamin-binding capacity in Human milk. Nutr. Res., 14: 22-33.
Ford,C., Rendle, M., Tracy, M., Richardson,V. & Ford, H. 1996. Vitamin B12 levels in Human milk during the first nine months of lactation . Int. J. Vit. Nutr. Res., 66: 329-331.
Srikantia, S.G. & Reddy, V. (1967). Megaloblastic anaemia of infancy and vitamin B12. Br. J. Haematol., 13: 949-953.
Roberts, P.D., James, H., Petric, A., Morgan, J.O. & Hoffbrand, A.V. (1973) Vitamin B12 status in pregnancy among immigrants in Britain. BMJ, iii: 67-72.
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