Population at Risk for Vitamin B12 Deficiency

Populations at risk for and consequences of vitamin B12 deficiency

Vegetarians

Because plants do not synthesise vitamin B12, individuals who consume diets completely free of animal products (vegan diets) are at risk of vitamin B12 deficiency. This is not true of lactoovo-vegetarians, who consume the vitamin in eggs, milk, and other dairy products.

Pernicious anaemia

Malabsorption of vitamin B12 can occur at several points during digestion. By far the most important condition resulting in vitamin B12 malabsorption is the auto-immune disease called pernicious anaemia (PA). In most cases of PA, antibodies are produced against the parietal cells causing them to atrophy, lose their ability to produce intrinsic factor, and secrete hydrochloric acid. 

In some forms of PA the parietal cells remain intact but auto-antiobodies are produced against the intrinsic factor itself and attach to it, thus preventing it from binding vitamin B12. In another less common form of PA, the antibodies allow vitamin B12 to bind to the intrinsic factor but prevent the absorption of the intrinsic factor–vitamin B12 complex by the ileal receptors. As is the case with most auto-immune diseases, the incidence of PA increases markedly with age. In most ethnic groups it is virtually unknown to occur before the age of 50, with a progressive rise in incidence thereafter. However, African American populations are known to have an earlier age of presentation. 

In addition to causing malabsorption of dietary vitamin B12, PA also results in an inability to reabsorb the vitamin B12 which is secreted in the bile. Biliary secretion of vitamin B12 is estimated to be between 0.3 and 0.5 μg/day. Interruption of this so-called enterohepatic circulation of vitamin B12 causes the body to go into a significant negative balance for the vitamin. Although the body typically has sufficient vitamin B12 stores to last 3–5 years, once PA has been established the lack of absorption of new vitamin B12 is compounded by the loss of the vitamin because of negative balance. When the stores have been depleted, the final stages of deficiency are often quite rapid, resulting in death in a period of months if left untreated.

Atrophic gastritis

Historically, PA was considered to be the major cause of vitamin B12 deficiency, but it was a fairly rare condition, perhaps affecting 1 percent to a few percent of elderly populations. More recently it has been suggested that a far more common problem is that of hypochlorhydria associated with atrophic gastritis, where there is a progressive reduction with age of the ability of the parietal cells to secrete hydrochloric acid. 

It is claimed that perhaps up to onequarter of elderly subjects could have various degrees of hypochlorhydria as a result of atrophic gastritis. It has also been suggested that bacterial overgrowth in the stomach and intestine in individuals suffering from atrophic gastritis may also reduce vitamin B12 contained in food but not to interfere with the absorption of the free vitamin B12 found in fortified foods or supplements. Atrophic gastritis does not prevent the reabsorption of bilary vitamin B12 and therefore does not result in the negative balance seen in individuals with PA. However, it is agreed that with time, a reduction in the amount of vitamin B12 absorbed from the diet will eventually deplete even the usually adequate vitamin B12 stores, resulting in overt deficiency.

When considering recommended nutrient intakes (RNIs) for vitamin B12 for the elderly, it is important to take into account the absorption of vitamin B12 from sources such as fortified foods or supplements as compared with dietary vitamin B12. In the latter instances, it is clear that absorption of intakes of less than 1.5–2.0 μg/day is complete – that is, for intakes of less than 1.5–2.0 μg of free vitamin B12, the intrinsic factor – mediated system absorbs all of that amount. It is probable that this is also true of vitamin B12 in fortified foods, although this has not specifically been examined. 

However, absorption of food-bound vitamin B12 has been reported to vary from 9 percent to 60 percent depending on the study and the source of the vitamin, which is perhaps related to its incomplete release from food. This has led many to estimate absorption as being up to 50 percent to correct for bio-availability of absorption from food.

Vitamin B12 interaction with folate or folic acid

One of the vitamin B12 – dependent enzymes, methionine synthase, functions in one of the two folate cycles – the methylation cycle. This cycle is necessary to maintain availability of the methyl donor S-adenosylmethionine; interruption reduces the wide range of methylated products. One such important methylation is that of myelin basic protein.

Reductions in the level of S-adenosylmethionine seen in PA and other causes of vitamin B12 deficiency produce demyelination of the peripheral nerves and the spinal column, called subacute combined degeneration. This neuropathy is one of the main presenting conditions in PA. The other principal presenting condition in PA is a megaloblastic anaemia morphologically identical to that seen in folate deficiency. Disruption of the methylation cycle should cause a lack of DNA biosynthesis and anaemia.

The methyl trap hypothesis is based on the fact that once the cofactor 5,10- methylenetetrahydrofolate is reduced by its reductase to form 5-methyltetrahydrofolate, the reverse reaction cannot occur. This suggests that the only way for the methyltetrahydrofolate to be recycled to tetrahydrofolate, and thus to participate in DNA biosynthesis and cell division, is through the vitamin B12 – dependent enzyme methionine synthase. 

When the activity of this synthase is compromised, as it would be in PA, the cellular folate will become progressively trapped as 5-methyltetrahydrofolate. This will result in a cellular pseudo folate deficiency where despite adequate amounts of folate an anaemia will develop that is identical to that seen in true folate deficiency. Clinical symptoms of PA, therefore, include neuropathy, anaemia, or both. Treatment with vitamin B12, if given intramuscularly, will reactivate methionine synthase, allowing myelination to restart. The trapped folate will be released and DNA synthesis and generation of red cells will cure the anaemia. Treatment with high concentrations of folic acid will treat the anaemia but not the neuropathy of PA. It should be stressed that the so-called masking of the anaemia of PA is generally agreed not to occur at concentrations of folate found in food or at intakes of the synthetic form of folic acid found at usual RNI levels of 200 or 400 μg/day. However, there is some evidence that amounts less than 400 μg may cause a haematologic response and thus potentially treat the anaemia. The masking of the anaemia definitely occurs at high concentrations of folic acid (>1000 μg/day). This becomes a concern when considering fortification with synthetic folic acid of a dietary staple such as flour.

In humans the vitamin B12 – dependent enzyme methylmalonyl coenzyme A (CoA) mutase functions in the metabolism of propionate and certain of the amino acids, converting them into succinyl CoA, and in their subsequent metabolism via the citric acid cycle. It is clear that in vitamin B12 deficiency the activity of the mutase is compromised, resulting in high plasma or urine concentrations of methylmalonic acid (MMA), a degradation product of methylmalonyl CoA. In adults this mutase does not appear to have any vital function, but it clearly has an important role during embryonic life and in early development. Children deficient in this enzyme, through rare genetic mutations, suffer from mental retardation and other developmental defects.

Assessment of vitamin B12 status

Traditionally it was thought that low vitamin B12 status was accompanied by a low serum or plasma vitamin B12 level. 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. 

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.

Lactation

It is estimated that 0.4 μg/day of vitamin B12 is found in the human milk of women with adequate vitamin B12 status. Therefore an extra 0.4 μg/day of vitamin B12 is needed during lactation in addition to the normal adult requirement of 2.0 μg/day, giving a total EAR of 2.4 μg/day during lactation and an RNI of 2.8 μg/day.

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. (Please see my comment below references)

References:

Weir, D.G. & Scott, J.M. 1999. Cobalamins Physiology, Dietary Sources and Requirements. In: Sadler M.J., Strain J.J., Caballero B., eds. Encyclopedia of Human Nutrition, 1: 394-401.

Chanarin, I. 1979. The Megaloblastic Anaemia 2nd Edition. London. Blackwell Scientific Oxford.

Carmel, R. 1996. Prevalence of undiagnosed pernicious anaemia in the elderly. Arch. Intern. Med., 156: 1097-1100.

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.

Carmel, R. 1996. Prevalence of undiagnosed pernicious anaemia in the elderly. Arch. Intern. Med., 156: 1097-1100.

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.

Weir, D.G. & Scott, J.M. 1999. In: Modern Nutrition in Health and Disease. Editors Shils M.E., Olson J.A., Shike M., & Ross A.C. Baltimore, USA. Willams and Wilkins.

Savage, D.G. & Lindenbaum, J. 1995. Neurological complications of acquired cobalamin deficiency: clinical aspects. In: Bailliere’s Clin. Haematol. Megaloblastic Anaemia Editor S.M. Wickramasinghe Vol. 8, pp 657-678. London, Bailliere Tindall.

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.

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.

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.

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.

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My comment:

It is said here the possibility of vitamin B12 deficient for vegetarians. In my younger years, I lived in a province where meat was hardly served on the table because of not being able to buy, especially beef. It's very expensive. Sometimes, our only source of meat was the native chicken meat (not the kind of chicken raised in poultry), but maybe we can only have it once in 3 months or more. Then sometimes we have also fish to eat but it is rare too, since we only depend on those small time fishermen if they can catch fish from the river. If we have extra money, we buy carabao's milk (fresh) from vendor's who have carabaos. This is the only source of vitamin B12 that we can afford.

However, we have our Moringa Oleifera tree in our backyard, and of course, that is our common "delicacy", the so called poor man's food, BUT, had been found out by the scientists that this "poor man's food" was actually the source of lots of vitamins and minerals that a body needs. Inspite of our poor situation at that time, or let's say less fortunate for not having the chance to buy foods for the "rich" so they say, and yet we are healthy and no disease that needs a doctor. That means,  Moringa Oleifera can provide the vitamins and minerals that our body needs. The scientists findings are true...am I right?