expert opinion

Causes, consequences and prevention of vitamin B12 deficiency

November 15, 2012

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Professor Yvonne Lamers, Canada Research Chair in Human Nutrition and Vitamin Metabolism; University of British Columbia, Vancouver, Canada

Vitamin B12 is an essential micronutrient acquired almost exclusively from animal-source foods, such as meat, eggs, cheese and milk. The digestion, absorption and transport of B12 to tissues are complex procedures requiring multiple transport pro-teins as well as the respective receptors. Intracellularly, B12 functions as a cofactor in one-carbon metabolism for e.g. the regeneration of methionine from homocys-teine. Low intracellular B12 levels reduce the rate of these pathways, leading to increased substrate concentrations, i.e. homocysteine, which is thought to increase the risk of cardiovascular diseases.

Vitamin B12 deficiency can be caused by a range of factors. The main causes of B12 deficiency relate to the complexities of acquiring B12 and successfully delivering it to metabolically active tissue. Healthy individuals with adequate B12 stores and restricted intake of B12 may not develop deficiency symptoms for many years because of efficient biliary reabsorption. However, individuals with impaired absorption (malabsorption) can develop symptoms within one to three years because the absorption of B12 from food sources and recirculated bile is impaired (1). Infants depend primarily on their mothers’ B12 intake rather than storage during pregnancy and breastfeeding. Children born to B12-deficient mothers show deficiency symptoms rapidly (within months), because of insufficient liver stores and immature guts. Symptoms central to classic clinical B12 deficiency include megaloblastic anemia – resulting from impaired DNA synthesis in red blood cells – and neurological sequelae. The latter are characterized by spinal cord and peripheral nerve degeneration, as well as sensory and motor impairment. Recent research has indicated a variety of possible health implications associated with subclinical B12 deficiency (also called marginal B12 deficiency or B12 depletion). Subclinical B12 deficiency has been linked to an increased risk of cognitive impairment (including mild cognitive impairment, Alzheimer’s disease, non-Alzheimer’s dementia, Parkinson’s (2), diabetes (3), cardiovascular disease (4), pregnancy complications (5), osteoporosis (6) and some can-cers (7). Children born to B12-deficient mothers develop symptoms, such as poor growth and developmental regression (8). For all age groups, evidence is lacking on whether low-dose B12 supplementation is beneficial in disease prevention and/or treatment.

Vitamin B12 status can be determined by direct indicators, such as serum or plasma concentrations of total B12, and functional biomarkers, such as plasma total homocysteine (tHcy) or methylmalonic acid (MMA). Because serum total B12 lacks the specificity to identify subclinical B12 deficiency, the preferred approach is to use a combination of biomarkers, such as serum B12 and plasma MMA (9). The measurement of the latter requires sophisticated technology and trained laboratory technicians. In areas where the more laborious assays are not feasible due to high costs and/or lacking infrastructure, dried blood spot (DBS) analysis can be an economical and field applicable substitute (10).

Vitamin B12 deficiency is common worldwide. The most frequent causes for B12 deficiency are low dietary intake and malabsorption. Dietary insufficiency could be more responsible for the prevalence of B12 defi-ciency in the developing world as opposed to industrialized countries. However, vegans, vegetarians, lacto-ovo vegetarians (vegetarians who consume milk and eggs, but not fish) and low animal-source food consumers in general have a higher deficiency risk compared to omnivores (11). In most cases, low B12 status caused by insufficient dietary B12 intake is reversible with increased intake of B12 (12). Malabsorption of B12 affects mostly older adults with progressive, age-related decline in gastric acidity in both developing and developed countries. In Canada, for example, 10% of older women (13) and 14% of women of childbearing age (14) were found to be B12 deficient (below 150 pmol/L).

While low-dose fortification would likely bypass the group of (mostly) older adults with impaired absorption capacity, adding B12 to food fortification programs would increase the nutritional status of population groups with low dietary B12 intake. The addition of B12 to flour fortification programs could improve the vitamin’s status and prevent its depletion and deficiency in the general population; reduce the occurrence of suggested health implications related to subclinical B12 deficiency; and reduce the risk of high-dose folic acid intake masking and/or aggravating clinical symptoms of B12 deficiency. The latter point refers to recent observa-tions and addresses the concern that B12 deficiency symptoms might be exacerbated if folate status is simultaneously high. For instance, increased risk of elevated homocysteine, cognitive decline, anemia and insulin resistance have been observed in populations with concurrent high folic acid intake and low B12 status (15, 16), although it has not been fully elucidated whether the relationship is causal or what the underlying mechanisms are. In fortification programs, the goal is to provide a consistent dose of the specific micronu-trient to – ideally – the entire population. The suggested additional intake of B12 through fortification is
1.0 μg/day (17) independent of the age group. The amount of B12 added to the fortification vehicle (e.g. wheat flour) would be determined by average consumption patterns. For example, the B12 fortification level of wheat flour would be 0.005 mg of B12 per kg of flour in a population with an average consumption of wheat flour of 200 g per day. Bioavailability of B12 greatly varies between cases of subclinical and clinical B12 deficiency, i.e. between impaired absorption and complete B12 malabsorption. In healthy individuals, only approximately 50% of a 1–2 μg dose of food-bound vitamin B12 is absorbed. With malabsorption or dysfunction of the transfer proteins, this can decrease to 1.2% absorption via diffusion. Those with B12 deficiency are therefore the least likely to benefit from a modest fortification protocol. The proposed 1 μg dose would not benefit individuals with complete malabsorption.

Vitamin B12 is currently considered safe at all levels of intake and does not have a tolerable upper intake level. In a dose-response trial in older adults (aged above 70 years), no adverse effects were reported after high-dose (1000 μg) supplementation with B12 for 16 weeks (18). As the effect of being exposed to high-dose supplements over a lifetime is unknown, safety evaluations of long-term exposure to high-doses of nonfood-bound B12 are needed.

If future research shows that low-dose B12 supplementation or fortification reduces the occurrence of B12 associated diseases, B12 fortification programs will have the potential to improve the quality of life and increase longevity in B12-deficient populations. In order to validate the proposal of population-based food fortification with B12, the potential health benefits and resulting economic savings and social gains need to be determined.”

Based on: Quay T. and Lamers Y. Food Fortification with Vitamin B12 – Potential Benefits and Open Questions. Sight and Life. 2012; 26(2):28–38.

References

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