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Vitamin B12

Plants do not have B12 unless fortified. Diets primarily or exclusively made of plants (e.g., vegan, vegetarian) often need vitamin B12 supplements. Other names: Cobalamin, Cyanocobalamin, Methylcobalamin, Hydroxycobalamin, Adenosylcobalamin

How it works

  • Supports DNA production Involved in energy pathways

  • Required for myelin that covers and protects nerve cells

  • Works with folate and other B vitamins to make red blood cells

  • Works with B vitamins to produce many amino acids for proteins

  • Fortified foods - some plant milks and yogurts, plant-based meat alternatives, cereals

  • Some nutritional yeast products

  • Some edible algae

  • A few mushrooms

  • Some fermented beans and vegetables ​​

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Plants are not a reliable source of B12 and amounts can vary widely in fortified foods. Supplements are recommended for diets containing little to no animal products. ​

 

Animal sources: Seafood, meats, liver, eggs

Sources of nutrient

No tolerable upper intake level has been set (i.e., no UL, the maximum daily intake amount unlikely to cause adverse health effects). [1,2,4]

Daily upper limits

Recommended daily amount

Bioavailability

Food-bound vitamin B12 requires stomach acid and enzymes for release from food and a stomach protein (intrinsic factor) and salivary R-binder (haptocorrin) for transport into the intestine. [8] B12 is primarily absorbed in the ileum, [4,8] some is stored in the liver, [4,8] and a substantial amount is resorbed with bile reuptake in the gut. [9] Vitamin B12 is bound to plasma haptocorrin (~70-80% of total B12; considered “inactive” or unavailable to all but hepatic cells) and transcobalamin (typically 10-20% saturated and carries 20-30% of “active” B12 to all cells). [8] ​

 

About 50% of dietary vitamin B12 is absorbed in healthy adults with normal gastric function. [4] However, when meals contain more than ~2mcg of B12, absorption decreases to about 20%. [1] There is a refractory period of about 6 hours before receptors in the gut can be replenished to allow further active absorption of B12. [8]

 

Passive absorption occurs throughout the absorptive surface of the digestive tract as well as via mucus membranes of the nose and mouth, but it is typically only a small fraction of the dose unless B12 is consumed in large doses (e.g., supplements >50 mcg). [8]

 

Supplements may have greater absorption than food-based B12. [4] However, studies suggest consuming a high dose of B12 can saturate the B12-intrinsic factor and decrease absorption. [4,8] For example, B12 retention from supplements was estimated at 50% of 1 mcg, 20% of 5 mcg, and 5% of 25 mcg dose. [8] Studies of B12-fortified foods (flour studied at the country level) also suggest small B12 doses throughout the day might be more effective in improving B12 status than high-dose supplements. [8] Supplement forms (e.g., methylcobalamin, cyanocobalamin; sublingual vs oral) do not appear to significantly differ in their absorption or efficacy in healthy persons. [2] ​

It is important to monitor B12 status in vegetarians and vegans, [10] particularly during pregnancy, lactation, infancy, and childhood, to avoid irreversible damage from B12 insufficiency. [8] ​

 

No single vitamin B12 biomarker provides sufficient specificity and sensitivity to diagnose B12 deficiency. [8] Several blood biomarkers should be used in conjunction with clinical findings. Clinical symptoms may occur with adequate hematological markers and vice-versa. [8,10,11] Therefore, the broad clinical picture must be taken into account when diagnosing vitamin B12 deficiency. [8,10] Treatment should not be delayed to avoid permanent neurological damage when a discordant agreement between strong clinical features and hematological values occurs. [10] ​

 

There are no gold standards in cut-off values for B12 biomarkers for defining status. [8] Commonly used cut-offs can vary and are somewhat controversial due to the high prevalence of subclinical B12 deficiency and limited data linking these to functional outcomes. [8] Note cut-off values for biomarkers for infants, children, and pregnant women will be different than for adults. [8]

 

Furthermore, laboratory “normal” ranges for B12 adequacy and test specificities and sensitivities vary. [10,12] Reference values and cut-offs should be interpreted with caution, particularly when assessing infants, children, and pregnant women. It is advised that laboratories establish values for different age groups. [13]

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In summary, [8]

  • ↓ serum holoTC (transcobalamin) and serum B12

  • ↑ plasma methylmalonic acid (MMA) and urinary MMA excretion

  • ↑ plasma homocysteine (tHcy)

  • Hypersegmentation of nuclei in neutrophils

  • Megaloblastic anemia (MCV, Hg, large RBC) ​​

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Note folate and B12 share common metabolic pathways and should also be considered when assessing status.[8]  Iron deficiency can mask macrocytosis due to B12 deficiency and also may need to be considered.[8,11]

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Measures of adequate status

  • Older adults Persons with pernicious anemia

  • Persons on a vegan diet without sufficient B12-fortified foods or supplements Infants of mothers with low B12 during pregnancy

  • Prolonged use of proton pump inhibitors or conditions that reduce stomach acid

  • Persons with gastrointestinal conditions - gastrectomy, ileal resection, pancreatic insufficiency, chronic diarrhea, and others  (e.g., Crohn’s, gastric bypass, gastritis, sprue)

Populations at risk for deficiency

Deficiency signs and symptoms

  • ​Nerve damage (demyelination), often presenting as tingling or numbness in hands or feet, which can be permanent, especially with deficiency beyond one year [1,2,4]

  • Memory loss, confusion, poor cognitive performance, impaired motor function, dementia, depression [1,2,4]

  • Sore tongue or mouth [2,4]

  • Fatigue, weight loss, loss of appetite [2]

  • Increased risk of birth defects (neural tube defects due to folate’s dependence on B12) [1]

  • Increase risk of bone loss [1]

  • Infant developmental delays [1,2]

  • Macrocytic anemia [1,4] (also due to pernicious anemia that can cause B12 deficiency [4])

  • Neutrophil hypersegmentation, leukopenia (also from pernicious anemia) [4] 

For diets that are low in/lack animal-sourced foods, suggested prophylactic therapy with oral vitamin B12 supplements are provided below.

Prevention and treatment of deficiency

Particularly, vegetarian and vegan patients often need B12 supplementation due to potentially low(er) stores and birth, low(er) breast milk concentrations, and lack of naturally-occurring B12 in plant-based foods. [8]

Prevention

​The suggested oral dose and schedule for the treatment of vitamin B12 insufficiency/deficiency when needed is provided below.

Treatment

​Dose and schedules for prophylactic/ treatment of vitamin B12 insufficiency are based on high-dose supplements resulting in ~1% of the amount passively absorbed (plus ~ 2mcg actively absorbed); [8] separating doses can increase B12 bioavailability. [8,19] It is recommended to monitor B12 levels to ensure adequate repletion when using oral vitamin B12 treatment. [20] ​

 

Plant-based infants should be screened at least by 12 months (with anemia screening). For plant-based children and adolescents, consider assessing B12 status every 1-2 years and possibly adjusting the B12 dose.

 

A typical vitamin B12 therapy protocol for intramuscular injections for children with vitamin B12 deficiency would be as follows: 1000 mcg every day for one week, 1000 mcg on alternate days for one week, 1000 mcg twice a week for one week, and then once a week.[21] (Typically of 150 mcg of a 1000 mcg i.m. dose is retained). [8]

 

B12 deficiency and pernicious anemia in adults are often managed with an intramuscular injection of 500 – 1000 mcg of B12 once or twice weekly for 6 weeks, then once per month.[1] In patients with neurological symptoms, initially 1000 mcg i.m. injections are recommended on alternative days until there is no further improvement observed.[10]

 

High-dose daily oral B12 supplements (e.g., 500 – 1000 mcg) can be also considered as ~1% of the dose is absorbed passively. [8] Oral schedules appear to be as effective as intramuscular injections at normalizing B12 levels [14,21] and may be more tolerated. Furthermore, vitamin B12 sublingual and intranasal forms provide good options to many patients. [11] ​ In patients with anemia who have adequate iron and folate levels, a reticulocyte response from B12 treatment should occur after 7 to 10 days; if not, the initial diagnosis should be reviewed. [10]

The content provided is for informational purposes only and may not be an exhaustive list of potential interactions.

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  • ​Chloramphenicol – limited evidence suggests it may interfere with red blood cell response to supplemental B12 in some patients. [2] Proton pump inhibitors (e.g., omeprazole) – may interfere with acidic needs of food-based B12 to be absorbed. [2,8]

  • Although the impact on B12 status is conflicting, prolonged use of these drugs may influence B12 levels. [2]

  • H2 receptor antagonists (e.g., Zantac) – may interfere with the absorption of food-based B12. [2,8]

  • Metformin may reduce serum B12 levels by causing B12 to accumulate in the liver.[8] For example, randomized controlled trials of patients taking metformin for an average of 4.3 years had a ~20% decrease in B12 levels and a 7% increased risk of B12 deficiency compared to placebo. [2]

  • Phenformin may reduce B12 levels when used over long periods of time. [9]

  • Oral contraceptives may reduce vitamin B12 binding capacity in serum, and serum B12 levels in oral contraceptive users have been reported to be lower than in non-users; however, mechanisms are not fully understood. [22]

  • Chronic exposure to the anesthetic gas, nitrous oxide, can cause a functional B12 deficiency. [8] ​​

Potential drug-nutrient interactions

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Notes

B12 deficiency can result in permanent nerve damage. A B12 supplement can help to ensure adequate B12 in persons consuming little to no animal-sourced foods and those with a higher risk of deficiency (e.g., older adults). ​

 

Breast milk B12 concentrations are strongly related to maternal status during pregnancy and postpartum and can be extremely low even in nonvegetarians lacking adequate B12 sources (e.g., animal products). [8] ​

 

High folate intake may mask a B12 deficiency; folate/folic acid intake from food and supplements should not exceed 1 mg of folic acid per day to reduce this risk. [2] ​

 

B12 is recycled through bile excretion-reuptake and helps conserve levels; thus, signs of depletion deficiency may take years to develop after the onset of inadequate intake. Persons with malabsorption conditions (e.g., pernicious anemia) may become depleted rapidly (<1 year). [8] ​

 

B12 deficiency can cause a functional folate deficiency by “trapping” folate-dependent enzymes in an unusable form. [8]

 

B12-deficient patients at risk for Leber’s optic atrophy from chronic cyanide intake (e.g., smoking) should not be given cyanocobalamin due to the risk of irreversible neurological damage; hydroxycobalamin should be used to treat B12 deficiency in these patients as it is a cyanide antagonist. [4]

Notes

1. Allen LH. Vitamin B12. Adv. Nutr. 2012; 3: 54–55.

 

2. Vitamin B12. Fact Sheet for Health Professionals. Office of Dietary Supplements. National Institutes of Health. Updated Mar 2020. Accessed Sept 2020. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/

 

3. U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans, 2020-2025. 9th Edition. December 2020. Available at https://DietaryGuidelines.gov.

 

4. Institute of Medicine 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. https://doi.org/10.17226/6015

 

5. FoodData Central. United States Department of Agriculture. https://fdc.nal.usda.gov/index.html

 

6. Watanabe, Vitamin B12-containing plant food sources for vegetarians. Nutrients 2014, 6, 1861-1873.

 

7. Nutrients: Vitamin B12. USDA National Nutrient Database for Standard Reference Release 28.

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8. Allen, et al. Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review. Supplement: Biomarkers of Nutrition for Development (BOND) Expert Panel Reviews, Part 6. J Nutr; 2018; 1995S.

 

9. Green, R. Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr; 2011; 94(suppl):666S–72S.

 

10. Devalia, for the British Committee for Standards in Haematology. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166, 496–513.

 

11. Green. Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood. 2017; 129, 2603–2611.

 

12. Harrington. Laboratory assessment of vitamin B12 status. J Clin Pathol. 2017; 70, 168–173.

 

13. Personal Communication. Nordmeyer, L. Remote Support Engineer 3. Siemens Medical Solutions USA, Inc. Siemens Healthcare. July 20, 2022.

 

14. Heiner-Fokkema Age dependency of plasma vitamin B12 status markers in Dutch children and adolescents. Pediatr Res. 2021 Nov;90(5):1058-1064.

 

15. Abildgaard, Reference intervals for plasma vitamin B12 and plasma/serum methylmalonic acid in Danish children, adults and elderly. Clin Chim Acta. 2022; 525, 62–68.

 

16. Henjum, Vitamin B12 concentrations in milk from Norwegian women during the six first months of lactation. Eur J Clin Nutr. 2020; 74, 749–756.

 

17. Personal communication with Joshua W. Miller, PhD, Professor and Chair, Dept. of Nutritional Sciences, Rutgers University, USA. July 20, 2022.

 

18. Baroni, Vegan Nutrition for Mothers and Children: Practical Tools for Healthcare Providers. Nutrients. 2018;11(1):5. Published 2018 Dec 20. doi:10.3390/nu11010005.

 

19. DiMaggio, Updates in Infant Nutrition. Pediatr Rev. 2017 Oct;38(10):449-462. doi: 10.1542/pir.2016-0239. PMID: 28972048.

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20. Rashid, et al. Review of Vitamin B12 deficiency in pregnancy: a diagnosis not to miss as veganism and vegetarianism become more prevalent. Eur J Haematol. 2021 Apr;106(4):450-455.

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21. Sezer, et al. Comparison of the efficacy of parenteral and oral treatment for nutritional vitamin B12 deficiency in children. Hematology. 2018 Oct;23(9):653-657.

 

22. Palmery et al. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013; 17:1804-1813.

References

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