A Deep Dive into Vitamin B12

Written by Trang Tran, Pharm.D. Candidate | Reviewed by Dr. Amy Knaperek, Pharm.D.


Because it contains a metal ion called cobalt, vitamin B12 is also known as cobalamin. Whereas methylcobalamin and 5-deoxyadenosylcobalamin are the active forms of vitamin B12, the two other forms, namely, hydroxocobalamin and cyanocobalamin, become biologically active after they are converted to methylcobalamin or 5-deoxyadenosylcobalamin.


Remarkably, vitamin B12 plays an important role in the body. Let’s dive in to explore vitamin B12, specifically looking at its function, causes of deficiency, signs and symptoms of deficiency, recommended dietary allowance, food sources, supplements, and safety.


What is the function of vitamin B12?

Methylcobalamin serves as a cofactor for methionine synthase, an enzyme that is required for the synthesis of the amino acid, methionine, from homocysteine. Methionine is needed to synthesize S-adenosylmethionine, which is involved in many chemical reactions with DNA, RNA, and proteins. Notably, inadequate vitamin B12 can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular disease.


Additionally, 5-deoxyadenosylcobalamin serves as a cofactor for L-methylmalonyl-coenzyme A mutase, an enzyme that accelerates the conversion of L-methylmalonyl-coenzyme A to succinyl-coenzyme A (succinyl-CoA), which plays a key role in the production of energy from fats and proteins and is also needed to make hemoglobin, the oxygen-carrying protein in red blood cells.


All in all, vitamin B12 is essential for DNA synthesis and cellular energy production as well as red blood cell formation.


What causes vitamin B12 deficiency?


Food-Bound Vitamin B12 Malabsorption

Most cases of vitamin B12 are due to intestinal malabsorption rather than inadequate dietary intake. Stomach acid is needed to release vitamin B12 bound to protein found in food, but people of advanced age tend to have diminished stomach acid production, thereby increasing the risk of vitamin B12 deficiency. Moreover, decreased stomach acid can lead to bacterial overgrowth in the small intestine which interferes with vitamin B12 absorption.


Pernicious Anemia

Pernicious anemia is an autoimmune condition in which one’s own antibodies destroy the cells that line the stomach, thereby decreasing secretion of acid that is required to release food-bound vitamin B12. Intrinsic factor (IF) is a special protein that binds to vitamin B12 so that it can be absorbed in the intestines, but antibodies to IF can further inhibit vitamin B12 absorption. Unlike the case where people who have difficulty absorbing vitamin B12 from food can absorb free vitamin B12 normally, individuals with pernicious anemia cannot absorb either food-bound or free vitamin B12. In a subset of individuals, Helicobacter pylori (a type of bacteria that infects the stomach) infection is thought to initiate the autoimmune response.


Treatment of pernicious anemia involves vitamin B12 intramuscular injections or large doses of oral vitamin B12.


Other Causes

The receptors (“lock”) for the IF-B12 complex (“key”) are located in the small intestines. Thus, the surgical removal of the small intestines may cause vitamin B12 deficiency.


Malabsorption syndromes such as celiac disease may result in vitamin B12 deficiency.


The pancreas produces enzymes and calcium that are required for vitamin B12 absorption. Thus, pancreatic insufficiency may contribute to vitamin B12 deficiency.


Since vitamin B12 is found in foods of animal origin, a vegan diet may result in vitamin B12 deficiency.


Other groups that may have increased risk of vitamin B12 deficiency include alcoholics (due to reduced intestinal absorption of vitamin B12) and individuals with acquired immunodeficiency syndrome or AIDS (due to the failure of the uptake of IF-B12 complex).


Some inherited disorders can also cause vitamin B12 malabsorption.


Prescription drugs such as proton pump inhibitors (PPI) or acid-suppressing drugs (e.g., omeprazole or Prilosec and lansoprazole or Prevacid) are commonly used in the elderly to treat gastroesophageal reflux disease. However, these medications decrease stomach acid secretion required for the release of vitamin B12 from food. Of note, vitamin B12 deficiency does not generally develop until after at least three years of continuous PPI therapy.


Other acid-suppressing drugs include the histamine H2-receptor antagonists (e.g., cimetidine or Tagamet and famotidine or Pepcid).


Some drugs found to inhibit vitamin B12 absorption from food include cholestyramine (a bile acid-binding resin used in the treatment of high cholesterol), chloramphenicol and neomycin (antibiotics), and colchicine (medicine for gout treatment).


Metformin, a medication used to manage type 2 diabetes, was also found to decrease vitamin B12 absorption which may be related to intestinal mobility changes or bacterial overgrowth competing for vitamin B12 in the gastrointestinal tract. Remarkably, it has been shown that calcium improves the uptake of vitamin B12 in metformin users.


What are the signs and symptoms of vitamin B12 deficiency?

Vitamin B12 deficiency is associated with elevated blood levels of homocysteine and/or methylmalonic acid or MMA due to impaired activity of the methionine synthase and L-methylmalonyl-CoA mutase, respectively. However, it is important to note that blood levels of homocysteine and MMA are also elevated with kidney impairment, common in older people, thereby making interpretation difficult.


Symptoms of vitamin B12 deficiency can take several years to appear because the body stores about 1,000 to 2,000 times as much as the amount typically consumed in a day.


Neurologic symptoms include numbness and tingling of the hands and feet, difficulty walking, memory loss, disorientation, and dementia with or without mood changes. The accumulation of methylmalonyl CoA is thought to be responsible for the neurological effects in vitamin B12 deficiency.


Gastrointestinal symptoms such as tongue soreness, appetite loss, and constipation may be related to stomach inflammation and destruction of the stomach lining.


Besides neurologic and gastrointestinal symptoms, impairment of vitamin B12 absorption can lead to megaloblastic anemia, a type of blood disorder characterized by large, abnormally nucleated red blood cells as well as tiredness, fatigue, and pale skin.


Recommended Dietary Allowance (RDA)

The RDA for male and female adults is 2.4 micrograms per day. However, the Food and Nutrition Board recommended that adults over 50 years of age obtain vitamin B12 from supplements or fortified foods due to the age-related increase in food-bound malabsorption.


What are the sources of vitamin B12?

Vitamin B12 is synthesized by certain bacteria in the gastrointestinal tract of animals and thus, vitamin B12 is concentrated in animal products such as liver, meat, poultry, fish, shellfish, and to a lesser extent, dairy products and eggs. Furthermore, fish or shellfish soup stocks and extracts are natural sources of free B12 which make them suitable for those with food bound B12 malabsorption.


Plant-based sources of vitamin B12 include certain fermented beans (e.g., tempeh) and vegetables, dried green and purple (nori) lavers, and mushrooms (e.g., black trumpet and golden chanterelle). The addition of Propionibacteria to cabbage during sauerkraut production has been shown to produce higher concentrations of B12.


Edible cyanobacteria (e.g., spirulina) contain large amounts of the biologically inactive forms of vitamin B12, making them unsuitable for use as a source of B12 for vegans.


Vitamin B12 can be degraded by heat (e.g., cooking). Interestingly, the combination of vitamin C and copper found in B12-containing multivitamin/mineral supplements significantly destroyed B12, but the degradation of B12 was reduced significantly by the addition of certain antioxidants such as carnosine or anserine.


Vitamin B12 Supplements

The main form of vitamin B12 that is used in oral supplements is cyanocobalamin, but methylcobalamin (the active form), adenosylcobalamin, and hydroxocobalamin are also available as a supplement. Vitamin B12 is available in multivitamin/mineral supplements, vitamin B-complex supplements, and single-nutrient vitamin B12 supplements.


In addition to oral dietary supplements, vitamin B12 is available in sublingual (under the tongue) tablets or lozenges.


Vitamin B12 supplements may be suitable for strict vegetarians or vegans (due to the lack of animal-derived food intake which are rich in vitamin B12), adults over 50 years of age (due to low stomach acid production), and those taking medications that interfere with vitamin B12 absorption (due to low stomach acid production in the case with acid-suppressing drugs).


Vitamin B12 in the form of a supplement does not require acid for its absorption, as it is in a free form and is not bound to protein as in food, thereby making it ideal for those of advanced age and those taking acid-suppressing medications.


Safety

Large intake of vitamin B12 from food or supplements in healthy people have not been associated with toxic or adverse effects, most likely due to limited absorption. No tolerable upper intake level has been set by the US Food and Nutrition Board due to low toxicity of vitamin B12.


Additionally, vitamin B12 is a water-soluble vitamin which means that it can easily get eliminated out of the system via the urine.


The Bottom Line

Vitamin B12 (cobalamin), which functions as a cofactor and is essential for DNA synthesis, cellular energy production, and red blood cell formation, comes in many forms including methylcobalamin, 5-deoxyadenosylcobalamin, hydroxocobalamin, and cyanocobalamin with the first two being the active forms.


Causes of vitamin B12 deficiency include food-bound malabsorption, pernicious anemia, surgical removal of the small intestines, celiac disease, pancreatic insufficiency, vegan diet, alcoholism, AIDS, genetic disorders, and certain medications such as acid-suppressing medications and metformin.


Symptoms of vitamin B12 deficiency include neurologic symptoms (numbness and tingling of the hands and feet, memory impairment, and mood changes).


Although animal-based food (liver, meat, poultry, fish, and shellfish) is rich in vitamin B12, plant-based food such as fermented beans, dried green and purple lavers, and certain kinds of mushrooms are also rich in vitamin B12.


Candidates for vitamin B12 supplements include vegans, individuals over 50 years of age, and individuals on prolonged acid-suppressing medications.


Vitamin B12 is relatively safe as it has limited absorption and is water-soluble.


Consult with your pharmacist to determine if vitamin B12 supplement is for you and the best form to use.


References:

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  2. Office of dietary supplements - vitamin B12. NIH Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/. Accessed March 4, 2022.

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  7. Watanabe F, Takenaka S, Kittaka-Katsura H, Ebara S, Miyamoto E. Characterization and bioavailability of vitamin B12-compounds from edible algae. J Nutr Sci Vitaminol (Tokyo). 2002;48(5):325-331. doi:10.3177/jnsv.48.325

  8. Watanabe F, Yabuta Y, Tanioka Y, Bito T. Biologically active vitamin B12 compounds in foods for preventing deficiency among vegetarians and elderly subjects. J Agric Food Chem. 2013;61(28):6769-6775. doi:10.1021/jf401545z

  9. Image link: https://diet.ind.in/wp-content/uploads/2019/03/Vitamin-B12-Rich-Indian-Foods.jpg

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