A Deeper Dive Into B12 and Adenosylcobalamin Insufficiency | OptimalDX Blog

Welcome to part 4 of the ODX B12 Deficiency Series. In this final post in our series on Vitamin B12, the ODX Research Team reviews how to correct a B12 deficiency, choosing the right type of B12, the right dosage, and food sources.

How to correct B12 deficiency, choosing the right type of B12, dosage, food sources, etc.

Dicken Weatherby, N.D. and Beth Ellen DiLuglio, MS, RDN, LDN

The ODX B12 Series

1. Vitamin B12 Part 1 - Biochemistry and Physiology
2. Vitamin B12 Part 2 - The Road to B12 Deficiency
3. Vitamin B12 Part 3 - Biomarkers & Assessing B12 Deficiency
4. Vitamin B12 Part 4 - How to Correct B12 Deficiency

Is the current RDA enough?

The RDA Dietary Reference Intake (DRI) for vitamin B12 is 2.4 ug/day for non-pregnant, non-lactating adults.[1]

Even if fully bioavailable, the RDA/DRI for B12 intake has been challenged. Researchers recommend higher intakes to maintain optimal B12 status even in those with adequate absorption.

One study determined that at least 4-7 ug B12/day was needed to positively impact plasma methylmalonic acid, homocysteine, cobalamin, transcobalamin, and holo-transcobalamin.[2]

Other researchers recommend intakes of at least 7 ug/day to support DNA replication and genomic stability,[3] while at least 17.6 ug/day is recommended to reflect average B12 intakes over evolutionary periods.[4]

Non-vegetarian adults in the United States consume an average of 4.6 to 6.3 μg of B12 per day.[5]

A meta-analysis of European surveys revealed that mean B12 intakes for adult men ranged from 3.8-9.3 ug/day and 3.5-8.8 ug/day for adult women.[6]

Sources of B12

The current “official” requirement for B12 is fairly low due to efficient recycling and retention in humans, as well as its utilization in just two enzymes (methylmalonyl-CoA mutase and methionine synthase). Animal-based foods are the best source of B12, including fish, shellfish, liver, and dairy, though some edible macroalgae (e.g. Nori), may produce B12. Serum B12 may plateau with a dietary intake of approximately 10 ug/day.[7]

Animal-based foods are excellent sources because they store B12 in muscle, organs, liver, milk, meat, and eggs. Meats contain primarily adenosylcobalamin while milk and eggs provide primarily methylcobalamin.[8]        

Some fermented foods may contain bioavailable B12 due to bacterial metabolism. Only specific bacteria produce bioavailable B12 (e.g. Propionibacterium freudenreichii sbsp shermanii and Lactobacillus lechmanii) and such strains may contribute to the B12 content of some fermented foods. However, despite label claims and common misconceptions, not all fermented foods, seaweed, algae, or mushrooms provide bioavailable B12. Instead, they can produce B12 analogs or “imposters” that compete with bioavailable B12 for transport and can jeopardize B12 status, especially in vegetarians.[9] Gastrointestinal bacteria may produce B12 as well but these forms may not be bioavailable forms or be absorbed efficiently in the colon.[10]

Researchers do suggest that utilization of cow manure fertilizer and soaking seeds with B12 prior to planting may increase bioavailable B12 in plant-based foods, However, sufficient B12 intake is not guaranteed and those at high risk should be closely monitored for B12 insufficiency and be supplemented accordingly.[11]

Examples of vitamin B12 dietary sources

NIH. ODS. Vitamin B12 Fact Sheet for Health Professionals [12]

*DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for vitamin B12 on the new Nutrition Facts and Supplement Facts labels and used for the values in Table 2 is 2.4 mcg for adults and children age 4 years and older. FDA required manufacturers to use these new labels starting in January 2020, but companies with annual sales of less than $10 million may continue to use the old labels that list a vitamin B12 DV of 6.0 mcg until January 2021.
FDA does not require food labels to list vitamin B12 content unless vitamin B12 has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

Dairy foods appear to promote the greatest increase in serum B12, followed by fortified cereals, and then by meat, fish, and poultry. The binding of B12 to transcobalamin in dairy products appears to optimize its absorption.[13]

Route and type of B12 supplementation

Supplemental B12 is available in the natural bioidentical forms of methylcobalamin, adenosylcobalamin, and hydroxocobalamin, as well as the synthetic form cyanocobalamin.

Although intramuscular injections of B12 have been used in the past, especially to treat pernicious anemia caused by loss of intrinsic factor, research suggests that high dose oral B12 (1-2 mg/day) should suffice for maintenance treatment in that condition.

Lower doses of 500-1000 ug/day may be used in the absence of pernicious anemia for those with a low-normal B12 level.[14]

A 1 mg dose of B12 taken orally may be indicated indefinitely for those who have had bariatric surgery. [15]  

High doses of supplemental B12 (sublingual, liquid, capsule, tablet) can be absorbed via passive diffusion without the assistance of intrinsic factor. Doses must be sufficient to account for less efficient absorption. A dose of greater than 50 ug B12 is considered “supraphysiologic” and should induce some degree of passive absorption.[16]

Though studies suggest absorption rates were similar between cyanocobalamin, hydroxocobalamin, and methylcobalamin, further research suggests that cyanocobalamin has inferior bioavailability due to its less efficient uptake into the cell and decreased metabolic activation. Concern about accumulation of the cyanide moiety led researchers to recommend discontinuation of cyanocobalamin supplementation.[17]

                        Dose                           Absorption

B12                 less than 0.5 mcg          50% (0.25 mcg)

                        1 mcg                             20% (0.2 mcg)

                        500 mcg                         1-1.2% (5-6 mcg)

                        1000 mcg                       0.01- 0.012% (10-12 mcg)

No Tolerable Upper Limit (UL) has been set for B12 since no adverse effects have been reported at high doses.[18]

Some researchers suggest a combination of B12 forms to best meet metabolic needs. i.e. methylcobalamin, adenosylcobalamin, and hydroxocobalamin. [19] However, as stated above, those forms will be reduced to cobalamin and then reassembled as MeCbl and AdCbl within the cell.

The main functions of vitamin B12 should be kept in mind during clinical and biochemical evaluations: [20]

• RBC synthesis and prevention of megaloblastic anemia [and white blood cell formation]
• Neurologic function including prevention of neuropathy and demyelination
• Support of cognitive function and prevention of dementia
• Prevention of hyperhomocysteinemia
• Support of DNA synthesis

Active forms of B12 within the cell [21]

Methylcobalamin (MeCbl)

• Cofactor for methionine synthase
• Facilitates conversion of homocysteine to methionine
• Insufficiency leads to “folate trap” and functional folate deficiency
• Supports hemopoiesis, formation of blood cells (in conjunction with folate)
• Involved in childhood brain development

Adenosylcobalamin (AdCbl)

• Essential to tricarboxylic acid cycle, metabolism of carbohydrates, fats, amino acids
• Essential to myelin synthesis and maintenance

Vitamin B12 - Optimal Takeaways

• Vitamin B12 is an essential micronutrient for humans.
• It is primarily found in animal-based foods and depends on complex gastrointestinal transport and absorption.
• Most plant-based sources of B12 contain “pseudo” B12 or inactive B12 analogues and should not be considered adequate sources of B12.
• Vitamin B12 deficiency may be asymptomatic and may progress despite levels of serum B12 being within normal standard range.
• Laboratory diagnosis of B12 deficiency should include at least two biomarkers, ideally include holotranscobalamin and serum MMA[22]
• Early screening can be based on homocysteine of greater than 9 umol/L. Additional testing for elevated MMA can help distinguish between B12 and folate deficiency in hyperhomocysteinemia.[23]
• Elevated serum B12 may reflect a functional deficiency or a pathological condition and must be investigated further.
• Genetic polymorphisms may affect B12 status despite adequate intake and absorption.
• Supplementation may be the best sources of B12 for some individuals.
• Absorption of B12 decreases as dose increases. Supraphysiological doses may be indicated in those with impaired absorption or other complicating factors.
• High does of 1000-2000 ug/day (1-2mg/d) may be indicated for life following bariatric or GI surgery.
• Oral supplementation, in sufficient doses, is comparable to intramuscular route for resolving B12 deficiency in most cases.[24]
• Ultimately, natural forms such as adenosyl-. hydroxo-, and methyl-cobalamin are recommended. Some researchers recommend discontinuing supplemental cyanocobalamin which is synthetic and contains a cyanide moiety.
• Methylcobalamin is the least expensive and most readily available supplement at present. It should suffice for most supplementation as it will be reduced to cobalamin and then transported into the cell where it can be reconstructed to methylcobalamin or converted to adenosylcobalamin

Additional Reading [25] [26] [27] [28] [29] [30] [31]  

References

[1] NIH ODS. Vitamin B12 Fact Sheet for Consumers. Retrieved October 22, 2020 from https://ods.od.nih.gov/pdf/factsheets/VitaminB12-Consumer.pdf

[2] Bor, Mustafa Vakur et al. “Daily intake of 4 to 7 microg dietary vitamin B-12 is associated with steady concentrations of vitamin B-12-related biomarkers in a healthy young population.” The American journal of clinical nutrition vol. 91,3 (2010): 571-7. 

[3] Fenech, M. “The role of folic acid and Vitamin B12 in genomic stability of human cells.” Mutation research vol. 475,1-2 (2001): 57-67.

[4] Cordain, Loren. "The nutritional characteristics of a contemporary diet based upon Paleolithic food groups." J Am Neutraceutical Assoc 5.3 (2002): 15-24.

[5] Rizzo, Gianluca et al. “Vitamin B12 among Vegetarians: Status, Assessment and Supplementation.” Nutrients vol. 8,12 767. 29 Nov. 2016, 

[6] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[7] Smith, A David et al. “Vitamin B12.” Advances in food and nutrition research vol. 83 (2018): 215-279.

[8] Paul, Cristiana, and David M Brady. “Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.” Integrative medicine (Encinitas, Calif.) vol. 16,1 (2017): 42-49.

[9] Paul, Cristiana, and David M Brady. “Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.” Integrative medicine (Encinitas, Calif.) vol. 16,1 (2017): 42-49. 

[10] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[11] Watanabe, Fumio. “Vitamin B12 sources and bioavailability.” Experimental biology and medicine (Maywood, N.J.) vol. 232,10 (2007): 1266-74. doi:10.3181/0703-MR-67 

[12] NIH. ODS. Vitamin B12 Fact Sheet for Health Professionals. 

[13] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[14] Smith, A David et al. “Vitamin B12.” Advances in food and nutrition research vol. 83 (2018): 215-279. 

[15] Langan, Robert C, and Andrew J Goodbred. “Vitamin B12 Deficiency: Recognition and Management.” American family physician vol. 96,6 (2017): 384-389. 

[16] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[17] Paul, Cristiana, and David M Brady. “Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.” Integrative medicine (Encinitas, Calif.) vol. 16,1 (2017): 42-49. 

[18] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[19] Thakkar, K, and G Billa. “Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion.” European journal of clinical nutrition vol. 69,1 (2015): 1-2.

[20] Allen, Lindsay H et al. “Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review.” The Journal of nutrition vol. 148,suppl_4 (2018): 1995S-2027S. 

[21] Thakkar, K, and G Billa. “Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion.” European journal of clinical nutrition vol. 69,1 (2015): 1-2. 

[22] Harrington, Dominic J. “Laboratory assessment of vitamin B12 status.” Journal of clinical pathology vol. 70,2 (2017): 168-173. 

[23] Hannibal, Luciana et al. “Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency.” Frontiers in molecular biosciences vol. 3 27. 27 Jun. 2016.

[24] Thakkar, K, and G Billa. “Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion.” European journal of clinical nutrition vol. 69,1 (2015): 1-2. 

[25] Dardiotis, Efthimios et al. “Vitamin B12, folate, and homocysteine levels and multiple sclerosis: A meta-analysis.” Multiple sclerosis and related disorders vol. 17 (2017): 190-197.

[26] Wolffenbuttel, Bruce H R et al. “The Many Faces of Cobalamin (Vitamin B12) Deficiency.” Mayo Clinic proceedings. Innovations, quality & outcomes vol. 3,2 200-214. 27 May. 2019. 

[27] Wu, Yang-Che et al. “Anemia, hematinic deficiencies, hyperhomocysteinemia, and gastric parietal cell antibody positivity in atrophic glossitis patients with vitamin B12 deficiency.” Journal of the Formosan Medical Association = Taiwan yi zhi vol. 119,3 (2020): 720-727. 

[28] Sun, Yangbo et al. “Inverse Association Between Serum Vitamin B12 Concentration and Obesity Among Adults in the United States.” Frontiers in endocrinology vol. 10 414. 27 Jun. 2019.

[29] Boachie, Joseph et al. “Low Vitamin B12 and Lipid Metabolism: Evidence from Pre-Clinical and Clinical Studies.” Nutrients vol. 12,7 1925. 29 Jun. 2020.

[30] Sanz-Cuesta, Teresa et al. “Oral versus intramuscular administration of vitamin B12 for vitamin B12 deficiency in primary care: a pragmatic, randomised, non-inferiority clinical trial (OB12).” BMJ open vol. 10,8 e033687. 20 Aug. 2020.

[31] Chan, Catherine Qiu Hua et al. “Oral Vitamin B12 Replacement for the Treatment of Pernicious Anemia.” Frontiers in medicine vol. 3 38. 23 Aug. 2016.