Vitamin B12 is a vitamin which regulates the metabolism of human cells and plays an important role in hematological and nervous systems. Vitamin B12 deficiency is considered a global health problem, with a worldwide prevalence of 10% to 40% of the population. Vitamin B12 is produced by microorganisms and the only source of absorption is by animal-sourced food intake. It can be found in high concentrations in the liver and kidney from ruminant animals, as well as other types of meat, fish, milk and eggs. Vitamin B12 is considered sufficient when blood levels reach more than 100 pmol/L to 350 pmol/L (Aparicio-Ugarriza et al., 2015; Gille & Schmid, 2015).

Biological function

Vitamin B12 is involved in the formation of blood cells, being also used as a cofactor for enzymes that are involved in the synthesis of DNA, fatty acids, and myelin (Ankar & Kumar, 2021).

Clinical relevance

Vitamin B12 deficiency causes pernicious anemia, and it has also been associated to clinical conditions such as gastrointestinal malfunction, neurological problems, depression and cancer. A daily dose of of 3.0 μg is safe and sufficient to avoid vitamin B12 deficiency (Aparicio-Ugarriza et al., 2015; Gille & Schmid, 2015).

Skin conditions

Vitamin B12 deficiency can lead to dermatological manifestations, including hyperpigmentation, hair and nail changes and glossitis. Additionally, several dermatological conditions, including vitiligo, aphthous stomatitis, atopic dermatitis, and acne are related to either vitamin B12 excess or deficiency (Brescoll & Daveluy, 2015).

Depression

Vitamin B12 supplementation may decrease the risk of relapse of depression, it can delay the onset and improve the effect of anti-depressants (Almeida et al., 2015; Sangle et al., 2020).

Gastrointestinal conditions

Vitamin B12 deficiency depends on its absorption in the gastrointestinal tract and it plays an important role in shaping the structure and function of human gut microbial communities (Degnan et al., 2014). Also, ileal resections greater than 20 cm in Crohn's disease predispose to deficiency of vitamin B12 (Battat et al., 2014).

Neurological symptoms

Homocysteine, which is a by-product of vitamin B12, has been associated to the onset of dementia. In fact, vitamin B12 and folate supplementation in patients with mild cognitive impairment can slow the rate of brain atrophy (Health Quality Ontario, 2013).

Vitamin B12 supplementation has been shown to slow gray matter atrophy and cognitive decline. It also reduces the risk of stroke in patients with normal renal function but can be harmful in patients with renal impairment (Spence, 2016). In fact, vitamin B12 deficiency is a risk factor for ischemic stroke and its possible outcome. Also, increased homocysteine levels are a well-established risk factor for ischemic stroke (Yahn et al., 2021). In fact, the effects of vitamin B12 on nitric oxide and homocysteine suggest also a therapeutic potential to treat chronic migraine (Urits et al., 2020).

Vitamin B12 deficiency can be accompanied by pathological lesions both in white and gray brain matter and it can be accompanied by subacute degeneration of spinal cord (funicular myelinosis), sensomotor polyneuropathy, optic nerve neuropathy and cognitive disorders (Pavlov et al., 2019).

Cancer

High vitamin B12 and folate concentrations have been positively associated with an increased risk of prostate cancer. However, the positive association of circulating B12 with an increased risk of prostate cancer could be explained by reverse causality (Collin, 2013).

Other clinical conditions

Vitamin B12 deficiency prevalence is high in patients with type 2 diabetes. A longitudinal prospective study in pregnant women has shown that low B12 status could independently predict the development of diabetes in newborns five years after delivery. Likewise, children born to mothers with low B12 levels may have excess fat accumulation which in turn can result in higher insulin resistance and risk of diabetes and/or cardiovascular disease in adulthood (Boachie et al., 2020).

Vitamin B12 is also considered as a treatment for pain. Animal studies support multiple beneficial effects of vitamin B12 including the regeneration of nerves and the inhibition of cyclooxygenase enzymes and other pain-signaling pathways. In addition, animal studies have demonstrated synergistic benefits of vitamin B12 combined with other pain medications, including nonsteroidal anti-inflammatory drugs and opiates (Buesing et al., 2019).

Endocannabinoid System

Since vitamin B12 deficiency is related to neurological conditions such as dementia, stroke, diabetes and pain, and these conditions are related to the endocannabinoid system, we could expect that there might be an interaction between the endocannabinoid system and vitamin B12. However, the potential relationship between vitamin B12 and the endocannabinoid system has not been researched yet.

Health Claims (EU/EFSA)

• Vitamin B12 contributes to normal energy yielding metabolism
• Vitamin B12 contributes to normal functioning of the nervous system
• Vitamin B12 contributes to normal homocysteine metabolism
• Vitamin B12 contributes to normal psychological function
• Vitamin B12 contributes to normal red blood cell formation
• Vitamin B12 contributes to the normal function of the immune system
• Vitamin B12 contributes to the reduction of tiredness and fatigue
• Vitamin B12 has a role in the process of cell division

References

Almeida, O. P., Ford, A. H., & Flicker, L. (2015). Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. International Psychogeriatrics, 27(5), 727–737. https://doi.org/10.1017/S1041610215000046

Ankar, A., & Kumar, A. (2021). Vitamin B12 Deficiency. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK441923/

Aparicio-Ugarriza, R., Palacios, G., Alder, M., & González-Gross, M. (2015). A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. Clinical Chemistry and Laboratory Medicine, 53(8), 1149–1159. https://doi.org/10.1515/cclm-2014-0784

Battat, R., Kopylov, U., Szilagyi, A., Saxena, A., Rosenblatt, D. S., Warner, M., Bessissow, T., Seidman, E., & Bitton, A. (2014). Vitamin B12 deficiency in inflammatory bowel disease: Prevalence, risk factors, evaluation, and management. Inflammatory Bowel Diseases, 20(6), 1120–1128. https://doi.org/10.1097/MIB.0000000000000024

Boachie, J., Adaikalakoteswari, A., Samavat, J., & Saravanan, P. (2020). Low Vitamin B12 and Lipid Metabolism: Evidence from Pre-Clinical and Clinical Studies. Nutrients, 12(7). https://doi.org/10.3390/nu12071925

Brescoll, J., & Daveluy, S. (2015). A review of vitamin B12 in dermatology. American Journal of Clinical Dermatology, 16(1), 27–33. https://doi.org/10.1007/s40257-014-0107-3

Buesing, S., Costa, M., Schilling, J. M., & Moeller-Bertram, T. (2019). Vitamin B12 as a Treatment for Pain. Pain Physician, 22(1), E45–E52.

Collin, S. M. (2013). Folate and B12 in prostate cancer. Advances in Clinical Chemistry, 60, 1–63. https://doi.org/10.1016/b978-0-12-407681-5.00001-5

Degnan, P. H., Taga, M. E., & Goodman, A. L. (2014). Vitamin B12 as a modulator of gut microbial ecology. Cell Metabolism, 20(5), 769–778. https://doi.org/10.1016/j.cmet.2014.10.002

Gille, D., & Schmid, A. (2015). Vitamin B12 in meat and dairy products. Nutrition Reviews, 73(2), 106–115. https://doi.org/10.1093/nutrit/nuu011

Health Quality Ontario. (2013). Vitamin B12 and cognitive function: An evidence-based analysis. Ontario Health Technology Assessment Series, 13(23), 1–45.

Pavlov, C. S., Damulin, I. V., Shulpekova, Y. O., & Andreev, E. A. (2019). Neurological disorders in vitamin B12 deficiency. Terapevticheskii Arkhiv, 91(4), 122–129. https://doi.org/10.26442/00403660.2019.04.000116

Sangle, P., Sandhu, O., Aftab, Z., Anthony, A. T., & Khan, S. (2020). Vitamin B12 Supplementation: Preventing Onset and Improving Prognosis of Depression. Cureus, 12(10), e11169. https://doi.org/10.7759/cureus.11169

Spence, J. D. (2016). Metabolic vitamin B12 deficiency: A missed opportunity to prevent dementia and stroke. Nutrition Research (New York, N.Y.), 36(2), 109–116. https://doi.org/10.1016/j.nutres.2015.10.003

Urits, I., Yilmaz, M., Bahrun, E., Merley, C., Scoon, L., Lassiter, G., An, D., Orhurhu, V., Kaye, A. D., & Viswanath, O. (2020). Utilization of B12 for the treatment of chronic migraine. Best Practice & Research. Clinical Anaesthesiology, 34(3), 479–491. https://doi.org/10.1016/j.bpa.2020.07.009

Yahn, G. B., Abato, J. E., & Jadavji, N. M. (2021). Role of vitamin B12 deficiency in ischemic stroke risk and outcome. Neural Regeneration Research, 16(3), 470–474. https://doi.org/10.4103/1673-5374.291381