What is B12? What are the consequences of B12 deficiency?
Vitamin B12 (or Cobalamin in its natural dietary (with hydroxocobalamin the active form in cells of the body or cyanocobalamin in its synthetic form) is a water-soluble vitamin that we must obtain solely from our diet. It can be stored in the liver for 3–5 years. It is found mainly in animal sources (as it is made in fermentation processes) such as meat, fish and dairy and algae and yeast extracts. It is an essential co-factor for methionine synthase and methylmalonyl CoA mutase and thus is essential for the production of methionine, where it helps in the conversion of 5-methyltetrahydrofolate (5-MTHF) to tetrahydrofolate, which is needed to make purines such as A and G via SAM (S-adenosylmethionine) which are essential building blocks of DNA, essential for new cell formation (such as red blood cells, white blood cells and gut cells).
B12 plays a vital role in the prevention of megaloblastic anaemia (a form of red blood cell deficiency caused by low folate or B12) and leukopenia (low white blood cell count). It also helps to make methionine which is needed for the methylation of many biochemical processes, including the conversion of amino acids from one form to another such as serine to glycine, the conversion of homocysteine to methionine and the conversion of histidine to glutamate (the main excitatory neurotransmitter and so deficiency in methionine is associated with Alzheimer’s disease and decreased cognitive function, (Lopes da Silva et al., 2014; Periñán et al., 2023)) and Adenosine (needed to regulate the sleep-wake cycle). It thus plays a vital role in cognition, vitality and mood, memory and focus.
B12 biochemical function as a cofactor for methylmalonyl coA mutase is needed for the conversion of propionyl coA to succinyl coA, which is essential as part of the TCA cycle (part of respiration which makes energy) to make Acetyl CoA. B12 thus plays an essential role in energy production and metabolism and deficiency is associated with fatigue, low energy and lethargy and poor mental health. A deficiency in B12 can also cause the 5-Methyltetrahydrofolate trap, where there is enough 5-MTF folate but insufficient B12 cofactor to convert it to TNF, resulting in reduced Methionine methylation via the Methionine cycle and reduced purine synthesis via the folate cycle. This can cause megaloblastic anaemia, abnormal gut mucosa (as it is needed to make gut cells), neuropathy, fatigue and lethargy, decreased white blood cell count, infertility and problems in pregnancy (He et al., 2022) such as neural tube defects (NTD) as well as cancers and DNA and RNA biosynthesis, repair and methylation disorders (Duthie, 2011). It can also cause demyelination of the spinal cord and optic and peripheral nerves. The test biomarkers for B12 are serum B12 (acute B12) with <180ng/L indicating a deficiency and testing the methylmalonic acid (MMA) level. If this is raised, it indicates an insufficient B12 to convert MMA to succinyl CoA and a B12 deficiency. Raised plasma homocysteine can also indicate insufficient B12 to convert homocysteine to methionine. We can also test holotranscobalamin levels as these can indicate how much plasma B12 is bound to TC protein, which is the only form to enter cells and therefore may be a more useful biomarker of deficiency than serum B12.
B12 deficiency can be caused by many things. It requires an acidic environment for absorption. This is because it is found in the diet bound to protein. An acidic environment is needed to separate it from the protein. It then binds to Haptocorrin and then to Intrinsic factor. A lack of an acidic environment (either due to persistent use of drugs that increase stomach pH such as anti-acids, or atrophic gastritis loss of stomach acid (achlorhydria) or pernicious anaemia which produces autoantibodies against parietal cells (so HCL and intrinsic factor not secreted)) can reduce B12 absorption. As can congenital intrinsic factor deficiency. H.pylori overgrowth can also impact B12 absorption from the stomach. Bariatric surgery can such as a gastrectomy for weight loss or post-stomach cancer removal of parts of the ileum or organ reconstructive surgeries, can impact stomach acid secretion and B12 absorption. Further causes of B12 deficiency include diets low in animal and dairy products such as vegetarian and vegan diets which can create a deficit in B12. Nitrous oxide abuse and the use of drugs such as Metformin for the treatment of diabetes can also impact B12 absorption.
Copyright Laura Campbell 13/03/2023
References
Duthie, S. J. (2011). Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis, 34(1), 101–109. https://doi.org/10.1007/s10545-010-9128-0
He, J., Jiang, D., Cui, X., & Ji, C. (2022). Vitamin B12 status and folic acid/vitamin B12 related to the risk of gestational diabetes mellitus in pregnancy: a systematic review and meta-analysis of observational studies. BMC Pregnancy Childbirth, 22(1), 587. https://doi.org/10.1186/s12884-022-04911-9
Lopes da Silva, S., Vellas, B., Elemans, S., Luchsinger, J., Kamphuis, P., Yaffe, K., Sijben, J., Groenendijk, M., & Stijnen, T. (2014). Plasma nutrient status of patients with Alzheimer’s disease: Systematic review and meta-analysis. Alzheimers Dement, 10(4), 485–502. https://doi.org/10.1016/j.jalz.2013.05.1771
Periñán, M. T., Macías-García, D., Jesús, S., Martín-Rodríguez, J. F., Muñoz-Delgado, L., Jimenez-Jaraba, M. V., Buiza-Rueda, D., Bonilla-Toribio, M., Adarmes-Gómez, A. D., Gómez-Garre, P., & Mir, P. (2023). Homocysteine levels, genetic background, and cognitive impairment in Parkinson’s disease. J Neurol, 270(1), 477–485. https://doi.org/10.1007/s00415-022-11361-y
