This article offers an up-to-date overview on the different forms, functions, and benefits of vitamin B12 with special attention to personalization and genetic and laboratory assessments.
OVERVIEW OF THE FORMS AND FUNCTIONS OF B12
WHAT IS B12?
Vitamin B12 is a water-soluble micronutrient that exists in several different forms, collectively called cobalamins. Cobalamins contain a cobalt molecule within a complex ring system that can bind to different ligands. These ligands, also known as side chains, determine what form vitamin B12 is in.
There are four forms of cobalamin. Hydroxocobalamin and cyanocobalamin are precursors to the active forms, methylcobalamin and adenosylcobalamin. Methylcobalamin is involved in homocysteine metabolism and the methylation pathway.° Adenosylcobalamin plays a central role in the mitochondria and supports energy production, muscle, and nerve health.‡
WHAT ARE THE BENEFITS OF B12?
There is a wide range of clinical applications for vitamin B12, especially if you’re trying to address metabolic, neurological, and cognitive needs. The active forms of B12 serve as coenzymes in reactions that support red blood cell function, DNA synthesis, homocysteine metabolism, energy production, ATP formation, neurological function, muscle health, and cognition.‡
HOW DO WE GET VITAMIN B12?
Vitamin B12 is naturally bound to proteins within animal products, and upon ingestion, is broken down by stomach acid and pepsin. B12 is transported through the gastrointestinal tract by forming a complex with transcobalamin I and is eventually absorbed in the small intensive or terminal ileum. It then is transported to the liver where most of it is stored. Interestingly, some B12 is secreted back into the gut where it needs to be absorbed again through a process called enterohepatic recirculation. The remaining fraction that doesn’t get stored in the liver or recirculated forms a complex with transcobalamin II and goes through the bloodstream, eventually crossing the cell membrane via endocytosis.‡
Once in your cells, B12 gets to work. One way in which B12 is used by the body is through methylcobalamin’s role in the methylation pathway. Methylation is a ubiquitous process with big implications. It entails the donation of a methyl group (CH3) to a molecule, which acts as a “green light” for subsequent reactions to occur. When methylation is going well, the process helps repair your DNA, regulates hormones, produces energy, supports detoxification, keeps your immune system healthy, supports the protective coating along your nerves, and strengthens the nervous system. The whole point of the methylation pathway is to generate SAMe, which is a methyl donor. A central step in generating SAMe is the conversion of homocysteine to methionine, which is performed by an enzyme called methionine synthase, which requires methylcobalamin as a cofactor.‡
The second function of vitamin B12 is in the form of adenosylcobalamin, which operates in the mitochondria as a critical cofactor for an enzyme called methylmalonyl-CoA-mutase or MCM, which converts methylmalonyl COA to succinyl-CoA in the Krebs cycle or the TCA cycle. The Krebs Cycle drives the formation of cellular energy in the form of ATP. If there is inadequate adenosylcobalamin to drive this cycle, it slows down, and you get a buildup of methylmalonyl COA and methylmalonic acid. This buildup is a key way to test as a marker of intracellular, mitochondrial, B12 status.‡
Now that we’ve reviewed the benefits of B12, we need to talk about what happens when you don’t have enough B12 to support optimal function.
COMMON SIGNS OF LOW B12
- Occasional fatigue
- Occasional irritability, apathy, mood changes
- Changes in tongue appearance
- Patients often complain about occasional burning or prickling sensation—primarily in the extremities—that results from low B12
PATIENT POPULATIONS AT RISK FOR LOW B12
Older people should remain aware of B12 levels and think beyond just consuming adequate amounts of animal products. This is important because while they may be taking in enough B12, they may have difficulty absorbing B12 since stomach acid production and enzyme secretion both decline with age.
Vegetarians and vegans should also be monitored for signs and symptoms of low B12. Because the primary source of B12 is through consuming animal products, individuals abstaining from eating meat will likely not be taking in sufficient vitamin B12. One caveat is that fermented products do contain small amounts of B12 due to the bacteria present in these foods. Vegetarians and vegans’ symptoms of low B12 tend to gradually develop over years, so while you may not be seeing any overt symptoms, it is important to test them regularly to assess their status.
Patients with intestinal conditions also require vigilance on vitamin B12 status. These individuals may not be absorbing enough vitamin B12 to maintain adequate body stores, and also might excrete more B12 because their gut may not adequately reabsorb it after enterohepatic recirculation.
The profound inter-individual variability in vitamin B12 requirements indicates the importance of taking a personalized approach to helping your patients achieve optimal B12 levels.
LABORATORY AND GENETIC ASSESSMENTS FOR B12
If you have a patient who you would like to monitor for B12, there are five main methods that are helpful for assessing B12 status.
Initial assessment of B12 status should include a complete blood count and serum test for vitamin B12 levels. These assessments will give you a birds-eye view to confirm B12 absorption, but it does not offer details pertaining to intracellular status.
Serum homocysteine can be used in conjunction with these tests to give you a better indication of a vitamin B12 assimilation and overall methylation competence, because it also takes into account folate and vitamin B6. If you have normal homocysteine levels, that means methylation is going quite well, but there is a possibility that folate and B6 may be doing the heavy lifting, thereby camouflaging a potential issue with B12.
Methylmalonic acid (MMA) is a test that is more specific to the intracellular status of B12 because it indicates absorption and transport status. This is a specific B12 biomarker that inversely correlates with mitochondrial assimilation; if you have high MMA levels, it means that you have lower B12 status. This is indicated when serum levels are in the low end of the normal range. In cases such as this, be on the lookout for neurological symptoms that suggest that B12 might be low. This test is not widely used but can be an important tool in assessing a patient’s B12 status.
The fourth method is holo-transcobalamin II (holoTCII), which is also helpful in assessing absorption and transport status of B12. Transcobolamin II is one of the important transporters of B12 and is responsible for carrying B12 through the bloodstream and delivers it to cells that need it. While this test is not widely available, it should be reserved if you have a refractory case of low B12 that is not responding, and you’ve already performed these other assessment methods.
Ordering a genetic test alongside labs testing can be helpful in guiding further assessment and personalization. Genetic tests are available for less than $100 and can be a cost-effective way to identify potential underlying challenges in absorption, transport and assimilation. These three insights not only pertain to B12, but to other vitamins and nutrients as well, such as folate and B6, which help paint a larger picture of what may be happening with your patients. Remember, it is important to understand both genotype and phenotype, so running a genetic test in conjunction with your lab assessments is key to guiding further personalization and dosages.
The genetic markers of relevance are:
- FUT2 (rs602662: GG, GA) is an enzyme that participates in the regulation of the microbiome and host microbe interactions, which plays a role in B12 uptake. This variant reduces the function of this enzyme and reduces B12 absorption.
- TCN2 (rs1801198: CG, GG) transport is affected by variations in the TCN2 gene, which codes the transcobalamin transport carrier protein.
- MTR (rs1805087: GG, GA) and MTRR (rs1801394: GG, GA) are important for assimilation. These polymorphisms affect methionine synthase, which is encoded by the MTR gene and MTRR, which supports the regeneration of methyl and affects the methylation cycle.
In conclusion, vitamin B12 has many benefits, and is essential for maintaining metabolic, neurological, and cognitive processes. It can exist in four forms, with methylcobalamin and adenosylcobalamin being the two active forms. Methylcobalamin is important for supporting the methylation pathway and is particularly involved in cognitive and neurological functions. Adenosylcobalamin is involved in ATP production in the mitochondria and is important for optimal muscular and cellular health, as well as neuronal health.‡
Low doses of B12 are obtained from consuming a diet containing animal products. Patients who do not consume animal products may develop low B12 and should be assessed regularly. Older individuals are also at risk of developing low B12 because absorption function naturally declines with age. Patients with GI conditions that affect absorption should also be routinely checked for adequate B12 levels. If patients are on acid-blocking medications or Metformin, there is strong evidence that shows a connection with long-term use of these drugs and decreases B12 status.
There are a variety of methods used to assess vitamin B12 in your patients, but the important note is that personalization is key, and using a genetic test in conjunction with lab testing can help elucidate an individual’s needs relating to B12 status.
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