Vitamin B12 is an essential water-soluble vitamin, often highlighted for its role in energy production, red blood cell formation, DNA synthesis and prevention of pernicious anaemia. Vitamin B12 has many benefits as it has an important role in so many metabolic reactions.
B12 deficiency was uncovered in the mid-18th century. A diagnosis once deemed fatal, it was soon discovered that a diet rich in liver could largely ameliorate the condition. Nowadays, B12 related fatalities are rare, however a ‘sub-clinical’ category of B12 deficiency is on the rise.
While B12 deficiency has primarily been identified in people who are under-nourished and in those with the autoimmune condition pernicious anaemia; more recent discoveries have identified several sub-clinical factors which can contribute to a reduction in B12 status. These include malabsorption issues – which may occur with increasing age or in those with gastrointestinal impairments, genetic factors, vegetarian and vegan diets and even certain medical interventions.
As such, with a broader understanding of the factors which can contribute to low B12 and with knowledge of the severe consequences which can result from deficiency, it has become more important than ever to raise our awareness around B12 status.
In this blog, we discuss the benefits of B12 and why it is so important, what factors can contribute to low levels, as well as exploring some of the conditions that can benefit from vitamin B12 supplementation.
So, why is B12 important and what are it’s benefits?
B12 participates in the metabolism of every cell in the human body, and is used for well over 100 essential daily functions, including:
- Energy Production
- DNA synthesis
- A co-factor in methylation
- Homocysteine metabolism
- Amino acid and fatty acid metabolism
- Normal nervous system function
- Foetal development in pregnancy
For this reason, deficiency can lead to widespread signs and symptoms, including:
- Pale skin
- Weakness, fatigue and light-headedness
- Constipation, diarrhoea or gas
- Loss of appetite
- Nerve issues like tingling, numbness and muscle weakness
- Impaired vision
- Hormonal and mood imbalances
- Sleep disturbance
- Reduced immunity
- Cognitive impairment
- Problems with balance
- Glossitis – a painful, inflammatory condition of the tongue
Absorption of B12
The molecular state in which vitamin B12 is introduced into the body can impact upon how efficiently it can be absorbed in the gastrointestinal (GI) tract. The absorption of B12 is a highly complex process which can be divided into three key phases: the gastric phase, the intestinal phase and the mucosal phase. Protein-bound B12 in food must be released through an extra separation reaction before it can be absorbed in the ileum; as supplements are already in their free-form, they do not require this stage.
Upon ingestion, free-form B12 will bind to a carrier protein known as R-binders or transcobalamin that is secreted by both the salivary glands and gastric mucosal cells in the stomach and will remain bound until it reaches the second segment of the duodenum in the small intestine.
In its protein-bound food form, it must undergo a proteolytic cleavage in the stomach or duodenum; a reaction that is dependent on the activity of the digestive enzyme, pepsin. Specialist ‘chief cells’ in the stomach secrete pepsinogen, where sufficient stomach acid is required to convert it into pepsin. The parietal cells in the stomach also release intrinsic factor.
Upon entry to the second segment of the duodenum, the pancreas will secrete protease, which will degrade the R-Binders bound to the B12, which will then bind to intrinsic factor for the remainder of its journey to the ileum of the small intestine for absorption.
Upon entry to the ileum, the B12-intrinsic factor complex is absorbed via the enterocytes (cells which line the small intestine) and binds to transcobalamin II; making it active B12. Generally, around 50% of this active B12 is delivered directly to the liver for storage, while the rest is circulated for use in the body tissues. In fact, the liver’s storage of B12 is significant enough that it could take a year or more before a B12 deficiency manifests as any visible symptoms.1
This complex process demonstrates how important effective digestive function is for B12 status.
Vitamin B12, also known as cobalamin is the largest and most complex vitamin in the human body and gets its name, in part due to its chemical structure and cobalt component. In vitamin B12, the active site utilises cobalt, which binds to different chemical groups including cyano, hydroxy, methyl, and 5’-deoxyadenosyl, the latter two being the active vitamin B12 forms utilised in the human body to catalyse specific enzymatic reactions.
In humans, vitamin B12 catalyses methyl transfers and isomerase reactions, the latter using B12 as adenosylcobalamin and being required for the metabolism of fatty acids, amino acids and cholesterol.
Methionine synthase, a methyltransferase, is the main enzyme in humans that utilises methylcobalamin as a methyl source and facilitates methylation reactions throughout the body. The amino acid methionine is produced from homocysteine by adding the methyl group donated from the active form of vitamin B12 methylcobalamin. Folic acid, in the form of methyltetrahydrofolate, is then required to recycle vitamin B12 back to its active methylated form.
Methionine from this reaction is then converted to S-adenosyl methionine (SAMe), one of the major methyl donors for methylation reactions throughout the body, including the methylation of myelin basic protein and DNA.12
Another benefit of vitamin B12 is that it displays antioxidant properties through the direct scavenging of reactive oxygen species (ROS), particularly superoxide in the cytosol and mitochondria, and indirectly by the preservation of glutathione.14
Factors which may contribute to low B12 status:
A deficiency of vitamin B12 may take years to develop in adults, as most of the B12 secreted into the gut via the bile gets reabsorbed, thus conserving the body stores. Therefore, a regular consumption of adequate B12 is important to avoid a sub-clinical deficiency that can go undetected for years.5
Due to the complexity of B12 absorption and synthesis within the body, low levels can often be observed even when there is adequate dietary intake. Some factors which can contribute to low B12 status include:
- Age: B12 deficiency is very common among the senior population and studies have suggested that in the UK, the prevalence of B12 deficiency among those over 60 is almost 20%, compared to just 6% in those below 60.6 Malabsorption due to reduced enzyme and stomach acid activity or a lack of cobalamin transport proteins are potential factors, as well as dietary insufficiency, prescription medications or pernicious anaemia; an autoimmune attack against the parietal cells in the stomach, thereby reducing the amount of intrinsic factor available for B12 to bind to for absorption in the ileum.2
- Dietary preferences: vegan and vegetarian diets can easily be lacking in B12 as it is primarily bound to animal protein. Lacto-ovo vegetarians may have marginal B12 intake, depending upon the use of dairy products. Vegans must obtain their vitamin B12 either from regular use of vitamin B12-fortified foods or from a regular B12 supplement. Unfortified plant foods such as fermented soy foods, leafy vegetables, seaweeds, mushrooms, and algae (including spirulina) do not contain significant amounts of active vitamin B12 to provide daily needs.5
- Parietal cell damage: intrinsic factor is secreted by the parietal cells and is needed for B12 absorption. Parietal cell damage occurs as a result of autoimmunity (leading to pernicious anaemia), hypochlorhydria, gastritis and in those with a history of high alcohol intake.
- Hypochlorhydria (low stomach acid): sufficient stomach acid is required to release B12 from food. Several factors such as old age, radiation for gastric cancer, the use of anti-secretory medications (PPIs, H2 blockers), antacids, hypothyroidism and Helicobacter pylori infection can all contribute to impaired stomach acid production.3
- Intestinal malabsorption: B12 is absorbed in the small intestine and so conditions such as ulcerative colitis, Crohn’s or coeliac disease which can cause damage to these cells could impede B12 absorption.4
- Intestinal bacterial overgrowth: B12 deficiency can occur from excessive gut bacteria in the small intestine (SIBO) as the pathogenic bacteria are capable of competitively utilising B12, decreasing its availability for the body.6
- H-Pylori infection: this gram-negative bacteria inhabits the gastric environment of around 60% of the population globally, and has been shown to be linked to low levels of Vitamin B12, regardless of gastric atrophy and dyspepsia.8
- Genetics: genetic polymorphisms affecting genes may alter vitamin B12 tissue status by affecting the proteins involved in vitamin B12 absorption, cellular uptake and intracellular metabolism. Current genetic studies of vitamin B12 status suggest that several single-nucleotide polymorphisms (SNPs) in multiple genes may affect the activity and/or availability of B12.22
- Medication: in addition to some of the medications mentioned above, the long-term use of metformin, histamine H2 blockers and proton-pump inhibitors have been implicated in B12 deficiency.6,19
- Surgical intervention: changes to the architecture of the gastrointestinal tract following bariatric surgery can result in reduced stomach acid and pepsin production, as well as a loss of cells that product intrinsic factor which can reduce B12 absorption from dietary sources, leading to deficiency.7
- Smoking: organic nitrites, nitro oxide, cyanides and isocyanides in cigarette smoke can all interfere with B12 metabolism and convert it into its inactive form.15
Forms of B12
B12 belongs to the cobalamin family of compounds as it has a cobalt atom at its centre. The structure of B12 is quite intricate, consisting of a corrinoid ring with an upper and lower ligand which attaches to a cyano, hydroxy, methyl or adenosine group.
There are three natural forms of vitamin B12: hydroxocobalamin, methylcobalamin and adenosylcobalamin. These three natural forms have all been shown in clinical studies to improve vitamin B12 status, and they are bioidentical to the B12 forms occurring in human physiology and animal foods and their use is preferable to cyanocobalamin, a synthetic B12 compound used for food fortification and in some supplements, due to their superior bioavailability and safety.10
You can read in further detail about the different supplemental forms of vitamin B12 here.
When supplementing can be supportive
It should be noted that in those with folate deficiency, evaluation for coexistent B12 deficiency is necessary. If folate alone is supplemented in a B12 deficient patient, the B12 associated hematologic abnormalities may improve; however, neurological symptoms can worsen.9
Aside from the groups at risk of B12 deficiency, as mentioned above, there are a range of conditions for which evidence suggests B12 supplementation could be an effective therapeutic option.
Neuropathic Pain – vitamin B12 is a neurotrophic substance with an affinity for neuronal tissues and has been found to be important in maintaining and regenerating peripheral nerves. It has been shown to act by promoting the process of myelination, leading to functional restoration, as well as decreasing ectopic nerve firing, and thus alleviating painful symptoms. Nerve damage related to vitamin B12 deficiency appears to be a direct result of the body being unable to keep myelin basic protein methylated, leading to degeneration of the myelin sheath.12 Research supports the use of vitamin B12 in conditions such as post-herpetic neuralgia, and painful peripheral neuralgia.11
One study demonstrated that supplementing with 1000mcg of oral methylcobalamin over 12 months showed significant improvements in all neurophysiological parameters, pain score and quality of life in patients with diabetic neuropathy.13
Cognitive Decline – based on the antioxidant properties of B12, as mentioned above, a deficiency of the vitamin has the potential to lead to oxidation of lipids, proteins and nucleic acids and might contribute to the development of age-related conditions in which oxidative stress is believed to be a major factor, including Alzheimer’s Disease (AD). B12 is also thought to protect against inflammation induced oxidative stress, and neuroinflammation is reported to play a fundamental role in the progression of Alzheimer’s.
Another important antioxidative mode of action of vitamin B12 that is closely linked to AD is a reduction in homocysteine-induced oxidative stress. As mentioned, subclinical B12 deficiency can reduce the conversion of homocysteine to methionine, resulting in an elevated intracellular homocysteine level, which can contribute to the accumulation of ROS by several mechanisms, including the auto-oxidation of homocysteine and the inhibition of cellular antioxidant enzymes, namely glutathione peroxidase and superoxide dismutase.14
Cardiovascular Disease – as a clotting factor, elevated homocysteine levels can also contribute to an increased risk of stroke and thrombosis.17 Although serum B12 levels can appear normal on a blood test, this figure represents total B12, of which only around 6-20% is active, so in order to asses functional B12 levels, it can be helpful to perform secondary tests to analyse plasma homocysteine levels, particularly in those with signs of deficiency, as a deficiency of B12 at the tissue level can lead to elevation of homocysteine even when serum vitamin B12 is found within the reference range.18
Depression – B12 deficiency can result in neurological and psychiatric problems which can manifest as irritability, changes in personality, depression and memory loss and is known to worsen depressive symptoms by excitotoxic reactions caused by the accumulation of homocysteine. In a recent review of the literature, authors concluded that lower levels of B12 in the body are associated with a higher risk of developing depression.16
Pregnancy – vitamin B12 deficiency in pregnancy has been linked to an increased risk of neural tube defects, low lean mass and increased adiposity, increased insulin resistance and susceptibility to chronic disease in the baby and an increased risk of pre-eclampsia in the mother.20 In the UK, B12 deficiency in pregnancy is common, particularly in obese women and is independently associated with gestational diabetes.21
Vitamin B12 is concentrated in the placenta, and transferred to the foetus down a concentration gradient, with newborn B12 concentrations approximately double that of the mother. The total requirement of the foetus in pregnancy is estimated to be 50mcg, while maternal stores in well nourished women are estimated at greater than 1000mcg: therefore adequate to meet the foetal needs in pregnancy. However, when we consider the prevalence of subclinical deficiency, particularly among those following a vegan or vegetarian diet, supplementing with vitamin B12 may be important in pregnancy.20
- Vitamin B12 participates in the metabolism of every cell in the body and facilitates functions such as DNA synthesis, methylation, normal nervous system function and foetal development.
- A range of symptoms could suggest deficiency, including nerve issues such as tingling, fatigue, impaired vision and weakness – but subclinical deficiency can occur for years before any visible symptoms appear
- Absorption of B12 is a complex, multi-step process and several factors can contribute to low B12 status, including advanced age, a vegan diet, malabsorption issues and certain medications.
- There are a number of conditions in which supplementing with vitamin 12 may be supportive, including neuropathic pain, cognitive decline, cardiovascular disease and depression.
- Adequate levels are essential for the health of both the foetus and mother in pregnancy .
- Busti AJ and Herrington JD (2015) ‘The Mechanism of Absorption of Vitamin B12 (Cobalamin) in the GI Tract’, Retrieved from: https://www.ebmconsult.com [Accessed 25th April 2023]
- Wong CW. Vitamin B12 deficiency in the elderly: is it worth screening? Hong Kong Med J. 2015 Apr;21(2):155-64. doi: 10.12809/hkmj144383. Epub 2015 Mar 10. PMID: 25756278.
- Fatima R and Aziz M (2018) ‘Achlorhydria’, StatPearls Publishing, Retrieved from: http://www.ncbi.nlm.nih.gov/pubmed/29939570
- Busti AJ (2015) ‘ Medical Indications or Conditions that Require Vitamin B12 (Cobalamin) supplementation’ Retrieved from: https://www.ebmconsult.com [Accessed 25th April 2023]
- Craig WJ, Mangels AR, Fresán U, Marsh K, Miles FL, Saunders AV, Haddad EH, Heskey CE, Johnston P, Larson-Meyer E, Orlich M. The Safe and Effective Use of Plant-Based Diets with Guidelines for Health Professionals. Nutrients. 2021 Nov 19;13(11):4144. doi: 10.3390/nu13114144. PMID: 34836399; PMCID: PMC8623061.
- Langan RC, Goodbred AJ. Vitamin B12 Deficiency: Recognition and Management. Am Fam Physician. 2017 Sep 15;96(6):384-389. PMID: 28925645.
- Ciobârcă D, Cătoi AF, Copăescu C, Miere D, Crișan G. Bariatric Surgery in Obesity: Effects on Gut Microbiota and Micronutrient Status. Nutrients. 2020 Jan 16;12(1):235. doi: 10.3390/nu12010235. PMID: 31963247; PMCID: PMC7019602.
- Santos MLC, de Brito BB, da Silva FAF, Sampaio MM, Marques HS, Oliveira E Silva N, de Magalhães Queiroz DM, de Melo FF. Helicobacter pylori infection: Beyond gastric manifestations. World J Gastroenterol. 2020 Jul 28;26(28):4076-4093. doi: 10.3748/wjg.v26.i28.4076. PMID: 32821071; PMCID: PMC7403793.
- Ramezanpour Ahangar E, Annamaraju P. Hydroxocobalamin. 2023 Feb 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32491564.
- Paul C, Brady DM. Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms. Integr Med (Encinitas). 2017 Feb;16(1):42-49. PMID: 28223907; PMCID: PMC5312744.
- Julian T, Syeed R, Glascow N, Angelopoulou E, Zis P. B12 as a Treatment for Peripheral Neuropathic Pain: A Systematic Review. Nutrients. 2020 Jul 25;12(8):2221. doi: 10.3390/nu12082221. PMID: 32722436; PMCID: PMC7468922.
- Buesing S, Costa M, Schilling JM, Moeller-Bertram T. Vitamin B12 as a Treatment for Pain. Pain Physician. 2019 Jan;22(1):E45-E52. PMID: 30700078.
- Didangelos T, Karlafti E, Kotzakioulafi E, Margariti E, Giannoulaki P, Batanis G, Tesfaye S, Kantartzis K. Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients. 2021 Jan 27;13(2):395. doi: 10.3390/nu13020395. PMID: 33513879; PMCID: PMC7912007.
- Lauer AA, Grimm HS, Apel B, Golobrodska N, Kruse L, Ratanski E, Schulten N, Schwarze L, Slawik T, Sperlich S, Vohla A, Grimm MOW. Mechanistic Link between Vitamin B12 and Alzheimer’s Disease. Biomolecules. 2022 Jan 14;12(1):129. doi: 10.3390/biom12010129. PMID: 35053277; PMCID: PMC8774227.
- Shekoohi N, Javanbakht MH, Sohrabi M, Zarei M, Mohammadi H, Djalali M. Smoking Discriminately Changes the Serum Active and Non-Active Forms of Vitamin B12. Acta Med Iran. 2017 Jun;55(6):389-394. PMID: 28843240.
- Sangle P, Sandhu O, Aftab Z, Anthony AT, Khan S. Vitamin B12 Supplementation: Preventing Onset and Improving Prognosis of Depression. Cureus. 2020 Oct 26;12(10):e11169. doi: 10.7759/cureus.11169. PMID: 33251075; PMCID: PMC7688056.
- Spence JD. Nutrition and Risk of Stroke. Nutrients. 2019 Mar 17;11(3):647. doi: 10.3390/nu11030647. PMID: 30884883; PMCID: PMC6470893.
- Vashi P, Edwin P, Popiel B, Lammersfeld C, Gupta D. Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer. PLoS One. 2016 Jan 25;11(1):e0147843. doi: 10.1371/journal.pone.0147843. PMID: 26807790; PMCID: PMC4725715.
- Infante M, Leoni M, Caprio M, Fabbri A. Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind. World J Diabetes. 2021 Jul 15;12(7):916-931. doi: 10.4239/wjd.v12.i7.916. PMID: 34326945; PMCID: PMC8311483.
- Rashid S, Meier V, Patrick H. Review of Vitamin B12 deficiency in pregnancy: a diagnosis not to miss as veganism and vegetarianism become more prevalent. Eur J Haematol. 2021 Apr;106(4):450-455. doi: 10.1111/ejh.13571. Epub 2021 Feb 2. PMID: 33341967.
- Sukumar N, Venkataraman H, Wilson S, Goljan I, Selvamoni S, Patel V, Saravanan P. Vitamin B12 Status among Pregnant Women in the UK and Its Association with Obesity and Gestational Diabetes. Nutrients. 2016 Dec 1;8(12):768. doi: 10.3390/nu8120768. PMID: 27916927; PMCID: PMC5188423.
- Surendran S, Adaikalakoteswari A, Saravanan P, Shatwaan IA, Lovegrove JA, Vimaleswaran KS. An update on vitamin B12-related gene polymorphisms and B12 status. Genes Nutr. 2018 Feb 6;13:2. doi: 10.1186/s12263-018-0591-9. PMID: 29445423; PMCID: PMC5801754.
If you have questions regarding the topics that have been raised, or any other health matters, please do contact our team of Nutritional Therapists.
Last updated on 2nd June 2023 by cytoffice