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.
With 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.
So, why is B12 important?
B12 participates in the metabolism of every cell in the human body. It contributes to normal nervous system functioning through its role in the synthesis of myelin (the fatty layer which surrounds our nerve cells); supports the maturation of red blood cells in bone marrow, as well as acting as a cofactor in fatty acid and amino acid metabolism and DNA synthesis.
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
Absorption of B12
The absorption of B12 in the body is a highly complex process which can be divided into three key phases: the gastric phase, the intestinal phase and the mucosal phase. Food-bound B12 must be released through an extra step before it can be absorbed in the ileum; as supplements are already in their free-form, they do not require this stage.
| Gastric Phase | Free-form (supplement): B12 binds to a plasma carrier protein known both as haptocorrin or transcobalamin I. This glycoprotein is secreted by the salivary glands and protects B12 from the acidic environment of the stomach. The B12-haptocorrin complex then moves towards the duodenum for the next step. Protein-bound B12 (food): unlike free-form B12, protein-bound B12 must first undergo proteolytic cleavage in the stomach to be released from its protein carrier before it can bind to haptocorrin. Proteolytic cleavage refers to the digestion of protein by pepsin in the stomach, which frees B12 for binding. Adequate stomach acid is vital to trigger the conversion of pepsinogen into the functionally active pepsin. The parietal cells in the stomach release intrinsic factor which will bind to B12 in the duodenum. |
| Intestinal Phase | As the B12-haptocorrin complex enters the second part of the duodenum, protease secreted by the pancreas degrades the haptocorrin complexed to the B12. It is here in the duodenum that the B12 binds to intrinsic factor to create a B12-instrinsic factor complex which will be carried toward the ileum of the small intestine. |
| Mucosal Phase | 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. |
Factors which may contribute to low B12 status
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 with estimates suggesting that at least 20% of people over the age of 50 may have low levels. 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.
- Dietary preferences: vegan and vegetarian diets can easily be lacking in B12 as it is primarily bound to animal protein. While vegetarians may fare better as some B12 can be found in dairy and eggs, levels should be monitored to ensure adequacy if attaining B12 through diet alone.
- 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 (PPI’s, H2 blockers), antacids, hypothyroidism and Helicobacter pylori infection can all contribute to impaired stomach acid production.
- Nitrous oxide: can irreversibly convert active B12 into its inactive form, thus preventing use in the body. Nitrous oxide is used in a number of dental and surgical procedures.
- 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.
- Genetics: genetic polymorphisms affecting genes including TCN, FUT2 and MTR/MTRR can disrupt the transport, use and recycling of B12 in the body.
- Medication: in addition to some of the medications mentioned above, other prescription drugs such as metformin and neomycin can impair B12 absorption.
- Surgical intervention: a significant loss in the number of cells which produce hydrochloric (stomach) acid and intrinsic factor can result from gastric bypass surgery. In addition, partial or full removal of the ileum drastically reduces the surface area available for absorption of B12.
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.
| Form | Natural or synthetic? | Biologically active? | No. of conversion steps required | Sustained release? | Unique properties |
| Cyanocobalamin | Synthetic | No | 4 | Average | None |
| Hydroxocobalamin | Natural | No | 3 | Very good | Detoxification of cyanide & nitric oxide |
| Methylcobalamin | Natural | Yes | 0 | Average | DNA, brain, nerves, blood, detoxification |
| Adenosylcobalamin | Natural | Yes | 0 | Average | DNA, brain, muscles, energy |
- Cyanocobalamin is an inactive form of B12, often used in supplements, which contains a cyanide molecule. It is therefore not recommended for those with liver or renal issues. Those who smoke should also be cautious as cyanide may not be eliminated effectively.
- Hydroxocobalamin is an inactive form of B12 found predominantly in food. This is a good option for B12 deficient patients with tobacco amblyopia (a condition related to cyanide metabolism), cyanide toxicity and/or B12 deficiency optic nerve atrophy.
- Methylcobalamin is an active form of B12 with a methyl group and is the only form able to cross the blood brain barrier without further metabolism. This form is a good option for the majority of the population due to its distinct neuroprotective effects. It is also recommended for those with certain genetic polymorphisms.
- Adenosylcobalamin is the mitochondrial form of B12 and co-factor for a metabolic enzyme involved in energy production. It is a good option for those experiencing severe fatigue or with certain genetic polymorphisms reducing their ability to synthesise adenosylcobalamin in the body.
- B12 status is most commonly tested via total B12 levels in blood serum. As this can be an unreliable indication of cellular B12 levels, it is recommended to consider holotranscobalamin, homocysteine, methylmalonic acid and/or genetic testing in conjunction with this, in order to create a more accurate picture of B12 status.