Vitamin B12

Function

Vitamin B12 acts as a cofactor in many essential reactions, particularly methylation reactions as B12 is required to convert homocysteine to methionine. B12 plays a vital role in:

• DNA stability – DNA methylation promotes error free replication
• RNA translation – the AUG start codon encodes methionine, which initiates all mRNA translation and protein synthesis
• Nervous system function – B12 maintains myelin integrity. Demyelination as a result of deficiency results in slower signalling

Absorption

B12 can be ingested bound to protein (in foods) or in free form (supplements). Animal products such as meat, fish, eggs, and dairy contain B12. Plant foods do not naturally contain B12, although they may be fortified. The body absorbs B12 through several coordinated steps.

Gastric phase

Together, hydrochloric acid (HCl-, secreted by parietal cells) and pepsin (secreted by chief cells) release B12 from dietary proteins. In the acidic environment of the stomach free B12 binds specialised R-proteins which protect B12 from degradation.

Intestinal phase (duodenum)

Pancreatic proteases degrade R-proteins to release free vitamin B12 again. In the relatively alkalotic environment of the duodenum B12 binds to intrinsic factor (IF) to form the B12–IF complex.

Though the complex is formed in the duodenum, intrinsic factor is released by gastric parietal cells and is necessary to allow absorption later in the GI tract.

Intestinal phase (terminal ileum)

Vitamin B12 is primarily absorbed in the terminal ileum. The small intestine is lined with a brush border, composed of numerous microvilli that increase the surface area available for absorption. Specialised epithelial cells called enterocytes absorb vitamin B12 through receptor-mediated endocytosis.

The B12–IF complex binds to specific receptors on the brush border of enterocytes. The complex is then internalised by endocytosis and enclosed within lysosomes.

Lysosomal enzymes degrade intrinsic factor, releasing free vitamin B12. B12 is transported across the enterocyte by transcytosis and released into the bloodstream by exocytosis.

Transport and Storage

Vitamin B12 is transported in the circulation bound to the specialised protein transcobalamin II. The liver stores the majority of B12, maintaining reserves that can last several years.

Created in BioRender

Fig. 1
Digestion of vitamin B12

Deficiency

Deficiency of any essential nutrient generally result from reduced intake, reduced absorption, increased requirements, or inability to use it (known as a functional deficiency).

Inadequate intake

Dietary insufficiency is a common cause of vitamin B12 deficiency. Groups at increased risk include:

• Vegetarians and vegans – requires supplementation as B12 is primarily found in animal products. Large hepatic stores may delay symptom onset for up to 3 years
• Older adults – risk factors include loss of appetite, changes to cooking practices and difficulty chewing or swallowing
• Pregnancy – increased requirements makes deficiency more likely

Malabsorption

Absorption of vitamin B12 requires a functional gastrointestinal system, with critical steps occurring in the stomach, duodenum and terminal ileum. Factors that alter acidity, enzymes or the mucosa may result in B12 deficiency, such as:

• Surgical disruption – via gastrectomy, gastric bypass surgery, and resection of the terminal ileum (commonly affected in Crohn’s disease)
• Infection or inflammation – e.g. H. pylori infection or inflammation secondary to chronic gastritis, coeliac disease, and alcohol-related damage
• Decreased gastric acid – may be associated with age or long-term proton pump inhibitor use
• Loss of Intrinsic Factor- Pernicious anaemia is an autoimmune disorder characterised by autoantibodies against intrinsic factor (and sometimes parietal cells). Treatment involves intramuscular injection of B12 to bypass the dysfunctional gastrointestinal tract.

Created in BioRender

Fig. 2
Factors impairing B12 uptake

Functional Deficiency

Recreational nitrous oxide use (“nangs”) oxidises and inactivates vitamin B12 leading to functional deficiency. Functional deficiency is difficult to identify as B12 serum concentrations are normal. However, as the available B12 is inactive the body cannot use it.

Clinical Manifestations of Deficiency

Clinical manifestations of B12 deficiency are most prominent in rapidly dividing cells (bone marrow, gastrointestinal epithelium) and the nervous system due to demyelination.

Symptoms include:

• Neurological – confusion, altered gait, and peripheral neuropathy
• Bone Marrow- fatigue and shortness of breath due to megaloblastic anaemia
• Gastrointestinal – atrophic glossitis (red, beefy, smooth, and swollen tongue)

Jihoon Kim, Moon-Jong Kim & Hong-Seop Kho, CC BY 4.0 <https://creativecommons.org/licenses/by/4.0>, via Wikimedia Commons, No changes made to original image

Fig. 3
Atrophic Glossitis