The discovery of vitamin B12 was a landmark achievement in nutritional science. In the early 20th century, pernicious anaemia was a fatal disease with no effective treatment. In the 1920s, George Whipple found that feeding liver to dogs with anaemia restored their red blood cell count, laying the groundwork for human studies.

In 1934, Whipple, Minot, and Murphy were awarded the Nobel Prize for their work when they moved from dogs to people , feeding them liver, sometimes raw. However, the active compound in liver responsible for the resolution of pernicious anaemia remained unidentified for over a decade. 

In 1948, two independent research teams led by Karl Folkers and Alexander Todd isolated vitamin B12. Dorothy Hodgkin later used X-ray crystallography to determine its molecular structure, earning her the Nobel Prize in Chemistry in 1964.

As if raw liver wasn’t enough, imagine being in the study, failing to recover from pernicious anaemia, despite the raw liver diet, only to be told they have another idea: to ask one healthy participant to regurgitate the liver and then give it to you through a nasogastric tube. Perhaps William Castle should have been given the Nobel prize for the science of persuasion. Fortunately for the participant, it worked and the theory of an intrinsic and extrinsic factor was confirmed.

Later studies confirmed that intrinsic factor, a glycoprotein secreted by gastric parietal cells, binds to vitamin B12 and facilitates its absorption in the ileum. Deficiency of intrinsic factor, whether due to autoimmune conditions or gastric surgery, results in malabsorption and pernicious anaemia. 

BACTERIAL ORIGINS

Vitamin B12 is uniquely synthesised by bacteria found in soil, water and the gastrointestinal tracts of animals. Humans obtain B12 through animal-based foods, such as meat, fish, eggs and dairy, as these sources concentrate the nutrients. Despite its bacterial origins, B12 is absent in plant foods unless contaminated or fortified, highlighting the risk of deficiency in plant-based diets. Synthetic B12, used to fortify foods such as plant milks, cereals and nutritional yeast, is highly bioavailable. A debate is ongoing around whether shitake mushrooms, nori and chlorella could provide adequate B12 naturally secondary to symbiotic bacteria. However, variability in analysed B12 content, presence of pseudovitamin B12 and the significance of different preparation methods deem these foods to be unreliable as sole sources of B12 at present.

Inherited Metabolic Disorder clinics often see people with raised homocysteine levels due to deficiency of the enzyme cystathionine beta-synthase However, patients have presented to clinic largely immobile and with raised homocysteine levels due to frequent recreational use of nitrous oxide.

Vitamin B12 normally acts as a methyl donor in the metabolism of homocysteine back into methionine. However, nitrous oxide can oxidise the cobalt ion in B12 rendering it inactive. Cessation of nitrous oxide use and high-dose vitamin B12 resolved this relatively quickly.

The NICE guideline (NG239) Vitamin B12 deficiency in over 16s: diagnosis and management (March 2024) now refers to nitrous oxide use as a potential risk factor in diagnosis.