Vitamin B12 deficiency: NICE guideline summary (2024)

GRADE Working Group grades of evidence

• High certainty—we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty—we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low certainty—our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

• Very low certainty—we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Box 1

Common symptoms and signs of vitamin B₁₂ deficiency

• Abnormal findings, such as anaemia or macrocytosis, on a blood count

• Cognitive difficulties, such as difficulty concentrating or short term memory loss (sometimes described as “brain fog”), which can also be symptoms of delirium or dementia

• Eyesight problems related to optic nerve dysfunction:

  • −Blurred vision

  • −Optic atrophy

  • −Visual field loss (scotoma)

    See Also

    Symptoms of Vitamin B DeficiencySigns and Symptoms of Vitamin B12 DeficiencyVitamin B deficiency: symptoms and treatmentMangel, Symptome, Therapie: Fragen und Antworten zu Vitamin B12

• Glossitis

• Neurological or mobility problems related to peripheral neuropathy, or to central nervous system disease including myelopathy (spinal cord disease):

  • Balance issues and falls caused by impaired proprioception (the ability to sense movement, action, and location) and linked to sensory ataxia (which may have been caused by spinal cord damage)

  • Impaired gait

  • Pins and needles or numbness (paraesthesia)

• Symptoms or signs of anaemia that suggest iron treatment is not working properly during pregnancy or breastfeeding

• Unexplained fatigue

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Box 2

Common risk factors for vitamin B₁₂ deficiency

• Diet low in vitamin B₁₂ (without regular use of over-the-counter preparations), for example, in people who:

  • Follow a diet that excludes, or is low in, animal source foods (such as a vegan diet or diets that exclude meat for religious beliefs)

  • Do not consume food or drinks fortified with vitamin B₁₂

  • Have an allergy to some foods such as eggs, milk, or fish

  • Find it difficult to buy or prepare food (for example, people who have dementia or frailty, or those with mental health conditions)

  • Find it difficult to obtain or afford foods rich in vitamin B₁₂ (for example, people on low income)

  • Have a restricted diet (for example, because of an eating disorder)

• Family history of vitamin B₁₂ deficiency or an autoimmune condition

• Health conditions:

  • Atrophic gastritis affecting the gastric body

  • Coeliac disease or another autoimmune condition (such as thyroid disease, Sjögren syndrome, or type 1 diabetes)

• Medicines:

  • Colchicine

  • H₂ receptor antagonists

  • Metformin (see the MHRA safety advice on metformin and reduced vitamin B₁₂4)

  • Phenobarbital

  • Pregabalin

  • Primidone

  • Proton pump inhibitors

  • Topiramate

• Previous abdominal or pelvic radiotherapy

• Previous gastrointestinal surgery:

  • Many bariatric operations (for example, Roux-en-Y gastric bypass or sleeve gastrectomy)

  • Gastrectomy or terminal ileal resection

• Recreational nitrous oxide use

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First line testing

Based on the experience of the guideline committee, active B₁₂ (serum holotranscobalamin) is a more accurate test than total B₁₂ (serum cobalamin) for vitamin B₁₂ deficiency because active B₁₂ measures the biologically active form of vitamin B₁₂ that is available for use by cells. Testing active B₁₂ is more expensive than testing total B₁₂, (active B₁₂ is £18 per test versus total B₁₂ which is £2 per test, mean costs reported by guideline committee members at the time of analysis). This is in part due to active B₁₂ testing mainly being performed by external referral laboratories rather than local hospital laboratories, and increases the turnaround time to receive a result for an active B₁₂test compared with a total B₁₂ test. Despite the suggestion that active B₁₂ is a more accurate test than total B₁₂, evidence is lacking to support a recommendation that would signal a significant and expensive change in practice. Either test is preferrable to not testing when suspicion of deficiency arises from symptoms or signs and risk factors.

This recommendation should not be applied to people who are pregnant or suspected of vitamin B₁₂ deficiency that results from recreational use of nitrous oxide, and guidance on testing for these groups is available in the full guideline.

Further testing

Interpretation and follow-up are dependent on the initial total or active B₁₂ test result. This was based on the experience of the guideline committee and limited, poor quality evidence. The committee recommended considering measuring methylmalonic acid (MMA) as a confirmatory test when initial test results were in an indeterminate range (table 1). Although MMA provides a more reliable diagnosis that reflects the functional status of vitamin B₁₂, it is unsuitable as a first line test. Testing for MMA is expensive (£11-80, range of costs reported by guideline committee members at the time of analysis), requires specialist analytical equipment, and often requires analysis in external laboratories, resulting in an increased time to receive a result.

A cost utility analysis was performed to evaluate the cost effectiveness of second line MMA testing if the initial B₁₂ test results were indeterminate. MMA testing before treatment is the most cost effective strategy compared with not testing MMA, with an incremental cost effectiveness ratio of £3946 per quality adjusted life year. Importantly, the model did not account for testing for other underlying causes and assumed that people who had not been diagnosed correctly as B₁₂ deficient on their first visit would attend primary care once more to gain the correct diagnosis. The model was not able incorporate multiple assumptions stemming from the lack of evidence for the model parameters, including accuracy of MMA testing, prevalence of elevated MMA in the population, variation in quality of life (utility) experienced by people who are B₁₂ deficient, and potential impact on resources because of testing, thereby potentially overestimating savings (owing to uncertainty).

• Use either total B₁₂ (serum cobalamin) or active B₁₂ (serum holotranscobalamin) as the initial test for suspected vitamin B₁₂ deficiency.

• Consider a further test to measure serum MMA concentrations in people who have symptoms or signs of vitamin B₁₂ deficiency and an indeterminate total or active B₁₂ test result.

  [Based on very low certainty evidence]

Malabsorption as the suspected or confirmed cause of vitamin B₁₂ deficiency

All evidence identified for vitamin B₁₂ replacement was in patient populations where the cause of deficiency was unspecified. This was a major limitation in application of the evidence, and was reflected in downgrading of all the evidence because of indirectness. Recommendations were based on seven randomised controlled trials and two observational studies reporting the effect of vitamin B₁₂ replacement on haematological values and experience of the guideline committee.

We identified three economic evaluations that compared oral and parenteral vitamin B₁₂ treatments, all of which assumed equivalent effectiveness between the two modalities.567 Studies ranged in patient selection, setting, and duration of follow-up. Two studies, including a short term cost utility analysis of patients with unexplained fatigue in an Australian primary care setting, concluded that oral treatment was the most cost effective strategy.56 Conversely, one study found that parenteral administration was cheaper unless accounting for the long term savings from avoiding additional GP appointments and blood tests costs.7 However, none of the studies reflect current treatment costs, and if the models were updated, then parenteral treatment would be the more cost effective option.

In our cost comparison, 50 μg tablets were priced at £0.43 compared with 1 mg tablets at £0.33 at the time of analysis. The guideline committee agreed that it is reasonable to assume that the higher dosage would be at least as effective as the lower strength tablet, and recommended considering the 1 mg tablet as the preferred oral treatment. If people are prescribed a higher dose than 50 μg daily, ie, 100-150 μg daily, then it would be appropriate to use 1 mg, which is the most commonly used dose in current practice. Prescribing a higher dose may be more effective and provide greater health benefit as a larger amount of B₁₂ is being delivered to the bloodstream, and therefore absorbed, while also being convenient to patients by reducing tablet burden.

In the short term, intramuscular treatment is more expensive than oral treatment. For individuals who require long term treatment, such as those with autoimmune gastritis, intramuscular treatment is preferred as it is more cost effective. This recommendation is based on its superior efficacy in the experience of the guideline committee and the economic evidence, as well as the rationale that oral replacement would not be effective if malabsorption were present.

For other malabsorptive states, excluding autoimmune gastritis, where absorption is reduced but not eradicated altogether, some members of the guideline committee suggested that oral replacement may be effective. During the covid-19 pandemic, many people were moved from in-person intramuscular to self-administered oral treatments, but the guideline committee agreed that the evidence to support this as an effective route of administration for this group of patients was inadequate. This view was reiterated by some lay members of the guideline committee, who had experienced a significant worsening of symptoms when switched to oral replacement.

Primary care teams and patients may prefer trialling oral treatment at diagnosis, as prescriptions can be issued directly to people and may be more convenient. No data were identified that support the effectiveness and safety of self-administration of intramuscular replacement.

• Offer lifelong intramuscular vitamin B₁₂ replacement to people if:

  • Autoimmune gastritis is the cause, or suspected cause, of vitamin B₁₂ deficiency or

  • They have had a total gastrectomy or a complete terminal ileal resection.

• If the person has a vitamin B₁₂ deficiency because of malabsorption that is not caused by autoimmune gastritis, or a total gastrectomy or complete terminal ileal resection (for example, malabsorption caused by coeliac disease, partial gastrectomy, or some forms of bariatric surgery):

  • Offer vitamin B₁₂ replacement and

  • Consider intramuscular instead of oral vitamin B₁₂ replacement.

• When offering oral vitamin B₁₂ replacement to people with vitamin B₁₂ deficiency caused, or suspected to be caused, by malabsorption, prescribe a dosage of at least 1 mg a day.

  [Based on moderate to very low certainty evidence]

Future research

Developing this guideline was challenging because of a lack of clinical and economic evidence, resulting in many recommendations being based on the expertise of the guideline committee. Nine research recommendations were made, and details can be found in the full guideline. The research recommendations most relevant to the topics covered in this summary are:

• What are the long term outcomes for people with suspected vitamin B₁₂ deficiency when comparing testing of total B₁₂, active B₁₂, serum MMA, or plasma hom*ocysteine?

• What is the clinical and cost effectiveness of vitamin B₁₂ replacement for vitamin B₁₂ deficiency, including the dose, frequency, and route of administration?

• What is the clinical and cost effectiveness of self-administration of vitamin B₁₂ replacement injections for deficiency compared with administration by a healthcare professional?

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