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Global review unpacks Vitamin B12 deficiency diagnosis and treatment

A deficiency of the important vitamin B12 may lead to a variety of symptoms, although diagnosing this can be difficult, suggests a global review in BMJ, because no single specific measurement exists to reliably pinpoint or refute the deficiency.

Vitamin B12 (cobalamin) is a water soluble vitamin required for several physiological processes, including normal nervous system functioning, and red blood cell development and maturation. It has antioxidant effects, is a co-factor in mitochondrial energy metabolism, and contributes to DNA synthesis, the methylation cycle, and epigenetic regulation.

It is present in foods of animal origin, like meat, eggs and milk, or via food fortification, and healthy adults require an average intake of 4-7 mcg daily to maintain B12 status.

The classic presentation of symptomatic deficiency occurs in Addison-Biermer’s disease, and is characterised by megaloblastic anaemia. This type of anaemia was the first condition to be linked to B12 deficiency, and probably because of that, many doctors have the misconception that B12 deficiency is ruled out in patients without anaemia.

This, in turn, has led to delayed diagnosis, notably in people presenting solely with neurological symptoms.

However, in many people, neurological and neuropsychological or cognitive symptoms are the main presenting symptoms.

Anaemia is present in fewer than 20% of people with B12 deficiency. Cobalamin analogue formation may be related to more prominent neurological manifestations.

The authors write that a serum B12 concentration below 148 pmol/L (depending on the assay) with symptoms is a strong indication of deficiency and is sufficient to start treatment. However, symptoms may also be present in individuals with serum B12 >148 pmol/L.

Frequently reported signs and symptoms of B12 deficiency can include;

• Brain function: “Brain fog”, memory problems, cognitive impairment, insomnia, headaches (especially migraine), behavioural changes, learning problems, nominal aphasia

• Mood: Mood swings, irritability, depression, anxiety, hallucinations, delusions, psychosis

• Sensory: Peripheral paraesthesia (“pins and needles”), numbness, neuropathic pains, poor balance, reduced vibration sense or proprioception (joint position sense), tinnitus, ataxia, taste impairment, sometimes myelopathy

• Constitutional: Fatigue, anaemia (either macrocytic, or normocytic when also iron deficient or associated with thalassaemia minor), other cytopenia, abdominal complaints, malabsorption, failure to thrive, weight loss, diarrhoea, hyperpigmentation, glossitis, (aphthous) stomatitis, infertility, urinary tract infections

• Motor: Muscle weakness, altered reflexes (increased in degeneration of the spinal cord, reduced when peripheral neuropathy dominates), spasticity, seizures, cardiomyopathy

• Autonomic: Urinary and/or faecal incontinence, postural hypotension or dizziness, erectile dysfunction

How is B12 deficiency treated?

The therapeutic goals of B12 treatment are the reversal of metabolic abnormalities and the prevention or reduction of clinical symptoms.

Treatment depends in part on the severity of symptoms and the cause of the deficiency. In people with symptomatic B12 deficiency despite normal dietary B12 intake, B12 malabsorption is the most likely cause and should guide parenteral therapy.

The key treatment areas are:

Insufficient dietary intake

To prevent deficiency, oral cyanocobalamin supplementation once daily 20-50 mcg or 50-150 mcg is most commonly recommended. In some countries, methyl- and adenosylcobalamin-containing preparations are available; however, one observational study suggests better efficacy with cyanocobalamin than with methylcobalamin.

Exercise caution when using combination preparations to avoid excessive folate or B6 intake.

With advancing age, B12 absorption declines, and a higher supplemental B12 dose may be needed. Yearly monitoring of B12 status and suitable adjustment of the supplementation dose is recommended.

For symptomatic deficiency caused by insufficient dietary intake, intramuscular B12 therapy is usually initiated with the aim of progressing to oral supplements once symptoms have resolved.

Symptomatic deficiency in people with B12 malabsorption

Suggested treatment schemes differ considerably between countries. The British National Formulary (BNF), for example, differentiates the prescription of hydroxocobalamin according to presenting symptoms, e.g, “For neurological involvement, it is advised to administer hydroxocobalamin by intramuscular injection, initially 1 mg once daily on alternate days until no further improvement, then 1 mg every two months.”

In the Netherlands, pharmacotherapeutic guidelines recommend (for the same neurological symptoms or abnormalities) administration of 1000 mcg once or twice weekly for up to two years.

Little robust, reliable evidence supports current recommended dosing schedules, and no clinical studies assess the effectiveness and optimal dosing of intramuscular cobalamin preparations for symptom relief, other than studies assessing attained serum B12 concentrations and sometimes haematological response.

Studies as early as the 1960s reported considerable differences between individuals in pharmacodynamics and dose requirements. Some patients may require a more frequent injection regimen, especially those with neurological symptoms, varying from twice weekly to every two-four weeks to become and remain asymptomatic.

A possible explanation may be the large inter-individual difference in biliary B12 excretion.

More than two-thirds of the B12 excreted in bile is reabsorbed in the small intestine, but this reabsorption is reduced in people with pernicious anaemia or other causes of B12 malabsorption.

Nitrous oxide toxicity

The Association of British Neurologists has recently issued guidance on recognising and managing nitrous oxide toxicity associated with B12 deficiency. It recommends rapid initiation of alternate-day intramuscular hydroxocobalamin therapy, and maintenance of this treatment until all symptoms have resolved or there is no further neurological improvement, with long term B12 therapy depending on the presence of deficiency on presentation, together with total abstinence from the use of nitrous oxide.

How well does B12 therapy work?

Treatment with B12 injections is efficacious in restoring normal metabolism, alleviating symptoms, and reversing haematological and some neurological complications of deficiency.

Anaemia usually resolves within six to eight weeks, but coexisting iron deficiency may be present and need oral iron supplementation and, in severe cases, parenteral iron infusion.

Neurological symptoms may take several months or even years to resolve completely.

Evidence from observational studies suggests that with longer symptom duration and more profound B12 deficiency, the likelihood that neurological symptoms will not completely resolve increases.

People often continue to experience mild neurological symptoms such as poor memory, impaired concentration, and fatigue even after “adequate” B12 replacement (eg, therapy according to the BNF suggested treatment regimen) and many patients report they need additional treatment.

Biomarkers normalise more rapidly than an improvement or reversal of (neurological) symptoms. Additionally, symptoms may reappear without changes in biomarker status.


The BMJ article – Vitamin B12 (Open access)


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