Vitamin B12 deficiency – time for a rethink?

Traditional view

NHS Choices offers a traditional view of vitamin B12 metabolism and diagnosis and management of vitamin B12 deficiency anaemia.

An up to date review was published recently link

Vitamin B12 deficiency anaemia or folate deficiency anaemia develops when a lack of vitamin B12 or folate causes the body to produce abnormally large red blood cells that cannot function properly.

The main symptoms of vitamin B12 deficiency or folate deficiency anaemia are:

• tiredness
• lethargy (lack of energy)

View from special interest group(s)

Conversations with members from Pernicious Anaemia Society and B12 deficiency support group indicate there is more to the cobalamin metabolism story than the traditional view describes.

Recent articles and abstracts scattered through the scientific literature point to a more sinister effect on human biology when there is functional deficiency of B12.

• Functional vitamin B12 deficiency may occur at any serum level of vitamin B12 [link]
• Vitamin B12 Deficiency Associated With Concomitant Metformin and Proton Pump Inhibitor Use [doi: 10.2337/dc12-0980Diabetes Care December 2012vol. 35 no. 12 e84]
• Metabolic Globus Pallidus Stroke in Transcobalamin II Deficiency. [JIMD Rep. 2013 Feb 21]
• Adenosylcobalamin essential cofactor for part of the Krebs Cycle, the key energy generator for cellular respiration by mitochondria. Details recently summarised by Hugo Minney at B12D

Adenosylcobalamine, the adenosyl form of Vitamin B12, is needed to keep the TCA cycle running smoothly, and many people with B12 deficiency suffer a “dreadful fatigue”. But it’s a complicated process getting B12 into mitochondria, and an awful lot of things can go wrong.

A key to better understanding is awareness of biochemical reactions in which vitamin B12 is a crucial. These include [link]:

• conversion of odd chain fatty acids (specifically propionate) into succinate
• conversion of homocysteine into methionine via methyl group donation

Medically Unexplained Symptoms – is this a B12 deficiency syndrome?

This week it was proposed that any patient with medically unexplained symptoms should be referred for CBT. It was estimated this may save the NHS £3 million per year. No mention by the authors of the report to explicitly exclude functional deficiency of vitamin B12 [Advances in Psychiatric Treatment (2009)15: 146-151doi:10.1192/apt.bp.107.004606]

Do not forget magnesium deficiency – it is important to ensure magnesium levels are normal in any patient who is taking high dose proton pump inhibitor especially if also prescribed a diuretic agent.

The neuropsychiatric changes caused by functional B12 deficiency may predate the typical changes seen in the blood by months (perhaps years). These are detailed by MacDonald Holmes [JMD Holmes – British Medical Journal, 1956].

McAlpine (1929) said, ” Mental changes occur not uncommonly in pernicious anaemia. They range from states of depression accompanied by loss of mental energy to definite psychoses…” [McAlpine, D. (1929). Lancet, 2. 643]

When there is doubt about the status of vitamin B12 rather than repeat the test in 6 weeks in “borderline cases” as is the present practice, serum methylmalonic acid levels and serum homocysteine levels should be measured.

Measurement of methylmalonic acid, total homocysteine, or both is useful in making the diagnosis of vitamin B12 deficiency in patients who have not received treatment. The levels of both methylmalonic acid and total homocysteine are markedly elevated in the vast majority (>98%) of patients with clinical B12 deficiency including those who have only neurologic manifestations of deficiency (i.e., no anemia). [Stabler, S NEJM 2013]

Implications for general practice

Clearly there is a need to review how we view vitamin B12 metabolism. Recognition in primary care of functional deficiency of vitamin B12 will require medical curricula to pay better attention to this. Haematology does not have a monopoly on clinical features of vitamin B12. There are too few haematologists and neurologists, at least in the UK to provide clinical opinions when vitamin B12 deficiency is suspected. This leaves it to general practice and family doctors to learn more about the protean manifestations of altered vitamin B12 metabolism.

With performance managed healthcare becoming the norm around the world, it may be time to press for explicit scrutiny of vitamin B12 levels in patients with long term conditions including many in the following systems: gastrointestinal, hepatic, psychiatric, neurological, endocrine, renal, and non-malignant anaemias. Only then might we be certain that a scourge of (modern) society will be beaten.

David Lewis

GP UK

Acknowledgement

I would like to thank @b12unme for educating me about this issue. Any errors and omissions are mine.