By Dr. Willemina Rietsema
In conjunction with the Pernicious Anaemia Society, The James Lind Alliance conducted a priority setting process for research into the autoimmune condition called Pernicious Anaemia (PA). Of the research questions voted into the top ten by patients and clincicians in the working groups, only one (priority number 1) is about diagnosis. Seven of the top ten priorities are about treatment and follow-up. Perhaps this reflects the fact that people involved in the process had already been diagnosed, and their main concerns were about getting the right treatment.
Diagnosis of B12 deficiency
For the diagnosis of B12 defiency, the NICE guideline published in March 2024 is a big step forward. The guideline contains tables of symptoms and risk factors to alert doctors to the possibility of B12 deficiency. A very important change in the guideline is the interpretation of test results for total B12 and Active B12. In addition to the low values which indicate deficiency, it adds a large ‘intermediate zone’ in which a secondary test may be done to confirm deficiency. Unfortunately, most labs don’t offer these secondary tests yet, due to budget constraints.
Researchers are looking for new, more accurate blood tests for B12 deficiency. Some work has been done on a symptom score for B12 deficiency. Unfortunately both will take many more years to get results to benefit patients.
Diagnosis of Pernicious Anaemia
Determining whether PA (called Autoimmune Gastritis in the NICE guideline1 ) is the cause of B12 deficiency remains difficult. If someone has antibodies against intrinsic factor (IF), this confirms a diagnosis of PA. But only about50%of PA patients are positive for these antibodies. We don’t know the best (and most feasible) way to identify the other half of PA patients. The guideline suggests blood tests for gastrin, antibodies against parietal cells, an absorption test, or gastroscopy (a camera into the stomach) may be considered. However, these are not commonly available for patients in the UK. In practice, it seems best to assume someone has pernicious anaemia (caused by auto-immune gastritis) when [1] other causes of B12 deficiency such as coeliac disease and Crohn’s disease have been excluded, and/or [2] when they or their relatives have other autoimmune conditions, e.g., thyroid disease, vitiligo, Sjögren’s disease or type 1 diabetes.
Treatment for B12 deficiency
Treatment for B12 deficiency is either by injections or by tablets or sublngual tablets. There are also sublingual sprays on the market, and skin patches, even nose drops! There is some ongoing research to find new ways to deliver small daily doses, like the small doses people with normal absorption get from their food.
Some people with PA manage their condition well with tablets or sublingual tablets. Some B12 gets absorbed in the mouth. A study which used toothpaste spiked with B12 showed that B12 blood levels went up after its use. Also, it is thought that about 1% of an oral dose can be absorbed passively, without the need for intrinsic factor and B12 receptors. Therefore, if someone takes 1,000-2,000 microgram tablets, about 10-20 microgram can be absorbed. This may be enough for some patient’s daily needs.
However, it seems that most people need injections to manage their PA well. Patients’ most frequent concern is around how often they get B12 injections. James Lind Alliance Priorities numbers 2 and 5-9 reflect these concerns. The NICE guideline does not make recommendations about the frequency of injections. First, there are no randomised placebo controlled trials (the gold standard in research) that have compared the usual 2- or 3-monthly injections to more frequent injections. Second, dosing is the domain of the BNF (British National Formulary).
There are new insights into why PA patients may need more frequent injections than once every 2 or 3 months. This is because most of the amount injected is excreted by the kidneys within 24 hours. Also, some B12 gets excreted in the bile every day. Most people can reabsorb this in the last 1.5 inch of the small bowel where B12 is absorbed (this is called the terminal ileum). But PA patients cannot reabsorb this, and they lose this amount daily. In this way, the amount injected could be used up within a week in some patients.
My research plans
In the coming four to five years I plan to do further research in the area of frequency of injections for people with B12 deficiency. Research takes many years to do. It starts with planning a good study, applying for (and getting) ethical permission, funding, recruiting participants, doing the study, analysing the results, writing articles and getting them published, then disseminating the results and ideally getting the results into guidelines. I’ll let you know on this page when there are updates on what is happening.
The Pernicious Anaemia Society has a long history of supporting researchers, commissioning topics for study and providing data and information. This costs money. The scientific community often imposes costs even on the publication of papers and if we are to conduct large scale research to credibly move the needle on these important topics we need significant funding. If readers are aware of sources for funding for projects like these then please get in touch with the Society.
1. Statement from the PAS on the Publication of the NICE Guidelines. The Pernicious Anaemia Society do not agree that these names are interchangeable.