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.
Thank you for this update. There is certainly not enough research into PA so any that is done is all good news.
I do wish however there was more attention drawn to the necessity of regular endoscopies, so important.
My only diagnosis has been strongly positive for parietal cell antibodies, the doctors laboratory refused to do an intrinsic factor antibody test as it is the parietal cells that produce intrinsic factor. Both tests should be undertaken on initial presentation with symptoms. Clearly both the serum B12 and active B12 blood tests are not fit for purpose and should be withdrawn as misleading. Mine run at 2000 (total) and above 150 (active) and bear no resemblance to what I take/inject or utilise. I undertook a micro biome test with Cerascreen and I do have groups of bacteria missing probably due to antibiotic use in the past. It must be taught more about bacteria – how some produce B12 and others utilise it. The other thing that doctors seem blissfully unaware of is adrenaline production and how methylcobalamin is necessary for it and hence periods of stress lead to a depletion of B12 and hence for anyone with low B12 stores or intake will lead to a period of depression. It’s basic knowledge that has been known for many years but simply seems to be “forgotten”! No scientific information seems to be available for how B12 is stored in the liver and why my liver storage seems to not be working. Also no knowledge seems to be available as to how hydroxocobalamin provides methyl groups and why methylcobalamin is not licensed and commissioned by the Health authorities as its obvious that it should be. I clearly do absorb sublingual methylcobalamin both orally and in the bowel as when I stop taking it symptoms return. I need it alongside my injections and have been buying my own since 2008. We do not have a health service in this country as it is unable to provide one of the body’s major vitamins to patients. Drugs such as antidepressants have severe side effects because they simply do not do what methylcobalamin does. Also homocysteine testing should be offered instead of cholesterol testing. It is the flexibility of arteries that matters not the amount of cholesterol. B12 lowers homocysteine and it is the thyroid hormone T3 that regulates uptake as well.
There is all the talk about the treatment for PAS but no talk about why our bodies are not absorbing B12 I understand people who’s diet is restricted by the way they wish to live but when we eat a normal diet why do we have these problems
I have b12 injections every 2 months and also take b12 tablets. I have the most horrific neuropathy. I was diagnosed with positive pareital antibodies 14 years ago and, I believe, my neuropathy has slowly crept up on me since then. I haven’t the faintest idea what to do.
Sylvia this is what happened to me. The neuropathy started slowly in my feet and progressed quite quickly to both feet and lower legs and fingers. After a 2 1/2 yr fight with my GP’s and 2 different neurologists, whole body MRI’s, nerve conduction studies, etc they finally agreed with me that it was my lack of B12 (I have PA and hypothyroiditis since 2005 and 2008) I was finally allowed to self inject every 3 weeks. The improvements were amazing and ongoing and I am now increasing the intervals to 4 weekly between injections, as I am almost back to normal now. It has taken nearly a year on 3 weekly injections and I don’t suppose my symptoms will completely go, but I’ll take that. All I can say is prepare to fight for what you believe, go armed with PAS documentation and don’t take no for an answer. Good luck.
I am thrilled there is research on PA going on now. I really want to see more effective treatment. I take B-12 injections every four weeks. However by the third week my fatigue is raging. I was diagnosed with PA 24 years ago and still other doctors will look at me like I’m making it up when I say I take B-12 for PA. So with your research hopefully this will bring PA to the forefront. Even over here in United States. Lol.