BMJ article 9/5/20

[spacey1]

This month's BMJ has an interesting article about PA. Three pages of what it is, why it gets missed, why that matters and how to manage it! I was really impressed!

Hopefully that will have landed on the desks of all our UK GPs 🙂

[fbirder]

Can't read the paper (not without splashing out £30) but the responses aren't encouraging - bmj.com/content/369/bmj.m13...

One says:

I would like to congratulate the authors for this review of current practice in pernicious anaemia and in particular to acknowledge the evidence for oral supplementation.

The other current relevant factor is that with COVID19 social distancing guidelines it is an ideal time to switch patients on 3 monthly injections to oral supplements, saving nurse appointments and reducing risk of covid19 transmission.

Then there is one from a member of the PAS, which includes:

I and many other PA patients with neurological symptoms would be very grateful if the authors could cite the clinical studies on which the two month injection interval was derived.

[carer999]

Is this the article "EASILY MISSED? Pernicious anaemia " in the education supplement part of the BMJ 9 May 2020.

bmj.com/bmj/section-pdf/102...

One concerning part towards the end of the article is:

" Patients with pernicious anaemia require lifelong cobalamin supplementation. Intramuscular vitamin B12 injections are typically recommended. Box 2 lists the treatment regimen recommended by the British National Formulary. Oral cobalamin therapy with high dose (1000-2000 μg) pills taken daily is shown to have similar efficacy in improving symptoms and haematological parameters of B12 deficiency in small studies. However, it is not preferred for initial treatment of patients with severe symptoms because of the possibility of slower response compared with intramuscular injection. Oral therapy may be used for long term maintenance treatment. "

Another nail in the coffin for injections as this document can be used by doctors as part of their "Continuing Professional Development Programme" which they have to do.

[fbirder in reply to carer999]

Well soptted.

[carer999]

Also worryingly are these comments to the original article especially where one surgery tested B12 on patients receiving injections and deciding not required. I have copied the responses I was able to see for anyone interested. Hopefully I have removed any personal identifiers

Response1

Dear Editor

I would like to congratulate the authors for this review of current practice in pernicious anaemia and in particular to acknowledge the evidence for oral supplementation. In my own GP practice , we have offered patients the choice or oral or injection therapy since 2007 and found that the majority of patients preferred an oral route both for convenience and avoidance of an injection that is sometimes quite painful.

There were studies in the 1950s and the1960s that showed that oral vitamin B12 could be absorbed by patients with pernicious anaemia and could lead to resolution of the anaemia (1,2). Passive diffusion of B12 where there is absence of intrinsic accounts for about 1% of total absorption, and this route of absorption is unaffected in patients with pernicious anaemia but needs high doses so that it is effective.

The other current relevant factor is that with COVID19 social distancing guidelines it is an ideal time to switch patients on 3 monthly injections to oral supplements, saving nurse appointments and reducing risk of covid19 transmission.

1. Meyer LM, Sawitsky A, Cohen BS, Krim M, Fadem R. Oral treatment of pernicious anemia with vitamin B12. Am J Med Sci (1950) 220(6):604–9.10.1097/00000441-195022060-00002

2. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand (1968) 184(4):247–58.10.1111/j.0954-6820.1968.tb02452.x

3. Chan et all Frontiers in Medicine accessed online on 25th may 2019. ncbi.nlm.nih.gov/pmc/articl...

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Response2

Re: Pernicious anaemia maintenance treatment

Dear Editor

I am a member of the Pernicious Anaemia Society [1] which is based in the UK, but has members all over the world.

In Box 2 (Treatment regimen for vitamin B12 deficiency) the authors state without reference that maintenance treatment of pernicious anaemia (PA) in patients with neurological symptoms is intramuscular injection of 1 mg hydroxocobalamin every two months. Many PA patients, however, find that they require injections more frequently to keep their symptoms suppressed [2].

I and many other PA patients with neurological symptoms would be very grateful if the authors could cite the clinical studies on which the two month injection interval was derived.

1. pernicious-anaemia-society....

2. Hooper et al. Patient journeys: diagnosis and treatment of pernicious anaemia. Br J Nurs. 23(7):376-81. 2014.

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Response3

Re: Pernicious anaemia

Dear Editor

We read the article with great interest. We would like to add a few points:

Macro-ovalocytes, Macrocytosis, poly-sygmented neutrophils with neurological symptoms are a clear giveaway of pernicious anemia. (1)

Intrinsic factor is just one of several etiologies of pernicious anemia. Pernicious anemia can exist without Intrinsic deficiency. (2)

The neurological symptoms in B12 deficiency are so broad that ANY neurological deficiency can exist in pernicious anemia.

B12 deficiency might co-exist with iron deficiency anemia, hence giving an erroneous microcyctosis instead of macrocyctosis. (3)

1. Voukelatou, P., Vrettos, I. and Kalliakmanis, A., 2016. Neurologic symptoms as the only manifestation of B12 deficiency in a young patient with normal hematocrit, MCV, peripheral blood smear and homocysteine levels. Oxford medical case reports, 2016(12), p.omw091.

2. Berlin, H., Berlin, R. and Brante, G., 1968. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Medica Scandinavica, 184(1‐6), pp.247-258.

3. Lagarde, S., Jovenin, N., Diebold, M.D., Jaussaud, R., Cahn, V., Bertin, E., Jolly, D., Thiéfin, G. and Cadiot, G., 2006. Is there any relationship between pernicious anemia and iron deficiency?. Gastroentérologie clinique et biologique, 30(11), pp.1245-1249.

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Response4

Pernicious anaemia. Easily over-diagnosed? Increasing unnecessarily workload?

Dear Editor

The article by Mohamed et al [1] clearly raises awareness about the need to diagnose pernicious anaemia (PA), but fails to alert practitioners about one important issue, over-diagnosis and its consequences.

Two years ago, we reviewed the matter in our practices, collaboratively. We were concerned about patients not tested (no record of Intrinsic Factor (IF)) before the diagnosis was coded in the records. Audits were carried out to identify patients with the diagnosis and if the IF result was not available on the electronic health records they were re-tested when they came for their next B12 injection (just before, to avoid unequivocal results). All patients were treated with injectable B12.

Between the two practices, there were seventy-five patients initially identified with a diagnosis of pernicious anaemia (fifty one cases in one practice and twenty four in the other). After testing, diagnosis was confirmed in just twenty-three cases.

The reduction of fifty-two patients needing three-monthly injections (some requiring visits) reduced the number of appointments needed in a year by 156 in our two practices.

A different matter still controversial is whether PA treatment should be via injectable or oral supplementation. Inappropriate B12 therapy is unfortunately common [2]. Reasonable alternatives like starting the patient with oral B12 and monitoring adequacy before switching to injectable treatment [3] are not common practice even though it would reduce discomfort to patients and free time to clinical staff to treat others.

It is paramount to diagnose these patients, but to do so properly; so adequate and efficient management is implemented.

References

1. Mohamed, M., Thio, J., Thomas, R.S. and Phillips, J.P. Pernicious anaemia. BMJ, 2020; 369 doi: doi.org/10.1136/bmj.m1319

2. Silverstein WK, Lin Y, Dharma C, Croxford R, Cheung M. Appropriateness of B12 Administration in a Real-World Population. Blood. 2018 Nov 29;132(Supplement 1):2227. doi: doi.org/10.1182/blood-2018-...

3. Butler CC, Vidal-Alaball J, Cannings-John R, McCaddon A, Hood K, Papaioannou A, Mcdowell I, Goringe A. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials. Family practice. 2006 Jun 1;23(3):279-85. doi: doi.org/10.1093/fampra/cml008

[spacey1]

So interesting. I read the paper copy, so didn't see the comments.

Although the article repeats the usual 2 month / 3 month plan, it does clearly state injections in that main 'treatment regimen' box. Interestingly, it also points to antibody negative PA as a likely diagnosis, which in my experience is a hard one to get!

The management section does refer to oral treatment as maintenance, and also to possible poor adherence to treatment. Honestly, how many people with low b12 would poorly adhere to their treatment?!

[Sleepybunny]

Hi,

I find response 4 particularly scary.

It appears they set out to try to get as many as possible off B12 injections and were boasting about how many appointments they'd saved.

What about the poor patients with Antibody Negative PA or with some other cause of B12 deficiency symptoms who have had their treatment stopped?

There is nothing in their response about whether they told patients whose injections they stopped to contact the surgery if they became symptomatic for b12 deficiency.

I bet a few months down the line and they will be inundated with patients with neurological symptoms.

I'd love to speak to the patients whose injections were stopped to ask them what they thought.

Can anyone comment on the article or do you have to be medically trained?

[Cherylclaire Forum Support in reply to Sleepybunny]

Me too Sleepybunny !

If IFab test was used to undiagnose PA status, and I'm assuming that it was in this surgery, why ? It won't always give the same result - and this is precisely why it has been discredited to such an extent that an AbNegPA diagnosis exists, whether it is ever implemented or not.

Martyn Hooper (founder of PAS) was tested 3 times before a positive result occurred. If he was tested again, he could easily become one of these patients with a negative result ! Would this mean his disability registration would be revoked ?

The crowing over money-saving and the lack of honesty and care for long-term patients is quite the opposite of what you would wish to see in the NHS. No mention at all of any treatment alternative offered to those who "failed" this underhanded testing- or any wish to discover what condition, if not PA, all these patients are suffering from.

Or are they all just "cured" now ? Of course, that would cost far less than sending them on a further round of consultants, scans, tests etc. - which might offset the gains made by freeing up the nurse for 5 minutes every 3 months !

NOTE: "If the IF diagnosis was not available on the electronic health records" is a far cry from "never been tested" - so please everyone , keep copies of all your results.

[fbirder]

More responses:

A good reminder about the pointlessness of measuring B12 after injections:

This educational article is a good overview of Pernicious Anaemia.

However in the section on "How is PA managed" the Australian authors state that regular monitoring of B12 levels is necessary. This is against usual practice in the UK and most haematology labs that I have assesed for the UK accrediation Service state in their lab user guides that this is not required as the level will always by way above the normal range for serum cobalamin. It may be occasionally required if it is unclear if adequate treatment has been given or in the case of oral supplementation which is not usually recommended in a confirmed case.

A doctor with PA who needs injections more often than every 2 months!

The review article on Pernicious Anaemia (PA) by Mohamed et al (BMJ 9 May 2020) is most welcome and explains the varied presentation and diagnostic difficulties well. I speak as a physician, now retired, who has had PA for 28 years. With regard to treatment, they repeat the standard guidance that maintenance treatment for patients without neurological symptoms should be 1000 microg hydroxocobalamin once every 3 months, and for those with neurological symptoms once every 2 months. However, some patients, myself included, become symptomatic before the next dose is due. In my case the symptoms generally appear about 5-6 weeks after a dose and consist of glossitis, aphthous mouth ulcers and taste disturbance. These symptoms vanish within 48 hours of a dose. In other patients the symptoms may differ. I have always self-administered my injection, and so, for many years, I have taken it once a month. The drug is inexpensive, and there are no side effects from excessive dosage. The main cost is in the nurse’s time to administer it. Maintenance treatment should be given according to the guide lines or sooner if symptoms occur.

There is, I think, a widespread view, which I myself shared before I was diagnosed, that PA is a haematological disorder, and if a patient has a normal blood count all is well. (No doubt this arises from the name given to the condition). This is far from true. It is a multisystem disease, and non-haematological systems are often affected.

I have heard from the Chair of the Pernicious Anaemia Society (Personal Communication) that, during the Covid19 crisis, many patients with PA are being advised by their doctors that their maintenance treatment can be put off until the lockdown is over. This practice will expose many patients to the risk, not only of unpleasant and avoidable symptoms, but also to the risk of neurological damage that could become irreversible.

There is a good case for patients being taught to manage this chronic condition themselves, as do diabetic and asthmatic patients. Intramuscular injections are of course painful, and some patients are squeamish about injecting themselves. As far as I know the efficacy of administering hydroxocobalamin subcutaneously has not been investigated. If this was effective, it would be more acceptable to patients, and more suited to self-administration.

This last one may be useful for people to show their own GP. So here is the URL for that particular response. bmj.com/content/369/bmj.m13... I suggest printing it out and sending it, with a covering letter to any GP that suggest you would be killing yourself if you inject more frequently.

[Cherylclaire Forum Support in reply to fbirder]

Good find.

I'm sure that this will provide useful information for the many people here who are struggling to get GPs to acknowledge the severity of B12 deficiency - whether the cause be diagnosed PA or not (yet?).