Oral (passive) treatment of B12 - Pernicious Anaemi...

Pernicious Anaemia Society

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Oral (passive) treatment of B12

jmc42 profile image

In a recent discussion I noticed an interesting point which I had not picked up.

"I am not sure that .... [it in in the interest of PA patients to assert] that passive absorption is completely impossible in patients who have PA - something which flies in the face of all of the evidence - a whole raft of scientific studies and even testimony from one member of the forum who finds high dose oral works for them and was diagnosed as having PA using the Schilling test. "

I had assumed that if you take oral supplements and that they raise your B12 levels then this rules out PA. I did notice a statement somewhere that there is a Cochrane review which says the evidence about oral treatment of B12 is shaky. This could just mean that for many PA has to be treated by injections where in some cases (not properly researched), oral treatment does work for people with PA and also that people whose levels are raised by oral treatment might still have undiagnosed PA.

The Schilling test has disappeared in the UK. Is there a UK (BMJ or NICE) reference that points out that successful oral B12 treatment doesn't rule out PA?

Note: edited by admin

26 Replies
Gambit62 profile image
Gambit62Administrator

Prior to the invention of the processes which allow injectable B12 to be used to treat patients with PA the treatment was actually a highly concentrated extract of liver. I doubt that liver extract on it2016 s own would have had any IF in it so the mechanism being relied on was passive absorption.

The real point is that there is lots of evidence for passive absorption in patients with all absorption problems and it doesn't require IF. The downside is that it does not seem to work for everyone, so, without further research into why it doesn't work for some but does for others and a way of distinguishing who it works for and who it doesn't before treatment it certainly shouldn't be the first line of treatment

This study from 2003 contained patients that had PA - its a small study but many are.

ncbi.nlm.nih.gov/pmc/articl...

This literature review from 2016 references a number of studies around oral B12 as a treatment strategy so references various studies

ncbi.nlm.nih.gov/pmc/articl...

as does this literature review from 2018

ncbi.nlm.nih.gov/pmc/articl...

PAS-admin profile image
PAS-adminAdministrator

It all depends on what you call successfull...do tablets raise blood values in patients with PA? Yes, in almost all cases (in varying degrees though) Does that make it succesfull? No... I'll quote the latest literaure:

There is no proof in large prospective, double-blind studies that oral supplementation is as effective in reducing symptoms associated with vitamin B12 deficiency as parenteral treatment.

No trial reported on clinical signs and symptoms of vitamin B12 deficiency, health‐related quality of life, or acceptability of the treatment scheme. (Wolffenbuttel, Bruce H R et al. “The Many Faces of Cobalamin (Vitamin B12) Deficiency.” Mayo Clinic proceedings. Innovations, quality & outcomes vol. 3,2 200-214. 27 May. 2019)

Low quality evidence shows oral and IM vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels, but oral treatment costs less. We found very low‐quality evidence that oral vitamin B12 appears as safe as IM vitamin B12. Further trials should conduct better randomisation and blinding procedures, recruit more participants, and provide adequate reporting. Future trials should also measure important outcomes such as the clinical signs and symptoms of vitamin B12 deficiency, health related‐quality of life, socioeconomic effects, and report adverse events adequately, preferably in a primary care setting. Wang, Haiyan et al. “Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.” The Cochrane database of systematic reviews vol. 3,3 CD004655. 15 Mar. 2018,

For some patients tablets also work well regarding symptoms, for a lot (possibly most, but speculation as not researched) it does not.

If you B12 level rises when you take tablets does that rule out PA?

Absolutely NOT!

jmc42 profile image
jmc42 in reply to PAS-admin

thanks for the reply. The problem of successful raising of b12 levels without a PA diagnosis is that it means that one will never get tested for PA.

I guess it depends on symptoms but they are different. I don't suffer from chronic fatigue, but I do suffer from chronic diarrhoea and chronic problems with swelling in the bone marrow clearly linked with B12 deficiency but not understood at all (asfaik). Hopefully oral B12 treatment will help with the bone marrow problems but it isn't going to help with the treatment of chronic diarrhoea which in patients with PA often appears to be linked with low stomach acid - see discussion:

(healthunlocked.com/pasoc/po...)

I have some of the other symptoms of achlorhydria like very brittle nails which means I cannot play a guitar any more but that's not a symptom that would cut any mustard in getting a serum gastrin test which looks like the most reliable test for establishing whether you have PA now that the Schilling test has gone.

PAS-admin profile image
PAS-adminAdministrator in reply to jmc42

Why would the method of treatment stand in the way of the diagnosis? The diagnosis should be done prior to treatment (unless very severe neurological involvement) The problem is looking only at haematogical values in everything B12def/PA and basing conclusions on those values. Tests are all flawed, there is no gold standard test, and that is before treatment. Once treatment has begun there is no need for further testing B12, but you could still try and find the cause, unless it is pretty obvious already (medication, Crohn, bowel surgery etc) Re symptoms: not having some of the symptoms does not mean it's not PA. Achlorhydria does point to PA (to gastritis at least which ca be looked at, unless you know that already as you know you have achlorhydria). You could start by testing (both) antibodies, if the GP is willing. Negative won't rule it out of course but positive will be an almost certain diagnosis. For gastroscopy and gastrin you'll have to go to a gastroenterologist.

jmc42 profile image
jmc42 in reply to PAS-admin

>Why would the method of treatment stand in the way of the diagnosis?

My B12 levels were 201 ng/L in a reference range of 197-711. I was told by one of the GPs that none of the further tests (IFAB, Parietal etc) could be done because I was in the normal range. Now that I've taken oral supplements for 6 months, the levels have raised to 311ng/L there's even less chance of getting them now.

She said that the symptoms of chronic diarrhoea could be down to other issues and be unrelated.

I have always found the distinction between primary care and secondary rather bogus. I would organise a health service into diagnostic services and treatment services. It's reasonable to wait 6 months for an expensive knee replacement costing £15K but having to wait 6 months to get permission for a serum gastrin test that costs the NHS maybe £50 makes no sense to me - the test is a fraction of the cost of the appointment where one gets permission for the test which would be costed at around £250 or more.

PAS-admin profile image
PAS-adminAdministrator in reply to jmc42

I agree, the healthcare system makes no sense..Not sure if testing for antibodies with a 'normal' B12 level is your GP's unwillingness or a general (local) 'rule' but have seen many being tested with same kind of level..you might want to try and ask again? If you have an(other) auto-immune disease or familial PA then that would be good argument as then PA is more likely. And sure, chronic diarrhea could be something else entirely, but should then be investigated (which would get you the referral to the consultant and further testing) Even if the GP would test gastrin and it came back (very) high you'd still need to be seen by a gastroenterologist to have a gastroscopy and further evaluation. If your B12 has only gone up that little in 6 months you either take to little or should take another supplement I think, or you have very clear absorption problems (any cause) which should be looked at as well (esp as then there might also be other deficiencies/if there are other)

jmc42 profile image
jmc42 in reply to PAS-admin

I am taking Solgar B12 100mcg tablets rather than 1mg tablets which might explain why the levels are rising slowly. I also have Vit D malabsorption problems - I take 3*800IU prescription tablets daily to maintain levels in the normal range (just above 50 nmol/L).

The bone marrow disease I have had for 15 years (academic.oup.com/rheumatolo...) is mainly associated with Vit D deficiency but I wouldn't be at all surprised that B12 deficiency plays a part. Dr Harrington's BMJ article (bmj.com/content/349/bmj.g5226) indicates that B12 deficiency is commonly associated with bone marrow problems.

Bone marrow oedema syndrome is the province of Rheumatologists who do not test B12 levels routinely. Dr Patel, the author of the OUP article is currently a Rheumatology consultant at KCH so I might write to him asking how plausible this is. He and Dr Harrington might even know each other via KCL.

It is only in the last 6 months that I have started looking at B12 levels which the NHS dietitian who is looking at the diarrhoea thankfully requested my GP to test - this is how I got alerted me to these problems. Unfortunately she cannot authorise the GE tests I would like - I'll probably get a GE appointment in about 6 months.

Any form of oral b12 has not worked for me. I was disappointed. Tried all sorts of sprays and doses.

I asked an interested neurologist.

He had PA himself.

S

He studied any medicsk papers ge coukd get his hands on.

He had a personal interest abd was not able to cope on the NHS regime even though caught very early.

I trust his readings and judgement.

He was not at all Convined of the so called evidence of a small study.

Alot of whom dud not seem to have ansorbtion issues.

He said a poor study .

Even if yiy can passively or otherwise absorb something it's whether it csn then be used by your body.

I trued to uses all sorts inbetwern Injections to try snd get a bigger gap.

It did not work

J think it's dangerous to try fir too long if yih have clear symltons that if left untreated may not only at best take years to heal or may jnfact leave yiu with a disability.

My daughter being one such casualty.

There is akso evidence I've read on here that once on Injections your body actually needs and relies on a higher level.

Depends on when yiy 'catch it'

My husband had no symptoms or vague at best.

His serum b12 was just below range.

In his case tablets worked ti raises kevejs so his absirbtion had slowed down do not getting enough fro. His b12 rich diet.

He continues to take a low doses b12 daily .

Very few are able to sustain b12 sprays and tablets with the odd b12 Injection .

One on this forum I know of.

So in my understanding an aborbtion problem csn be partial so needs topping up with oral b12 .

I was really hoping to have monthly b12 injections with top ups.

Now my only mission is to get as well as possible.

A scientist, not a medic, and with a fascination in the history of PA diagnosis & treatment.

Pernicious Anaemia, before any treatment became available, was a rapidly fatal condition. When the first practical, if somewhat unpleasant, treatment became available, large quantities of raw/lightly cooked liver had to be ingested. This did deliver a good response in patients who otherwise would have been unlikely to survive a couple of years. Minot, Whipple and Murphy received a well-deserved Nobel Prize in 1934, for this ground-breaking work.

It was believed at the time that there was an 'Extrinsic Factor' in food that was required. (This was eventually given the name Vitamin B12). It was also realised that an 'Intrinsic Factor' was required, and together these formed a 'Haematopoietic Principle'. We're still using the term 'Intrinsic Factor'.

Dr William Bosworth Castle demonstrated the effect of Intrinsic Factor by means of an experiment that would be unlikely to receive ethical approval nowadays. The experiment showed that 'Raw Hamburger Mince treated with Normal Human Gastric Juice' could elicit a response in PA patients. This was in the days when an effective treatment (Raw liver) was available. Castle and his volunteers are heroes of mine!

For those who don't know how the Mince was treated with Gastric Juice, it's a bit gruesome. Castle ingested quantities of raw beef, it sat in his stomach for something like an hour, and then it was aspirated via a naso-gastric tube. This was then fed to (presumably consented) PA patients, and a reticulocyte response was demonstrated, showing that something in the gastric juice made a difference. Raw beef on its own wouldn't have delivered this result.

The early experiments using raw liver [no IF] showed a response, presumably because of a large quantity of (extrinsic) B12. This worked on patients with PA.

Various other studies have shown that massive doses of B12 can result in a sustained response, even in patients with IF antibodies, but this doesn't seem to work for every case, and the 'alternative pathway' for absorption of B12 isn't clearly understood either.

If I was faced with the choice of regular B12 injections, or daily tablets, to give the same response, personally I'd take the tablets. That would be a personal choice based on sound medical advice and evidence. The 'tablet' approach only became possible once B12 was being produced in 'industrial quantities'. I know this is contentious, but it has been shown to work in some cases.

Cherylclaire profile image
CherylclaireForum Support in reply to FlipperTD

"It has been shown to work in some cases" - not quite enough science there for me to ditch regular injections in favour of tablets and risk having to relive the past five years !

Everyone here would take the tablets over injecting "to give the same response" - the trouble is that, as has become evident lately from posts here, some GPs are not taking a patient's response into consideration and are using serum numbers only as confirmation. This leaves a patient whose symptoms are unresponsive one option : to continue to deteriorate for a second time to the point of "below range" - in order to prove that the successful original treatment should be reinstated.

But who in their right minds would want to do that ?

Certainly not Nackapan 's consultant !

jmc42 profile image
jmc42 in reply to Cherylclaire

The academic studies posted by Gambit62 above are very "numbers" orientated. They don't correlate increasing B12 levels with decreasing levels of chronic fatigue.

On the other hand doing a statistically meaningful study driven by the symptoms rather than the numbers is very expensive without a national patient records system. Finding say 300 patients who have fatigue caused by PA rather than by Thyroid disease is currently an expensive process. I volunteer as an NIHR reviewer of clinical trials and typically an administrative trial that recruits 300 patients to run over 3 years costs £1M; by "administrative", I mean a trial that is not attempting to develop a new drug but is just seeing how effective an existing drug (e.g. oral B12) is.

Clinical trials will remain incredibly expensive until we get a national patient records system. The NHS App is the current way forward but faces massive technical (and political) challenges.

There are dozens of small charities like the PA Society, Lupus UK, Thyroid UK all funding quite small scale research in their own way. It would be much better if they all combined together with the cancer charities who have massive budgets and went to talk to the DOH about getting an effective national patient records system that all charities can use to do much cheaper patient driven research.

Cherylclaire profile image
CherylclaireForum Support in reply to jmc42

Numbers orientated ?Well not really true of the first link about a research study from 2003 where, of those involved, only 10 had PA - and of these 10, no-one knows how many completed the study.

Perhaps the other links will prove more fruitful.

Gambit did also say that tablets do not work for everyone, and that this would require further research.

PA-admin has pointedly quoted "no proof.." , "no trial..." and "very low quality evidence..."

When cost of research gets mentioned, I try to imagine what I have cost the NHS since 2016 in consultations alone, which include several appointments with each of the following -gastroenterology, neurology, haematology, dietitian, ENT, oral medicine, metabolics, rheumatology. Add on the tests, scans, physios, nurses etc etc .....then add the cost to me personally.

Not just fatigue involved here - which raises something else: why are clear and specific symptoms, known about by so many with PA/B12 def, completely ignored as significant pointers by these consultants ?

Take, for just one example, the yawns (sighs) -that are of a type that do not seem to exist elsewhere as part of any other condition. No, not everyone gets them, but wouldn't this set off alarm bells or recollections of previous patients, sufficient to explore a patient's family history, perhaps looking for autoimmune problems etc. ? An earlier start along a road to answers might cost the NHS less, might cut out a few years of suffering for patients, and may not have cost me my career.

Why did I choose, of all the many symptoms, this one ? Because I have had the yawns (sighs) in just about every one of the waiting rooms for all of the appointments mentioned. Hours spent on the underground and then in small crowded rooms, uncomfortably upright chairs, often with no open windows.

Air hunger.

Dear Cherylclaire

I write as a scientist, not a medic.

Likewise, I do not suffer from a deficiency of B12, so in many respects I'm an interested outsider.

The first effective treatment for PA involved giving oral B12 with no intrinsic factor, (raw liver) and patients survived. A Nobel Prize was awarded in 1934 for this finding.

Your observation that 'It has been shown to work in some cases' isn't enough science for you. There is abundant evidence 'out there' in published, peer-reviewed journals that gives enough evidence that the oral route can work. (Minot, Murphy and Whipple demonstrated that about a hundred years ago.)

There is plenty of evidence from a variety of sources that high dose oral B12 can work despite the lack of intrinsic factor. It can be found easily via Google, for a start.

Your assumption that 'everyone here would take the tablets over injecting' is, I hope, based on patient data rather than assumptions. (If not, then you might just be surprised!)

I know one clinician who took the view that, once diagnosed, regular injections 'for life' was the way forward because it was an effective treatment. Likewise, regular injections assured compliance with the therapy, because 'elderly patients might not comply with the tablets.' (His view, not mine.)

I believe that in Sweden, the oral route was adopted a long time ago.

I hope this helps!

Cherylclaire profile image
CherylclaireForum Support in reply to FlipperTD

There are a number of research papers that I could (and probably have) read both for and against high dose oral B12. I am familiar with Google too.In any case, for many, high dose oral B12 was not what was offered. Not during the pandemic and not since.

My assumption that everyone here would rather take the tablets over injecting IF it gave the same response comes from here. I read the posts and replies here every day.

Most people don't particularly like injections. Does that make you wonder why so many of them self-inject ? It should do.

The viewpoint of one clinician you know holds no more weight than my saying that Nackapan's neurologist needs more injections than the NHS will give him.

It is true - but it's not research and it's certainly not science.

Thank you for your response. I have seen numerous disturbing reports of patients who have been switched to oral B12 during this pandemic, and I'm appalled.

I don't have details of the dosages offered, but I am sure you're correct that the dose would have been inadequate, as the typical high dose oral regime would be at least 1 milligram per day.

Your assumption regarding injections is probably correct, but short of hard data, it's an assumption. It is hard to imagine why anyone would choose injections ratherthan daily tablets, but we're all different and I wouldn't presume that they all agreed with me. I have experience of clinical trials in other areas, in what would be considered 'Cinderella Conditions' and I learned a great deal from them, but that's another story entirely and way beyond the scope of this forum.

Properly organised, ethically approved clinical trials are both expensive to conduct and difficult to perform. It would be difficult to argue that when a condition which has a very effective treatment, (as in parenteral vitamin B12 therapy), then it's unlikely to get support. A major new study of the efficacy of high dose oral B12 therapy compared to injection would be a low priority given the other pressures faced. This is yet another case of a 'Cinderella Condition' which should get more resources, and it's good that this forum exists.

Nackapan profile image
Nackapan in reply to FlipperTD

Yes my personal choice would be tablets too.

As in everyone I guess.

I remember my husband given a trial of tablets for diabetes ax he was ovef 30 and seemed less likely to be type one.

When his blood sugar remained sf 30 he waz admitted to hospital and put on a insulin pump. Monitored for organ failure and response to treatment.

I wonder if that is facility there if b12 tablets don't work. ?

There are so many theories with oral b12.

.

It only seems to work well enough if lacking in your diet.

Or with age abdorbtion slows then all of all nutrients need topping up.

I'm very grateful b12 injections were found the most efficient way to treat you.

As we all know thd sooner the treatment the better the outcome.

Give my GP her due ,she only got me to trial b12 tablets to see if j coukd have fewer injections .

Even with her honesty with lack of knowledge on b12 deficiency and the devastating consequences she was not willing to give me b12 tablets at the start.

So shown to work in some cases

Is a dangerous pursuit for a possible lifelong disability if you are not one of those it works for.

'the some cases'

That's why it's response to treatment that is vital.

Hyperthetical theories okay if well and not affected.

I dispute 'sound medical advice and evidence' to have b12 tablets

I think its more than contentious it's actually insulting to insinuate anyone woukd rather have b12 injections than a tablet .

I agree research is needed.

I'm not sure if the new trend on this forum pushing oral b12 as a solution.

We have enough of that ftom ill nformed Gps

Especislly in thd covid pandemic.

So not quite sure why that reply ?????

FlipperTD profile image
FlipperTD in reply to Nackapan

We are all different.

You and I would expect that oral B12 would be preferable to injections if it worked reliably and consistently. It would be reasonable to expect others to have the same view as us, but that might be a mistake.

The 'old regime' of one injection every few weeks might be seen as simpler by those prescribing, than one tablet each day, but if we don't ask the patient, then we won't know, will we?

😀

Cherylclaire profile image
CherylclaireForum Support in reply to FlipperTD

....It's not going down too well so far with these patients, is it ?

I'm trying to help!

PA is a dreadful but eminently treatable condition, and different approaches have been taken in different countries. This forum [I believe] is there to inform interested individuals, and I applaud its existence for that purpose, and also to give them a chance to be heard.

If I'm mistaken in these assumptions, it might be better if I kept quiet.

Cheers.

😀

Cherylclaire profile image
CherylclaireForum Support in reply to FlipperTD

Natural to be a little wary of something foisted on you without consultation during a pandemic, especially when no-one is around to monitor outcomes though, no ? Then having to be 'sufficiently deficient' to be allowed previously successful treatment to get reinstated later on really takes this to another level.

Cherylclaire profile image
CherylclaireForum Support in reply to FlipperTD

Different approaches have been taken in different counties.

jmc42 profile image
jmc42 in reply to Nackapan

>I'm not sure if the new trend on this forum pushing oral b12 as a solution.

That was not my intention when posting the question.

The research study by the GP practice in Birmingham is imo very weak indeed. It should not have been published or authorised.

It would have been far better to have given the PA Society the money wasted to conduct the study itself.

Oral b12 does not get into your system if you have pa it’s like impossible. We are missing th enzyme that helps the body take in the b12. The only way it’s works for us is with injections!! Why do people not know this?

charks profile image
charks in reply to Pretty55

People don't know this because it is untrue. Please don't give false information.

Hi,

Some links relating to oral treatment for B12 deficiency

These suggest the evidence that oral B12 treatment is as effective as IM injections is of low quality.

cochrane.org/CD004655/ENDOC...

pubmed.ncbi.nlm.nih.gov/295...

smw.ch/article/doi/smw.2017...

ncbi.nlm.nih.gov/pmc/articl...

In the interests of fairness, this is an article that suggests oral B12 treatment is effective.

bmjopen.bmj.com/content/10/...

However I can't find details of what the patients B12 deficiency was caused by...could have been dietary.

PAS news item on Oral Tablets

pernicious-anaemia-society....

Link aimed at health professionals about oral B12 available in UK.

sps.nhs.uk/wp-content/uploa...

Mentions a 1mg oral cyanocobalamin tablet available to prescribe in UK from May/June 2020

Responses to BMJ article on PA

bmj.com/content/369/bmj.m13...

Oral treatment is discussed.

I found the 7th response from 11th May 2020 concerning.

I think there is likely to be more emphasis in UK on moving more patients currently receiving B12 injections onto oral tablets over next few years .... although it is sometimes promoted as easier for the patient, my feeling is that a move towards oral treatment is more likely to be due to it being cheaper.

The UK area mentioned in blog post below has a flowchart in their guidelines that suggests most patients should be on oral treatment.

b12deficiency.info/blog/202...

I suggest UK forum members keep an eye on the local guidelines for their CCG/Health Board as they are reviewed every few years.

I am not medically trained.

I'd like to add a question to this thread:

Take the example of someone who is low in B12 and has symptoms.

If they receive injections, their B12 will rise very quickly (especially if a properly scheduled loading regime).

If they receive oral B12, even very high dose, their B12 will, I suspect, rise less quickly.

Therefore the injection route would likely be faster to arrest any possibility of further damage even if, long term, the person would do fine on oral.

Further, if they do NOT absorb acceptably on oral B12, they will continue to deteriorate until that is recognised and they are switched to injections. Causing further possibly irreparable damage.

On these grounds, surely the only possible decision is to prescribe injections?

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