CONUNDRUM

[Chenders]

Hello, this is my first post. Here's a conundrum. Can anyone out there please help out? A 22 year old patient who last month tested positive for intrinsic factor antibodies in keeping with pernicious anaemia has remained symptomatic for B12 deficiency despite 7 months of oral cyanocobalamin 50 mcg per day and last month her blood tests demonstrated NORMAL active B12 (Holo-TC) and methylmalonic acid (MMA), but slightly raised total homocysteine (tHcy).

Her ongoing symptoms, which are typical of B12 deficiency, include depression, anxiety, brain fog, memory problems, headache, pain in her lower back and legs, sensitive tongue, bruising, extreme foot sensitivity, chronic urinary symptoms including cystitis, mouth ulcers, extreme fatigue.

Her total serum B12 responded following oral cyanocobalamin 50 mcg daily (together with 5mg folate daily) initiated by her GP in November 2020 by increasing from a low level of 201 ng/L back in December 2020 to 293 ng/L 2 months later and then a further marginal increase to 329 ng/L last month (normal range 211-911), that is after 7 months of oral cyanocobalamin (admittedly not a great increase in total serum B12 - she was still in the lower half of the 'normal' range for total serum B12). Last month further blood testing revealed that her active B12 (Holo-TC) was 137 (normal), MMA was 105 (also normal) and tHcy was 15.2 (slightly elevated). They were not measured at baseline (7-months ago) - i.e. prior to initiation of oral cyanocobalamin and folate.

I wonder, given the continuation of her severe symptoms and in spite of her now normal blood values of active B12 and MMA, could this patient STILL be B12 tissue deficient and if so, by what possible biochemical mechanism? A full spine MRI was normal. All other blood values including MCV were within the normal range when tested in December 2020 . A head MRI is now being considered.

A haematologist who recently reviewed the patient's blood results has concluded that since her active B12 is in the normal range there is no requirement for B12 loading, but there may be a place for 3 monthly B12 intramuscular supplementation which could either commence in the next 3 months or else it would be reasonable to take an annual active B12 test (Holo-TC) and commence im injection according to if and when active B12 is trending downward.

This is a quite reasonable and rational response to the blood data but this of course accepts the (unsatisfactory) status quo and essentially ignores her ongoing clinical symptoms. Recent reviews of B12 deficiency advise that in the event of any discordance between symptoms and laboratory results to rely on the symptoms. The BSH Guidelines state that the clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status since there is no 'gold standard test to define deficiency

I should be very grateful for any comments regarding this apparent discrepancy between ongoing symptoms and normal Holo-TC and normal MMA. At the end of the day should she be treated conservatively as advised by the Haematologist, or else more aggressively e.g. by alternate days of intramuscular B12? i.e. essentially ignoring the normal Active B12 and MMA blood results. Personally, (given that we now know that she has pernicious anaemia from last month's positive Intrinsic Factor antibody test), I would prefer to see a trial of intramuscular hydroxocobalamin given every other day to see whether or not her symptoms respond and if they do then continuing until there is no further neurological improvement, But what do you think?

Thank you VERY much for your patience in reading and considering this. All contributions most gratefully received.

R.

[Nackapan]

Is there a reason you are talking in the third person?

I think you've answered your own question 🤔

[Chenders in reply to Nackapan]

The patient is my daughter.

[Nackapan in reply to Chenders]

I woukd go for the trial of Injections and see her response.My daughter was undiagnosed for too many years abd has permanent damage .

[Chenders in reply to Nackapan]

Very sorry to hear that Nackapan. Will do!

[Hidden]

It is likely that the person you are referring to has PA. The positive IF test and the borderline homocysteine are indicative of this. The increase in B12 through tablets is small and crucially isn’t improving symptoms. Insist on injections or otherwise ask for a second opinion.

[Chenders in reply to Hidden]

Thank you very much Martin 2812 - the problem is that the GP is most likely to take the Haematologist's view as the second opinion which says she should have only 3 monthly intramuscular injections because she is already loaded on the basis of the Holo-TC and MMA tests. Incidentally, she was on Vitamin B6 for a month to stimulate hair growth and stopped a week before her homocysteine blood test. But B6 is known to reduce blood homocysteine levels.

[prillyb12]

You might consider listening to a medical lecture and also having DNA testing done to see if she has the MTHFR variants, which are common. Here is the link to the lecture. It's for drs treating problem patients. youtu.be/QRHif2aVPvw(Not working as expected?)

[Chenders in reply to prillyb12]

Lovely PrillyB12 thank you very much for this I will certainly watch it. I did consider genetics but I reasoned that because she has tested positive for antibodies to intrinsic factor then that proved it was an auto-immune attack on the parietal cells that produce the intrinsic factor, rather than being genetic in origin. Because if it was purely genetic then there would be no antibodies. Is that correct? Are you or someone reading this able to enlighten me on that important point please? Because I know nothing about the genetics of intrinsic factor and your link will also be an excellent starting point.

[prillyb12 in reply to Chenders]

The human body is complicated. B-12 is about methylation and that is a cycle that effects many things that go on in the body. The dr starts out by saying that "If you're working with patients that are doing everything right but are still not improving, then you need to look at genetics. And everyone has genetic mutations that cause problems." Not his exact works, but close. I had DNA testing from a few years ago, and only needed to know what site to go to to upload the file and get a methylation profile. There are so many variables. It's not a simple matter. Good luck.

[Chenders in reply to prillyb12]

Thanks again Prilly

[prillyb12]

I just heard about a new book that is out by one of the experts in the field, "Dirty Genes." It has questions we can answer that point to different gene mutations, so we don't need to have done the DNA testing to figure out what might help us. One of the reviews was bad, but most were raving about how the book has helped them.

[Chenders in reply to prillyb12]

Thank you again prilly B12.

[Elijahhawk]

Hi, Chenders

First of all, I'm not a doctor, but someone that has PA. My father also had PA (passed away). Having said that, it looks as if it could probably be safely assumed that your daughter has PA. Apparently the physician didn't think so else why only 50mcg/day? That's unheard of. Her serum B12 levels are on a very very slow trajectory north. I think what you said...

"Recent reviews of B12 deficiency advise that in the event of any discordance between symptoms and laboratory results to rely on the symptoms. The BSH Guidelines state that the clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status since there is no 'gold standard test to define deficiency" ..... is something I would concentrate on. Until my physician was able to come up with a diagnosis for me, he went on empirical evidence... clinical presentation. I had neuro manifestations and neither of us wanted to wait.

If you have questions for me I'll respond as I can as I'm spending much of my time with my hospitalized mother who just had a stroke. Btw, a doctor here is putting her on an aggressive treatment of 1ml/day IM of B12.

[Chenders in reply to Elijahhawk]

Thank you very much Elijahawk. I am sorry to hear about your mother. It is very kind of you to get involved with someone else's problems when you have your own major issues at the moment and I have certainly taken heed of your comments.

[Elijahhawk]

Another btw....you can have normal MMA levels and still be B12 deficiency/PA. All my notes and links are home and not with me. I spoke with my mother's physician today and we both agreed that this field of B12 deficiency can be a mine field to navigate with patients and doctors. ALL tests can look respectable yet someone can receive a retrospective diagnosis of subacute combined degeneration of the spinal cord. It's crazy and can lead to devastating consequences.

[Chenders in reply to Elijahhawk]

Thanks again Elijahawk

[Chenders in reply to Chenders]

If you have some notes on B12 deficiency despite normal MMA I should be most interested to see these when convenient Elijahawk, because I really need to try and influence my daughter's GP to provide her with alternate day i.m. hydroxocobalamin on the basis of her neurologic symptoms and the fact she tested positive to intrinsic factor antibodies DESPITE her normal MMA and Holotranscobalamin. I hope that you might be able to kindly help me in this respect when you are able.

[Elijahhawk in reply to Chenders]

Yup another day at the hospital..and thanks for your well wishes.

I'll try to get some links for you that can address your concerns. I'll have to wait till I'm home this evening, and being in US, there is that time difference. So hopefully I can find them. I have several computers so there's that too!

[Elijahhawk in reply to Chenders]

This link was actually posted not long ago which I had bookmarked as well. Talks of MMA and holotranscobalamin. Direct your attention to Patient B....

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

The following paper looks at holotranscobalamin specifically....

degruyter.com/document/doi/...

These happened to be a couple bookmarks I had on my phone and aren't the ones I was thinking to share. It can be very simple or a very big messy b12 world to unravel.

[Chenders in reply to Elijahhawk]

Hi Elija and thank you very much indeed for finding those 2 references when all you probably wanted to do after being at the hospital was relax. I am very grateful to you. I had already seen the Knoepfel et al paper 'Failure of the holotranscobalamin assay in B12 deficient patients' which says:

"There have been many reported cases of cobalamin assay failures involving PA ...usually with high serum titres of intrinsic factor antibody(IFAB). "

(My daughter tested positive to IFAB).

I had not seen the other reference that you sent me, Bruce HR Wolffenbuttel et al, from the Mayo Clinic entitled 'The Many Faces of Cobalamin (Vitamin B12) Deficiency) . It is absolutely superb Elijah and just what I was looking for to help persuade her GP not to rely on MMA, homocysteine and HoloTC to the exclusion of the symptoms:

"...normal levels of serum B12 and MMA do not exclude symptomatic B12 deficiency."

"The most prevalent symptoms of vitamin B12 deficiency are neurologic.."

"...many people with symptoms related to cobalamin deficiency may have serum B12 levels above the lower reference level of 140 pmol/L."

"Oral supplementation may increase the serum vitamin B12 level but not enough to replenish the vitamin B12 levels in the tissues unless very high doses (1000-2000 mcg/d) are used."

"Hydroxocobalamin is not toxic and successful treatment should not be stopped. Usually, the period between injections can be prolonged when all symptoms have disappeared."

My working hypothesis at the moment is that my daughter may have had PA (she tested positive for IFAB last month) for some years, which will have seriously depleted her body stores of B12. Although she now has normal MMA and HoloTC blood test results after 7 months of daily oral cyanocobalamin 50mcg/day, she is still grossly symptomatic. So whereas the daily cyanocobalamin might be meeting daily B12 requirements the drip feeding of cyanocobalamin is doing little to replenish her exhausted body stores of B12 and that is why she is still symptomatic. She would requires alternate day high dose B12 injections until there are no longer any symptoms which could then be reduced to once monthly or else titrated against symptoms. Does that sound reasonable?

[ottiliefloyd]

I too am no doctor, but have PA. I can relate to a lot of your daughters symptoms and the stress you are facing doing the round robin of Drs and specialists. Even when they eventually conceded B12 IM was the cure, I had to take the SI route like so many others on this forum as the frequency of prescripted injections after loading was nowhere near enough. You cannot overdose on B12 so you have nothing to lose in trialling injections if your Dr refuses and your daughter is willing to SI. SI is a hurdle for many of us, but I wouldn't consider stopping as the benefits far outway the pain of living with the symptoms.

I wish you all the best.

[Chenders in reply to ottiliefloyd]

Otilie I really appreciate your post and I am very sorry to hear that you have had to take the SI route like so many others. I know absolutely nothing at all about SI and wonder if you could please point me in the direction of reliable quality source / information.

[ottiliefloyd]

Which country are you from? wedgewood has posted some very extensive lists of where to source B12 vials.I had a real fear of needles and wouldn't be without the auto injector which is very simple and easy to use. unionmedico.com/product/sup... its of any use, here's what I use;

2ml syringes to inject 1ml of Rotexmedica b12 Hydroxocobalamin, an 18G Blunt Filter needle to draw up and 25G x 25mm needle to inject IM into the thigh. I use the Z track method (YouTube will help you with this) and place a heated wheat bag over the vial for about 1 min before injecting. I find it stings less if warmed to body temperature.

Hope this helps!

[Chenders in reply to ottiliefloyd]

In the UK. Thank you Ottilie!

[Chenders in reply to ottiliefloyd]

Hi Ottilie I followed up on your wedgewood suggestion above and have found this source of B12 injection in Germany (not available without a prescription in the UK).

bodfeld-apotheke.de/product...

Thanks again Ottilie!

[ottiliefloyd in reply to Chenders]

Yes that's it. All the very best!

[Chenders in reply to ottiliefloyd]

You too Ottilie!