I've seen a few posts on this forum regarding the seemingly inexplicable variations in B12 dosing schedules needed to keep different individuals from experiencing signs of deficiency. Furthermore, it seems that every MD believes one should store enough B12 in the liver for lengthy periods of time without supplementation, which in reality, just doesn't seem to work for many people with PA.
I was reading an article about interstitial cystitis (another chronic disease potentially linked to B12 deficiency) and came across an interesting passage that mentioned deficiencies in B12 transport proteins (specifically TC II) and a failure of hepatic B12 storage in people with porphyria. Perhaps a genetic mutation in B12 transport proteins is the reason some people not only develop PA (especially in the absence of detectable intrinsic factor antibodies), but also require far more frequent doses of the vitamin than should be "necessary" if B12 is being properly stored in the liver. Here is the specific portion of the article that deals with the subject:
"Throughout this lengthy investigation, I tried to interest various IC researchers in porphyria but not one IC researcher would bite. I finally realized the sad truth: I would have to do the work myself. This was not completely unrealistic, because there were a limited number of possibilities left to explore. I was pretty certain that the missing patients would most likely be at the beginning of the heme equation, even before ALA- S. I discussed this with my first enzyme researcher before he retired and he thought this was impossible. As mentioned previously, I had asked Dr. Nordmann about the very beginning of the heme equation in Paris many years earlier. He stated: “Succinyl and glycine, they are like air and water.” Yes, they are, but there is something else at the very beginning of this equation. There is vitamin B-12. Vitamin B-12 is needed for DNA and RNA transcription and it is also the cofactor necessary for the synthesis of Succinyl CoA, which sits at the very top of the heme equation. There actually are several additional sites where low levels of vitamin B-12 could potentially wreak havoc at the beginning of the heme pathway. My mentor assured me that this would result in giant cells and anemia. However, I already had my doubts.
My good fortune was actually a medical mistake. Some years earlier, a lab put down the wrong code for what was supposed be a regular vitamin B-12 test in serum. They tested for vitamin B-12 unsaturated binding capacity (UBBC) instead and it was abnormally low. The test is used to pick up elevated UBBC levels associated with two other disorders. No one could tell me what low levels meant. I was given the royal runaround. A couple of years later, when I had more stamina, I had the test repeated and the levels were substantially lower than on the first test. This time I managed to get in touch with the lab director who explained that low levels could mean, among other things, that I do not make enough vitamin B-12 transport proteins.
Unfortunately, the tests to determine which are low, were no longer commercially available. This unusually helpful man also provided some references to make this more understandable. A paper by vitamin B-12 researcher Ulf Hakan Stenman explained that: “TC II delivers vitamin B-12 to both the liver and to other tissues, but the relative magnitudes of these pathways are not known.” In times of plenty, the liver is stocked with large reserves of B-12. However, in times of starvation, when B-12 is in limited supply, the peripheral tissue may get priority, with the larder in the liver only being restocked intermittently whenever the supply of B-12 is greater than the demand.
In light of the Stenman paper and the fact that the two heme pathways, erythroid and liver, are substantially different, a vitamin B-12 deficiency limited to liver became more plausible. Then one day, it all fell into place. I plugged vitamin B-12 UBBC into the computer again. Up popped a paper by Teplinsky, V. et al. titled: Hereditary partial transcobalamin II deficiency with neurologic, mental and hematologic abnormalities in children and adults. Apparently, no one paid much attention when this paper was published in 2003, but I knew exactly what to do with the result. The authors traced 24 relatives of a couple with a hereditary deficiency of the vitamin B-12 transport protein TC II and found that they had substantial neurologic morbidity in spite of normal B-12 levels in serum and as well as an absence of giant cells and anemia. If you will recall, TC II is one of three vitamin B-12 transport proteins which could have caused the low levels of my UBBC test ( the one that was run by mistake ). Dr. Teplinsky also theorized that the underlying problem here was a deficiency of vitamin B-12 in storage in the liver. I quickly had myself tested for folate, methylmalonic acid and homocysteine. My folate and MMA were normal and my homocysteine was elevated. These tests are needed to eliminate other potential causes and narrow down the list of suspects. As a result, TC II deficiency becomes much more likely, and I am now awaiting DNA testing. This is also where the strange risk factor for IC fits in. I had mentioned before that dieting and weight loss was associated with the onset of IC. Yes, it makes perfect sense. TC II reduces the amount of B-12 that reaches the liver. Severe diets reduce B-12 levels even further."
If anyone else here struggles with interstitial cystitis (or knows someone who does), I will say that I've recently been able to completely stop all bladder medications for the past 3 weeks, which is the only time this has ever happened for me in 11 YEARS of dealing with completely debilitating bladder symptoms. The only thing that has changed is the introduction of daily B12 injections earlier this year. My B12 was somewhat low from the start (11 years ago), but like many other IC sufferers, I found an oral B-complex multivitamin exponentially exacerbated my symptoms and assumed I was unable to tolerate supplementation. However, it turns out it was not the B12 causing the issue, but likely the synthetic form of B6 in the supplements.
I wanted to post this because it highlights just how many biochemical pathways (and individual proteins) are involved in B vitamin metabolism, transport, and function, and subsequently underlines just how unethical the "one size fits all" approach to B12 supplementation is, especially since nobody is being tested for every possible mutation in these proteins. When I was in veterinary school, we were taught to treat the patient's symptoms, not follow rigid guidelines from a textbook. However, it seems this good advice has been altogether discarded in modern human medicine, which is a great disservice to anyone dealing with an illness that does not match the textbook description..
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Thank you so very much for your post . I’m no scientist , but your explanation is more than feasible . In the meantime , describing what happens to Pernicious Anaemia patients who get the “ one size fits all” treatment from doctors , is, I’m afraid , more than a “ great disservice “ . It is a massive scandal , especially as the science exists to bring this scandal to an end . People’s lives are being ruined for lack of a very cheap vitamin They have years of being dismissed as hypochondriacs , losing their jobs , relationships and quality of life . The under treatment is enough to prevent death( the pernicious bit) but too little to allow a normal life . Their only hope is to stumble across this forum to get some help .( as I did) But many patients may not have the wherewithal ( internet , computer etc ) I’m honestly haunted by this thought. .
I often wonder if the fact that vitamins cannot be patented plays any part in the disinterest shown by pharmaceutical industry in this condition .
But thank you so very much again for your post. I hope that the “ powers that be “ will take note, but I doubt it . Great that the knowledge has helped you with your health problem . Can’t thank you enough . Best wishes .
My reply wasn’t well thought out at all ! It was the rage inside of me . It all just rushed out . I wrote it without much thought at all in about one minute . My rage has no end when I read about the disdain with which P.A. patients are treated when they are feeling so very ill . If there’s anything that “ gets me going “ , it’s injustices of any kind . And the treatment of P.A. patients is a massively gross injustice . But thank you for your kind comment, deniseinmilden. You always make a great contribution to this forum 👍
I have to believe that one day this injustice will be put to rights .
I wish I could write half that eloquently - with or without much thought! 😀
Perhaps it was your genuine, heartfelt reaction that came across so well and really resonated with me but I always avidly read your replies and am so pleased to hear from you each time.
I feel our contributions here are one way that we can slightly tip some of the injustice in the other direction - but, like you, it scares me to think of all the poor souls without access to this forum and similar platforms.
There are so many things in your post which strike a chord with me:
I too have veterinary training and ethos.
I have liver structure damage from a form of hepatitis 30 years ago and my B12 symptoms have been worse in this time.
I am inclined towards gut bacterial overgrowth and have extra B12 issues as a result.
I produce very few digestive enzymes and have problems as a result - although supplementation is a huge help.
I know the frustration of knowing the information is out there but not collated or disseminated so that we all have to do our own research. (But things shared like this are great and so promote understanding - thank you!).
I know that some of my problems are hereditary.
I'm frustrated by the lack of individual B vitamin testing available [to me] as I'm becoming sure that I have a problem with another B vitamin but I'm not sure which one or at what level to supplement as I don't want to "overdo" my intake of others that are OK.
I need daily B12 jabs.
I obviously don't metabolise things properly even when I get them into my blood stream.
I seem to have a big problem with my haem/heme cycle and don't make my own haem iron. I was sure that this was/is all connected and your article supports this.
One size does not fit all!
There are more things too but this gives you an idea of how much I appreciate your posting this! I'd love to hear more of your information.
I get relatively few UTI problems these days (having done daily jabs for 6+ years) but was terrorised by them at times and so you have my full sympathy and more and I hope that frequent jabs help you as effectively as they have helped me.
So VERY reassuring to see Veterinarians in this feed - not that I would wish this on you. After watching a colleague go through Vet school I learned a few things - it’s way harder than being an MD. You have to comprehend a wide range of physiologies - and your patients can’t speak. There are times I think I need a vet! Wishing you health.
I'm afraid I'm not a vet, just a livestock manager with a lot of veterinary training and a focus on nutrition.I'm the one who has to interpret what my special "person" - cow/sheep/horse/cat/dog/alpaca/goat/chicken/pig, etc - is "saying" to me is wrong with them so that I can give the vet the best chance of offering us a positive/appropriate outcome!
I "speak" - or more particularly "hear" - lots of silent languages!
I have learnt huge amounts from my furry friends over the years which has stood me in good stead for working with people with autistic spectrum personalities and dementia sufferers.
Many vets are superb beyond words and I always try to get a handle on my ills and ails from a trusted vet first so I can present a considered case to any Dr I subsequently need to see.
Thank you. I suffered IC, improved since B12 injections.
What a good informative read that was thank you.I had horrendous bladder problems before I started my 12 shots for confirmed p.a.
I had tried all sorts of hrt treatments because I had what was best described as bad paper cuts in my undercarriage and so much pain with the sores I had developed,every time I peed it was like acid burning me,I had so many antibiotics it caused develop adverse allergic reactions to most of them but no uti infections were ever confirmed by labs.
I didn’t do well at all with the likes of Vagifem pessaries or creams as I reacted badly with the fillers in them,I couldn’t go far as my bladder constantly leaked if I laughed coughed sneezed ,the usual stuff and I was so miserable,I saw privately every so called hrt specialist going and felt like a cash cow but getting no help or relief and the pain continued,the treatment on offer was so horrendous I refused it,my already inflamed bladder was in no fit state to have invasive bladder washes done etc it was a no brainer for me so I struggled on learning as much as I could to reduce that pain and inflammation and try and heal those painful sores and paper cuts that made even a simple walk feel agonising.
Then I discovered I had p.a and started the b12 shots,which I now self inject,around 2 years ago.
One of the first things I noticed was I suddenly had relief from the constant night time visits to the toilet,my cortisol was rock bottom because of the sleepless nights I suffered with this,suddenly I was no longer up every hour dribbling acid then washing and putting cream on my cut areas,even that stung.
Fast forward now two years later I have absolutely none of these bladder issues,I do have kidney stones but that seems be a genetic thing,
I’ve never had any doubt that the lack of b12 and p.a caused this horrible affliction that they’ve named intersystinal cystitus and I so wish that they would at least trial b12 on these patients because the relief I now have from that is priceless.
You have to ask do they real want something as simple as a cure or do they see it as something that just messes up their multi discipline world of specialities that is such a lucrative business.ty again.x
Have you (I hope you don't mind me asking) had improvement in your "undercarriage" symptoms? I have had similar for about 3 years, the skin is thin and seems to spontaneously split open... it's sore but not as bad as your experience. I have seen gynecology twice with no diagnosis or treatment except steroids suggested, but this only offers mild improvement. I'm 46 and they say I'm too young for menopause related skin changes.
Hi curlygal sorry about the late reply.Yes I’ve had massive improvements,it’s one of those things that you can only understand if you’ve suffered from it,the pain it causes it’s so life changing because it’s so taboo and no one talks about it in the family arena do they.
I found the gynies used to make all sorts of faces when I explained it but could never actually provide any form of relief that worked for me and I tried every combination of things available. One of the best things for healing that didn’t sting like hell was raw organic coconut oil stored in the fridge it goes solid so you can make little pessaries and pop them inside when you go to bed and they really get the chance to do some good that helped me a lot but the game changer for me was starting the b12 injections,hope this gives you some help xx
Thanks 🙂 I was already on B12 injections when this started though so I doubt it is B12 related in my case.
They gave me petroleum jelly to use at one point, which felt really horrible so I don't know if I could tolerate coconut oil!
Some of the symptoms are like lichen sclerosus but I don't have the skin colour changes so probably not that. I just wish they would give me an actual diagnosis 😢
I never had this problem before so I feel there must be something there to diagnose.
Morning curlygal.I wouldn’t use Vaseline as you say it’s horrible,coconut oil is antibacterial and very soothing and healing and well worth a try,you can get the small blue tubs of it in Holland and Barret for around 2 quid,if you put it on at night when you go to bed the changes in the morning will amaze you.just put a panty liner on with it so there’s no mess,it has a very fine runny consistency unlike the clagginess of Vaseline.You could also try some lemon juice in warm water to drink and neutralise your urine so that’ll help reduce the acidity and give the cuts time to heal,it takes a long time to resolve this so research vaginal atrophy for more tips and make sure all your vitamins and minerals are at optimal levels as this all helps,ive been “healed” for about two years now and I put it all down to doing these things along with the more obvious stuff like hand wash your underwear,no soap powder,don’t wash your hair in the shower until you start healing downstairs,no baths,I neutralised the urine as much as possible and I used the bottle washing method after every pee,pain in the butt but it all helped and the relief was worth it.If they’re checking for lichen they’ll usually do a biopsy to rule it out.good luck you can help this and reduce your discomfort.x
Thank you for this. I have found this deficiency to be a series of very long rabbit holes. So glad to find others here with me. Reporting back and adding to our collective knowledge. Wishing you health.
Thank you for your research. I didn't understand all of your post but what I did was impressive. I wish I knew how to get the medical community interested in researching pernicious anemia and B12 deficiency. We need to start a "movement" and publicize this issue.
In the world of thyroid, the Total T4 and T3 tests very largely tell you how much binding proteins you have. (Of which there are three - thyroid binding globulin, transthyretin and albumin.)
Some people have inherently low levels (there are known genetic reasons) and they are affected by other things (oestrogen).
Hence, the Total tests have questionable utility in an individual, and can be very bad across a population which includes those with low and high levels. And why Free tests have become very much the standard - at least, most places other than the USA, where Total tests are still all too common.
Obviously, binding proteins have a huge effect on the amount of a substance we can store and circulate.
Thank you for posting this! My cluster of autoimmune conditions includes primary biliary cholangitis (PBC) a liver disease caused, essentially, by clogged ducts leading to the liver. My hepatologist, 2 GI docs and 3 primary care providers missed the PA diagnosis for 20 years, despite labs showing low B12 20 years ago. (Once the B12 labs were normal again they all seemed to forget about it, so I did too, thinking they knew better than I). Once the PBC diagnosis was made, they also found hypothyroidism and very low vitamin D, and of course a very scary low B12. Neurologists dismiss my symptoms as insignificant, and I’m pretty sure they think I’m a hypochondriac, although they’ve never said it to my face. Now, this team of docs, each with their own specialty, seem to approach each problem as if they were separate, not related to any underlying biochemical disruption in transportation and absorption.
So thank you again for sharing this. I join others in believing this will be understood in the future. This scholarship is a stepping stone out of the present.
I am going to look into a genetic test for TC-II deficiency in hopes to get solid evidence that will back up my need for frequent injections in perpetuity because I just don't see any other reason I would ever need to back off of injections if I am a meat eater and got this low, then there is something wrong and unless they find the cause I don't see that it can ever be fixed. And without a diagnosis of PA, I have no real support from physicians.
I'm following up on this post with some supporting information. I finally managed to get a neurologist to test me for transcobalamin II deficiency (Quest Diagnostics UBBC test, aka Unsaturated B12 Binding Capacity test), and I was extremely low (< 88 pg/mL compared to a 650-1340 pg/mL reference range), lending some credence to my theory that functional B12 deficiency, via transcobalamin deficiency, is the cause of my symptoms for all these years. Without transcobalamin II (or enough of it) an individual can't transport B12 to the liver or other cells, so all the rhetoric about a single injection lasting for months does not apply.
In addition to the links thoughtfully provided by B12life in the above post, I also found this resource on transcobalamin II deficiency (not yet fully investigated for validity, but the literature on this disorder is scarce):
It notes that maintaining extremely high blood B12 levels is the only known treatment, although it recommends hydroxycobalamin for some reason. Other resources recommended methylcobalamin.
I've edited this post after doing some additional research. I cannot scientifically link my TCII deficiency to any special requirement for a specific form of B12, but since other genetic polymorphisms are possible and some individuals subsequently respond better to different forms of the vitamin, I'm going to experiment to find what works best for me.
So there you go - a real-world example of someone with documented functional B12 deficiency causing urinary and neurologic symptoms. Hopefully this can help others in the same boat before they face decades of decline, medical mistreatment, and financial strain as I have.
The orpha.net link contains this note: "Reduction of unsaturated B12 binding capacity (test must be carried out before starting treatment with vitamin B12) "... so does this mean that the UBBC test isn't useful if we are taking B12?
I am intrigued by this post. I just received a diagnosis of PA a few months ago after decades of symptoms. At one point many years ago I was diagnosed with porphyria, although additional testing ultimately ruled it out. I require self injection every other day of hydroxocobalamin to function properly. Cyanoconbalamin injections didn’t help. I also had severe bladder issues (and IC diagnosis) for many years that peaked right before my diagnosis. My bladder troubles resolved shortly after starting injections.
Thank you very much for sharing your story! I really do think it is all related, yet the medical community insists on their practice of slapping an "idiopathic xxx" label onto every unexplained condition and washing their hands of responsibility to diagnose what is truly going on. Since medical research funding is scarce, sharing our stories is probably the single most useful thing for those suffering from ill-defined ailments. I'm very glad to hear that your bladder symptoms (among others) resolved after commencing self-injections. I think I will be giving hydroxocobalamin a try as well. The cyanocobalamin has certainly improved my life, but I still struggle with daily migraines. I hope at least some people newly diagnosed with IC stumble upon this, because it would truly have changed my life to avoid over a decade of misdiagnosis and truly crippling pharmaceutical side effects (and surgery gone wrong) had I known that simple B12 supplementation could "cure" my IC.
I have PA and took years to diagnose it, I see in medical records from the age of 26yrs old till I had B12 injections just over 2 years ago that I had round then Oval macroctis.I have had years of undiagnosed pain that they always told me was endometriosis, but when opened up no endometriosis was found, Well it was once when I was 26rs old but layered off , but I must have had about 15 laparoscopy that were clear..
Anyway My Father had a rare type of Porphyria and I have recently been looking to rule it out, I have had the urine tests but were negative, But I think my flares would of been when I was very hormonal and I stopped periods about 20 years ago, so that excruciating pain had gone , but moree recently I was having urine problems and pelvic pain, This I had a cystoscopy for and told it is Intestrial Cystitis, they want to line my bladder with something, Im not to keen.
I read the Barnra Flanagan article the other day, and with my recent diagnosis I did wonder again about Porphyria, My GP had already sent me a while back for referel to genetics in Porphyrias as my father had it and as hes dead now I wasnt sure which one he had.. I do react badly to prodrugs run on CYP 450 genes , Which my GP tells me is another Porphyria side effect. I will be having genetic testing I hope in 8 weeks to see if I have my dads porphyriaa genes...
I will come back and let you know if I have the porphyria genes.. I would say If I do have Porphyria I either have AIP or AHP as Im not sun sensitive although can be when I have taken certain drugs.. so I wouldnt say Im not totally not sun sensitive,,,
I have had my genome done but its really hard to see what actual genes and rs numbers are porphyria related, so I will have to wait and hope they test all my genes or at least look ay my genome, I am going you a Porphyria centre so hopefully they will know what genes need to be rested...
Has anyone else on here with PA and IC ended up positive for any Porphyrias ?
I was told by my pro gene Prof to take D-Manose and cranberry for my UI as I was allergic to many long term AB they had I ended up in hospital with them so prefer to take natural drugs if I can and tbh worked better than any anti biotic I ever used, which seemed to keep pain at bay but recently run out and in all sorts of problem with the pain, I asked NHS to supply as allergic to all alternatives and the evil CCG said no, OIam complaining to ombudsman about them as not fair if I cant take the other drugs they offer, its not like its my choice,,
The NHS CCG can be very insensitive, they are not even proper drs Grrr.
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