Total and 'Active' Serum B12

I had a few blood tests done this week at a private lab and got some very unexpected results back.

Before I give them, here's a little basic information about B12:

There are three carrier proteins that are bound to B12 in the serum.

• When B12 is bound to transcobalamin I, also known as haptocorrin, it is considered to be inactive. The purpose of haptocorrin bound B12 in serum is not well understood despite normally comprising 75-80% of all serum B12.
• B12 bound to transcobalamin II is the active form. It binds to the B12 receptors on cell membranes and is taken up by the cells.
• For completeness, there is a third binding protein, transcobalamin III. Again, this form is not well understood and is rarely mentioned.

The proportion of active B12 in the serum is generally considered to be about 20-25% of the total B12 but it does vary and can be much lower. Therefore, total B12, although a reasonable indicator of B12 status, is not always reliable.


I had my total B12 measured about six years ago and it was around 350 pmol/L. This is considered sufficient in the UK and many other countries. Japan changed their reference range some time ago and anything below 500 pmol/L is deemed a deficiency.

Shortly after my previous test, I started taking 1000mcg of methylobalamin sublingually, and did respond in a way that some would consider a sign of existing neurological damage being repaired - a burning sensation in the soles of my feet and increased tingling in my fingers. Methylcobalamin also helped me to sleep (which is reported by a minority of people taking it) and I have continued to use it sporadically whenever I have phases of troubled sleep. This generally means taking a lozenge every evening over the course of about a week. The last time I did this was about two months ago and it was only for three or four days.

I'd always intended to get my active B12 measured but had never gotten round to it. However, my 83 year old mother has been showing potential signs of significant neurological damage over recent months and in the absence of any other diagnosis, I decided to get us both tested.

These are my results:

Total Vitamin B12: 352 pmol/L (IN RANGE)
(Deficient <140 / Insufficient 140 - 250 / Consider reducing dose >725)

B12-Active: 167.9 pmol/L (MARGINALLY HIGH)
(25.1 - 165)

Serum Folate: 4.25 nmol/L (DEFICIENT)
(8.83 - 60.8 nmol/L)

Note that the active B12 is 47% of total serum B12. Serum folate is deficient but my haemoglobin and mean cell volumes are mid range.

Potentially relevant neurological symptoms: Tingling in feet, occasional tingling in fingers, poor sense of balance, twitchy muscles and tinnitus but all these have been present for years. Recently, walking has become more awkward in that it feels stilted and I almost trip up quite frequently. (I feel like I'm walking now at 48 similar to my mother did when she was about 65.)

So far not really all that interesting apart from the unusual active B12 percentage. Now we come to my mother's results.

Total Vitamin B12: 352 pmol/L (IN RANGE)
(Deficient <140 / Insufficient 140 - 250 / Consider reducing dose >725)

B12-Active: 216.2 pmol/L (VERY HIGH)
(25.1 - 165)

Serum Folate: 8.3 nmol/L (MARGINALLY DEFICIENT)
(8.83 - 60.8 nmol/L)

The sharp-eyed will notice that my mother's total B12 is identical to mine.

She also has an identical mean cell volume (91 fl) and we are both on the border of a vitamin D3 insufficiency, being separated by only 1 nmol/L. Her results showed a haemoglobin deficiency which is consistent with what we already know.

So similar were most of the results that I was worried that a mistake had been made. We have been reassured that this is not the case.

My mother's active B12 is 60% of the total. When I asked about our unusual percentages, the doctor replied:

My understanding is that haptocorrin's function is to protect B12 in the stomach. Low stomach pH is required to release the B12 but once released the B12 is at risk of being denatured until it can be absorbed. In the absence of all other factors it seems surprising to me that someone deficient in TCN1 could ever end up with a high active B12 even though most of their B12 would be in the active form.

He's right that I eat a lot of meat but my mother doesn't. She has also never supplemented and she is showing signs of a potentially severe deficiency yet she has an even higher level of active B12 than I do.

Her symptoms are:

• Severe mobility problems over the past few months. It doesn't seem to be a simple weakness, although that's certainly true on occasion. It appears more like her legs aren't obeying her.
• Balance is terrible.
• Her vision appears to be getting worse all of a sudden although there could be an alternative explanation for this.
• She is extremely fatigued and mostly stays in bed.
• Appetite has declined.
• Frequent nausea. Has dry retched a couple of times (no bile).
• Breathless at the slightest effort (sometimes even without any effort).
• Tachycardia - always either in the 100s or 110s at rest.
• Yellowish tinge to the skin on her body. Face is very pale.
• Bouts of confusion and disorientation.
• Poor short term memory / concentration problems
• Pale diarrhoea which has persisted for months.
• Tremulousness

To an extent, a lot of the above symptoms are not unexpected in an 83 year old but what concerns me is the speed with which it has happened.

She'll be seeing her GP on Thursday. I am dreading bringing up this topic.

For myself, the next step will be to test homocysteine and methylmalonic acid to try to get an idea of what is happening within the cells. Does anyone have experience of getting these tests done privately? Any advice?

For those who are knowledgeable about B12, is it possible that my mother and I could have a problem with cellular uptake? Could this explain the relatively high active B12 in the serum even though we appear to have an apparent a likely genetic variation that would otherwise be expected to lead to an apparent deficiency?

Anyone else have odd active B12 findings?

 

I can't help with testing for MMA and homocysteine in the UK (in Australia I can get those and active B12 tested free on the NHS) but I do know a bit about B12 so can comment on some of the aspects you raise.

I couldn't find anything about the significance of high active B12 as a percentage of total B12 but it does seem logical that this could reflect a deficiency of TCN1.

The latter doesn't seem to be a real problem, ie people with documented deficiency (or virtual absence) of TCN1 due to homozygous genetic changes don't seem to have any serious health problems. They do have low total serum B12 but not functional B12 deficiency. Heterozygotes may have marginal serum B12 but again no problems.

Here is a paper which correlates serum TCN1 and B12 concentrations. It estimates about a 15% prevalence of low TCN1 in patients with low serum cobalamin and about 0.6% prevalence of very low TCN1 (from family studies it is likely that these may reflect +/- and +/+ variants respectively). The same authors have characterised the genetic changes which underlie TCN1 deficiency here.

TCN1 does preferentially bind B12 in the stomach and passes it on to IF in the small intestine, but if TCN1 were deficient I can't see any reason for IF not to substitute in the stomach. It can still bind B12, it's just that under acid conditions, TCN1 has higher affinity and so tends to do the binding. In theory then this could explain how TCN1 deficiency doesn't necessarily lead to B12 deficiency.

What could be going on with you and your mother?

What has been going through my mind in thinking about the issues you raise is the role that TCN1 plays in the enterohepatic circulation of B12. Essentially this is a salvage pathway that aims to conserve as much B12 as possible. That 80% or so of B12 that is bound to TCN1 goes to the liver and from there is sent to the small intestine via bile where it is processed in exactly the same way as the B12 bound to TCN1 that has come from out food.

B12 is extracted and sent for another circulatory pass to allow cells to take up what they need.

Very little B12 exits the body (unless high levels of supplementation are taken when excess will be eliminated via the kidneys), it is just endlessly recycled in this enterohepatic loop to scavenge virtually every last molecule of what is a very rare substance. Food sources are just a top-up.

The studies in the literature indicate that even with low TCN1, this loop plus diet seems to be sufficient to supply B12, but studies have not been extensive.

This might apply in healthy people but what about someone like yourself with ME/CFS? Maybe this is placing additional demand that you are not quite able to fulfill.

In your mother's case there may be several things going on that are not B12 related. Alternatively, maybe TCN1 deficiency plus the ageing process which has been observed to be associated with marginal B12 status, often through decline of the absorption process in the gut, has come together to start to cause problems.

Apparently the enterohepatic loop can supply B12 for many years even without any input from food, until it suddenly collapses because one element in the loop no longer works. In this document, a long-term vegan describes how this happened to him.

Once the loop has collapsed, it can be very difficult to reconstitute; continuous supplementation at fairly high level may then be required.

I am speculating of course and you may never really get to the bottom of what is going on. The best you may be able to do is determine empirically whether more consistent B12/folate supplementation is helpful. Once you start supplementing, serum B12 levels, whether active or total, will no longer be very helpful.

I agree testing of B12 function through MMA and homocysteine tests is the next step. This should give insight into what is actually happening inside your cells. If one or both are elevated then B12 and folate supplementation would be in order, sufficient to eliminate the neurological symptoms and you may need to keep taking this for a long time, if not indefinitely.

 

Thank you @alicec

Your theory about IF binding in the absence of TCN1 would certainly explain the high active levels.

I haven't got around to looking at the links yet but shall study them when my brain is up to it.

 

Warning: this post has sod all to do with ME. May be of interest to some for the B12 element.

So, as predicted, that didn't go well; dismissive but not hostile.

Last Wednesday, I spoke to my mother's GP on the phone at around midday.

Mum had her blood drawn for the B12 test the day before but we didn't yet have the results. I gave her a portion of a 1000mcg lozenge that night and the rest on Wednesday morning. When I spoke to her GP, without me bringing up the subject, the GP mentioned that B12 had been one of the tests done at the hospital and her level was normal. I didn't say anything about the tests I'd ordered, just thinking at the time that at least that was something that could now be ruled out. The GP advised me to increase my mother's prednisolone from 7 to 15 mg. As she had only just had her pills, I gave her the extra to take her up to the new dosage and she has continued at that level from then until today.

By late Wednesday evening my mother seemed more alert. In view of the news about her B12 levels, there didn't seem to be any point continuing to supplement but, at the same time, it seemed like a strangely, rapid reaction to the increased prednisolone. The following morning, she was up and dressed for the first time since coming out of hospital and able to knit, making a few mistakes and dropping stitches. She was still struggling to walk but had improved some.

The next day (Friday) she was up for much of the day but not dressed. She tried to knit but soon stopped and napped quite a bit.

On Saturday she was up later in the day to watch 'Strictly'. Sunday was spent in bed, back to the level she had been at prior to the improvement.

On Sunday, I thought that B12 might be worth a try after all, so split a lozenge for her to take throughout the day. She has been taking the same since.

Monday, she was up all day and in good spirits, knitting quite a lot without making mistakes.

Tuesday and Wednesday were similar but she slept in her chair quite a bit.

So far, today is like Monday.

In general, she is rarely confused now and doesn't keep asking questions that I already answered five minutes before. She can follow 'light' TV programmes for a short while. Her appetite is markedly improved, still eating small amounts but definitely more interested in food and enjoying it. This morning she commented that her hand isn't shaking any longer when she eats. Apologies in advance for this graphic and strange detail, but her stools have changed from a pale, orangey diarrhoea, which she has had for months, to a normal coloured firmer stool.

The doctor has advised not to give her any more B12 and doesn't consider her improved enough to justify continuing at the increased dosage of prednisolone. (What does she know about improvement? She hasn't been here for the past week. . It's been a huge improvement for my mum and me.)

So we'll do as the GP requests and see how things go from here.

 

@Scarecrow I'm curious to know if the hospital gave you the results for her B12 status as being "normal"?

My doctor told me a few years ago that my levels were 'normal', but I obtained my labs and it was BORDERLINE normal/low at 210! She refused to give me B12 injections so I started supplementing on my own.

I took supplements for 6 months to get it back up.

Good for you for taking care of your mum, and I'm glad she's doing better

 

Yikes! I assume that was your total serum B12? My understanding is that 210 has always been outwith the reference range. The private lab that did our testing would have flagged that as insufficient.

Unfortunately, I haven't seen the lab results the hospital ran but her GMP considered them to be normal.

If you look at both of our private lab results in the OP, you'll see that our total serum levels are fine and our active B12 is high in my case and very high in hers. So on the face of it neither of us has a deficiency.

I've started researching cellular aspects of B12. This NIH article describes the ABCD4 gene and mutations.

This mutation Mutation of this gene is very serious and affects development so cannot be directly relevant to our situation. But it shows that even where B12 is being successfully absorbed, transported in the blood and delivered to cells, things can still go wrong.

There are an awful lot of anecdotal reports of B12 deficiency symptoms, even where serum levels are normal, that are resolved with supplementation. I do wonder if there may be mutations that cause subtle problems with B12 metabolism over the decades.

Did you do this as a sensible precaution or did you have actually have symptoms which resolved?

Thank you. I hope it continues but if not, we're both decided that supplementation is the way forward, despite her GP's opinion.

 

@Scarecrow thanks, sorry I missed the OP.

I had tingling sensation in my feet and tongue, at times my tongue went numb. I also had a pale/yellow tinge to my face. After bringing up my levels this all went away.

I also had an MMA test done a year before that which was in the High range of normal, also indicating low B12.

I take maintenance dose of B's and extra B12.

I'm not familiar with the gene mutations but I think supplementing regularly is safe from what I've read.

 

Are you in the UK, Mij? Did you get it done privately? If so, do you recall the lab?

Yes, I think that's because the cobalamin is already bound to the methyl group and is absorbed directly into the bloodstream. It isn't picked up by the usual carrier proteins found in the enteric route. Any that isn't quickly absorbed by cells will be excreted within a fairly short period in the urine.

 

I've just posted that and only now is my memory telling me that you're in Canada. Yes?

 

@Scarecrow yes I'm in Canada. It was my functional integrative doctor that did the MMA test, my GP had never heard of it.

 

I could be wrong but i think biolab do an MMA test
My GP didn' t have much of a clue either re B12 levels.

 

Thanks, @Amw66.

Biolabs do offer the tests but, unfortunately, they are a referral only service.

https://privatebloodtests.co.uk/ look like my best option at the moment.

 

You can get tested on NHS in some places - ( Teeside do it) probably a postcode lottery like many other things - list of various tests here.
http://www.b12deficiency.info/b12-testing/

 

With my active B12 level, I don't think that's going to happen.

Thanks.

 

@Scarecrow
I had my MMA tested at the European Laboratory Of Nutrients in the Netherlands:
http://www.europeanlaboratory.nl

Here's the pricelist, it's €50 for Methylmalonic acid:
http://www.europeanlaboratory.nl/documents/en/pricelist_en.pdf

 

Thanks @MarcNotMark

I can't believe how much cheaper those prices are. I could be tested and have a nice trip to the Netherlands for the amount I'll have to pay a British lab. Welcome to Rip Off Britain.

Unfortunately, that's another referral service, so no good for me. Useful information for others, though.

 

NHS lab were willing to do an MMA test for me, recommended by private endo, my GPs had never heard of it. But it got bounced back by lab because I had a normal/high serum B12 on record.

GP wasn't willing to fight for me and I couldn't afford to get the endo involved so it never happened.

FWIW I had elevated out of range serum B12 and what I assume to be very elevated Active B12, the report just said it was over >256 or something like that without giving a specific figure. I had not supplemented B12 for 6 months prior. Before when I had supplemented with sublingual B12 my folate tanked and became deficient (oops, should've read up more!!)

 

@Scarecrow You can self refer and have the tests done by MediChecks in the UK. MMA and homocysteine are £100 each. Serum B12 & Active B12 together are £60. A blood draw was something like £19 at my local hospital last time I did it.

20% off all tests at the moment...black Friday is everywhere apparently!
https://www.medichecks.com/tests/methylmalonic-acid

 

Thanks @Ryan31337

That looks like a great option and definitely cheaper than the other place I found.

Your elevated active B12 profile seems similar to mine. Did you test high for MMA despite that?

 

MMA never got done because the NHS lab had a high (aka 'normal' as far as they are concerned) serum test on record.

I should really follow it up as I've had numbness, tingling etc. in one foot for a long time.