Implications of elevated HoloTC (active B12) and HoloTC > 20% of serum B12?

[looking_for_answers]

I've read a few times here and in research papers that HotoTC (active B12) is generally up to 20% of serum B12.

Mine is not (in my case: HoloTC = 31% of serum B12), and beyond that my HoloTC is higher than the reference range.

Notes:

*I've never injected B12

*The test (results below) was done 11 days after I've stopped taking 1000mcg Methylcobalamin sublingual 2x a week (I took this for 3 years)

My question: What are the implications of high HoloTc /active B12 (specially when it accounts to more than 20% of serum B12?

My latest results:

* Vitamin B12 (Serum) 366.0 ng/L (187.0 - 833.0)

* Methylmalonic acid 163 nmol/L (0 - 280)

* Active B12 (HoloTC) 113 pmol/L (25 - 108)

* Homocysteine 7.7 umol/l (0.0 - 15.0)

* serum folate 16.0 ug/L (3.1 - 20.5)

Note2: When B12 hit 366 (from 593 - went down in 11 days of no supplementation), I got the following added to my symptoms (all waking me up from sleep):

* numbness and tingling on hands

* restless legs

* face formication

*nerve pain on one palm of the hand (this resolved within 1 hour of me taking a sublingual 1000mcg Methylcobalamin)

The more I research, I do not seem to have a B12 deficiency (despite my symptoms - more in my first post in my profile - and accentuated macrocytosis (which has been deemed "undiagnosed" by haematologist)), but as I continue my research I need further pointers, so writing here as many members have been immensely helpful and have a ton of knowledge to share and I could get some help with pointers to further research to look into.

Note3: For those versed in biochemistry, my B6 is borderline high (I take no B6 supplementation)

* Vitamin B6 (Pyridoxal-5'-phosphate) 109.7 nmol/L (35.2 - 110.1)

Many Thanks!

[fbirder]

Serum B12 is notoriously inaccurate so it's entirely possible that your real serum B12 level was 400 ng/L. That would get you closer to 20%.

The '20%' is an average. Some will be well above 20%, some will be below 20%. But the ratio matters not. What matters is that you have enough Active B12 - and yours is above the top of the range, so you obviously do.

Your MMA and hCys are normal, suggesting there is no functional deficiency (where B12 isn't getting into the cells).

You do not have a B12 absorption problem as you're obviously absorbing the oral B12 you've been taking (stopping for 11 days will have zero effect on serum levels).

You need to see a neurologist. There are dozens of things that can cause your symptoms.

[looking_for_answers in reply to fbirder]

Thanks a lot for your message fbirder .

A question on the dynamics of serum B12: My serum B12 with 11 days of no supplementation actually moved drastically: From 593 to 366 (so, a 38% decrease). Seems like too much of a crash for only 11 days of no oral supplementation, no? Anything off in this?

[fbirder in reply to looking_for_answers]

That does sound a big drop.

It makes me wonder if you have a problem with one of the steps in the enterohepatic recirculation of B12. When some is eliminated in the bile, then reabsorbed in the ileum.

[looking_for_answers in reply to fbirder]

It is the first time in years someone says something that may fit into my non-standard case (when I know there is something off with me). Thank you very much for reading fbirder !

What do you suggest I research? Can you point me to something? What tests should I do? What to read?

[fbirder in reply to looking_for_answers]

Try B12 injections?

[looking_for_answers in reply to fbirder]

I'm going full round, now back to thinking about b12 injections Human body is so complex Thanks a lot fbirder

I'd really like to understand more. Should someone have pointers to what to read on this "enterohepatic recirculation of B12" and whether that could lead me to my symptoms and macrocytosis (despite my apparently “normal” blood results), I'd appreciate it.

Will research myself as well sometime tonight.

PS: I need to equip myself as with those blood results (despite macrocytosis), no GP will listen to me

[FlipperTD in reply to looking_for_answers]

Scientist, not medic. Often in error, but never in doubt...

We normally expect macrocytosis to be linked to either B12 or folate deficiency[or both]. However, a degree of macrocytosis can be associated with thyroid problems. Have you had your thyroid investigated?

Hope this helps.

[looking_for_answers in reply to FlipperTD]

Thanks for reading FlipperTD

Yes, in addition to all b12 panel of tests as per above, I did a Thyroid panel. Results here in my post in the thyroid community (all normal): healthunlocked.com/thyroidu...

So, a high MCV like this means my bone marrow is under stress and struggling, correct? It means my red cells lack DNA to split in two and become normal in size, right? It is tough to not ask myself what suddenly started missing to my red cells and what else this might lead me to. And the MCV continues going up:

* MCV (April 2016/August 2017/March 2018/July2018/June 2019/July 2020/July2020 one week laterAugust2020/Sept2020/Sept2020 one week later)

95.1/95.7/96.2/101/100/104/105/103/104/106 normal range [83.5-99.5]

[FlipperTD in reply to looking_for_answers]

Cheers for that; it looks like you've been investigated appropriately.

I will now try to hide behind reference range statistics. The usual quoted reference range is (Mean +/- 2 Standard Deviations) which describes 95% of the population, and assumes an underlying normal distribution. So, one in 20, whilst being normal, fall outside that range. To capture most of the remaining 5%, then +/- 3 SD will include 99.7%, so only 3 in a thousand will fall outside the quoted reference range whilst still beng 'normal'! Trying to derive reference ranges, which many call 'normal ranges' drove me up the wall for decades. It's generally better (in my opinion) to apply the argument 'Has it changed from last time? Is it better, or worse?' We're all different. Keep investigating.

[looking_for_answers in reply to FlipperTD]

Thanks again FlipperTD . Very much appreciated.

Yes, the reference ranges can be misleading. My concern comes from the progression (as per above). My cells were clearly normal in size back in 2016/2017, then to date I've had an 11% increase in red cell size (my poor red cells are missing something, but I can't figure out what).

Then there is the response my body has to B12 (nerve pain resolved in hours of a simple sublingual 1000mcg methylcobalamin pill) and the massive crash in serum b12 described in comments above. Despite that, I feel uncertain about B12 injections, given my MMA/Homocysteine/HoloTC (not to mention I'll never get this approved by my GP), but at the same time I wonder if an overdose of B12 might fix some pathways (that I don't understand) and this might give my cells what they need.

Anyways, I'll continue researching and will leave an update if I find something.

[FlipperTD in reply to looking_for_answers]

Oh dear, this is where I might get a sharp response from you, but I should say this and you may ignore it, and I apologise for even suggesting it! Consumption of alcohol is a common cause of an increased MCV, but it affect folks differently. The changes resove upon abstinence. Good luck. Keep looking!

[looking_for_answers in reply to FlipperTD]

Actually, thanks for covering all basis, no need to apologize

I wish that was the reason, because then I'd know what to do: stop drinking.

The reality is that I've never drank to get drunk and cut all alcohol (health nut) since 2017. So, this can't be the reason.

Also, beyond supplements (B12, Vitamin D and since COVID times: Zinc plus now because rock bottom ferritin: Iron), I do not take medicines/drugs.

[FlipperTD in reply to looking_for_answers]

There was always one [at least] we couldn't explain! Sounds like you're another. If your doctor is happy with you, then that's good. It still doesn't explain it. When you get a reticulocytosis following effective replacement therapy, the retics [juvenile red cells] are bigger, and then settle down in size as they mature.

You're correct that the red cell precursors miss out on a division because their DNA synthesis is impaired; they exhibit nuclear/cytoplasmic asynchrony, and this is generally believed to be down to shortage of B12 and/or folate.

Listen to your doctor/s, as they'll know more about this than I do, and they're qualified to advise, unlike me, who is just a humble scientist!

Good luck.