B12 Injections vs Transdermal vs Lozenges

aaron_c

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I've recently been exploring some B12 deficiency groups, and one thing I've seen reported by members and also one good friend of mine is that sometimes B12 injections help where lozenges do not. (I'm not saying this will be true for all of us, but it makes me curious about whether we can rule out B12 issues without doing injections).

But my question here is how to square that with what I understand to be the case regarding B12 lozenges: That they do increase serum B12. I say this both from a vague recollection of what people here said over a decade ago and also from https://perniciousanemia.org/b12/levels/ which theorizes that the reason normal serum cobalamin doesn't rule out a positive response to cobalamin injections is that you could have a high proportion of your serum cobalamin in a somewhat unusable form (in other words not bound to transcobalamin II but bound to haptocorrin or...I can't tell what transcobalamin III is but bound to that).

So I have some pieces that I can start to put together: It seems like maybe in some people with normal serum B12 who nonetheless respond to B12 injections the problem was (partly?) that much of their serum B12 was still bound to haptocorrin, which according to wikipedia initially gets a chance to bind to B12 in the mouth where it can subsequently protect the B12 from degradation in the stomach. After that it's normally broken down by pancreatic enzymes. Or some of it is, I'm not clear on how much. And then the free B12 is bound to Intrinsic Factor so it can be absorbed in the ilium.

To me this looks like maybe people with problems producing pancreatic enzymes (and I think that's most of us in the chronic illness community?) would then have trouble separating cobalamin from haptocorrin and so perhaps we'd wind up with a higher-than-normal amount of haptocorrin/cobalamin in the blood? And that that might explain why some people benefit from injections over lozenges.

But that's a theory based on pretty thin evidence. Now the questions that I hope yall might have ideas on:

-What is transcobalamin III?
-What is the function of haptocorrin (aka transcobalamin I) when it's in the blood?
-Do folks have experience with B12 injectables? (I know there's a thread on transdermal and I'm interested in that, but I didn't find a good thread on injectables)
-If you do believe that B12 injections work for some people where lozenges fail...what is your explanation for that? Does it explain (or do you dispute) the poor reliability of the serum cobalamin tests? I'm truly asking.

Thanks!
 

aaron_c

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PS To be clear I don't want to sound like I'm thinking "oh I found the solution, everyone just has to inject B12 instead of take lozenges." If that were the case for all of us I think we'd know it by now. So I suspect that IF cobalamin dysfunction is a common part of our illness then there will be more pieces than just this, perhaps an issue with the transcobalamin II receptor or something.
 

aaron_c

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Update: Here are my thoughts on how this fits together, including a summary of how B12 is normally absorbed. I'm posting this mostly so I can refer to it later.

There's some debate about whether oral B12 is always utilized as well as injected B12 is. I know for myself injectable B12 has provided the benefits--reliably, for over half a year now--that oral B12 only did for maybe two weeks or so. The boost in energy and cognitive ability, mainly. I'm not the only one who reports this--indeed, it's not limited to the ME/CFS community, there are folks with pernicious anemia who report the same. Incidentally I tested negative for the pernicious anemia antibodies, though I'm told that test may have a high false negative rate.

Normal B12 Absorption

B12 aka cobalamin is easily oxidized and it can also be broken down by stomach acid in the stomach. And then beyond that I'm not clear how well it gets into cells without the correct transport protein, Transcobalamin II. In any case b12 is normally handed off from one carrier to another before it gets into the cells and there are a number of things that can go wrong along the way:

When we eat a food with b12, the b12 is first released from the food in our stomach, where it binds to haptocorrin (transcobalamin 1) which is released I think from our salivary glands. This protects the B12 from being destroyed by stomach acid.

Past the stomach, pancreatic enzymes break down haptocorrin. Along with the change in pH that accompanies ... I think it's bile release but maybe pancreatic enzymes too ... anyhow so pH change plus pancreatic enzymes allows the B12 to bind to intrinsic factor, which itself only gets released from parietal cells when the chyme is acidic enough.

As you can imagine, low stomach pH would throw a real wrench in the works here, as not only would it prevent the production of intrinsic factor, prevent the release of pancreatic enzymes (which are also released in response to acidic chyme), but it would also allow the haptocorrin to "hold" on to the B12 more tightly and prevent the B12 from binding to what little intrinsic factor was there.

Unsurprisingly, it's fairly easy to throw a wrench into a cycle this complex. Coeliac disease, for instance, is often associated with low b12. Also a whole host of drugs can cause low b12, usually by reducing stomach acid I think: Antacids [maalox, MOM, Mylanta, Tums], histamine (H2) blockers [Zantac, Tagamet, Axid, Pepcid], proton pump inhibitors [Prevacid, Prilosec, Nexium,. Omeprazole, Acidhex], antidepressants [Celexa, Effexor, Elavil, Nardil, Paxil, Prozac, Zoloft, Wellbutrin], benzodiazepines [Ativan, Librium, Valium, Xanax] and more [https://www.celiac.com/articles.html/vitamin-b12-and-celiac-disease-r3657/].

But back to the chase: So ideally, B12 is now bound to intrinsic factor, and that allows it to be absorbed in the apical membrane at the terminal ilium. Inside those cells the intrinsic factor is removed and the B12 is handed off to transcobalamin II, which then circulates in the blood and is taken up by the cells. Incidentally, transcobalamin II's binding affinity for B12 increases markedly in the presence of glutathione (https://forums.phoenixrising.me/thr...tamin-b12-so-high-for-me-cfs-treatment.15006/). How our glutathione issues would impact B12 transport, I'm not sure. But I suspect it won't be helpful.

So that's how it's supposed to work. But there's one more twist: Most of the b12 in our blood is not actually bound to transcobalamin II. It's bound to haptocorrin or transcobalamin III, and I don't think we don't actually know much about the purpose of this, but as far as I can tell the B12 bound to haptocorrin and transcobalamin III is not taken up by most cells. (It's hard to get information on this so the most recent paper mentioning this that I can get is a small blurb from sciencedirect.com (https://www.sciencedirect.com/topics/medicine-and-dentistry/transcobalamin-ii). Search the text "Transcobalamins I and III bind the greater proportion of plasma vitamin B12 but does not liberate it efficiently." Or if you're at a university with access, go here (https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780702072123000232).)

This matters, I think, because of the possibility that oral B12 lozenges may fail to help where B12 injections will help because with oral B12 or lozenges some—perhaps most—of the B12 that makes it into the blood will be bound to haptocorrin instead of transcobalamin II. Usually when people test for B12 deficiency they test for total serum B12, meaning that if you boosted your B12 that was bound to transcobalamin I it might look like your B12 was fine when actually you didn't have enough B12 that was bound to transcobalamin II. There's a new test that looks just for the B12 bound to transcobalamin II called the "holotranscobalamin" test (holoTC) but it's expensive.

So this is a long way of saying that B12 in food is all well and good, but if there's a holdup somewhere in the long chain of custody from your mouth to your cells then B12 from food (or from lozenges) may not be helping you much, and you may need B12 injections.
 
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Victronix

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I've read some horror stories, initially, of people who tried injecting and nearly passed out, although I know that most people probably don't have that reaction. I'm an extreme "sensitive", so I've always been afraid to even try injecting. Lozenges have mostly worked for me, but never fully ideally. The oils sound interesting, although I've also been afraid to try those... Paranoid, basically. For example when I started taking estrogen, my cortisol went up and I had a total meltdown, had no idea what was going on. My doctor said she'd never seen that reaction. It's just how I am, so I have to be careful.
 

aaron_c

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@Victronix Yeah the oils seem promising as well--in theory they would bypass all the same problems that injectable B12 does. I tried to order some last year but....I can't remember if I never received any or if it was just delayed for way too long. And so I went with the injections and they worked and haven't looked back.

For what it's worth I used to have atypical (or typical for ME but atypical for everyone else) reactions to all sorts of stuff too. One DHEA pill gave me insomnia for 48 hours. Et et. And I do know of some very sensitive people in situations that were making them more sensitive than they might have been, and they did benefit from B12 injections. But obviously we're all individual. I mostly thought this might be of interest to people who tried oral B12 and had the somewhat typical response where they feel (relatively) great for maybe two weeks and then it kind of loses it's power and it becomes questionable if it's doing anything.