No love of B2 here - a warning about riboflavin

[Gondwanaland]

Hi izzy, I'm taking ionic molybdenum drops. Possibly not enough, since I've got sulfur issues, too.
The itchy face & scalp had a hot quality, so I'm thinking that was more inflammation. How the B2 would cause that, I don't know.

Moly never worked for me, probably b/c together w/ B2 it increases uric acid.
http://forums.phoenixrising.me/inde...bolism-simplified-chart-and-b-vitamins.34375/

 

[aaron_c]

Hi @picante

Yes, I should backpedal. I see now that B2, in addition to being required for MTHFR is also required for methionine synthase reductase, the enzyme that regenerates methylcobalamin in methionine synthase when the methylcobalamin becomes oxidized to cobalamin(II), which under normal conditions occurs once every 2000 cycles. (See this study, which also indicates that at least one MTRR mutation would decrease enzyme activity 10-14 fold.) So theoretically, B2 might play a role in methylcobalamin recycling for some people. Of course, since B2 also plays a role in MTHFR, it may be that B2 deficiency would deplete one of methylfolate enough that a moderate jam in methionine synthase reductase would not matter. Perhaps genetics play a role here in deciding where the problem is prior to taking supplements.

Well. That is what I get for picking nits. I appreciate you willingness to take the time to converse.

I had forgotten about the methylation-hashimoto's link. I see a lot of what you pointed out about thyroid hormone being needed to convert riboflavin to the active forms. But all I can find in terms of low riboflavin (and thus, low folate cycling) causing thyroid disease is Rich Van K suggesting that the improvement is due to improved glutathione preventing the thyroid from tearing itself apart and providing little pieces for the immune system to learn to attack.

I'm sorry that I cannot help with the itching sensation, although I hope you will let us know if you find a solution (other than backing off of B2).

I thought I'd move the discussion of BH4 metabolism to this thread.

 

[picante]

Well. That is what I get for picking nits. I appreciate you willingness to take the time to converse.

To misquote a phrase, "You're very clever, young man, but it's nits all the way down." In this business of tweaking our protocols to improve methylation / NOS / etc., my impression is that nits is all there is.

And don't mind me -- I like to joke around (in a very INTJ sort of way). I'm teasing you when I ask you to send nits to Montana. You are waaaay ahead of me in both the breadth and depth of your understanding. I just started learning about methylation in June.

Rich Van K suggesting that the improvement is due to improved glutathione preventing the thyroid from tearing itself apart and providing little pieces for the immune system to learn to attack.

That's helpful. Any little hint of a mechanism is always helpful.

I'm still undoing a bunch of recent changes in reverse order. The itching is gone. The low back inflammation is almost gone. The depression is gone, although I haven't yet had any inexplicable bursts of happiness (something that was actually happening in early December -- a hint of my former self!).

Next step: Try and find out whether the one itty-bitty dose of dessicated pig thyroid is helping or harming. I'll have to go back to all T3 to find out. I sure wish I knew whether T3 can convert riboflavin. I haven't found a blessed thing.

 

[dannybex]

My ideal dose of riboflavin is 5mg daily divided in two (along with the other Bs). When I tried to up it to 8mg I got multiple chemical sensitivities symptoms (e.g. difficulty breathing). When I went back to 5mg things got better.

With just a 3 milligram increase? Your digestion must be amazing!

 

[Gondwanaland]

With just a 3 milligram increase? Your digestion must be amazing!

That was during magnesium deficiency and I was extremely sensitive to supplements that raise ammonia/uric acid like B2.

 

[Freddd]

This FMN supplement contains 18 mg riboflavin from 25 mg flavin mononucleotide. It's not a lot, and I could easily cut it in half. And no, I didn't experience a greater need for potassium while I was taking it, including the one day when I took 2 tablets.
What concerned me was the inflammation. I still don't understand why it would trigger inflammation. It has continued to diminish today. The depression is gone, so presumably that was from the B2 as well.
If the B2 was helping me make nitric oxide, I would have felt better, not worse. I assume, then, that I'm missing a co-factor, which could be T4, or B3, or both, or....

Hi Picante,

You are remembering half of what I said about B2. Half was about needing more potassium. The other half is that the need for methylfolate goes up too. B2 drives the need for folate. When that happens paradoxical folate deficiency or different/increased partial methylation block occurs and immediately inflammation increases, itching on scalp and face the day before acne type lesion come out, increased asthma, allergies, multiple chemical sensitivity, edema, IBS and so on.

here is the most recent update to the folate section of the potassium and folate induced deficiency symptoms

Group 2a/b

IBS – Diarrhea alternating with constipation, IBS – Normal alternating with constipation
Headache, Increased malaise, Fatigue


Group 3 - Induced and/or Paradoxical Folate deficiency or insufficiency

These symptoms appear in 2 forms generally, the milder symptoms that start with partial methylation block and the more severe symptoms that come on as partial methylation block gets worse or very quickly with methyltrap onset.

Edema - An additional thing I would like to mention. I would never have found it without 5 years of watching the onset of paradoxical folate insufficiency and trying to catch it earlier and earlier and to figure out what was causing it and to reverse it. For me the onset order goes back to the day of onset now with edema and a sudden increase of weight. I noticed that within 2 hours of taking sufficient Metafolin I would have an increase in urine output.

Old symptoms returning
Edema

Angular Cheilitis, Canker sores,

Skin rashes, increased acne, Increased itchy acne on scalp and face, Skin peeling around fingernails, Skin cracking and peeling at fingertips,

Increased hypersensitive responses, Runny nose, Increased allergies, Increased Multiple Chemical Sensitivities, Increased asthma, rapidly increasing Generalized inflammation in body, Increased Inflammation pain in muscles, Increased Inflammation pain in joints, Achy muscles, Flu like symptoms

IBS – Steady diarrhea, IBS – Diarrhea alternating with normal, Stomach ache, Uneasy digestive tract,

Coated tongue, Depression, Less sociable, Impaired planning and logic, Brain fog, Low energy, Light headedness, Sluggishness, Increase irritability, Heart palpitations,

Longer term, very serious

Loss of reflexes, Fevers, Forgetfulness, Confusion, Difficulty walking, Behavioral disorders, Dementia, Reduced sense of taste, bleeding easily

 

[picante]

You are remembering half of what I said about B2. Half was about needing more potassium. The other half is that the need for methylfolate goes up to. B2 drives the need for folate.

Woot woot! THANK you, @Freddd. My ND & I were just scratching our heads over this. That makes total sense, I will tell him.

BTW, I printed up @sheclimber's very recent & very clear summary (http://forums.phoenixrising.me/index.php?entries/my-understanding-of-freddds-protocol.1697/) and I gave the ND a copy. He was impressed and called it a "really good protocol".

 

[Gondwanaland]

My ND & I were just scratching our heads over this.

You forgot about the diagram I posted here

 

[Freddd]

You forgot about the diagram I posted here

Hi Gondwanaland,

I don't see the AdoCbl associated with the Krebs cycle end of things. Also the B12 associated with B6 and folate should be MeCbl. Without AdoCbl the mitochondria don't work. I consider that a sizable flaw in this diagram, to not show the absolutely required AdoCbl.

 

[Freddd]

Hi @picante

Yes, I should backpedal. I see now that B2, in addition to being required for MTHFR is also required for methionine synthase reductase, the enzyme that regenerates methylcobalamin in methionine synthase when the methylcobalamin becomes oxidized to cobalamin(II), which under normal conditions occurs once every 2000 cycles. (See this study, which also indicates that at least one MTRR mutation would decrease enzyme activity 10-14 fold.) So theoretically, B2 might play a role in methylcobalamin recycling for some people. Of course, since B2 also plays a role in MTHFR, it may be that B2 deficiency would deplete one of methylfolate enough that a moderate jam in methionine synthase reductase would not matter. Perhaps genetics play a role here in deciding where the problem is prior to taking supplements.

Well. That is what I get for picking nits. I appreciate you willingness to take the time to converse.

I had forgotten about the methylation-hashimoto's link. I see a lot of what you pointed out about thyroid hormone being needed to convert riboflavin to the active forms. But all I can find in terms of low riboflavin (and thus, low folate cycling) causing thyroid disease is Rich Van K suggesting that the improvement is due to improved glutathione preventing the thyroid from tearing itself apart and providing little pieces for the immune system to learn to attack.

I'm sorry that I cannot help with the itching sensation, although I hope you will let us know if you find a solution (other than backing off of B2)
I thought I'd move the discussion of BH4 metabolism to this thread.

Hi aaron_c,

I would be more inclined to go along with the idea of hyper-sensitive responses that methyltrap folate deficiencycauses for Hashimoto's. The thyroid contains a lot AdoCbl (working, in mitochondria) and when the mitochondria crank out MMA instead of ATP all sorts of tissues tear themselves apart. So you have damage caused by low AdoCbl, methyltrap caused by low MeCbl and manifesting as severe folate deficiency with all it's hyper responses and suspected autoimmune cause.

 

[Gondwanaland]

@Freddd I even modified the diagram to erase "folic acid" from it (so it isn't a complete diagram at all, not even up to date). I consider it as a trouble shooter only, when something goes whacky. It helped me to understand why I felt worse on folate and then later on B2

 

[picante]

Dear izzy, I looked at that diagram and said, ooh, isn't that pretty, and with those colors I can pick out B2 -- look, there it is in the Krebs cycle! -- and over there, too, somewhere between folate and uric acid!

I will not elaborate, I think this info speaks for itself...

And then I wondered, what is this diagram saying to izzy the scientist that it's not saying to me the linguist?

That's as far as I got, .

 

[Gondwanaland]

@picante I never thought the colors would be THAT distracting

 

[Gondwanaland]

With just a 3 milligram increase? Your digestion must be amazing!

I call that liver overload

 

[aaron_c]

@Freddd: Very interesting. I've had poor luck finding an article that I can read (for free), but in googling around I have found quite a few that claim a morbidity of pernicious anemia and Hashimoto's, which would seem to support what you are saying.

 

[Freddd]

@Freddd: Very interesting. I've had poor luck finding an article that I can read (for free), but in googling around I have found quite a few that claim a morbidity of pernicious anemia and Hashimoto's, which would seem to support what you are saying.

Hi Aaron-c,

If we were going in after the fact and naming things in a way that made sense, they wouldn't end up the way they are. So "B12" is officially only CyCbl, the worst possible analog that works at all because of a lab mistake that won the Nobel prize. "Folate" unspecified is folic acid, the worst possible folate that works for some people to some degree. "An intrinsic factor" became "The Intrinsic Factor". So a deficiency of The Intrinsic Factor became known as The Pernicious Anemia even though the anemia is a macrocytic anemia identical in every way no matter how it is caused. In fact a person with Pernicious Anemia may not even have any macrocytic anemia, all they need is the lack of IF.

The difference between MS and Sub Acute Combined Degeneration is that MS has a serum cobalamin level > 160pg/ml whereas SACD might have 159pg/ml body cobalamin level. They both have cerebral B12 deficiencies even though b12 deficiency is ruled out for an MS diagnosis. And to top it off, MS tends to be unilateral instead of bilateral. And early stages with > 160pg/ml cobalamin without IF problems but the same cerebral b12 deficiencies and tons of common symptoms are called CFS and FMS.

If you go by diagnoses and the tests and the NAMES (that are very arbitrary in many ways) you will rapidly find that they don't make a lot of sense which may have a lot to do with how poorly they are treated.

 

[picante]

I would be more inclined to go along with the idea of hyper-sensitive responses that methyltrap folate deficiencycauses for Hashimoto's.

Trying to put this all together: So methyl trap is too much Mefolate for the amount of MeB12/AdB12? And this produces folate-deficiency symptoms? And this somehow ties in with Hashimoto's -- to produce hyper-sensitive responses?

The thyroid contains a lot AdoCbl (working, in mitochondria) and when the mitochondria crank out MMA instead of ATP all sorts of tissues tear themselves apart.

So if the thyroid is lacking AdoCbl, then do we get anti-thyroid antibodies? And if the mitochondria (anywhere in the body) are lacking AdoCbl, we get more MMA?

My MMA was smack in the middle of the range (174 nmol/L) in July, which was before I started your active B12 protocol, @Freddd. Does MMA fluctuate a lot?

Half was about needing more potassium. The other half is that the need for methylfolate goes up too. B2 drives the need for folate. When that happens paradoxical folate deficiency or different/increased partial methylation block occurs and immediately inflammation increases, itching on scalp and face the day before acne type lesion come out, increased asthma, allergies, multiple chemical sensitivity, edema, IBS and so on.

This told me that when I try adding B2 again, I will need more Mefolate. It's very clear: the B2 triggered inflammation, itchy face & scalp, low mood, impaired planning and logic, brain fog, and low energy. I just hadn't learned to recognize all of these symptoms as low Mefolate.

So you have damage caused by low AdoCbl, methyltrap caused by low MeCbl and manifesting as severe folate deficiency with all it's hyper responses and suspected autoimmune cause.

This balancing act has been giving me so much grief! It didn't help that I went on the Australian Ad/MeB12 oil for the month of December. The ratio is 3:1. That means it is 25% MeB12, which is getting very close to the 20% ratio you talked about here: http://forums.phoenixrising.me/index.php?threads/mixing-b12-types-and-brands-ratios.31434/
Presumably, with transdermal absorption, you would wind up with both B12s in your bloodstream, and the AdoB12 could block the MeB12, according to your analysis. My experience was a very gradual dive into lower energy, much lower brain function, and lower mood.

OR WAS IT SIMPLY mefolate deficiency???

 

[Freddd]

Trying to put this all together: So methyl trap is too much Mefolate for the amount of MeB12/AdB12? And this produces folate-deficiency symptoms? And this somehow ties in with Hashimoto's -- to produce hyper-sensitive responses?

Hi Picante,

No, not at all. Methyltrap is caused by lack of MeCbl in the cell so that then methylfolate is expelled from the cell when there is no MeCbl for it to work with, which then causes a fail with severe folate deficiency symptoms. The extreme hypersensitivity-responses is caused by methylfolate deficiency along with suspected auto-immune responses

This told me that when I try adding B2 again, I will need more Mefolate. It's very clear: the B2 triggered inflammation, itchy face & scalp, low mood, impaired planning and logic, brain fog, and low energy. I just hadn't learned to recognize all of these symptoms as low Mefolate.

More B2, beyond getting healing going can increase the need for methylfolate and potassium and decrease healing. B2 can push the needs to insatiable levels with less healing. So B2 has an optimum effect and is less effective on both sides, over and under the optimum dose.

So if the thyroid is lacking AdoCbl, then do we get anti-thyroid antibodies?

That is unknown. In the thyroid, as elsewhere, if there is inadequate AdoCbl working in the mitochondria, functionality falls off and eventually damage is done. How the damage is done is not determined. Some blame it on the MMA and some blame it on the failure to produce ATP. Then if there is additional damage it is said to be caused by autoimmune antibodies. Methyltrap caused low folate, or low folate from any cause produces widespread inflammation in those triage levels affected. How the autoimmune and inflammation are connected causally, if they are, I don't know.

And if the mitochondria (anywhere in the body) are lacking AdoCbl, we get more MMA?

When the series of reactions leading to ATP fails, one way it fails associated with lack of AdoCbl is to produce MMA. However, as failure appears to happen by layers, and sometimes in different pharmacokinetic compartments (brain produced MMA is in the cerebral spinal fluid), before the uMMA is "high" considerable damage may already be done on some triage levels. High MMA basically says that the body is already suffering multi-organ failure.

 

[nandixon]

Now notice in the diagram that when glycine is used to make 5,10-methylene THF, ammonia is released. What do you need to get rid of ammonia? BH4. What is one of the things you need to make serotonin? BH4.

The one clue I might have is that if the depression that is accompanying your other symptoms is related to ammonia, perhaps the riboflavin is allowing NOS to function better, thus allowing it to use up BH4 as it moves ammonia towards urea. About a year ago I was on a thread discussing if NOS uses up BH4, and if so, how. My experience at least points towards it doing so, but we never did find out how.

I'm sure you two are aware of this now, but I just wanted to update this thread so that other people reading this later know that we actually figured out that ammonia does not cause a biochemical consumption of BH4. (It can cause a pathological consumption via neurotoxic effects on microglia, for example.)

The following 2012 reference (and the earlier references cited within it) tells us that BH4 acts as a catalyst for NOS and is not actually consumed. (Yasko apparently mistakenly thought it was consumed at the time she formulated her ideas.):

Therefore, BH4 is not consumed during NOS catalysis, but is necessary for both NO synthesis and release.

Recoupling the Cardiac Nitric Oxide Synthases: Tetrahydrobiopterin Synthesis and Recycling

Thus, arginine (from ammonia) moving from the Urea Cycle to NOS does not use up BH4.

(Also see the following post for a caveat - which may not be very important, because the amount of arginine moving from the Urea Cycle and actually used by NOS is probably fairly controlled, at least in the sense that that extra arginine is not going to significantly drive NOS on its own, I don't think - at least with respect to eNOS:
http://forums.phoenixrising.me/inde...s-this-a-myth-or-something.34538/#post-537781)

 

[picante]

Thank you, @nandixon. I'm quoting you from the post you linked:

And while it's true that BH4 only acts as a catalyst for this reaction and is not actually consumed (which Yasko may not have realized), if sufficient methylfolate is not present to protect the BH4 from peroxynitrite, then decoupling occurs and significant loss of BH4 could result as a vicious cycle ensues (i.e., decoupling->superoxide-> peroxynitrite->destruction of BH4-> more decoupling-> superoxide, etc.).

I'm so grateful to everyone who is helping me put the pieces together here on PR, and the biggest piece for me is the need for methylfolate on so many levels. I could not distinguish between low active B12s and mefolate deficiency symptoms.

I know @ahmo has been hot on the track of this ONOO issue, and I haven't seen her yet on this thread.