The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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Pyroluria, is it real? I'm really skeptical and here is why.

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Deltrus, Apr 24, 2016.

  1. Deltrus

    Deltrus Senior Member

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    - The original schizophrenia claim that brought attention to pyrroles has been disproven.

    Originally pyrroles were blamed for schizophrenia because people who took LSD had elevated levels of pyrroles in their urine.

    Already this is a fallacy, the elevated pyrroles may have no effect on cognition, they may just be an inconsequential downstream effect of LSD.

    Secondly, we know that hallucinogens bind to and antagonize different serotonin receptors, which then have a direct effect on our mind. Hallucinogens do not cause people to hallucinate through pyrroles. This is extremely well studied.

    In conclusion the original reason researchers were drawn to pyrroles has already been disproven. Pyrroles are not responsible for the hallucinations during LSD.


    - B6 and Zinc, do they really bind to pyrroles? Is this effect actually significant?

    I have seen no proof of this anywhere, everyone just says it is a fact. I'm starting to believe that this was just made up. You would think this would be a very easy thing to test.

    - Even if B6 and Zinc deficiency correlate with elevated pyrroles, these two vitamins/minerals are involved in almost every metabolic pathway in the body. Wouldn't it make more sense if B6 and/or Zinc deficiency caused elevated pyrroles?


    - Websites say stress increases pyrroles which decreases b6 and zinc. You know what else causes decreases in b vitamins? Oxidative stress, which can be a result of emotional stress.

    Due to mechanisms described in the numerous refeeding syndrome threads, a deficiency in one nutrient will cause a deficiency in others. Zinc deficiency will coincide with b vitamin deficiency. B vitamins are heavily influenced by oxidative stress. Pyrroles are not necessarily the mechanism of stress induced vitamin depletion.

    - It is entirely possible that something else, such as lead etc, causes elevated pyrroles, and also zinc/b vitamin deficiency.

    Overall:

    The original claim that brought attention to pyrroles was bogus.

    The "B6 and Zinc binding to pyrroles in significant amounts" claim has no proof that I can find and seems to be made up.

    Pyrroles and B6/Zinc deficiencies might be related, but we can't say how.

    Refeeding syndrome, heavy metal poisoning etc may give long lasting B6/Zinc/Nutrient deficiency that resembles pyroluria.

    Pyroluria might be real, b6 and zinc might bind to pyrroles in significant amounts, but we have no proof available.

    Pyrroles might be correlated with nutritional deficiencies, not the cause of them. The same thing could be said with hundreds of substances in our body.

    It seems very likely that pyrroluria is a case of someone looking too hard for patterns, and then sensationalizing their claims without actually verifying anything with rigorous systemic study.


    If someone has good reasoning against my thinking, I'd love to hear it. I can't prove pyroluria doesn't exist, but once I stepped back and considered all the possibilities, it just doesn't seem likely.

    I'm all for B6 and Zinc supplementation though, just not this reasoning behind it.
     
    Last edited: Apr 24, 2016
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  2. alicec

    alicec Senior Member

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    I agree. I became a bit interested in this some time ago but didn't find anything convincing in my reading and didn't pursue it.
     
  3. Gondwanaland

    Gondwanaland Senior Member

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    B6 and zinc are recommended for diabetics, so I am pretty sure they get deficient due to insulin resistance. B6 is the #1 vitamin to improve sensitivity to insulin (as I have read in many sites for diabetics - haven't really looked up research papers on it).
    EDITING to add references:
    http://diabetes.diabetesjournals.org/content/38/7/881.abstract
    http://www.ncbi.nlm.nih.gov/pubmed/19955400
     
    Last edited: Apr 25, 2016
  4. garyfritz

    garyfritz Senior Member

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    There is a long list of odd symptoms that identifies pyroluria, including things as strange as being born into a family of lookalike sisters, not remembering your dreams, not liking to eat protein, being hypersensitive to criticism, and others. That seems like a very strange combination of symptoms. But my 20-year-old son shows about 20 of those symptoms. I just got a pyroluria test kit for him. I'm crossing my fingers that it IS real, and that we can help his situation with zinc and B6.
     
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  5. Gondwanaland

    Gondwanaland Senior Member

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    Last edited: Apr 25, 2016
  6. barbc56

    barbc56 Senior Member

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    I'm not familiar with this disorder though I've heard the name. I read the following article and I found it very confusing. But it might be helpful to others who understand this better so I'm posting it.

    It does say something about B6 decreasing the side effects of medication given to people with schizophrenia. The authors seem to think it does not exist but then talk about King George, the one from the movie The Madness of King George who had it. I'm curious about how the disorder is described, even if it doesn't exist.

    Maybe I'm just not comprehending what I read and will reread it later as well as other sourced when I'm not so foggy and it's not so late. Sometimes the links will provide more detail.

    https://www.sciencebasedmedicine.org/pyroluria-and-orthomolecular-psychiatry/

    Edit. I think it's saying that what is described as Pyroluria today by some doctors is not the same disorder.
     
    Last edited: Apr 24, 2016
  7. CCC

    CCC Senior Member

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    Have a read of this article. It covers:
    • urine collection procedures (to avoid a false negative)
    • a good simple overview of the biology
    • suggested supplements - zinc, vitamin B6 and/or pyridoxal 5-phosphate (activated B6), GLA (an essential omega 6 fatty acid found in evening primrose, borage and black currant oil), Vit E and magnesium (scroll down to see more detail, and a few extra cofactors such as vitamin C)
    It also contains a warning that saved us - don't go wantonly supplementing with zinc without keeping an eye on copper levels. My son's copper level crashed just before Christmas and needed urgent correcting.

    Our doctor started my son on the pyrrole treatment a year ago. It did nothing; you're supposed to see something within days to weeks. It wasn't until we started methylation with the FP (as of Jan16), added FMN (March16), then went added zinc and P5P back in (to manage dogdy Zn/Cu balance - April16) that we started to see the effect of extra Zn and B6 (as a pyrrole treatment, on top of low doses in multi vitamins/minerals).

    I should add that the evening primrose oil and magnesium are now essentials for us. I suspect the vitamin E is too, but we haven't been tinkering long enough with that to be certain.
     
  8. Deltrus

    Deltrus Senior Member

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    @CCC I'm glad you got something that worked for your son.

    I still don't think getting good results from that supplementation plan proves pyroluria is real. Zinc and b6 would be in very high demand after fixing methylation blocks and restarting cellular growth. Thus, they would be constantly low. Pyrroles may have nothing to do with it.

    I normally wouldn't be so contrary, but this is more of a debate thread rather than a pro-pyroluria thread. And I want people to realize that getting good results with b6 and zinc doesn't mean pyrroles are are causing a deficiency. There are many likelier explanations, the simplest one being that pyrroles are elevated as a result of b6/zinc deficiency. This is assuming pyrroles are even related, which they may not be.


    My question is, why would zinc primarily bind to pyrroles and not the other +2 cations such as calcium? Calcium is over 200 times more concentrated in the blood.

    Why b6 and not the other b vitamins? Do we even know at what location pyrroles are supposed to bind to on the b6 molecule?

    Are we all just going to accept that these two nutrients bind to pyrroles without any proof? Why didn't the guy who invented this thing release his proof?

    I swear, anyone could release a theory that is just as solid as this pyrrole theory. Any claim is "credible" if you say that you have 40 years of unreleased research, state things as facts, and make everything sound good.
     
    Last edited: Apr 24, 2016
  9. CCC

    CCC Senior Member

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    @Deltrus

    Sorry to have appeared to have sidetracked your thread, but @garyfritz made some comments that needed a response - especially in relation to collecting procedures and then treatment. It's more than Zn and B6.

    I'll add some comments here for the sake of debate, but I hope they aren't too 'pro pyrrole' for you:

    The article I linked to has a nice explanation that described how it works. It oversimplifies the biochemistry, but if you have enough biochemistry, you'll be able to fill in the gaps.

    There is no doubt that some people have very, very high KPU levels, and they benefit enormously from the supplements. They have a label for a condition that is treatable, and the treatment works. Note that the symptoms aren't always psychiatric - for my son and many others, they aren't.

    My own opinion is that KPU (in urine) is just an indicator of metabolic issues, just as other urine outputs are also indicators of other metabolic issues. Indicator development is a tricky field, and contentious, but very high levels of KPU do seem to be useful indicators.

    The trick with indicators is to realise they they aren't two-way: having high KPU indicates a problem; having a condition does not always mean high KPU is to blame. Even the KPU literature says that only a certain percentage of schizophrenia will have high KPU. What KPU does as an indicator is help a doctor identify a group for which a certain treatment might be helpful.

    As for my son, his KPU was borderline high. For a long time I thought it was the result of other things that we'd discovered around the same time (and this is a consensus view of borderline results). But now the huge doses of Zn and B6 are having an effect, and there's never been b6 toxicity issues, I'm rethinking that idea. This is a work in progress for us.
     
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  10. Deltrus

    Deltrus Senior Member

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    I think that is fair. KPU being high may be an indicator that zinc and b6 are low, and metabolic abnormalities are occurring.

    Pyrroles may be a biomarker for certain deficiencies without actually causing these deficiencies. Thus the "pyroluria" movement would be functionally useful, despite the reasoning behind it being pseudoscience as far as I can see.

    This is exactly the type of discussion I wanted, thanks :thumbsup:.

    Also I'm totally fine with people being pro-pyroluria in this thread, I just wasn't fine with MOST posts being pro-pyroluria so I felt I had to at least add some dissenting opinion. All is good :).

    I just fully read the part of the article you linked, I missed the bottom part before.
    The bolded point is the point of contention. It seems like a plausible explanation, if we actually observed the liver doing this. But have we? I'm not 100% sure how the liver works, I just am pretty sure we have no actual data on this phenomenon.

    If we had data on this actually happening, I'd be a huge proponent of pyroluria. As things are now though... there's still no proof pyrroles actually bind to b6/zinc. Pyrroles may be a biomarker of metabolic abnormalities, I admit this, but I'm still very skeptical of the "classical pyroluria" pathology.
     
    Last edited: Apr 24, 2016
  11. CCC

    CCC Senior Member

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    @Deltrus
    From memory, it's something to do with the P450 pathway thingy in the liver. There's a bit of literature around, but it takes some digging to find it. I did a lot of reading a year ago, but that was a year ago. I wouldn't know where it is now.
     
  12. Deltrus

    Deltrus Senior Member

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    Perhaps I'l try to learn more about the liver. I'l have to find some khan academy videos tomorrow to start me off.
     
  13. junkcrap50

    junkcrap50 Senior Member

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    Briefly searching after reading this thread, I found this quote from this link: http://www.lumigrate.com/forum/pyro...llactamuria-hmu-many-names-causes-connections . Some of the its phrases seems to be widely copied on other sites about pyroluria, so I don't know where this claim originated from.

    If you search google, "pyrroles" and "aldehydes," you'll see results indicating that they do seem to react with each other. However, these results appear to be mostly in regard to synthetic molecular chemistry, not biochemistry neccessarily. (I didn't dig too deeply).

    As for the claim that a pyrrol-aldehyde then likes binds to zinc. I'm not sure. Couldn't find evidence for that claim so easily.

    This information should be helpful in guiding anyone to search more deeply on this topic. Hope it helps.
     
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  14. alicec

    alicec Senior Member

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    King George is thought to have had porphyria which is a well characterised and documented metabolic disorder (usually of genetic origin) which can include psychiatric symptoms. It is not the same as pyroluria though there are links.

    Porphyrins, which are heme precursors, accumulate in porphyria. Pyrroles are actually components of the more complex porphyrin molecule.

    Maybe this link between porphyrins and pyrroles is relied on to give pyroluria the same status as porphyria. However the same degree of evidence is just not there.
     
  15. PeterPositive

    PeterPositive Senior Member

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    @Deltrus
    The evidence in favor of "pyroluria" is an examination of lab tests results, correlating HPL (hydroxyhemopyrrolin), not Kryptopyrroles, with levels of Zn, B6 and biotin.

    http://www.walshinstitute.org/uploa...rning-mauve-factor-part-1-galley-feb-2008.pdf

    I am equally skeptical about this "Pyroluria" business, which seem to be taken as a fact by many alternative practitioner. I did the urine HPL test in 2014 which came back moderately elevated (see signature). Later I tested my levels of Zinc and B6 after supplementing for several months (Zn=30mg and P5P=60mg) and the results showed low zinc in both serum and RBC and high B6.

    Maybe it's coincidence or maybe there's a correlation... in any case it looks like I have problems maintaining decent levels of Zinc even with daily supplementation.

    This could be caused by poor absorption (and not HPL) as I suffer from chronic GI inflammation, which the article I linked indicates as a likely cause of elevated HPL.

    By the way... I don't think it would be that difficult to settle this "controversy" by simply assessing the amount of excreted Zn and B6 in people who have elevated HPL. If this turned out to be a thing then it would make the pyroluria symptoms more plausible.
     
    Last edited: Apr 25, 2016
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  16. barbc56

    barbc56 Senior Member

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    Thanks! My brain is processing all the pee words as the same! :rolleyes:

    This does make me want to watch The Madness of King George again.

    @PeterPositive

    There are several studies in the article but I haven't had a chance to read them. ​
     
  17. alicec

    alicec Senior Member

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    I've tried to follow up on some of the references linked in various replies to once again see if I can make any sense of the claims about pyroluria.

    I haven't been exhaustive - not enough energy or interest - but if there were something to be found I think I would have found it by now.

    I'll just go through some of the claims and note what I have or haven't been able to find along with my own interpretation of garbled reports.

    The intermediates of haem biosynthesis are porphyrins, which are tetrapyrroles. The biosynthetic steps are under very tight control so that potentially toxic intermediates do not accumulate. Rare genetic defects (or acute heavy metal poisoning) in various enzymes in these pathways do lead to accumulation of different porphyrins - resulting in the various porphyria disorders. You can just google porphyria and you will see each of the different enzymes involved and the various forms of porphyria which result when they don't function well.

    I could find nothing indicating that any pyrrole (which presumably would result from breakdown of porphyrins) accumulates though presumably it might.

    The second part of the quote suggests that there is nothing wrong in haem pathways as such, but that there is a problem with the P450 enzymes which normally break down these accumulating pyrroles.

    The cytochrome P450 enzymes (of which there are many) are our phase I detox enzymes, responsible for the first part of the processing of an enormous range of exogenous and endogenous compounds, ultimately leading to their disposal via the kidneys or bowel.

    I can find nothing whatsoever about any defects in P450 which results in pyrrole accumulation.

    Phase I detox chemically changes substances, making them more water soluble. Phase II enzymes then add (ie conjugate) various substances - eg glycine, glutathione, glucuronide, to further assist with processing.

    B6 and zinc are not included among these things. They may well be cofactors for some of the enzymes involved, but they are not the conjugants. It is impossible to know what pathway this garbled quote is really referring to.

    I can find an industrial process which starts with a reaction between a pyrrole and an aldehyde to synthesise a porphyrin. Otherwise nothing whatsoever which supports anything in this quote.

    I then followed up on two old references from Pfeiffer which the Walsh article quotes as showing that kryptopyrrole binds to B6 and zinc. Both references make the statement but give no reference. They most certainly do NO studies that establish this fact, as Walsh implies. Now it may be that Walsh made a mistake with the references but I don't have the energy to follow it up any further.

    If the evidence exists, it shouldn't be this hard to find.

    Finally I tried to follow up on HPL, supposedly the real culprit behind pyroluria.

    I could find no scientific studies of this compound, just the usual websites endlessly repeating the same stuff.

    To be really confusing, I did find one article which shows how HPL is chemically formed. It shows the starting point as an arachidonic acid derivative (one of the E2 prostaglandins) and states that Mauve factor is derived from oxidative injury to lipids.

    What, I asked myself, does this have to do with haem metabolism which others say is the source of pyrroles.

    Nothing as far as I can tell!

    As an aside, this article implies that glutathionation might be the phase II pathway that the garbled quote above is really referring to.

    I have a strong scientific background and can understand the various papers I have been looking at. I also have a very open mind and am willing to accept the weird and unconventional. However I can find no evidence whatsoever that supports these various claims.

    I think the stuff proliferating on the internet about pyroluria is bunk.

    I presume a lot of it started from someone speculating about possible mechanism to explain some of the early observations. Over time the speculations have become fact and have then been completely garbled by others with poor scientific understanding.

    There might be something to it but it doesn't work the way its proponents claim.
     
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  18. Deltrus

    Deltrus Senior Member

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    @alicec you are pretty much saying what my intuition has been telling me. I'm not experienced with this area enough, like you are.

    If someone has an increased need for zinc and b6, I find it very likely that the body is sucking them up very quickly, perhaps because of:

    - Refeeding syndrome.

    - Nutrient/enzyme bottle necks that can be overcome with megadosing. People have this with b12, b1, b2 etc. Higher concentrations of a substance make a single enzyme output more end products. And yet the body still tries to maintain a non-megadose concentration so you have to keep megadosing.

    - Heavy metals confusing the body and deactivating b6/zinc dependant enzymes.

    - Autoimmunity / oxidative stress damaging zinc and b6 dependant structures.

    These things actually have endless amount of solid research I could read for days and still not get caught up. They are plausible alternate explanations for increase zinc and b6 need.

    Meanwhile, I see no research on pyrroles binding to B6 and zinc. I see zero other cases of vitamins getting bound to random substances.

    There are stuff like anti-thiamine factors. These mess with the absorption of thiamine, or they mess with the enzymes which process thiamine. They don't bind to thiamine.

    If anyone has a proven example of stuff that binds to specific vitamins, that would prove my line of thinking wrong.
     
    Last edited: Apr 25, 2016
  19. Deltrus

    Deltrus Senior Member

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    Also correct me if I'm wrong, aren't things that float around in our blood and bind to things randomly, called oxidants and anti-oxidants? Isn't there constantly millions of stuff binding to things weakly and separating etc all the time? And strongly positively charged things, or negatively charged things, aren't they oxidants and anti-oxidants?

    Actually my minds not good enough to be posting. The problem is, either I don't post because I know I can't hold myself up to my standards of quality, or I post and make some good points but can also lead people astray because nobody has the energy to verify things.

    Good research, solid arguments, are something that need to be crafted and that takes up so much energy.
     
  20. ahmo

    ahmo Senior Member

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    After scoring only marginally high on pyroluria questionnaire, I started the supps. They made a great difference for me. this included halting the sun intolerance I'd had since onset of ME. Also within 5 days, my negative thoughts reversed. There were an odd collection of symptoms that I and my natal family all had, including loose joints. In fact, my loose shoulder cleared when I removed sulfur from my diet. I followed Klinghardt's suggestions re pyroluria and detoxxing. The things he says about zinc and toxic metals occupying zinc receptors appeared to be true for me. In a final detox push, my body needed a lot of zinc. It's never needed a large dose since. And many aches and pains were relieved in the process of chelation.
     
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