The 12th Invest in ME Conference, Part 1
OverTheHills presents the first 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. Johnmac

    Johnmac Senior Member

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    I was very skeptical that pyroluria existed, even as I was preparing to treat it. As with @garyfritz, the long list of strange & anomalous symptoms seemed almost laughable. ("Pyrolurics tend to crave bacon on the third Saturday of every month...") I made myself a bit unpopular on the facebook Pyroluria forum with jokes like that.

    I tested 10.9 for pyyroles (borderline of borderline). That was about a year ago. I began the zinc & B6, & immediately felt calmer (literally overnight). For me it did away with the "dread" or "pit-of-the-stomach" type anxiety - which has never returned. There were other improvements such as softer skin. Six months in, I suddenly started having more vivid dreams again, and better dream recall, as promised. (The other morning I dreamed I was playing football, & threw myself out of bed & smashed my bedside clock. I cut my head & hand. That was a first. I took it as a sign to cut back on the B6.)

    My daughter began the protocol not long after me, & noticed a big drop in anxiety right away. Others noticed she was much more engaged socially, & happy. She hates pills, but she's sold on the zinc & B6 & P5P.

    We both tried the add-ons for a while - manganese, biotin, primrose oil. They didn't seem to do anything; and stopping them didn't either.

    A big problem for me was overdoing the zinc (up to 150 mg/day the first few months), which appeared to give me a nasty copper deficiency: raging skin infections including a boil (my first) about 2 inches wide, much worse psoriasis, crappy mood, cold hands & feet. I got the flu for the first time in years. With the boil the staph bacteria appeared to enter my bloodstream, giving me headache, nausea & fever. It took a week to knock that out, using garlic compresses. (These brought the fever down very reliably.) Anything but antibiotics - which in this day & age may not have worked anyway.

    -Cu really is one to avoid. Probably the most horrible suite of side-effects of anything I've had, bar carnitine overdose.

    In the course of treating pyroluria, OD'ing on zinc, & adding in copper to rebalance, I cured my 40-year psoriasis - twice. Then it came back. Dr Walsh says that absolute zinc & copper can have a big effect on psoriasis, but it is the Cu/Zn balance that seems to be the most important thing. I obviously hit the sweet spot a couple of times, but couldn't hang on to it.

    By the way, if you get copper deficiency, you are open to horrendous infections - it could actually be a medical emergency. You want to know how to reverse the deficiency as soon as you can. I took copper chelate 2.5 mg every 4 hours round the clock. A better way appeared to be grinding up the pill in a mortar & pestle, mixing it with some coconut oil, & strapping it to my arm in a compress: copper works best of all transdermally. (Maybe lower the dosage for TD.) I also took potassium & calcium, which hasten copper uptake, and avoided vitamin C & zinc, which slow it. The transdermal copper seemed to bring the best results. Within 4 days the infections had stabilised.

    So does pyroluria exist? No idea. Maybe some other syndrome or mechanism is at play here. The biochemist who runs B12Oils, Dr Greg Russell-Jones, says that high pyrroles happen when you are "trying to insert iron into the pyrrole ring to make heme. If there is no iron the pyrroles are excreted form the cell and you get high pyrroles."

    And:

    "Pyroluria comes either from functional B2 deficiency or iron deficiency. We are addressing this, but the concept is kind of cure, because you should be able to monitor what is going on by reduction in pyroluria."

    So once I get my iron up, I won't need pyroluria supplements according to Greg.

    (By the way, he believes the iron ranges are way too low & he is absolutely right about this. My daughter had ferritin 30, & two doctors declined to give her an iron infusion because 30 is "normal". I finally talked one into it. She had two infusions, and each one has made a dramatic difference to her functioning.)

    The copper deficiency has put me off oral supplements. I'm doing a spreadsheet on food sources of the nutrients I need, & am gradually replacing the pills etc with foods.

    As for methyl & adenosyl B12, I've found transdermal to be many times more effective than sublingual, which has anyway rotted some of my teeth. So many less pills per day there.

    Also the Greg approach is that if you get sufficient B2 (currently from a pill, but I'll soon swap that out for dairy), you don't need much or any folate, & no carnitine or potassium. I've been able to drop them too - more simplification. I've been popping pills for years, & I'm really sick of it.

    Sorry for the jumble of topics.
     
    Last edited: Apr 29, 2016
  2. garyfritz

    garyfritz Senior Member

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    @Johnmac, sounds like you got some really great results. I'm looking forward to getting my son's test results. He's vegetarian and eats mostly simple carbs, very little protein or dairy, etc, so I think things like iron might very well be helpful for him.

    Thanks for the warning about low Cu. 150mg of Zn seems like an incredibly high dose... was that much necessary? Did you start off at that level? How much B6, P5P, B2, iron, ...?

    Most of the online descriptions of pyroluria say you should be treated by a doctor so you get the "right kind" of zinc & B6, and also I think so you don't overdose and cause problems like your Cu deficiency. But I wonder how many doctors actually understand pyroluria treatment?
     
  3. TheChosenOne

    TheChosenOne Senior Member

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    I'm also a pyruloric and supplementing zinc and B6 make a huge difference.
    I believe pyroluria is just the result of something else. I still have an important candida infection and some mercury poisoning. Maybe some infections are involved as well. I'm doing a blood test next month to check this out.
    I woudn't be surprised if a huge portion of the people with pyrolle disorder have borrelia.
     
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  4. alicec

    alicec Senior Member

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    Yes both @Deltrus and I are suggesting that the mechanisms proposed on various internet sites don't add up. B6 and zinc may well be helpful but not for the reasons claimed. It could be the other way around - B6 and zinc deficiency cause pyrrole accumulation.

    Greg doesn't tell the whole story here but what he says illustrates what I think is behind the whole garbled tale of pyroluria mechanism.

    First remember that porphyrins are tetrapyrroles. A biochemist like Greg could well use the term pyrrole in a generic sense to include the whole class of porphyrins. He doesn't necessarily mean the specific substance tested for in pyroluria tests.

    Porphyrins are intermediates in haem biosynthesis. Genetic or acquired (heavy metal poisoning) defects in enzymes in this pathway lead to various porphyrias which are very well characterised.

    The very first step in the pathway is catalysed by a B6 dependant enzyme. It creates a linear compound (ALA) from glycine and succinylCoA. This is the rate limiting step in the whole pathway, the place where the tightest regulation of haem synthesis occurs.

    This step goes wrong when there is a genetic defect in the enzyme AND IN B6 DEFICIENCY. A microcytic anaemia results.

    The next step in the pathway uses a ZINC-DEPENDANT ENZYME. It turns two linear ALA molecules into a 5-membered ring structure, a type of pyrrole, called porphobilinogen. A type of porphyria results when this step goes wrong.

    The next step condenses four porphobilinogen molecules into the first of a series of porphyrins. The ultimate porphyrin in the chain is protoporphyrin IX. With the addition of ferrous iron, this forms haem b. Different porphyrias result from problems at each of the steps in the pathway.

    Details are described here if you are interested.

    As Greg notes, if iron is deficient, there are problems at the end of the chain and protoporphyrin IX accumulates.

    He doesn't mention that B6 and zinc deficiencies can result in accumulation of intermediates at an earlier stage.

    Nor does he mention the effects of heavy metal poisoning on these steps. The first two and the last step are adversely affected by lead.

    Protoporphyrin IX accumulating for whatever reason can grab a zinc molecule, forming zinc protoporphyrin (ZPP). This accumulates in RBCs and spills over into blood and urine. Indeed detection of ZPP is used to support a diagnosis of iron deficiency or lead poisoning. It is also a means of depleting zinc stores.

    Problems at the end of the line overwhelm the tight control at the beginning and feedback inhibition is lost - ALA also accumulates.

    Thus iron, zinc and B6 deficiencies as well as lead poisoning can lead to pyrrole accumulation - the term used in a generic sense. The relationship of the particular pyrrole measured in pyroluria tests is a bit of a mystery and I suspect something of a side issue, a bystander in the real events.

    I'm not sure exactly what Greg is referring to when he mentions B2 deficiencies but it could be that B2 is involved in forming succinyl CoA, needed at the first step of haem biosynthesis, or that it is involved in mobilising iron from ferritin, needed at the last step.

    The other thing of relevance that may explain some of the garbled info about phase I detox, is that the cytochrome P45O enzymes use a slightly different form of haem (haem c) as a co-factor. The same problems affecting the haem in haemoglobin could affect the cytochromes.

    The inborn errors of metabolism and acute lead poisoning show us the extremes of what can go wrong in pyrrole pathways (again in a generic sense). There is every reason to suspect that the same types of problems could occur on a lesser scale as a result of certain nutrient deficiencies resulting from metabolic disturbances in chronic illnesses.

    This is what I suspect is behind the pyroluria claims.
     
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  5. Violeta

    Violeta Senior Member

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    The accumulation of ALA (aminolevulinic acid) in the brain is what causes the schizophrenic type behavior.
     
  6. alicec

    alicec Senior Member

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    Yes, along with several porphyrins. I didn't want to over complicate an already complicated post but the porphyrias are notable as metabolic disorders which can produce psychiatric symptoms (eg the madness of King George). Even if acute psychiatric symptoms are not present, there is often depression and anxiety.

    All of the haem intermediates are potentially toxic in one way or another leading to a wide range of possible symptoms - neuropathies, paralysis, seizures, abdominal symptoms, photosensitivity, skin problems, depending on which ones accumulate.

    The prophyrias are very rare and extremely serious. The various things labelled under pyroluria may be better understood as very mild porphyrias resulting from metabolic disturbance, rather than the convoluted schemes proposed on the internet .
     
  7. Johnmac

    Johnmac Senior Member

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    Well, yes, @garyfritz, great results with the pyroluria (or whatever it is), tho not so great with the zinc OD.

    Now I've got some kind of anemia thing from too much copper I think: time to wind that back too.

    I must remember to learn moderation before I die. But this also underlines the perils of supplements: it'd be hard to do this to yourself with food.

    Having a family member with major deficiencies from vegetarianism - Fe, B12, A, D, Mg, Zn, omega 3s & God knows what else - I am fiercely opposed to it. We're just not a vegetarian species. (Prince was a vegan.)

    Few docs understand pyroluria, & those who do cost hundreds of dollars & have six-month waiting lists. I don't have that much time or money, thus the perils of self-dosing. We did actually see one Walsh-trained practitioner in Melbourne, & she was a disaster.

    I take 100mg/day of B6 & 50 of P5P, tho as I said I might try & swap that for food soon. Also, if Greg's theory is right, I may fix the pyroluria with iron and/or B2... TBC.

    All the best...
     
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  8. Johnmac

    Johnmac Senior Member

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    Thanks @alicec. I don't have any science training, so over my head - but excellent to have it here for those who do.

    I think Greg was just giving a brief and probably partial explanation for a layperson.

    Treating 'pyroluria' certainly works in the experience of many of us - only it might not be pyroluria.
     
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  9. Violeta

    Violeta Senior Member

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    @Deltrus Here's some information about pyroluria. There are a lot of brilliant doctors who know a lot about it and fortunately figured out how to test for it and treat it. If they didn't know everything about it, others can come along side and help out.

    http://www.drkaslow.com/html/pyroluria.html

    Extra citations at the bottom of the page.
     
    Last edited: Apr 29, 2016
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  10. alicec

    alicec Senior Member

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    Yes the same old statements. What we have been discussing is that when you try to find the basis of them and the scientific studies to back them there is little or nothing to be found.
     
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  11. Violeta

    Violeta Senior Member

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    Last edited: Apr 30, 2016
  12. Johnmac

    Johnmac Senior Member

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    I actually like some of Walter Last's stuff, however he does get gulled by snake-oil at times. For example he approvingly quotes Joel Wallach, one of the worst pseudo-medical hucksters in the US:

    Wallach claimed that US physicians have a life expectancy of 58 years (it's actually 75-88), that five societies drinking colloidal-rich "glacial milk" live an average of 120-140 years (no such societies exist), and that he has authored 70 scientific papers (standard electronic searches have failed to discover these).

    The colloidal minerals story began in the 1920s (Wallach tell us), when ailing rancher Thomas Jefferson Clark was told about a healing stream by Chief Soaring Eagle, a Paiute medicine man. Curiously, the present-day Paiute have never heard of either Clark or their famous Chief.


    [Forgive me for quoting that from my own website: http://john-macgregor.com/entry.php?entid=108 ]

    So I'm afraid @alicec's objection remains: there is much 'explanation' of pyroluria - even more now we've seen Walter's effort - but no sources (for example peer-reviewed studies) to tell us if it is factual.
     
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  13. Violeta

    Violeta Senior Member

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    I don't know what your information from your website has to do with pyroluria, but I hope you (or others reading here) found something helpful from Last's information on pyroluria.

    I can see why there are no peer reviewed studies on pyroluria, there is no way for drug companies to make money off of it.

    Klinghardt says that 80% of his Lyme patients have high pyrroles in their urine and won't get over Lyme until they deal with it.

    C. Pneumoniae is often complicated with secondary porphyria, something one might want to consider looking into if one has that pathogen.
     
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  14. Johnmac

    Johnmac Senior Member

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    You're probably right, sorry. It was a lengthy way to make the point. Basically, I meant that if Last cites Joel D Wallach as a source - one of America's more notorious medical conmen - you don't necessarily want to trust what he writes elsewhere.

    True, there's no cash in pyroluria. On the other hand an awful lot of research scientists work in this general field, & you'd think one of them might have been able to demonstrate a mechanism by now.

    Like most here, I think treating PD symptoms with zinc & B6 seems to work, but I just don't know why.
     
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  15. Dominic Pukallus

    Dominic Pukallus Mental illness survivor with Medical ambitions.

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    I don't think I ever had ME or CFS but when I got hit with what ended up being diagnosed as (amongst other things) clinical depression in my first year at university, ME was a very good candidate. I also had a very nasy bout of Candida around the same time. 28 years of debilitation later I was diagnosed with Pyrrole Disorder (what Pyroluria is referred to now by Dr Walsh and his camp), with an urinary HPL level of 46.6 ug/dL which is more than twice the 'elevated' level. Within 2 weeks of taking 250 mg pyridoxine hydrochloride (B6), 50 mg pyridoxal 5'-phosphate (PLP/P5P), 75 mg elemental zinc in picolinate form, grams of vitamin C, and lesser amounts of suppkements like vitamin E and magnesium, I was pretty much 'cured'.

    You could say I'm certain that whatever Pyrrole Disorder is, it's real at least in its diagnostic and treatment aspect. I did a lot of research in the 6 months since I got better and while I'm dismayed it's not taken seriously enough that I would have heard of it earlier, I can see why. The only people (of which the Walsh Institute are probably most prominent) who seem to be doing any real research in this are clinical researchers with little funding which cannot sustain both the clinical and the laboratory aspect required for good medical research. As such they are limited to making observations with regards to diagnosis and treatment methods and clinical studies with which they hope to attract interest in anyone with funding for the required double-blind RCTs as well as the lab work which would identify the actual mechanism of HPL production and pathology involved.

    I was diagnosed and treated by a Medical Doctor trained in the Walsh approach, so I'm a bit of a fanboy. I intend to go into Medicine next year and train with them once I graduate, so that's my disclosure concerning bias. My observation regarding the garbled and confused information that I see on many websites (by both proponents and skeptics) is that there is so little research into the mechanism of this disorder, only a lot of theories which have evolved over the years. This is not added to by the constant reference to 'kryptopyrroles' as the marker (and hypothesised cause) for the disorder and which was 'debunked' by several studies in the late 70s despite the fact that the scientist who identified the Mauve factor as kryptopyrrole in 1969 realised his error as better technology became available, and published as early as 1975 that it was actually the molecule more commonly known as HPL.

    What I can say about what's certain about Pyrrole Disorder is that it's a black box. My understanding from wading through articles on the subject is that oxidative stress goes in, HPL and illness come out and can loop back to cause further oxidative stress. Note that elevated HPL is associated with all kinds of illness, but seems to be higher in mental illness and other brain disorders. Putting in B6 and zinc (mostly) seems to inhibit the outputs. The lack of definite knowledge of the mechanism involved to me does not invalidate the concept but I really would appreciate some money being put behind it if it would help suffering people to know about it and not get discouraged by people telling them it's "snake oil" as I nearly was from information gleaned on the Wikipedia article where it's mentioned.
     
  16. Johnmac

    Johnmac Senior Member

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    Welcome to Phoenix Rising, @dominic!

    My sentiments exactly. I may not know what it is: but when put in the zinc & B6, freedom from anxiety, better skin & a few other nice things came out.
     
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  17. Violeta

    Violeta Senior Member

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    Is possible that biotin helps with pyroluria by inhibiting morphing of candida to the fungal stage or by ensuring heme b production and therefore improving mitochondrial function by providing heme b. This might stop zinc wasting.
     
  18. Gondwanaland

    Gondwanaland Senior Member

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  19. Violeta

    Violeta Senior Member

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    This sounds like an acute form of pyroluria, doesn't it?

    Here's what they list as triggers for flares:
    "Causes inducing acute attack of AIP are: infection of upper respiratory tract, stress, starvation, use of various drugs (estrogenes, progesterone, contraceptive drugs, barbiturates, fibrates, statins, antifungal drugs, propaphenone, amiodarone, lidocaine, nifedipine, alfa-methyl dopa, hydralasine, ACE-inhibitors, sulfonamide, meprobamate, glutethimide, carbamazepine, allopurinol and others [13,40]."

    I wonder if chronic estrogen dominance or chronic infection would cause chronic porphyria? Secondary porphyria, such as found so commonly in chlamydia pneumoniae.
     
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  20. alicec

    alicec Senior Member

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    I found two things of interest here.

    First they show significant B6 deficiency (especially in RBCs) in porphyria patients. This seems to be the result of the genetically driven overproduction of ALA and porphobilinogen (see my post above), which is characteristic of the disease. The first step in the pathway is B6 dependant, so the disease causes excessive B6 demand which can't be supplied by normal dietary means, hence patients become B6 deficient.

    It seems to be a vicious circle, since it is also known that B6 deficiency, even without genetic defects, can lead to porphyria (this is my own observation, not one made in the paper).

    They didn't look at zinc but if they had done, I suspect they might have found something similar, since the second step in the pathway is zinc-dependant. In other words, the genetically driven disease would be depleting zinc also.

    Second they find hyperoxalaemia and hyperoxaluria, secondary to the B6 deficiency, in the porphyria patients.

    Some of us on this thread are very familiar with oxalates but it might be a new area for others. Here is a thread (among many others) which will give some background.

    Suffice it to say that there are a couple of rare genetic disorders which result in excessive oxalate production with serious clinical consequences, of which kidney stones are only one. Relatively recently, it has also been recognised that endogenous oxalate production can occur in the absence of genetic abnormalities, probably as the result of chronic oxidative stress which disables a B6-dependant enzyme at the beginning of a particular metabolic pathway which can lead to oxalate formation.

    This seems to be the case with the porphyria patients. They don't have the genetic defects associated with primary hyperoxaluria, but they acquire the disorder because of depletion of B6 (driven by other genetic abnormalities)

    The oxalate model is worth considering a bit more closely. All B6-dependant enzymes are homodimers held together by B6. What seems to go wrong with the non-genetic hyperoxalurias that have been studied, is that oxidative stress somehow causes a conformational change in the subunits of the AGXT enzyme so that they can no longer bind B6 properly. Thus the enzyme doesn't assume the right shape and so cannot function well.

    B6 might be available but it is not able to do its job properly. There is a functional deficiency. Adding large amounts of B6 seems to be able to overcome the problem at least in part by strongly driving the poorly functioning enzyme.

    With the porphyria patients, simple unavailability of B6 seems to be the problem. It is all being used up in the haem intermediates pathway. Just adding more should help overcome the problem.

    In general, the notion of regarding the so-called inborn errors of metabolism as very rare events with no relevance to the non-genetically compromised is starting to change a bit. Some researchers are starting to recognise that there might be acquired syndromes which mimic these disorders, often in a less serious form.

    We've just talked about how this can happen in hyperoxaluria, and it is known that some porphyrias can be acquired.

    If we think of pyroluria as mild porphyria, then functional or actual B6 deficiencies could be the CAUSE, not the consequence. Similarly functional or actual zinc deficiencies could also be causal.
     
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