HPL molecule artwork free to use and modify.
Hydroxyhemopyrrolin-2-one.
1. Mauve and mental illness.
When pursuing their investigations into the possible biochemical causes of mental illness, Dr Abram Hoffer working with Dr Humphry Osmond in the early 1950s noticed that a particular chemical tended to show up in greater quantities in the urine of people with more severe psychotic symptoms.
Although the technology of the day precluded an actual identification of this substance, it was characterised by its mauve colour on a paper chromatogram developed with Ehrlich’s reagent which led to it being dubbed the “Mauve factor”. This led to the postulation of a biochemical condition implicated in the development of psychotic symptoms which they termed “Malvaria“, deriving the name from the word “mauve”.
2. Kryptopyrrole and HPL, the confusion.
In 1969 Donald Irvine et al, working with Dr Hoffer, announced that with advances in technology they had succeeded in identifying the Mauve factor as “kryptopyrrole”. This was a pyrrole ring similar to many such produced in the human body each with their own unique variation in composition, some of which are used in the production of heme which is a porphyrin used to carry iron in haemoglobin. From this the term “Pyrroluria”, later reduced to “Pyroluria” was coined to rename Malvaria.
In 1975 Irvine had already announced that with further technical improvements it had been established that ‘kryptopyrrole’ was the wrong identification for the Mauve factor, and that it was instead the similar pyrrole most commonly known today as Hydroxyhemopyrrolin-2-one or HPL. Despite this a number of studies attempting to find kryptopyrrole in the urine of people with psychotic illness using the new techniques were conducted and failed to find it in elevated quantities, leading to the discrediting of the hypothesis.
Irvine restated in 1978 that the Mauve factor was HPL but by then the term “kryptopyrrole” had taken root and is still used to this day interchangeably albeit erroneously with HPL both by detractors and proponents of the hypothesis. A more detailed account of the process of identification can be found here and here. Whether the people using the term ‘kryptopyrrole’ are aware it is erroneous depends on their level of education in this area and this can be confusing.
With the adverse 1973 report by the American Psychiatric Association (see Hoffer’s reply) and the subsequent findings against kryptopyrrole, Orthomolecular Psychiatry under which the Pyroluria diagnosis and treatment fell, was abandoned from consideration by mainstream Medicine. Undeterred, Hoffer and his associates continued with their research.
3. Pyroluria, niacins, and folates.
It had been observed early on by Hoffer et al that large amounts of vitamin B3 (the niacins) reduced both HPL and symptom severity in people with schizophrenia. It was later discovered that B3 along with B9 (the folates) were the primary treatment for a condition with symptoms typical of a form of schizophrenia known as “Histapenia” due to the associated low levels of whole blood histamine (WBH).
It was then discovered later that in general the less WBH present, the higher the amount of methyl groups in the methylation (one carbon) metabolic cycles. This was due to the need for these methyl groups in breaking down histamine, and Histapenia was therefore eventually renamed “Overmethylation” (OM) since the WBH levels were seen to be just a marker for the methyl group levels. The name was due to the theorised cause from too many methyl groups in the methylation cycles leading to excess levels of neurotransmitters such as dopamine and serotonin, causing the psychotic symptoms. This is now seen as mainly due to the epigenetic effect of the high methyl group levels on the DNA.
Conversely a low level of methyl groups correlated with low levels of these neurotransmitters was identified associated with high levels of WBH. This was conversely named “Histadelia” and subsequently “Undermethylation” (UM) as per the previous paragraph. It was found that symptoms were improved by treatment with methionine, a precursor to S-Adenosyl methionine (SAMe) which donates methyl groups to the methylation cycles (“methyl donor”). As per OM, the cause of this improvement is now seen to be the effect of increasing the general epigenetic methylation of the DNA, especially at the histone tails.
The mechanism of action of B3 in this is now seen to be in its role as an indirect cause of the reduction of methyl groups in the cycle, known as a “methyl sink”. That of B9, paradoxically itself a methyl donor, is now thought to be due to its role in reducing methyl groups at the DNA histone tails as per the previous paragraph. It may well be that the people diagnosed with schizophrenia in those days happened to be those whose symptoms coincided with those attributed to OM, and the HPL reduction was a byproduct of their symptom relief. Later on, a distinction was made between the different symptoms associated with methylation issues and high HPL. The association of HPL with oxidative stress will be discussed later.
4. Pyroluria, zinc, and B6.
In the 1970s Hoffer and his team were joined by Dr Carl Pfeiffer and working together it was established that patients with high HPL and symptoms of schizophrenia responded even better to large doses of vitamin B6 (pyridoxine) and zinc. Since the patients had been receiving adequate amounts of dietary B6 and zinc the condition was described as a metabolic or functional deficiency which required massive supplementation though the mechanism was yet unclear.
It was around this time that the theory was first formulated that zinc and B6 were bound to the HPL and excreted, though this was only due to observations in the laboratory with kryptopyrrole and not HPL. The predicted HPL/zinc/B6 complex in urine would remain elusive. Plasma zinc and blood B6, however, are usually low in such cases even though they are still in the normal ranges. Since the body maintains a balance between zinc and copper, low levels of plasma zinc are then associated with high levels of serum copper and these values are used in formulating treatment dosages.
Picture source: www.walshinstitute.org/uploads/1/7/9/9/17997321/biochemical_imbalances_in_mental_health_populations.pdf
The reason for the effect of B6 and zinc deficiencies on mental health may be due to the fact that, apart from the essential roles these play in biochemistry in general, “activated” B6 (pyridoxine) into P5P/PLP (pyridoxal-5-phosphate) using a zinc-dependent enzyme is required to help make neurotransmitters such as serotonin and dopamine. As well, excess copper due to low zinc can lead to excess noradrenaline/norepinephrine, or converting whatever low dopamine already exists.
Much has been made of the link between neurotransmitters and mental illness as the “biochemistry imbalance” requiring medications to address. Up until now general understanding of the mechanism of this seems to have been murky and allowed skepticism of this connection in some quarters.
5. Pyrrole Disorder and oxidative stress.
In the 1980s, with Dr Hoffer having retired, Dr Pfeiffer was joined by Dr William Walsh who had met him on the very day that Dr Pfeiffer had been nominated for a Nobel prize by double Nobel laureate Linus Pauling. Together they made a number of findings about what eventually came to be called Pyrrole Disorder due to the fact that the symptoms that were associated with the elevated HPL were eventually theorised to be caused by oxidative stress (OS).
One reason for this view is that proteins are prone to degradation by OS. HPL may then likely be a residue of oxidative heme degradation. Enzymes are proteins which play vital roles such as in the function of B6 and zinc in creating neurotransmitters among other metabolites. Previously mentioned low-normal levels of B6 and zinc needing massive supplementation may be explained by the need to increase the activity of related enzymes depleted by OS.
High supplementation is needed to increase concentrations to get the same metabolic effect when enzyme levels are low (C) as with normal enzyme levels (A) otherwise function is impaired (B).
The HPL (“pyrrole”) was recast as mostly just a marker of this OS although it had also been shown to have neurotoxic effects of its own in animals and is itself a source of OS. These symptoms were varied but were typically associated with diagnoses of depression, schizophrenia, and other brain, behavioural, and affective disorders.
Picture source: www.walshinstitute.org/uploads/1/7/9/9/17997321/biochemical_imbalances_in_mental_health_populations.pdf
It has been reported recently that, as a metric of oxidative stress, HPL is found in elevated amounts in people with any kind of illness, stress, toxicity (especially heavy metal), or injury, though the levels are highest in those exhibiting symptoms of the mental or behavioural disorders mentioned previously.
There has been a report presented to the Australian Parliament House of Representatives on a pilot study of the effectiveness of treatment of these disorders, though due to constraints the various conditions which make up this field of Nutrient Therapy were not differentiated in the aggregated results . It is thus impossible to determine precisely what the effectiveness of Pyrrole Disorder treatment alone is, though an idea may be had from the overall results.
6. Ongoing research and treatment.
Today the most comprehensive clinical research on Pyrrole Disorder and the other associated conditions such as UM, OM, and copper overload is conducted by Dr William Walsh and his associates of the Walsh Research Institute in Illinois, USA. Physician training is also conducted in these treatment methods, and physicians all over the world have undertaken this for use in their practices.
Also involved are close associates Drs Albert Mensah and Judith Bowman of Mensah Medical. Many other physicians have received training in methods derived from the primary research though other channels at levels depending on their levels of qualification and how up-to-date and comprehensive the training institutions are. Of these others no assessment can be made by the author, not having had the experience of any of their care.
The author was tested, treated, and given a dramatic increase in well-being and productivity by a Medical Doctor (General Practitioner) who was trained by the Walsh Institute (WRI). This was done through Bio-Balance Health Australia, an Australian partner organisation of the WRI. Australians are lucky to have the highest number per capita of such trained physicians.
It is through this treatment that it may be possible to safely reduce or even cease the use of pharmaceutical medications such as was achieved in the author’s case. Of course, Pyrrole Disorder is seldom found alone but often in combination with the methylation and copper disorders as was also the case with the author. These will be discussed in other articles.
The people who are conducting the valuable clinical research are operating from public charities which are funded to a large extent from the fees charged to the physicians training with them. There are not enough resources to conduct the level of pure research required to extend the understanding of the mechanisms involved, or to conduct the required complex trials which would facilitate the acceptance of this paradigm back into the “mainstream” of Medicine from which it was ‘exiled’ in 1973. Interestingly, it seems that other researchers and academics are coming to the same conclusions perhaps even independently.
It basically comes down to funding which is desperately needed, the kind that can realistically be provided only by government or large businesses. There is ample evidence which points to the potential for successfully passing such trials if they are properly administered with the proper understanding and application of the painstakingly acquired clinical research theory over the years.
Wider pure research into the mechanisms involved will only facilitate this. It can only be hoped by the author that this will eventuate, as the potential cost benefits to Humanity from treatment, welfare, corrective, and social services savings as well as greater work productivity are immense if his own experience is anything to go by. Not to mention the potential reduction in the overall burden of misery.
7. Getting tested, and treated.
The author can only recommend the services of physicians who have had the same training as those whose care he has been under so successfully. This (and its related conditions) is a highly complex issue involving the widely differing biochemistries of individuals due to a combination of genetics and circumstances. There is no “one size fits all” approach to this which is ultimately effective, though there are basic rules.
In order to properly treat these conditions one must have a thorough understanding of Human physiology, nutrition, and biochemistry. In the closed Australian Facebook support group and the international one of which the author is a member there are many people attempting, through lack of funds or access, to treat themselves without the supervision of a physician with these attributes.
This is understandable as proper treatment requires adequate consultation times the remuneration of which are not covered by government funding due to lack of recognition. The same goes for testing, and treatment supplementation. As per the last paragraph of the previous section, there is hope this might change.
In that light here is presented a list of physicians trained by the Walsh Research Institute all over the world, though the majority of them are in the USA. In Australia specifically there is this list of those trained through Bio-Balance Health Australia. Many Medical Doctors and allied practitioners are also trained in this through the Australasian College of Nutritional and Environmental Medicine (ACNEM). It is the wish of the author that those suffering may find the same relief he has, and those wishing to learn more may find what they seek.
The author’s experience as well as a very short summary can be seen in this video:
Better Living Through Biochemistry 
Dominick, you are a wonderful man.
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Thank you Steve. I only wish that people who suffer like I did will get the same relief, and I dedicate the rest of my now-productive life to this.
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AMEN!
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Why, thank you!
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Thank you for the explanation Dominic. Easy to read and understand.
Will mainstream doctors in Australia, who haven’t yet been enlightened on the subject, still test for the disorder and what do I ask for? I’m desperate for some relief and I don’t respond to drugs.
My current way of combating this insidious invasion of living well is to deep cleanse my whole body, starting with the bowel, then liver and kidneys, all the while eating as clean and unprocessed as possible. Then to add particular foods and herbs that wipe out viruses and pathogens that probably caused all this genetic expression in the first place.
Your thoughts on this idea of getting to the root cause and perhaps turning off the expression of the genes that stopped our bodies from healing themselves. Is not the turning on of the genes that eat up zinc and B6, screw with methylation and turn our worlds upside down, a result of the viruses or bacteria or heavy metals that happen to us well before anything else?
Would love to hear your views. Thanks
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From reports I hear, whatever ‘Mainstream” doctors do depends on whether they are prepared to look beyond the negative ‘debunking’ blogs out there which appear high in ranking whenever anyone Googles this. I must say I was almost put off from testing from these, and in light of what I know now they make their conclusions based on woefully inadequate ‘research’ which misunderstands the issue of the misidentification of HPL as kryptopyrrole, treats the 1973 APA Task Force report as a bona fide neutral report conducted using trials which replicated the methods of Hoffer et al from a proper understanding of the theory. This ‘research’ usually ends there with a dimissive mention of Hoffer disappearing into obscurity which in a sense is true as it all dropped off the “official” radar.
From this it is understandable the average overworked GP will give this short shrift, coupled with the usually contradictory, muddled, and downright ‘kooky’ claims made by certain proponents who it seems to me operate on the principle that if it is unrecognised by the Medical community then they can make any claim they see fit in their effort to make money out of it. This, to me, is the dark side of the ‘alternative’ Medicine field which has suffered in its quest for largely legitimate recognition. Many are denied basic fair consideration due to being tarred with this brush.
Cleansing the body of all possible pathogens can only be a positive thing to do. I have come to the conclusion that many of us are operating under a chronic toxic load which is unrecognised simply because the baseline keeps lowering insidiously over the decades. Of course this is difficult to prove except that actively reducing this has immensely improved my health to a level I could have only dreamed of, and my improved mental health can only take some of the credit. Physical and mental health go hand-in-hand, I believe that is not a controversial statement. Diet, lifestyle, personal consumption choices, relationship choices, spiritual, psychological, and even aesthetic decisions all have an important place to play. This is the part of the essence of the “functional” or “holistic” strains of Medicine.
In my mind if the original source of Pyrrole Disorder (PD) is oxidative stress, then the avoidance of all causes (some of which are outlined above) will only make treatment more effective. I attribute my success to this, having already changed my life in that direction before supplements in my view broke the vicious circle of stress caused by the by then established mental illness. Once the supplements had done this I was able to keep the stress and its effects at bay. It goes without saying that following this philosophy one should invest as much as possible in effective antioxidant supplementation as well. I take what would be normally be considered excessive amounts of ascorbate (up to 15,000 mg per day) in various forms with sodium, potassium, and calcium. So far, so good.
As for the genes, the oxidative stress associated with PD is known to establish deviant epigenetic markers. This is considered to be a great cause of either over or under methylation symptoms (OM/UM) in that the genes responsible for neurotransmitter reuptake are either over (UM) or under (OM) expressed. Methionine, or more directly SAMe, will help reestablish the proper markings for UMs (such as myself) while the niacins and folates will do so for OMs. This is a more long-term proposition than with PD, at least with methionine such as I take. Luckily for me UM was never my main problem. I even credit the “drive” it is supposed to give those afflicted with it for keeping me going through the worst of the PD.
I am still a rank beginner with all this, having never even heard of it until October 2015 when my lovely fiancée floated the idea to me in desperation. It has been a steep learning curve which is why this article has only now just come out, as well as having a great deal of activity associated with my newfound capacities taking up my time. Studying Medical Science at university even at a very junior level has been extremely useful especially as far as the Biochemistry is concerned. I’m sure I have made mistakes and omissions. My understanding is still extremely sketchy beyond the broad strokes, but I expect that will improve over the years until I finally (if all goes well) am allowed to train in this as a licensed GP.
I wish you the best in your journey to Recovery. I would recommend not to attempt to convince any skeptical Doctors (or anyone else for that matter) to follow your wishes. That’s swimming against the tide, which people in the position I was then and you may be in now are even less equipped to do if anyone is. I recommend the GPs which can be found through Bio-Balance in my article. Many other practitioners purport to treat this, but I cannot personally vouch for them. I understand the Australasian College of Nutritional and Environmental Medicine (ACNEM) does good work in this field also though my reports are only second-hand.
Yours, Dominic.
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Great article explaining pyrrole disorder.
The video and personal story gives hope.
Thanks
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Thank you Andy. I was criticised for giving “false hope” when I went a bit overboard just after getting well and posted the same message about this with the little I knew then on many related subreddits on Reddit.com. Mostly I was treated like a snake-oil salesman, and knowing the prejudice against treatments that are not seen as the ‘norm’ I can understand that. I would have been inclined to do the same before my own ‘miraculous’ result.
In fact for my Social Science degree I got great marks for writing an essay on just this sort of thing in which I savaged a whole field of Medicine for just that reason, and which I now recognise was most likely completely wrong in the light of my new understanding of these matters. I keep that as a reminder of how you can legitimately come to the wrong conclusions with just a little bias and consequent limited research.
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Great article. Really well written to embrace good perspective of the history of how it evolved… something I really find value in when I’m seeking root understandings and ways I can improve personal exploration of topics.
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Thanks Krista. I had been puzzled why this wasn’t taken more seriously, especially in light of my own dramatic results. Several circumstances in my own experience suggested to me that those results were unlikely to have been due to a mere placebo effect, as was summarily dismissed by some less familiar with my situation. I was dismayed by the amount of unfortunate historical confusion and misunderstanding out there from detractors and even many proponents which persists to this day. That sad condition is an explanation for my own initial puzzlement, which compelled me to put all this disparate information from my own research in one place. I’m glad others find it useful.
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Thanks for this info as there is so much confusion surrounding this diagnosis. Ive tested positive HPL via a lab in the Netherlands which is supposed to be very good. Not quite sure on the amounts and types zinc should use. Have 30 mg tablets of zinc glycinate but not sure how high I should go – ALso have B6 tablets in form of p-5-p at 40 mg. I know you can’t give medical advice but just wondering what sort of levels people use. Have you found that reducing oxidative stress by using high viit C etc that your requirement for zinc and B6 has reduced. Do you think this is a lifelong issue or if you dramatically reduce oxidative stress then you will no longer require high doses. I have SIBO ( small intestinal bacteria overgrowth ) that is probably creating oxidative stress to some extent so wondering if this is resolved then I will no longer have this issue. I suspect I have copper issues- worry that I have both toxicity and lack of bioavailable copper – do you have any info on this. Thanks so much for any info!
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You’re welcome! You’re right in that I can’t give Medical advice, but I can say that for me my HPL tested around 46 ug/dL. For that I was prescribed 75 mg zinc picolinate daily, and I’m told picolinate is the most effective form of zinc. I was given a whole slew of tests mind you, and all of these went into the formulation of my prescription.
As it is increasingly seen that this disorder is simply a result of excessive oxidative stress, it would stand to reason that antioxidants would help deal with the cause along with the other supplements dealing with the effects. The Walsh approach is to try to promote the body’s own natural antioxidant defenses (glutathione, metallothionein) and for this I was prescribed N-acetyl cysteine (NAC) and selenium in the form of selenomethionine. On top of this there are different forms of vitamin E prescribed along with ascorbic acid (vitamin C).
I’m not a big fan of ascorbic acid for various reasons, and I prefer buffered ascorbates (sodium, potassium, magnesium ascorbates) which have the advantage of being both better absorbed and provide electrolytes at the same time. I also have been taking very large doses of this, up to 15,000 mg per day depending on tolerance levels. I follow the method outlined in this video https://www.youtube.com/watch?v=p-vsTp4yRNY&index=4&t=0s&list=PLN6ZFd7eQWEf3pB1SuT9Jwbc4LZ10aHx4
I think this approach to dealing with what seems to be the root cause of Pyrrole Disorder/Pyroluria could be bearing fruit. At my last tests a year ago it was found that my HPL had almost halved, as well as the free copper which is itself a free radical. I’m getting new tests done soon, but if the trend continues this time around I should be below the levels required for positive diagnosis. I don’t know if that means I could then reduce my supplements, that’d be something to discuss with my treating MD. Perhaps once the damage has been done, there may bee a need for some kind of maintenance dosage in the long-term.
I very much recommend not doing this yourself, if that can be helped. Not only is effective treatment dependent on a very complicated Biochemical system which is still being unraveled, but there is the great possibility of causing harm to oneself out of ignorance. It’s for this reason I’d personally consider the Telemedicine option in the list of practitioners trained by the Walsh Research Institute who have the most advanced database of clinical research outcomes on this. As for SIBO, from what I hear it’s not so much the amount of bacteria which is the problem but the type, and the chemicals they create. Personally I think I’m protected against this from my ketogenic diet but that’s best left to someone with more authority. I wish you the best in this.
https://www.walshinstitute.org/clinical-resources.html
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Quite Inspirational Dominic
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Thank you Frederick. Leonie and I had intended this to be inspirational in those heady days after what looks like the ‘fixing’ of my biochemistry when I felt like I had awoken from a nightmare lasting decades. I was hoping that this alone would lead someone at least to get some of the relief I had been blessed with. I had been skeptical myself about what this might lead to.
I need to re-read it and get some inspiration myself sometimes. It’s still just as true but dealing with the psychological and emotional backlog of that nightmare can be demanding. I’m lucky I have good therapists to help me on this hopefully last leg of my recovery journey.
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