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Pyroluria, is it real? I'm really skeptical and here is why.

alicec

Senior Member
Messages
1,572
Location
Australia
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

That seems like a very fair description, one that I have no problem with.

I'm not saying the condition doesn't exist, there clearly has to be some reason for symptoms responding to B6 and zinc. It is the proposed mechanisms and the garbled explanations of the disorder that I object to. These also give the proponents a bad name and lead to comments about snake-oil salesmen (which some of the websites I looked at came close to).

For the sake of completeness I'll just add two more articles from the proponents which I tracked down via @Violetta's second reference above - here and here. These seem to be the most complete summaries that I have found with the best attempts at scientific references and without the garbling of most of the websites.

Essentially some very interesting observations were made quite some time ago, largely by clinicians. Certain clinical interventions were found to be effective and these have remained the mainstay of pyroluria. A few mechanistic studies were done early on but these have not been followed up.

Perhaps the thing I found most interesting was the statement at the beginning of part 2, that the biological origin of HPL is unknown. It does not appear to be a direct breakdown product of porphyrins, though it is often associated with elevated porphyrins and porphyrin intermediates.

One suggestion, and there was some experimental evidence to support this, is that HPL arises via the action of gut bacteria on an unusual porphyrin intermediate, isocoproporphyrin. So there could be a gut link and maybe a genetic link, since there is a hint that appearance of this unusual intermediate might have a genetic basis.

There was quite a bit of discussion about the role of oxidative stress in the disorder. This just reinforces for me the discussion in my previous post about functional B6 deficiency induced by oxidative stress.

As a complete outsider looking in on this story, it seems to me that the pyroluria proponent have maybe become their own worst enemies. They have a position to defend which they can't deviate from and thinking has become stuck in a groove. They see the primary defect as whatever leads to HPL accumulation. This in turn leads to B6 and zinc deficiencies since these are bound up by HPL. Treating with B6 and zinc reverses these problems and in some unknown way fixes the HPL accumulation also.

I could find no evidence whatsoever that HPL binds to B6 and zinc (not even in their own studies). If we set this notion aside, then we could start to think that B6 and/or zinc deficiencies might be causal rather than consequential, more like the porphyrias discussed above. This would also explain why B6 and zinc reduce HPL. This could be a very fruitful line of thinking with an enormous porphyria literature to call upon.
 

garyfritz

Senior Member
Messages
599
If you thought you had pyroluria-or-whatever-it-is, how much B6 and Zinc should you take? Any particular forms? I want to try putting my son on a B6/Zinc regimen and see how he responds.
 
Messages
27
If you thought you had pyroluria-or-whatever-it-is, how much B6 and Zinc should you take? Any particular forms? I want to try putting my son on a B6/Zinc regimen and see how he responds.

Here is a good summary of the protocol, forms and dosages:

http://growyouthful.com/ailment/pyroluria.php#remedies-for-pyroluria

30 mg of Zinc Picolinate and 34 mg (it is often sold in that amount per pill) of Pyridoxal-5-Phosphate (P5P) can be a good start. Some apparently need to take much more, but start with this, if no reaction after a month, double doses of both.
 

garyfritz

Senior Member
Messages
599
Thanks. That's a good starting point. Looks like I should also find him some Omega6 and arachidonic acid sources. He is vegetarian (and he eats crap, tons of sugar, refined grains, simple carbs, etc) so he probably doesn't get much of either from his diet. Very tough to get Omega6 and AA, especially without Omega3, in a vegetarian source...

For various logistical reasons (and him being a stubborn PITA) I can't get him to do the test for a few weeks. If I start him on B6/zinc, will that invalidate the test?
 
Messages
27
Thanks. That's a good starting point. Looks like I should also find him some Omega6 and arachidonic acid sources. He is vegetarian (and he eats crap, tons of sugar, refined grains, simple carbs, etc) so he probably doesn't get much of either from his diet. Very tough to get Omega6 and AA, especially without Omega3, in a vegetarian source...

For various logistical reasons (and him being a stubborn PITA) I can't get him to do the test for a few weeks. If I start him on B6/zinc, will that invalidate the test?

Well, Borage Oil is the best GLA source and is vegetarian. But the gelatin softgel it comes in is animal source probably. Maybe there is some borage oil in vegetarian capsules.

It is recommended not to take any B6 or zinc for a month before the test. Although I took 100 mg P5P for many days before a test and still tested slightly over the range for both urine Kryptopyrroles and HPL (these are two separate tests, ideally do both). But that's me, in someone else a bit B6 might push the kryptopyrroles below the threshold. Also better do a 24h urine collection as some people release kryptopyrroles only some part of the day, when they are stressed for example. Also don't do the test on relaxed days, vacation etc, as it may be negative then, but positive in more stressful days.
 

garyfritz

Senior Member
Messages
599
Hm. How do you do a 24h collection? You're supposed to freeze it immediately, and you end up with a fairly small sample. You couldn't just add to it through the day...
 
Messages
27
Hm. How do you do a 24h collection? You're supposed to freeze it immediately, and you end up with a fairly small sample. You couldn't just add to it through the day...

I didn't freeze it, just kept it in the fridge. I know not freezing can deteriorate the kryptopyrroles, but I think just 24 hours, and in reasonably cold temperature close to freezing point, is not gonna deteriorate them below detection in many cases. There is no perfect method for detecting them. The Dutch testing lab http://www.hputest.nl/ewhat.htm has a different approach, they claim to be the only lab to actually measure the Hydroxyhemopyrrol pyridoxal-5-phosphate zinc chelate (HPL), and measuring that doesn't require freezing, they actually discourage freezing. Other labs measure either Kryptopyrroles or HPL, which are both different. So there are actually 3 different substances you can measure. I did all three, some of them twice with different laboratories.
 

student

Senior Member
Messages
166
Measure in the blood – will not show the manganese need – in brain and bones. So it seems false normal.
Starting of – you give half zink (15 mg) dose plus manganese (7- 14 mg) for 10 days.
Aim at: 30 zink, 10- 14 manganese, Taurin 40 mg, P5 P (aktive B6) 50- 100.
A personaliesed regime - can go much higher, as discussed above...

with p5p you titrate – for dream recall. There is a nomber of others to add. Later
https://en.wikipedia.org/wiki/Superoxide_dismutase Zink and Manganes play a role in SOD (1 and 3 zink) enzyme / 2 with manganese in mitochondria.
After 2- 3 month measure copper and support also.
 
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student

Senior Member
Messages
166
In CFS – Manganese is an important supplement. See SOD II for inside the mitochondria. (Do not leave that one supplement out. Next on my List might be Taurin... aminoassids).The hope is that Zink dependent interstitial SOD can clear Transsulfur pathway (amino/ amoniak) NO OHNO products. Oxidative stress can turn into nitrosative pathway products. The body can not move them on easily. The 50 years old and good Hoffers experience is continued and followed by Kansteeg, Klinghardt and Striens plus others in Europe. Ritter (has written „HPU Stoffwechsel“ pathway) 2014 german book and gives plenty of details that were most helpfull to me. The CFS/ME commity „fatigatio eV.“ had invited Kamsteeg for their anual 2015 (german text in journal NO 38) meeting. An internet discussion with some quality is found at libase.de (german forum) with a KPU (HPU) subforum. / Klinghardts yT videos follow most of this threatment protocoll in english language. Some of his HPU films were not easy to (google search) find.

I have not found any more english resources – that follow the same supplementation principals. (The medical explanation given here/ discussion page II– tries to cover much more of the other 6 conditions that are named polyuria.) There is a compleatly diffrent understanding of the HPU (hpl) Testing. A more general liver desease concept – follows not the same explanation of this HPU condition in the relation to fatigue. Some say Lyme (Boreelliose) will test after some month in HPU supplementation treatment. There is a high correlation to autism .
The metylation cycle and its blocks may probably bee influenced with these cofactor supplements. Zink Managanese and B6 (aktivated p5p).

The patients case historie, Methylation genes, other illnesses and symptomes involved are highly variable. Hopes are raised – to simply influnce and also lift some of the burdon of biochemical pathway with the tool of a familiy constalation work –clearance strategies. More reacent studies never done much and are not known
It may be difficult to give more than a vage summery of the plenty patients histories. In this phaes – eaven after 50 years experience with a treatment - the medical knoledge of the specialist will still count more than studies. Specialists are buisy treating the variety of there patients. There is a good number of sucess stories that backs up what that treatment can change. HPU was often diagnosed in the patients with CFS pathologie. In general this keac.nl Kamsteeg HPU questionair was 10 000 times (2014) in use – (says Ritter „HPU Stoffwechsel“ book).

There is important changes that we expect within this supplement therapie: – one is that detox capacity will start to function. It is good to be prepaired (have specialist support) to be guided in this. You want to have detox binders – on bord and than continue supplement treament.
After a time of zink supplements the need for copper starts to come. Expect after 2 month and more and measure copper.
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
C. Pneumoniae is often complicated with secondary porphyria, something one might want to consider looking into if one has that pathogen.

It's been awhile @Violeta, but could you shed some light on this? I think I may have this problem, but haven't been satisfied with what I saw over on cpnhelp. What lab results or characteristics would one have? (Hint: are abnormal demands for B6, B12, etc. involved?)

Many thanks!
 

alicec

Senior Member
Messages
1,572
Location
Australia
could you shed some light on this?

It is a hypothetical possibility. There are two publications that I am aware of, a theoretical proposal and a patent application both by Stratton quite some time ago. I just did a quick google and could find nothing recent.

Essentially it is proposed that Cpn uncouples the electron transport chain from ATP production by siphoning off ATP. The final steps of haem formation occur in the mitochondrion and need a functioning ETC, therefore Cpn will disrupt haem formation.

The lack of haem will feed back to the first steps in porphyrin synthesis causing up-regulation. This will lead to an accumulation of porphyrin precursors, ie an acquired porphyria.

It's plausible but I have no idea how likely. If this causal chain really operated one would presumably sometimes see acquired porphyria associated with mitochondrial diseases which have inborn errors in enzymes in the ETC. I haven't heard of it but it could be worth searching for.

If it did happen it could increase need for B6 since this is required at the first step in synthesis, as described here. In Stratton's scenario, this step is upregulated.

He also makes some claims about B12 which seem even more iffy to me. I would like to see the evidence. Essentially he says they have detected anti-porphyrin antibodies and these might cross react with B12, hence B12 might be depleted also.
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
I am aware of, a theoretical proposal and a patent application

Essentially it is proposed that Cpn uncouples the electron transport chain from ATP production by siphoning off ATP. The final steps of haem formation occur in the mitochondrion and need a functioning ETC, therefore Cpn will disrupt haem formation.

If it did happen it could increase the need for B6

He also makes some claims about B12 which seem even more iffy to me. I would like to see the evidence. Essentially he says they have detected anti-porphyrin antibodies and these might cross react with B12, hence B12 might be depleted also.
I'm right up there with you. I'd already read all of the shared links and patent before coming here. I was hoping for something more recent as the info is a little older and a little iffy... anyone other than Stratton either agreeing with or fine tuning these points? I seem to be in trouble:

1) Been fighting cpn for 15 months, going round and round, using several good strategies.

2) B12 need has dramatically increased. Doc says I have a MTRR methylation block. No methionine... I have to take it and TMG. Am getting IV, IM, and oral MB12 + some HB12 and AB12, around 75mg a week, which is enormous. Historically was fine with 10mg a week.

3) Iron study numbers have suggested either hemochromatosis or B6 deficiency anemia on and off for 3 years, and problems making hemoglobin. Was on 180mg P5P, then went to 300, now at 400 daily, which is a whopping smount. Upping dose seems to resolve numbers, and though serum ferritin had been 300-600, doc thinks it's B6 deficiency anemia though I'm compound heterozygous for the 2 main HFE SNPs. My sed rate is 2 and hematocrit drops everytime my numbers go wild and returns every time I consume enough P5P. But this is a persistent, ongoing problem. And I'm starting to get neuropathy...

4) Keeping the tank full on B1, B2, B3, MTHF, magnesium and aminos, which have all been low.

5) I also have some snarky toxicity though I got rid of mercury for good 4 years ago, and have been getting rid of arsenic, cadmium, lead, platinum, and who knows what else slowly over time. Occasionally I have a major sulfur flare, beaten back with molybdenum, curcumin, and charcoal.

6) And ATP production is a problem. Am on robust mito cocktail, lipid replenishment, and ketogenic diet which seem to help. I have BH4 recycling and peroxynitrite problems and homozygous SOD2 SNPs.

So, I'm in this constant mode of feeding the B6 and B12 beasts. We keep working on the cpn, but I think I've had it a long time and it's embedded deep in me. Doc thinks it's in my liver and we're working on that. I'm also on the 6 month Stanford wait list...

Given all of Stratton's literature and in the absence of anything further, I'm wondering:

1) Does it make sense to test for porphryns? What info would I get that would change anything?

2) What's causing the B12 problem? What can be done to fix it besides endless B12 supplementation?

3) Should I worry about leukemia with the persistence of this B6 heme problem? I'm a cancer survivor and one if the possible long term side effects of my chemo drugs is leukemia....

4) Has anyone looked at Stratton's B12 and porphyria observations in the context of general methylation and detox? And did I catch something about impact on CYP450 enzymes?

5) P5P is used everywhere... any way of knowing whats using it and what's being starved? Like, is this affecting my sphingolipid production?

Thanks. I'd be grateful for any insights...
 
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alicec

Senior Member
Messages
1,572
Location
Australia
I'd be grateful for any insights...

Sorry I can't really help much - I don't have deep knowledge of many of the issues, just an interest in B6 and B12 since I have found supplementation so helpful and a love of metabolic pathways so I often chase these down just for interest sake (until I run out of energy of course).

1) Does it make sense to test for porphryns? What info would I get that would change anything?

It does. You would then hopefully know if porphyria or a mild porphyria-like entity is an issue. There is a lot of literature about porphyria and various treatments (I've never looked at the detail) - maybe something there would be of help.

Stratton somewhere talks about the testing issue and why his proposed porphyria might not be detected. It could be worth reading that carefully to work out what exactly should be tested for.

Here is info that I have found helpful in understanding porphyrins and haem. There might be something there which could be helpful to you.

It struck me in looking at this again that if Stratton's hypothesis is correct, the resultant porphyria should be most like one arising from a ferrochelatase defect, since this is the step which inserts the iron into haem, the step that he says can't proceed because the iron is not in the right form as a result of ETC problems.

There is a useful section on differential diagnosis of microcytic anaemias. Note the heavy metal poisoning leads to acquired porphyria. I doubt that anyone has studied the effect of chronic heavy metal accumulation but it could be a contributing factor in a milder form of acquired porphyria which could be possible for you. The ZPP test could be useful here.

2) What's causing the B12 problem? What can be done to fix it besides endless B12 supplementation?

Can't help much here. It's unlikely that the common methylation SNPs that are discussed endlessly are behind it. At best these might be making a contribution.

At various times I have tried tracking down the B12 literature but it just proved too difficult.

One person who has delved deeply into that literature is Freddd (who devised the active B12 protocol which has generated an enormous amount of discussion on PR).

He only appears intermittently on the forum these days but if you explained you position (ie much like you have already done perhaps emphasising the B12 related things that puzzle you) and specifically alerted him by using @Freddd, perhaps he might answer. Maybe in his survey of the B12 research he has come across something that could be useful to you.

Freddd has adult onset CblC disease (see this thread) so has an enormous need for B12 because of genetic issues. It took a long time to work this out since it is usually diagnosed in infancy. Anyhow his case is extreme but his protocol, worked out by self-experimentation, actually does point to many of the consequences of deranged B12 metabolism and suggests that our understanding of this is very poor.

3) Should I worry about leukemia with the persistence of this B6 heme problem? I'm a cancer survivor and one if the possible long term side effects of my chemo drugs is leukemia....

Can't help here. Are any of your treating doctors amenable to thinking outside of the box?

4) Has anyone looked at Stratton's B12 and porphyria observations in the context of general methylation and detox? And did I catch something about impact on CYP450 enzymes?

Don't know about the first part apart from stating the obvious. Anything that compromises B12 status will compromise the methionine synthase reaction and hence methylation, and also methylmalonyl mutase in the mitochondrion, and hence delivery of fatty acids for energy metabolism.

The cytochromes use a form of haem (different from the one used in haemoglobin) so in Stratton's scenario, cyctochromes in the ETC would be adversely impacted (a double whammy) along with the P450 enzymes in the liver.

Defects in phase I reactions are well known in porphyrias necessitating careful use of certain drugs - or strict avoidance.

5) P5P is used everywhere... any way of knowing whats using it and what's being starved? Like, is this affecting my sphingolipid production?

Possibly an OAT test would give a little insight but you would really need metabolomics testing to work this out.

There has been a lot of discussion about this on PR as a result of the Naviaux paper and the work of Ron Davis. They are trying to set up an international testing service based on the company Ron Davis has used in San Francisco, but not quite there yet.

@Ben Howell was co-ordinating this. Perhaps he can give you an update. Perhaps he can give us all an update.

Depending on where you live it might be possible to organise this anyhow.

Here is someone living in the UK who made his own arrangements.
 

Dainty

Senior Member
Messages
1,751
Location
Seattle
Just chiming in to say, my naturopath went the whole route of thinking pyroluria was the "root cause" of ALL of my health problems (how many of us have been down this road before with whatever thingie) and really really wanted me to do it. I figured I had nothing to lose. I tested highly positive.

After taking the supplements irregularly for a month or so, it became really clear that the days I became overwhelmed by stress were the days I didn't take any of it. That was enough for me to add it permanently to my regime.

I'm on 30mg zinc citrate twice daily, as well as 40mg Pyridoxal-5-Phosphate (the B6) twice daily. My naturopath wants me to get up to 3X daily with both of these but I'm pretty comfy with where I'm at.

A lovely side effect, besides the reduced stress, is my fingernails are growing out long and strong! All on their own, totally neglecting them and abusing them. And one day I look down and notice they're all super long. That's never happened before. (This is after.....I think about 8 months on it?)

For me personally, I have enough evidence that this helps, so I'll continue. I'll be sure to mention the copper concern to my doctor, though. Thanks for the thread!
 

Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
@alicec, I cut the quotes down to make this more manageable, but haven't mastered this task yet, so apologies in advance.

Sorry I can't really help much - I don't have deep knowledge of many of the issues, just an interest in B6 and B12 since I have found supplementation so helpful and a love of metabolic pathways so I often chase these down just for interest sake (until I run out of energy of course).

Thank you so much, I did get some helpful insights... not everything , but every little bit helps!

Here is info which could be helpful to you. It struck me in looking at this again that if Stratton's hypothesis is correct, the resultant porphyria should be most like one arising from a ferrochelatase defect,

Thanks! This is a helpful depth. And I think your conclusion is right.

There is a useful section on differential diagnosis of microcytic anaemias. Note the heavy metal poisoning leads to acquired porphyria. I doubt that anyone has studied the effect of chronic heavy metal accumulation but it could be a contributing factor in a milder form of acquired porphyria which could be possible for you. The ZPP test could be useful here.

Hmm... I seem to have a lot of chronic toxicity due to longstanding methylation issues and glutathione depletion. I'd gotten rid of all the easy stuff a while back.

Lately have been pulling toxic stuff out of my mitochondria with PolyMVA for 8 months, like a bucket brigade.... get it mobilized, then provide ample detox pathway support to get it out.
Occasionally, it's gone too fast, at which point I start emitting sulfur from everywhere, (using more B6) which we tackle with curcumin and charcoal.

We'd thought the c. pneumoniae was well under control before starting it, but it seems to have been under everything along with my genetics, complicating things greatly.

Wonder if the ZPP test would change my treatment...or just add to my cost!

It's unlikely that the common methylation SNPs that are discussed endlessly are behind it. At best these might be making a contribution
.
Oh, I have an interesting assortment, and they definitely are...

One person who has delved deeply into that literature is Freddd (who devised the active B12 protocol which has generated an enormous amount of discussion on PR).
perhaps he might answer. Maybe in his survey of the B12 research he has come across something that could be useful to you.

Thanks for the suggestion. I've learned a lot from him over time. I'll have to think of what question to ask... my SNPs seem to be much different than his.

Can't help here. Are any of your treating doctors amenable to thinking outside of the box?

I can't get an MD, like my oncologist, to bat an eye at ANY of this, though I have pages of weird lab results. They think I should see a psychiatrist or have a sleep study...LOL....

My ND is great, but I already take too much of his time... I try to do my homework and go in prepared with any new ideas. That's why this discussion is so valuable.

Don't know about the first part apart from stating the obvious. Anything that compromises B12 status will compromise ...

The cytochromes use a form of haem (different from the one used in haemoglobin) so in Stratton's scenario, cyctochromes in the ETC would be adversely impacted (a double whammy) along with the P450 enzymes in the liver. Defects in phase I reactions are well known in porphyrias

I agree. But am puzzled, as my Phase I (CYP 450s) works really great, it's phase II that's a Herculean effort. Maybe Phase II is so slow this doesn't matter as much?

Possibly an OAT test would give a little insight but you would really need metabolomics testing to work this out.

I've done a NutrEval and LabCorp amino testing, would I be missing anything? They showed I'm running through a lot of aminos like the research says, and I have almost no methionine (!)

They are trying to set up an international testing service based on the company Ron Davis has used in San Francisco, but not quite there yet.

Depending on where you live it might be possible to organise this anyhow.

Good to hear. I have family near there, so I'll plan to watch for that.

Thank you so much for taking the time to share with me. I really appreciate it - it gets a little lonely in the trenches sometimes...

Still, I wonder why there doesn't seem to be more updated info out if Vanderbilt on the c. pneumoniae causing some of this and a more comprehensive treatment protocol, including the cofactors and perhaps something other than a high carb diet... or underlying methylation genetics or heavy metals that could be exacerbating the problems Stratton so perceptively identified 12 years ago... wonder if anyone else has looked at this..

Thanks again!
 
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Learner1

Senior Member
Messages
6,305
Location
Pacific Northwest
I'm on 30mg zinc citrate twice daily, as well as 40mg Pyridoxal-5-Phosphate (the B6) twice daily. My naturopath wants me to get up to 3X daily with both of these but I'm pretty comfy with where I'm at.

Dainty, thanks for chiming in!

So, the zinc and P5P is how you fix it? Any other components, aside from copper?

Wonder what your ND would say to my crazy need for 450mg P5P and 65mg of zinc picolinate? (copper is fine)

Is there something we're missing, or do we keep feeding the beast? As we've been discussing, B6 does a lot of important tasks...
 

Ben H

OMF Volunteer Correspondent
Messages
1,131
Location
U.K.
Sorry I can't really help much - I don't have deep knowledge of many of the issues, just an interest in B6 and B12 since I have found supplementation so helpful and a love of metabolic pathways so I often chase these down just for interest sake (until I run out of energy of course).



It does. You would then hopefully know if porphyria or a mild porphyria-like entity is an issue. There is a lot of literature about porphyria and various treatments (I've never looked at the detail) - maybe something there would be of help.

Stratton somewhere talks about the testing issue and why his proposed porphyria might not be detected. It could be worth reading that carefully to work out what exactly should be tested for.

Here is info that I have found helpful in understanding porphyrins and haem. There might be something there which could be helpful to you.

It struck me in looking at this again that if Stratton's hypothesis is correct, the resultant porphyria should be most like one arising from a ferrochelatase defect, since this is the step which inserts the iron into haem, the step that he says can't proceed because the iron is not in the right form as a result of ETC problems.

There is a useful section on differential diagnosis of microcytic anaemias. Note the heavy metal poisoning leads to acquired porphyria. I doubt that anyone has studied the effect of chronic heavy metal accumulation but it could be a contributing factor in a milder form of acquired porphyria which could be possible for you. The ZPP test could be useful here.



Can't help much here. It's unlikely that the common methylation SNPs that are discussed endlessly are behind it. At best these might be making a contribution.

At various times I have tried tracking down the B12 literature but it just proved too difficult.

One person who has delved deeply into that literature is Freddd (who devised the active B12 protocol which has generated an enormous amount of discussion on PR).

He only appears intermittently on the forum these days but if you explained you position (ie much like you have already done perhaps emphasising the B12 related things that puzzle you) and specifically alerted him by using @Freddd, perhaps he might answer. Maybe in his survey of the B12 research he has come across something that could be useful to you.

Freddd has adult onset CblC disease (see this thread) so has an enormous need for B12 because of genetic issues. It took a long time to work this out since it is usually diagnosed in infancy. Anyhow his case is extreme but his protocol, worked out by self-experimentation, actually does point to many of the consequences of deranged B12 metabolism and suggests that our understanding of this is very poor.



Can't help here. Are any of your treating doctors amenable to thinking outside of the box?



Don't know about the first part apart from stating the obvious. Anything that compromises B12 status will compromise the methionine synthase reaction and hence methylation, and also methylmalonyl mutase in the mitochondrion, and hence delivery of fatty acids for energy metabolism.

The cytochromes use a form of haem (different from the one used in haemoglobin) so in Stratton's scenario, cyctochromes in the ETC would be adversely impacted (a double whammy) along with the P450 enzymes in the liver.

Defects in phase I reactions are well known in porphyrias necessitating careful use of certain drugs - or strict avoidance.



Possibly an OAT test would give a little insight but you would really need metabolomics testing to work this out.

There has been a lot of discussion about this on PR as a result of the Naviaux paper and the work of Ron Davis. They are trying to set up an international testing service based on the company Ron Davis has used in San Francisco, but not quite there yet.

@Ben Howell was co-ordinating this. Perhaps he can give you an update. Perhaps he can give us all an update.

Depending on where you live it might be possible to organise this anyhow.

Here is someone living in the UK who made his own arrangements.

Hi @alicec

Update regarding metabolomics testing is as follows.

The lab at Stanford have managed to source a clinic where they are now due to be taking the healthy samples/aged matched controls for the trial of the metabolomics test. Once this is completed the metabolomics will be run, and after these results the test will be made available to the public.

Its turned into a bigger trial than expected, and finding participants for the healthy samples was a time consuming process. So hopefully, not too long now.

Hope that helps!


B
 

Johnmac

Senior Member
Messages
756
Location
Cambodia
@alicec & @Learner1 & @dominicpukallus:

I supposedly have borderline pyroluria (formally diagnosed) & did indeed respond quite well to zinc & B6, which I'm still on. I put the pyroluria theory to a B12 scientist I know. He doesn't believe it's real, so far as I can tell. He explained the 'pyroluria effect' to me as below (little of which I understand - but you may).

I'll just paste the (somewhat disconnected) pars in his emails that seem to relate to 'pyroluria' & you can make of it what you will:



At this stage there are two likely causes of low iron apart from diet.

1. Low active B2, as this is required in the process of uptake and trapping iron. Low iron is a feature of hypothyroidism.

2. Lack of functional activity of an enzyme called cystathionine beta synthase (CBS), which will occur due to CBS SNPs, lack of heme iron, lack of P5P, but more likely low B2. The iron is recruited to unsuccessfully make Fe-S proteins, and so is consumed at a higher than normal amount. The longer CBS has been non-functional the lower the iron. This is where one of the great similarities between CFS and AD is. Same mechanism for lack of energy, although it seems that there don't seem to be any people with major smarts working in the AD area, as the effects I would put in the "bleeding obvious" category.


_______ is incredibly iron deficient. The ranges that they give are BS. For a menstruating woman, she should be above 150 ug/L for ferritin... She is critically iron deficient. Also she backs this up by having high Pyrroles. These come from when she is trying to insert iron into the pyrrole ring to make heme. If there is no iron the pyrroles are excreted from the cell and you get high pyrroles.


The pyroluria should go away with increased iron and increased B2. Anxiety may have dropped because you need B6 to make GABA your inhibitory neurotransmitter.


There are many theories on pyroluria, but curiously the diseases linked to it are also mitochondrial diseases.

In order to make heme, you need iron, so no surprise there. If you have low iron, you can't make heme, and the pyrole ring that was made to try to make heme is discarded. You also get high bilirubin. The missing bit though is that you also need B2, because it is used in the last step of closure of the pyrole ring, before you add the iron. So in B2 deficiency, you also get pyroluria as once again the pyrole ring is discarded. In this case though you get iron precipitation, such as you see in MS. There is another problem in that you also need CBS to be functioning, a well-defined but poorly known fact. So if you have elevated homocysteine, or you don't make much SAM you don't have CBS working. It also doesn't work when B6 is low or B2 is low. You can see this in the biochemistry in CFS in the OAT, but you have to know the biochemistry.
 

Learner1

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Thanks for sharing... very interesting. One note, Ben Lynch says you need FAD (B2) to make thyroid work.

My problem seems to be the opposite of your notes, but I have no doubt it's related somehow. My serum ferritin has been running 250-600, with iron sat as high as 75, and iron study suggests B6 deficiency anemia.

Homocysteine has been 3-4 lately, and typically ranges from 3-8 no matter what I take. I have almost no methionine, and always have a tremendously upregulated CBS, and been low in B2 and folate, as well as severely B6 and B12 deficient, so supplement all folate and methionine nutrients and cofactors. Having adequate GSH is always a challenge...

Your post points out how complex this all is. Do you have more info on this to share? I'm wishing for a diagram... I think this is important, as there are also links to immune system function and sphingolipid production aside from the obvious.

Many thanks!
 
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