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Revision of the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS

richvank

Senior Member
Messages
2,732
Hi, all.

I have made a revision to the GD-MCB hypothesis based on recent discussions with Prof. Martin Pall. The revised version is below. The important change is shown at number 5 below. In the past, I had hypothesized that the folates were depleted by the so-called "methyl trap" mechanism. Marty Pall has convinced me that this explanation does not fit the observation that the plasma level of 5-methyltetrahydrofolate (5-MTHF) decreases in ME/CFS patients, rather than increasing, which would be expected from the methyl trap mechanism. It has been shown by Antoniades et al. that 5-MTHF will react with peroxynitrite, and there is some evidence that peroxynitrite does rise in ME/CFS, as would be expected from the well-documented state of oxidative stress in this disorder. Reaction with peroxynitrite would be consistent with the observed lowering of plasma 5-MTHF. Therefore, I agree that this is currently the most plausible explanation for the loss of folates from the cells in ME/CFS, and I am therefore modifying the GD-MCB hypothesis accordingly.

This does not impact treatment based on the GD-MCB hypothesis, but it does give a better match to the observations.

Best regards,

Rich


Revised Summary of the Glutathione DepletionMethylation Cycle Block Hypothesis for the Pathogenesis and Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Rich Van Konynenburg, Ph.D.

January 13, 2012

1. There is a genetic predisposition toward developing ME/CFS, only part of which has been characterized.

2. Some combination of a variety of stressors (physical, chemical, biological and/or psychological/emotional), the combination differing from one case to another, together with the genetic predisposition, lead to depletion of glutathione by several mechanisms, including oxidative stress, conjugation by toxins, and depletion of amino acids needed for synthesizing glutathione.

3. The depletion of glutathione causes a functional deficiency of vitamin B12, so that both methylcobalamin and adenosylcobalamin become depleted.

4. The depletion of methylcobalamin inhibits the activity of the enzyme methionine synthase in the methylation cycle, producing a partial block.

5. Peroxynitrite, which rises as a result of the glutathione depletion, reacts with methylfolate, lowering the intracellular folates in general.

6. The partial block of the methylation cycle also deranges the sulfur metabolism in general and stabilizes the depletion of glutathione by a vicious circle mechanism, making ME/CFS a chronic condition.

7. The many abnormalities and symptoms of ME/CFS stem directly from the several aspects of this vicious circle mechanism.
 

richvank

Senior Member
Messages
2,732
Thank you for the update. Do your treatment recommendations differ substantially from those of Dr. Pall?

Hi, determined.

In the past, the Pall protocol focused primarily on antioxidants. More recently, Prof. Pall has changed his protocol to include 5-MTHF together with hydroxocobalamin, so I would say that the treatments are pulling together more. He believes the results of our clinical study, but his view is that we have interpreted them incorrectly. He believes that the role of hydroxocobalamin is to scavenge nitric oxide, and the role of 5-MTHF is to scavenge peroxynitrite. Nitric oxide and peroxynitrite play major roles in his "NO-ONOO theory."

Best regards,

Rich
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Rich, this is in line with how I think things will progress. The models are merging, leading us closer to a complete theory. I still think there might be an underlying driving force, pathogenic or autoimmune, but its still nice to see these developments.

The reason why Prof. Pall prefers hydroxocobalamin, iirc, is that it is a peroxynitrite scavenger. So if you really need methylcobalamin to get around a block, a combination of methyl and hydroxo might be even more powerful.

Bye, Alex
 

richvank

Senior Member
Messages
2,732
Hi, Alex.

Yes, things should come together as we get closer to understanding the truth about this disorder. All of us need to keep open minds and be willing to change our hypotheses so that they will track with observations in the real world. I don't think many of us are smart or lucky enough to be exactly right with our first hypothesis. I know I certainly am not, and as I think you know, I have made a few other changes over the past few years as more has been learned.

As I understand it, Marty has focused on hydroxocobalamin as a scavenger for nitric oxide, and more recently on 5-MTHF as a scavenger for peroxynitrite. I think that the latter has assumed more importance in Marty's theory more recently, as he has focused on the nitric oxide synthase reactions and the role of tetrahydrobiopterin.

I think our differences at present are on emphases. He believes that these scavenger roles are the most important, while I view them as temporary impediments to the use of these two substances for their crucial normal role in the metabolism, which is to support the methionine synthase reaction.

Whichever is most important, we are homing in on similar treatment, and I think that is a positive development. You may be right that a combination of hydroxo and methyl B12 might be more effective. I think that adenosyl B12 might also help, as Freddd has emphasized. I think Amy Yasko is using all three of these in some autism cases.

I agree with you that there is an underlying driving force in at least some of the cases, and I think it is a pathogen (or pathogens) rather than an autoimmune issue. I think this explains why the various MAF treatments are helping some PWMEs, and also why the methylation treatment does not bring very many people to full recovery, though it helps most of them significantly. I consider that the pathogen or pathogens are lumped into what I refer to as "biological stressors" that help to deplete glutathione, and that some of them are still present when people do the methylation treatment, and they are still placing demands on glutathione and preventing it from rising completely to normal. These pathogens will likely need to be better identified and treated specifically to bring about complete recovery.

I still think that the vicious circle mechanism I have described is the core of the pathogenesis and pathophysiology, but when it comes to treatment, it looks as though just treating to break this vicious circle is not enough for most PWMEs. We also need to deal specifically with the pathogen or pathogens that started the whole process in many cases, I think. In other words, we also have to treat the etiology, if we can identify it in a specific case. I think that in some cases it is a biotoxin, such as from molds, or heavy metals, especially in cases where the glutathione transferases have serious polymorphisms, so that metals such as mercury are allowed to build up. Probably in most cases is it viral (or retroviral--time will tell about that).

Thanks for your thoughts.

Best regards,

Rich
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Rich, when I state autoimmune I do not necessarily mean auto-antibodies. Complex immune hormone cascades and cycles could well interlink with the kind of chemistry both you and Marty discuss. Indeed, one pathway I have been looking at for well over a decade is highly sensitive to glutathione, oxidative stress and nitric oxide - the eicosanoids, which include many inflammatory hormones. Cytokines are another class, but I do not know much about oxidative stress and cytokine reactions. Indeed, these kinds of chemistry patterns were what I was investigating when I had better memory and more resources over a decade ago and I know you are familar with them.

These kinds of hormones are very complex and still not well understood. I quickly became lost in the literature. We keep discovering more of these hormones, and keep discovering many more ways they interact with other pathways. So an autoimmune issue might well dovetail with the kind of chemistry you describe, but it may just be that we don't know enough about such a complex subject to easily tease out the interactions. It might be useful to see if you can interest a cytokine researcher to get involved for example, or an expert on inflammatory eicosanoids. Of course that might mean diverting research from other areas, which might not be the best idea. Its so hard to know when so much is probably still undiscovered.

I do agree though that pathogens draining glutathione could be a huge problem. Let me give two interactions, based on the eicosanoids, which I am sure you are aware of but which some readers might not be. The desaturases regulate overall production of eicosanoids. What chemical has the single largest impact on desaturase regulation? Glutathione. So there is one distubance right there.

A second major factor is nitric oxide: it increases cyclooxygenase activity if I recall correctly (its been a while), which leads to series 2 eicosanoids.

So the models you are describing have a foot on both the brake and accelerator for some eicosanoids. The body will try to regulate this, but if it pushes the brake we are hormone deficient, and if it pushes the accelerator we have too much of the inflammatory hormones. Either result is bad. The real fix, in this simplifed view anyway, is to remove the brake and accelerator effects: restore glutathione and lower nitric oxide. What a surprise. Of course I have ignored other factors, like substrate damage from oxidative stress, impact of insufficient cortisol and so on. Also the enzymatic literature search I did that points to glutathione as the main regulating factor for eicosanoids is old: it probably did not look at other aspects of oxidative stress, glutathione may only have been a surrogate marker.

Bye
Alex
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Hi Rich, when I state autoimmune I do not necessarily mean auto-antibodies. Complex immune hormone cascades and cycles could well interlink with the kind of chemistry both you and Marty discuss. Indeed, one pathway I have been looking at for well over a decade is highly sensitive to glutathione, oxidative stress and nitric oxide - the eicosanoids, which include many inflammatory hormones. Cytokines are another class, but I do not know much about oxidative stress and cytokine reactions. Indeed, these kinds of chemistry patterns were what I was investigating when I had better memory and more resources over a decade ago and I know you are familar with them.

These kinds of hormones are very complex and still not well understood. I quickly became lost in the literature. We keep discovering more of these hormones, and keep discovering many more ways they interact with other pathways. So an autoimmune issue might well dovetail with the kind of chemistry you describe, but it may just be that we don't know enough about such a complex subject to easily tease out the interactions. It might be useful to see if you can interest a cytokine researcher to get involved for example, or an expert on inflammatory eicosanoids. Of course that might mean diverting research from other areas, which might not be the best idea. Its so hard to know when so much is probably still undiscovered.

I do agree though that pathogens draining glutathione could be a huge problem. Let me give two interactions, based on the eicosanoids, which I am sure you are aware of but which some readers might not be. The desaturases regulate overall production of eicosanoids. What chemical has the single largest impact on desaturase regulation? Glutathione. So there is one distubance right there.

A second major factor is nitric oxide: it increases cyclooxygenase activity if I recall correctly (its been a while), which leads to series 2 eicosanoids.

So the models you are describing have a foot on both the break and accelerator for some eicosanoids. The body will try to regulate this, but if it pushes the break we are hormone deficient, and if it pushes the accelerator we have too much of the inflammatory hormones. Either result is bad. The real fix, in this simplifed view anyway, is to remove the brake and accelerator effects: restore glutathione and lower nitric oxide. What a surprise. Of course I have ignored other factors, like substrate damage from oxidative stress, impact of insufficient cortisol and so on. Also the enzymatic literature search I did that points to glutathione as the main regulating factor for eicosanoids is old: it probably did not look at other aspects of oxidative stress, glutathione may only have been a surrogate marker.

Bye
Alex

Hi Alex,

The first sporadic cases at the site of the 1934 epidemic were in 1932



Can you explain or post a link please? I'd very much like to know. I was caught in several local epidemic outbreaks of things that made me very sick for prolonged periods prior to Incline Villiage outbreak. They were prolonged and widespread enough that one year multiple school and college opeings were delayed, the CDC was involved and clammed up instantly saying "it's nothing". I have my suspicions but who knows.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Freddd, about a year or two ago, in a thread in which George was participating, I did some extensive online searches and found several articles. There were two patients with exactly the same symptoms as in the 1934 epidemic at the same location, in 1932. Nobody was recorded as becoming ill in 1933.. I do not know any more than this. I do recall that the 1934 epidemic resulted in substantial damages payouts after legal action. I wonder if much of the information was suppressed as part of the settlement, or if the information was simply never copied to the web. Any historians living in the L.A. County area? That used to be George's thing, a member who does not post here any more. I may or may not have a copy of the articles, I think I looked for them on my harddrive once before but failed to find them. They were very difficult to find, requiring extensive search. Essentially I kept adding keywords from each little bit of info I found until I found combinations of keywords that found something. Bye, Alex

PS I just remembered something else. This same hospital (LA County I think) was doing research on mouse encephalitis. They were using mice and monkeys I think it was reported.
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Hi Freddd, about a year or two ago, in a thread in which George was participating, I did some extensive online searches and found several articles. There were two patients with exactly the same symptoms as in the 1934 epidemic at the same location, in 1932. Nobody was recorded as becoming ill in 1933.. I do not know any more than this. I do recall that the 1934 epidemic resulted in substantial damages payouts after legal action. I wonder if much of the information was suppressed as part of the settlement, or if the information was simply never copied to the web. Any historians living in the L.A. County area? That used to be George's thing, a member who does not post here any more. I may or may not have a copy of the articles, I think I looked for them on my harddrive once before but failed to find them. They were very difficult to find, requiring extensive search. Essentially I kept adding keywords from each little bit of info I found until I found combinations of keywords that found something. Bye, Alex

PS I just remembered something else. This same hospital (LA County I think) was doing research on mouse encephalitis. They were using mice and monkeys I think it was reported.

Epidemic of WHAT?
 

richvank

Senior Member
Messages
2,732
Thanks Rich. Does methyl b12 scavenge NO as well as or better than hydroxy b12?

Hi, Adster.

You're right on with this question. It's a key question in trying to decide between Marty's model and mine. I don't have a complete answer for it yet (because it's important to consider that some methyl B12 may be converted to hydroxo B12), but am working on it.

Best regards,

Rich
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Hi, Adster.

You're right on with this question. It's a key question in trying to decide between Marty's model and mine. I don't have a complete answer for it yet (because it's important to consider that some methyl B12 may be converted to hydroxo B12), but am working on it.

Best regards,

Rich

Hi Rich,

Considering that hydroxcbl and maybe dozens more temporary forms found at all in the body kind of indicates that it came from one one of the two main active forms as at least mb12 "the main circulating form" according to various studies, easily breaks down to it. The question is whether light through the skin is enough to trigger the breakdown, other avenues of breakdown and how besides HTC2 is it protected. I was reading of a method being developed that will be able to easily identify the many varieties. The author was proposing that the body produces possibly dozens of special purpose cobalamins for a multitude of reasons that can only begin to be understood when the specialized cobalamins can be easily identified.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Epidemic of WHAT?

Of ME, or presumed ME, it was I think considered atypical polio. This epidemic was the first that was really well characterized that I can find. There might have been earlier ones but I have not found them. This might have had something to do with occuring in a hospital to the doctors and nurses. Bye, Alex

I have a little time so here is more info, from: http://www.name-us.org/ResearchPages/ResEpidemic.htm#M.E._Epidemics

1934 1. Los Angeles City and California State, USA
Epidemic among personnel at L.A. County Hospital, Ruth Protection Home and throughout California, paralleling poliomyelitis, often diagnosed as atypical poliomyelitis, sometimes including arthropathy.

It is worth noting that many ME outbreaks occurred in the same location as polio outbreaks, or right after, or in the medical personel who treat polio patients.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1700895/?page=1

The 1934 atypical polio epidemic was extensively written up by the US Public Health Service. Please note that this paper leans toward hysteria as an explanation. Its the crazy hysterical female explanation all over again. However, it does give details of the 34 epidemic, just ignore the feeble attempts at explaining it away.
 

voner

Senior Member
Messages
592
Rich:

Hey I just had a thought.

The unbelievably complexity of the biochemistry of the human body never ceases to amaze me. This led me to the question -- have you ever heard of anybody who is working on computer software modeling of the methylation cycle/etc. etc.?? After watching Dr. Eric Schadt talk about the modeling he is doing -- it seems feasible. That might help tease out some information

Having said that -- I am fully aware of the pitfalls of computer models and simulations -- but if the coding done well, etc., sometimes it can be quite helpful on these ultra-complex problems.

Just a thought.
 

richvank

Senior Member
Messages
2,732
Rich:

Hey I just had a thought.

The unbelievably complexity of the biochemistry of the human body never ceases to amaze me. This led me to the question -- have you ever heard of anybody who is working on computer software modeling of the methylation cycle/etc. etc.?? After watching Dr. Eric Schadt talk about the modeling he is doing -- it seems feasible. That might help tease out some information

Having said that -- I am fully aware of the pitfalls of computer models and simulations -- but if the coding done well, etc., sometimes it can be quite helpful on these ultra-complex problems.

Just a thought.



Hi, voner.

Yes. Right on. Michael Reed at Duke does this kind of modeling. Here's a recent abstract:

Theor Biol Med Model. 2008 Apr 28;5:8.
A mathematical model of glutathione metabolism.
Reed MC, Thomas RL, Pavisic J, James SJ, Ulrich CM, Nijhout HF.
Source

Department of Mathematics, Duke University, Durham, NC 27708, USA. reed@math.duke.edu
Abstract
BACKGROUND:

Glutathione (GSH) plays an important role in anti-oxidant defense and detoxification reactions. It is primarily synthesized in the liver by the transsulfuration pathway and exported to provide precursors for in situ GSH synthesis by other tissues. Deficits in glutathione have been implicated in aging and a host of diseases including Alzheimer's disease, Parkinson's disease, cardiovascular disease, cancer, Down syndrome and autism.
APPROACH:

We explore the properties of glutathione metabolism in the liver by experimenting with a mathematical model of one-carbon metabolism, the transsulfuration pathway, and glutathione synthesis, transport, and breakdown. The model is based on known properties of the enzymes and the regulation of those enzymes by oxidative stress. We explore the half-life of glutathione, the regulation of glutathione synthesis, and its sensitivity to fluctuations in amino acid input. We use the model to simulate the metabolic profiles previously observed in Down syndrome and autism and compare the model results to clinical data.
CONCLUSION:

We show that the glutathione pools in hepatic cells and in the blood are quite insensitive to fluctuations in amino acid input and offer an explanation based on model predictions. In contrast, we show that hepatic glutathione pools are highly sensitive to the level of oxidative stress. The model shows that overexpression of genes on chromosome 21 and an increase in oxidative stress can explain the metabolic profile of Down syndrome. The model also correctly simulates the metabolic profile of autism when oxidative stress is substantially increased and the adenosine concentration is raised. Finally, we discuss how individual variation arises and its consequences for one-carbon and glutathione metabolism.

PMID:
18442411
[PubMed - indexed for MEDLINE]
PMCID: PMC2391141


The full paper is available free from PubMed. He has published some other papers about this modeling, too. Note that Jill James is a coauthor on this paper. She is the one who showed the connection between the methylation cycle partial block and glutathione depletion in autism, which is what caused me to suspect that the same mechanism is going on in ME/CFS.

Best regards,

Rich
 

Freddd

Senior Member
Messages
5,184
Location
Salt Lake City
Of ME, or presumed ME, it was I think considered atypical polio. This epidemic was the first that was really well characterized that I can find. There might have been earlier ones but I have not found them. This might have had something to do with occuring in a hospital to the doctors and nurses. Bye, Alex

I have a little time so here is more info, from: http://www.name-us.org/ResearchPages/ResEpidemic.htm#M.E._Epidemics

1934 1. Los Angeles City and California State, USA
Epidemic among personnel at L.A. County Hospital, Ruth Protection Home and throughout California, paralleling poliomyelitis, often diagnosed as atypical poliomyelitis, sometimes including arthropathy.

It is worth noting that many ME outbreaks occurred in the same location as polio outbreaks, or right after, or in the medical personal who treat polio patients.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1700895/?page=1

The 1934 atypical polio epidemic was extensively written up by the US Public Health Service. Please note that this paper leans toward hysteria as an explanation. Its the crazy hysterical female explanation all over again. However, it does give details of the 34 epidemic, just ignore the feeble attempts at explaining it away.

Hi ALex,

You have just come up with my favorite hypothetical cause of FMS/CFS virus, or I should say, families of viruses, Echo and Coxsackie virues, about 32 of them, that used to be lumped into that now forbidden word, Polio. When epidemic numbers were reported these were reported as "non-paralytic polio". After all, post polio syndrome and FMS are basically identical exept that the FMS person hasn't had a polio diagnosis though they very possibly had an Echo or Coxsacki virus. These days they are referred to as "miscellaneous virus" or miscellaneous entero virus". Since polio is wiped out in the USA they can hardly say non-paralytic polio. There are no vaccines developed against these viruses so people still get sick. The outbreaks are often focused around water as a carrier for fecal material jsut as polio was. Incline villiage is another example. They also follows nerve pathways just as polio does. I assumed that the word "Polio" has become totally forbidden hence the sudden clamming up on the part of the CDC about all these things trying to avoid a panic.

Now these things are on Wikipedia.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
Hi Freddd, back in 89 I was told I had coxsackie 3B, and I was told it probably caused my illness, now the new disease CFS (Holmes) and I shouldnt exercise ever. Then the story started changing with other docs. Bye, Alex
 

voner

Senior Member
Messages
592
Duke University methylation cycle researchers, etc..

Rich:

Wow! These folks at Duke University and their associates (like Jill James) are deep into this type of modeling. I also like that they are into looking at neurotransmitters in the brain, like serotonin, etc.

rich: thanks for the response.

Do you think Virginia Falkenburg talks with any of these folks?

Has anyone from the ME/CFS researcher community communicated much with any of these folks? I assume that you must comunicate with Jill James??

After looking at Dukes big-walk webpage, it sure strikes me that computer modeling is necessary, along with careful analysis.

For anyone interested, check out these links at Duke University (the methylation cycle picture is quite nicely done):

http://metabolism.math.duke.edu/

http://metabolism.math.duke.edu/big-walk.html

http://fds.duke.edu/db/aas/math/faculty/reed/publications.html

I would love to see these people involved in methylation in ME/CFS research.

regards,

voner
 

richvank

Senior Member
Messages
2,732
***Hi, voner.

Wow! These folks at Duke University and their associates (like Jill James) are deep into this type of modeling. I also like that they are into looking at neurotransmitters in the brain, like serotonin, etc.

***Yes, I agree.

rich: thanks for the response.

***You're welcome.

Do you think Virginia Falkenburg talks with any of these folks?

***I don't know. I think she has worked mainly on the genomics, and now, how methylation affects the genomics, rather than on the biochemistry of the methylation cycle.

Has anyone from the ME/CFS researcher community communicated much with any of these folks? I assume that you must comunicate with Jill James??

***I've only communicated with Jill James. She has worked on methylation in connection with autism, and I think the biochemistry of ME/CFS and autism are very similar.

After looking at Dukes big-walk webpage, it sure strikes me that computer modeling is necessary, along with careful analysis.

***I agree. The thing that limits the computer modeling is knowing the numerical values of the parameters, and these have to be measured biochemically. But when you have both, it's very powerful. There may also still be some subtleties in the biochemical interactions that are not yet completely known, and it isn't possible to put into a computer model something that isn't known. But I think the methylation cycle is pretty well nailed down now.

For anyone interested, check out these links at Duke University (the methylation cycle picture is quite nicely done):

http://metabolism.math.duke.edu/

http://metabolism.math.duke.edu/big-walk.html

http://fds.duke.edu/db/aas/math/facu...lications.html

I would love to see these people involved in methylation in ME/CFS research.

***I think they would need to be convinced that ME/CFS involves methylation, and they would need a source of funding. I have sent papers to Michael Reed in the past, but haven't heard anything back from him. Jill James is very familiar with my work, and I email with her occasionally. I think methylation's time is coming in ME/CFS, but isn't quite here yet, in terms of the larger research community. The interest in methylation both at the new Mt. Sinai research center and at the CDC are promising developments, I think.

regards,

voner

***Best regards,

***Rich