***Hi, Mr. Kite.
***Thank you for the response. My comments are at the asterisks below.
Still, in all these examples, glutathione depletion isn't the actual *cause.* It's merely a problem that then leads or contributes to the cause, whether the actual cause is the impaired aconitase enzymes, impaired methylation, or otherwise dysfunctional mitochondrial and cellular energy production, and so on.
***This may be partly an issue of semantics, but my view of pathogenesis is that it is like a row of dominoes, or more properly, a branching row of dominoes. The falling of each domino is an effect of the falling of the preceding domino, and is also the cause of the falling of the next one (or ones, if there is a branch point there). In other words, the pathogenesis is described by a cause and effect sequence, or more properly, a cause and effect "tree."
***So in this paradigm, glutathione depletion would be an effect of several possible causes (physical, chemical, biological, and/or psychological/emotional stressors, each of which independently can place demands on glutathione). Glutathione depletion would also be a cause of several effects, including a rise in oxidative stress, dysfunction of the detox system, a shift in the immune response away from Th1, and many more.
Based on my own experience, it's also possible to have impaired GSH and not have full blown chronic fatigue syndrome, which then can come about following an immunological activation. Not to say that the CFIDS development is not tied to the pre-existing glutathione depletion, or that it doesn't have the stage set by the depletion (or the dysfunctional GSH systems), but that GSH depletion in and of itself is not always enough to cause CFS.
***I agree with you on this. In my hypothesis, CFS does not develop unless the glutathione depletion leads to a partial block in the methylation cycle, which involves a loss of protection of vitamin B12 in the cells. Whether this occurs seems to depend on the person's inherited genomic polymorphisms. There are many illnesses that produce low glutathione, but I suggest that they don't go on to produce a chronic partial methylation cycle block, which is the hallmark of CFS.
In that case - CFS-like syndrome without immunological component - the "cause" of CFS appears to be more neurobiological and neurohormonal, involving a dysfunctional HPAA and corticosteroid receptor function, dysfunctional NMDA receptor complex, possibly dysfunctional neurotransmitter function (perhaps why some people improve with SSRI/SNRIs, wellbutrin, etc.), and related neuro functions, which themselves somehow cause the mitochondrial dysfunction. I suspect it's something very complex and yet undiscovered regarding NMDA function, ion channel and other 'downstream' system functioning having to do with NMDA, brain glutamatergic systems, etc., or maybe even some as yet entirely undiscovered neurobiological function.
*** I agree that the phenomena you have discussed in this paragraph are features of CFS, but I suggest that they fit within the cause and effect tree that starts with glutathione depletion as a result of the action of a variety of stressors. I described where I think most of them fit in in my 2007 poster paper, which can be found at www.cfsresearch.org.
I could also tell you some interesting stories about Co Q-10 that would definitely fit your theory (and some of Cheney's observations), including a CFS crash following fructose consumption (Cheney warns against fructose now, I recently found out) that led to increased fatigue and widespread muscular "fibro" pain (burning, aching, "lactic acidosis" feeling, etc.) that lasted for weeks, and then was alleviated 50-75% in one day merely by increasing Co Q-10 from 100mg. to 200mg., and eventually improving almost to baseline again over the following weeks by continuing the 200mg. dosage.
Since then I had a fever that led to actual immunological CFS and can't tolerate more than probably 25mg Co-Q 10 per day -- and can't tolerate NADH at all, both of which lead to congestive heart failure symptoms (which itself was caused a by bad reaction to an SSRI!) -- so the tie-ins, often contradictory, both to Cheney's ideas and your own (and the mito-dysfunction, electron transport chain dysfunction, etc.) I think are obvious. It's not just a simple 1 ingredient problem, or answer, imho!
***Thanks for this information. In my hypothesis, the reason for Co Q10 depletion in CFS is that it is known that its synthesis requires methylation. So its depletion is a direct effect of the partial block in the methylation cycle. Supplementing Co Q10 helps some people, but others don't respond well to it. As an antioxidant, it is capable of prooxidant behavior if it is present in concentration that is too high relative to the concentrations of the other network antioxidants. That may explain what occurred in your experience.
***Fructose in large amounts is really not good for any of us, and some people are intolerant of even small amounts. Dr. Kenny de Meirleir tests his patients with a fructose loading test, followed by breath analysis. He finds that fructose is feeding unhelpful bacteria in many PWCs. Dr. Cheney has emphasized that fructose enters the glycolysis chain at a point beyond where it can support the pentose phosphate shunt. That means that it can't be used to produce NADPH, which is needed to recycle oxidized glutathione.
***I suggest that what happened in your case is that you were pushed into a more severe state of oxidative stress by the fructose, which blocked your glutathione recycle. The Co Q-10, being an antioxidant, was able to compensate for the oxidative stress and improve your situation.
***I suggest that later on, the problem has been that your supply of glutathione has been more severely depleted, so that just adding NADH (which can also be used for glutathione recycle) is not sufficient, because you don't have enough glutathione to recycle. The Co Q-10 is probably having a prooxidant effect at higher dosages now, because your network antioxidants (glutathione being the basis of the network) are too low.
***You might want to consider treating to lift the methylation cycle block, which can raise glutathione. As always, I want to emphasize that it is necessary to be working with a physician when one does this type of treatment.
***Best regards,
***Rich
***Thank you for the response. My comments are at the asterisks below.
Still, in all these examples, glutathione depletion isn't the actual *cause.* It's merely a problem that then leads or contributes to the cause, whether the actual cause is the impaired aconitase enzymes, impaired methylation, or otherwise dysfunctional mitochondrial and cellular energy production, and so on.
***This may be partly an issue of semantics, but my view of pathogenesis is that it is like a row of dominoes, or more properly, a branching row of dominoes. The falling of each domino is an effect of the falling of the preceding domino, and is also the cause of the falling of the next one (or ones, if there is a branch point there). In other words, the pathogenesis is described by a cause and effect sequence, or more properly, a cause and effect "tree."
***So in this paradigm, glutathione depletion would be an effect of several possible causes (physical, chemical, biological, and/or psychological/emotional stressors, each of which independently can place demands on glutathione). Glutathione depletion would also be a cause of several effects, including a rise in oxidative stress, dysfunction of the detox system, a shift in the immune response away from Th1, and many more.
Based on my own experience, it's also possible to have impaired GSH and not have full blown chronic fatigue syndrome, which then can come about following an immunological activation. Not to say that the CFIDS development is not tied to the pre-existing glutathione depletion, or that it doesn't have the stage set by the depletion (or the dysfunctional GSH systems), but that GSH depletion in and of itself is not always enough to cause CFS.
***I agree with you on this. In my hypothesis, CFS does not develop unless the glutathione depletion leads to a partial block in the methylation cycle, which involves a loss of protection of vitamin B12 in the cells. Whether this occurs seems to depend on the person's inherited genomic polymorphisms. There are many illnesses that produce low glutathione, but I suggest that they don't go on to produce a chronic partial methylation cycle block, which is the hallmark of CFS.
In that case - CFS-like syndrome without immunological component - the "cause" of CFS appears to be more neurobiological and neurohormonal, involving a dysfunctional HPAA and corticosteroid receptor function, dysfunctional NMDA receptor complex, possibly dysfunctional neurotransmitter function (perhaps why some people improve with SSRI/SNRIs, wellbutrin, etc.), and related neuro functions, which themselves somehow cause the mitochondrial dysfunction. I suspect it's something very complex and yet undiscovered regarding NMDA function, ion channel and other 'downstream' system functioning having to do with NMDA, brain glutamatergic systems, etc., or maybe even some as yet entirely undiscovered neurobiological function.
*** I agree that the phenomena you have discussed in this paragraph are features of CFS, but I suggest that they fit within the cause and effect tree that starts with glutathione depletion as a result of the action of a variety of stressors. I described where I think most of them fit in in my 2007 poster paper, which can be found at www.cfsresearch.org.
I could also tell you some interesting stories about Co Q-10 that would definitely fit your theory (and some of Cheney's observations), including a CFS crash following fructose consumption (Cheney warns against fructose now, I recently found out) that led to increased fatigue and widespread muscular "fibro" pain (burning, aching, "lactic acidosis" feeling, etc.) that lasted for weeks, and then was alleviated 50-75% in one day merely by increasing Co Q-10 from 100mg. to 200mg., and eventually improving almost to baseline again over the following weeks by continuing the 200mg. dosage.
Since then I had a fever that led to actual immunological CFS and can't tolerate more than probably 25mg Co-Q 10 per day -- and can't tolerate NADH at all, both of which lead to congestive heart failure symptoms (which itself was caused a by bad reaction to an SSRI!) -- so the tie-ins, often contradictory, both to Cheney's ideas and your own (and the mito-dysfunction, electron transport chain dysfunction, etc.) I think are obvious. It's not just a simple 1 ingredient problem, or answer, imho!
***Thanks for this information. In my hypothesis, the reason for Co Q10 depletion in CFS is that it is known that its synthesis requires methylation. So its depletion is a direct effect of the partial block in the methylation cycle. Supplementing Co Q10 helps some people, but others don't respond well to it. As an antioxidant, it is capable of prooxidant behavior if it is present in concentration that is too high relative to the concentrations of the other network antioxidants. That may explain what occurred in your experience.
***Fructose in large amounts is really not good for any of us, and some people are intolerant of even small amounts. Dr. Kenny de Meirleir tests his patients with a fructose loading test, followed by breath analysis. He finds that fructose is feeding unhelpful bacteria in many PWCs. Dr. Cheney has emphasized that fructose enters the glycolysis chain at a point beyond where it can support the pentose phosphate shunt. That means that it can't be used to produce NADPH, which is needed to recycle oxidized glutathione.
***I suggest that what happened in your case is that you were pushed into a more severe state of oxidative stress by the fructose, which blocked your glutathione recycle. The Co Q-10, being an antioxidant, was able to compensate for the oxidative stress and improve your situation.
***I suggest that later on, the problem has been that your supply of glutathione has been more severely depleted, so that just adding NADH (which can also be used for glutathione recycle) is not sufficient, because you don't have enough glutathione to recycle. The Co Q-10 is probably having a prooxidant effect at higher dosages now, because your network antioxidants (glutathione being the basis of the network) are too low.
***You might want to consider treating to lift the methylation cycle block, which can raise glutathione. As always, I want to emphasize that it is necessary to be working with a physician when one does this type of treatment.
***Best regards,
***Rich
