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Nitric oxide and its possible implication in ME/CFS (Part 2 of 2)
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Revised Glutathione Depletion--Methylation Cycle Block Hypothesis for ME/CFS

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Apr 15, 2012.

  1. richvank

    richvank Senior Member

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    Hi, all.

    Here is the latest revision of the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS:

    1. Genetic predisposition is present (perhaps including SNPs in genes coding for enzymes related to glutathione that cause it to be more easily depleted, as reported in autism by Bowers et al., 2011).

    2. Stressors (physical, chemical, biological and/or psychological/emotional, the mix varying from one case to another, based on patient histories) deplete glutathione by various means, some by oxidative stress, some by conjugation, some by lowering its rate of synthesis. The depletion of glutathione is demonstrated by the methylation pathways panel.

    3. The state of oxidative stress worsens as a result of the depletion of glutathione, and peroxynitrite rises, due to reaction of rising superoxide with existing nitric oxide.

    4. Glutathione depletion lowers the affinity of the CblC complementation group for cobalamin (as reported by Jeong and Kim, 2011), producing a functional B12 deficiency, thus lowering intracellular methylcobalamin and adenosylcobalamin. Anecdotal observations of elevated urine methylmalonate in the presence of normal or elevated serum B12 in ME/CFS patients confirm the presence of a functional B12 deficiency.

    5. The lowered methylcobalamin inhibits the methionine synthase reaction, since it is the necessary coenzyme for this reaction.

    6. The methyl trap mechanism continues the conversion of other forms of folate into methylfolate, but the lowered rate of the methionine synthase reaction decreases the demand for it.

    7. The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma [NOTE: THIS STEP WAS CONTRIBUTED BY PROFESSOR MARTIN PALL, BASED ON PUBLISHED LITERATURE, FOR WHICH I AM GRATEFUL.]

    8. The above process depletes the intracellular folates in general (as inferred from measurements with the methylation pathways panel).

    9. Homocysteine drains into the transsulfuration pathway, since its conversion to methionine is inhibited, and over time, methionine therefore becomes depleted (as found by Bralley and Lord,1994), leading to dysregulation and depletion of the sulfur metabolism in general.

    10. The above combination of steps produces a stable vicious circle mechanism, and this is the reason ME/CFS is chronic.

    11. The elements of this vicious circle mechanism lead to the abnormalities observed and the symptoms experienced in ME/CFS. Among them is mitochondrial dysfunction, which leads to an increased rate of the main glycolysis pathway and a decreased rate of the pentose phosphate shunt. The latter decreases the level of NADPH, which exacerbates the glutathione depletion by slowing the rate of the glutathione reductase reaction.

    12. Boosting glutathione directly is not a successful treatment, because the glutathione reductase reaction cannot keep up with the oxidation of glutathione, due to the depletion of NADPH. [THIS IS BASED ON DISCUSSIONS WITH DR. PAUL CHENEY, FOR WHICH I AM ALSO GRATEFUL.]

    13. Treatment must include a high dosage (relative to the RDA) of a form of vitamin B12 delivered to the bloodstream, such as sublingually or by injection, together with an RDA-level dosage of folate, which can be given orally. The high dosage of B12 is necessary to compensate for the greatly lowered affinity for cobalamin of the CblC complementation group, so as to overcome the functional B12 deficiency, and the oral route is not adequate to supply this necessary high dosage (first reported by Lapp and Cheney, 1993 and 1999). The folate is necessary to compensate for the loss of methylfolate from the cells due to the peroxynitrite catabolism reaction. The B12 is best given as hydroxocobalamin or methylcobalamin. The folate is best given as methylfolate, though folinic acid works for some patients. There are individual differences in genetic polymorphisms that determine the best forms of B12 and folate for individual patients. If there are deficiencies in cofactor vitamins and minerals or in necessary amino acids, these must be supplemented in addition. Replacement of oxidatively damaged essential fatty acids is also needed. If toxic metals levels are high enough to significantly block enzymes in this part of the metabolism, chelation may be necessary before this treatment will be successful.

    14. This treatment is directed at the core of the pathophysiology. However, it does not directly treat the etiologies ("stressors" in step #2 above) that brought about this pathophysiology, nor does it directly treat pathogens and toxins that may have accumulated since the onset of ME/CFS, while the body's immune and detoxication systems have been dysfunctional as a result of the dysfunction of the sulfur metabolism. Additional treatments are needed in most cases to deal with them directly, to work toward achieving full recovery, because even though the immune system and the detoxification system may be largely restored, they are often not able to overcome these etiologies and accumulated factors on their own. Some of the etiologies and accumulated factors in various cases are Lyme disease and its coinfections, biotoxin illness, entrenched viral infections (and perhaps retroviral infections), and high body burdens of toxins.

    Best regards,

    Rich
  2. garcia

    garcia Aristocrat Extraordinaire

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    Hi Rich, thanks for that.

    I have a question. If the SMP is directed at the "core of the pathophysiology" as you say, why do so many people do so badly on it? As currently stands 32% had minor improvement, 45% either had no improvement or couldn't continue the protocol due to side effects. Only 21% had a major improvement (surely it should be more?) and only 1 person (1.6%) had an effective remission.

    Don't get me wrong, I think glutathione depletion / methylation block is a part of the pathophysiology, but IMHO not the core part.

    Saying we need to address additional pathogens / toxins doesn't really help either since many of us are too sick to do that.
  3. fla

    fla Senior Member

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    So what are the key changes in this revision? For a neophyte it's hard to tell exactly.

    Since evolution is a relatively slow process I don't think #1 genetic predisposition can explain the increasing rates of M.E.. I would think #2 stressors (particularly environmental, including nutritional) have changed the most in the last decades. We should all look at fixing #2 for ourselves before trying this protocol to break the vicious cycle.
    garcia likes this.
  4. Vegas

    Vegas Senior Member

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    The SMP is obviously, in most instances, not curative. In my view it is a supplemental treatment that has the potential to facilitate other therapies. One can enhance the efficiency of that part of the metabolism while never addressing the central etiology of the dysfunction, but using the nutrients in the protocol, at least for myself, gave me just enough improvement in GSH or GSH/GSSG to effect sufficient symptomatic improvement. Improvement to such an extent that I was able to tolerate what I hope will be a curative therapy.

    I think the more significant contribution (as compared to the SMP) comes from Rich's unified hypothesis for the pathophysiology and how this will influence treatment of ME/CFS in years to come. Glad to see this constantly evolving, including the statement about direct supplementation of glutathione. Actually I think this list could extend to a number of other supplements that results in more oxidized glutathione...most of the stuff Cheney has been preaching against for a few years.
  5. anniekim

    anniekim Senior Member

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    Hi Vegas,

    Is the curative therapy you allude to the chelation you are doing?

    Can heavy metals be one of the stressors mentioned in point two and/or a downstream accumulating factor?

    I was about to order some immunoprop from Dr Enlander which includes glutathione. I take it this post suggests that is not a good idea? Why does Dr Enlander use it, if so?

    Many thanks
    garcia likes this.
  6. Merry

    Merry Senior Member

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    Thank you, Rich.
  7. nem201

    nem201

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    Hi,

    Is it possible to still have a problem with the methylation cycle even if urinary measures of methylmalonic acid are normal?

    Thanks
  8. richvank

    richvank Senior Member

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    Hi, garcia.

    Thanks for your response. With regard to "so many people doing badly" on the SMP treatment, I certainly acknowledge that this treatment has not been successful for everyone. We could probably quibble about the percentages, since an informal poll such as the one you cited has quite a few uncontrolled variables, compared to, for example, even the less-than-rigorous clinical study that Dr. Nathan and I carried out, in which about two-thirds of the patients reported significant benefit:

    http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf

    But evenso, clearly this treatment does not work for everyone. I have been trying to understand why, and I discussed this briefly in point number 14 in my post above, and in more detail in a previous post:

    http://forums.phoenixrising.me/show...ing-and-treating-ME-CFS-today&highlight=today

    Also, please note that in the CureTogether.com ratings, methylation treatments are ranked fairly near the top of the list of treatments and lifestyle modifications that have been rated for CFS:

    http://curetogether.com/chronic-fatigue-syndrome/treatments/

    But clearly there is more work to be done to figure out how to help everyone who has this disorder.

    I do understand that a lot of treatments are not feasible for many people here, either for financial reasons, inability to leave home or one's bed, or inability to find a physician who is ready to help with treatments that are truly beneficial. We need to continue to work on treatments that are low in cost and high in availability via the internet.

    Thanks again.

    Rich
  9. richvank

    richvank Senior Member

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    Hi, fla.

    Thanks for the response. I think the main changes are as follows:

    Point #1: I am narrowing down to polymorphisms involving glutathione as the genetic predisposers.

    Point #3: I am getting more specific about the rise of peroxynitrite.

    Point #4: The newly published work of Jeong and Kim provides a specific explanation for how glutathione depletion causes the functional B12 deficiency.

    Point #7: Marty Pall has set me straight on how peroxynitrite lowers methylfolate, explaining why it goes down in the blood, rather than up.

    Point #9: I've tentatively settled on methionine depletion as an important factor in the dysfunction of the sulfur metabolism, though I know it isn't low in everyone. This may need some more work.

    Point #11: I've added a discussion of why NADPH goes down.

    Point #12: I've settled on an explanation for the lack of success of boosting glutathione as a stand-alone treatment, at least in many cases.

    Point #13: I've offered an explanation for why both B12 and folate are needed, why the B12 dosage must be high and non-oral, and what forms of each are best.

    Point #14: I've acknowledged that methylation treatment doesn't do the whole job for most PWMEs, and I've pointed toward what else I think may be needed.


    I agree that the genetic predisposition cannot explain the rise in incidence of ME/CFS, but I do think it is necessary for a person to develop a sporadic (non-cluster) case of ME/CFS. I think it explains why not everyone who is subject to a high load of stressors develops ME/CFS.

    I agree that the rise in stressors is the likely cause of higher incidence of ME/CFS. I think that toxins and poor nutrition are involved in many cases. I also think that societal and economic changes since the 60s and 70s have placed greater stress on women, particularly, as society seems to expect women to do so many things simultaneously.

    I know that it is unpopular with some to suggest that psychological or emotional stress is a factor in causing some cases of ME/CFS, because they interpret this to mean that there must be a psychiatric problem or a character flaw involved. I don't see it this way at all. The fact is that the body's stress response system (whether responding to physical, chemical, biological or psychological/emotional stress) does place demands on glutathione. If these demands become too high, compared to the body's capacity to make and recycle glutathione, ME/CFS is the result. We are all human, and if subjected to a large enough load of stress for a long enough time, our health will crack. It's just a question of how it will crack. For people who have inherited certain polymorphisms, this "crack" will involve the development of ME/CFS. This is my opinion, and I realize not everyone agrees with it.

    Best regards,

    Rich
    fla likes this.
  10. richvank

    richvank Senior Member

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    Hi, Vegas.

    Thanks for your comments. I agree with them, and am glad the SMP helped you to tolerate other treatment.

    Best regards,

    Rich
  11. richvank

    richvank Senior Member

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    Hi, anniekim.

    With regard to glutathione boosting, what I meant is that this doesn't work well as a stand-alone treatment. It seems to be helpful to some PWMEs as an adjunctive treatment, but used alone, it is either only temporarily beneficial, or it is not tolerated, I think for the reason I wrote.

    Best regards,

    Rich
  12. richvank

    richvank Senior Member

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    You're welcome, Merry.

    Best regards,

    Rich
  13. richvank

    richvank Senior Member

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    Hi, nem201.

    Yes, it is, if any of the following are deficient: branched-chain amino acids (isoleucine and valine), vitamin B6, vitamin B2, or biotin. Deficiencies in any of these will result in the methymalonate pathway not being challenged, so that methylmalonate will not be found high in the urine. Because of this, it is better to run the methylation pathways panel to get direct information about the methylation cycle, the folate metabolism, and glutathione.

    Best regards,

    Rich
  14. Sushi

    Sushi Moderator and Senior Member Albuquerque

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  15. richvank

    richvank Senior Member

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    Hi, Sushi.

    You're welcome!

    NAD might help with NADPH. Quite a few PWMEs test low in NAD (based on results I've seen from AcumenLab in the UK), which can be due to low niacin (B3), so supplementing B3 may also help.

    However, low NADPH can also be due to what I mentioned in my post above, i.e. mito dysfunction that causes greater reliance on glycolysis to produce ATP and lowers the reduction of NADP+ to NADPH. I think the only thing that will help this is to correct the mito dysfunction, which will require fixing the methyation cycle partial block and the low glutathione, which is what the methylation protocol attempts to do.

    Best regards,

    Rich
  16. adreno

    adreno 3% neanderthal

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    Hi Rich, and once again thank you for your work.

    In the study I quoted in the NADPH thread, children with autism were found to have low levels of NADPH, just as in CFS. The authors were able to increase NADPH levels by about 25% using NADH or ribose.

    You have yourself stated that you believe autism and ME /CFS is the same disorder, acquired at different time points. So the same defect in the pentose phosphate pathway should be present in both.

    The authors also stated that there is an alternative pathway for creating NADP, utilizing NAD kinase, and NADPH, utilizing NAD hydrogenase. This avoids the pentose phosphate pathway.

    In all I see no reason why it wouldn't work for in ME /CFS also. I'm guessing NAD would be just as efficient as NADH.
  17. richvank

    richvank Senior Member

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    Hi, adreno.

    Thanks. It does sound promising.

    Yes, there are other routes to NADPH, but I think the pentose phosphate shunt is the main producer, and in red blood cells, it's the only producer of NADPH.

    Best regards,

    Rich
  18. hixxy

    hixxy Woof woof

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    I'm starting to believe that #2 is a road block for many of us to even tolerate the treatment. I suspect that a lot of the intolerance of the protocol comes from a complex web of nutrient deficiencies for me, as well as the affect that #2 has on the nervous system -- making it sensitive to almost any change. It seems like as soon I find another deficiency any attempt to correct it, it sets off another cascade of reactions that result in yet another deficiency that I have to track down. This seems to be neverending.

    I recently discovered my intolerance of 5MTHF was related to magnesium deficiency -- despite taking 600mg orally / day. This brings me back to having a dysfunctional gut that I've tried fixing for several years now and don't seem to be getting much closer. Upon trialing transdermal magnesium from magnesium oil, a fair bit of the over-stimulation from the 5MTHF decreased. The annoying thing with this is, after a few days on the magnesium oil, I then developed low body temperature and freezing cold hands which I haven't had in a while and don't really want back (especially as the weather is getting colder)!

    If only I could fix my absorption (... #2), the web of deficiencies might be a lot easier to manage.
  19. richvank

    richvank Senior Member

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    ***Hi, hixxy.

    I'm starting to believe that #2 is a road block for many of us to even tolerate the treatment. I suspect that a lot of the intolerance of the protocol comes from a complex web of nutrient deficiencies for me, as well as the affect that #2 has on the nervous system -- making it sensitive to almost any change. It seems like as soon I find another deficiency any attempt to correct it, it sets off another cascade of reactions that result in yet another deficiency that I have to track down. This seems to be neverending.

    ***I understand. I have studied metabolic panels of various types from many cases of ME/CFS, and there are often several deficiencies present. These commonly include the B-complex vitamins and magnesium, as well as others.

    I recently discovered my intolerance of 5MTHF was related to magnesium deficiency -- despite taking 600mg orally / day.

    ***Intracellular magnesium deficiency is very common in ME/CFS. The problem seems to be to get it into the cells and keep it there. Vitamins B6 and B2 are involved, and it seems that glutathione deficiency is also involved in the magnesium problem.

    This brings me back to having a dysfunctional gut that I've tried fixing for several years now and don't seem to be getting much closer.

    ***This is also very common in ME/CFS, and can be hard to fix. I think that the methylation cycle partial block and the gut problems must be worked on together, because they interact with each other, and neither can be fixed by itself.

    Upon trialing transdermal magnesium from magnesium oil, a fair bit of the over-stimulation from the 5MTHF decreased.

    ***It's nice when something works!

    The annoying thing with this is, after a few days on the magnesium oil, I then developed low body temperature and freezing cold hands which I haven't had in a while and don't really want back (especially as the weather is getting colder)!

    ***I can't say I understand what caused this, unless, as you suggest, another deficiency became the bottleneck for your energy metabolism.

    If only I could fix my absorption (... #2), the web of deficiencies might be a lot easier to manage.

    ***The best route I know of for that is to do a comprehensive stool analysis and try to deal with the things that are found amiss: raise the stomach acid level with betaine HCl or other alternatives if it is low, which it usually is in ME/CFS, knock out the yeast with Candex or other anti-yeast treatment, knock out the unhelpful bacteria, preferably with herbal antimicrobials but antibiotics if necessary, supplement with digestive enzymes, supplement with probiotics, take glutamine if you can tolerate it, take folinic acid if you can tolerate it (the latter two to build up the cells that line the gut), take activated charcoal to bind toxins and take them out of the gut, eat a diet with enough fiber to keep things moving, etc. Consider a fecal transplant if these things don't do it.

    ***Best regards,

    ***Rich
  20. Sushi

    Sushi Moderator and Senior Member Albuquerque

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    Hi Rich,

    You mentioned low intracellular magnesium and some of the co-nutrients that might help. Do you have ideas about how to deal with low intracellular calcium? My doctor said something about calcium channels being "stuck open?"

    Also, re: gut problems, I've found that prescription pancreatic enzymes (brand name Creon [very pricey in the US], or generic Kreon [my choice] available in Canada) is also helpful.

    This balance thing is surely a challenge!

    Thanks,
    Sushi

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