Status of methylation hypothesis and treatment based on it

Discussion in 'Fibromyalgia Main Forum' started by richvank, Sep 19, 2009.

  1. richvank

    richvank New Member

    Hi, all.

    This is a repost of a post I just made in response to Mark on another thread. I'm reposting it in a new thread with its own title, in case there are people who are interested by didn't find it there.


    Hi, Mark.

    It's been about two and a half years since I proposed the Glutathione Depletion--Methylation Cycle Block hypothesis for the pathogenesis of CFS, and a simplified treatment approach based on it. About six months ago, I presented a poster paper proposing that Lyme disease is a route of entry into CFS for people who are genomically predisposed to developing a partial methylation cycle block, based on the observed depletion of glutathione by Borrelia burgdorferi.

    During the past two and a half years, I estimate that at least several hundred, and probably now over a thousand PWCs have tried this treatment. There are several physicians who have added methylation cycle treatment to their protocols. Dr. Neil Nathan and I also carried out and reported on an open-label clinical study of the simplified treatment approach on patients in his practice in Missouri.

    There have also been a large number (I don't know how many, but I have probably personally seen a couple of hundred) methylation pathways panels run by Vitamin Diagnostics in New Jersey and the European Laboratory of Nutrients in the Netherlands. For people who have CFS, nearly all have shown a partial methylation cycle block and/or glutathione depletion, most showing both.

    The treatment used by itself seems to help about two-thirds of those who try it. When it is combined with other treatments, it has brought what appears to be complete recovery to at least a few people, who have been able to return to full-time work. Some of the other treatments have been treatments for Lyme disease, mold illness, or toxic metals overload.

    Based on all of this experience, I continue to believe that this model does describe the pathogenesis of CFS for many and perhaps most PWCs.

    With regard to viruses or other pathogens, I believe that they are responsible for the onset of CFS in some cases, especially in the cluster or epidemic cases, such as the one at Incline Village. These cases fit within the GD-MCB model, except that the genomic predisposition aspect does not seem to be as important, or is not involved at all. But the rest is likely the same, i.e. that the viral infection depletes glutathione and brings on a partial block in the methylation cycle. I think the explanation for this is that the virus in the cluster cases has been particularly virulent, at least until it mutated and became less so, ending the local epidemic.

    So as far as the pathogenesis model is concerned, I think it is correct and that it is able to explain essentially all the features of CFS. The model allows for a variety of routes into this pathogenesis, i.e. a variety of etiological factors. These include the whole variety of stressors--physical, chemical, biological and psychological/emotional. The stressors involved in the onset of each case can be differerent from those involved in other cases, but they all channel into causing oxidative stress and a partial methylation cycle block.

    In most cases the oxidative stress is accompanied by a depletion of glutathione, but in a minority of cases, there is a genetic polymorphism in the glutathione peroxidase enzyme. In those cases, glutathione does not drop, but the effect is the same, because it cannot be used effectively to counter the oxidative stress without a functional glutathione peroxidase.

    There's still an issue in the model that is unsolved, and that is how the partial methylation cycle block interacts with glutathione synthesis to deplete glutathione. We know that it does, in both autism and CFS, because when the methylation cycle block is lifted, glutathione comes back up automatically. But the details of this interaction are still undefined from a theoretical biochemical standpoint.

    Note that the issue of whether the methylation cycle block is at the root of the pathogenesis is a separate issue from what is the best way to treat it. There may be, and likely are, better ways to treat it than the simplified treatment approach. I proposed that as a simple and relatively inexpensive, and thus accessible treatment for PWCs, and at the same time a way to test the model for pathogenesis. I would say that it has been successful in testing the model, and the model has survived the test. I think we still have more to learn about treatment, though the simplified treatment approach has made a significant contribution, and for some PWCS, has been the last thing they needed to get well.

    I don't know if you have been following the "demonstration project" for treating M.E. patients that is going on in Ohio at present, which is updated on the forum called "A New Day," part of Cort Johnson's forums. The approach to treatment being used there involves IV nutrition, homeopathic neural therapy, acupuncture, proliferative therapy, and laser therapy. This is quite an innovative approach to treatment, and I can't say that I understand how it works from a fundamental scientific viewpoint. It does, however, so far appear to be a promising approach, and I am following the updates.

    I don't know the details of what is included in the IVs, and perhaps there is some B12 and folate involved, which would seem to be important for lifting the methylation cycle block. On the other hand, perhaps the other techniques used are able to cause the body to make more effective use of the resources of B12 and folate that it already has. In any case, I do think there is good evidence that many or most PWCs have a methylation cycle block, and to lift this block, the methionine synthase activity has to be increased, which entails greater functional use of B12 and folate. So I'm trying to understand how this treatment intersects with that need.

    You asked about treatment timescale. This seems to vary, depending on a variety of factors. If the simplified treatment approach is used by itself, the experience is that improvements usually occur within a couple of months, but full recovery hasn't happened for many people over a year later, though it has for a few. Lately I've been studying some of the cases with slow improvement, and I think that the lack of enough of the cofactors or enough of the amino acids to feed the methylation cycle and associated pathways may be the reasons for the slow progress in at least some of the cases. B-complex vitamins, minerals including zinc, copper, magnesium and selenium, and amino acids including methionine, serine, and the precursors for glutathione (glycine and glutamine or glutamate) are frequently found to be low.

    Dysfunction of the gut seems to be at the basis of the low amino acids. I think that's why the IV amino acids are an important part of the treatment in Ohio, but for many PWCs, it may be possible to take oral free-form amino acids in order to increase their absorption, even with gut dysbiosis going on.

    Beyond this, there are other treatments that may need to be added, depending on the particular case. These include attention to food sensitivities, efforts to improve the condition and function of the gut, support for the adrenal and thyroid axes, treatment of infections, treatment for mold illness if present, and treatment of heavy metal toxicity. There are various ways of approaching these issues in treatment, and physicians differ in their methods, but I think these are the things that can be required.

    So in summary, I think the theoretical model and the lab test are holding up well, and though there is more to be learned in treatment, lifting the methylation cycle block and thereby bringing up glutathione seem to be essential parts of the treatment.

    Best regards,

  2. AllWXRider

    AllWXRider New Member

    Lots of clues, pieces of the CFS (ME) puzzle.

    Digestion of protiens into amino acids begins in the stomach with HCL (hydrochloric acid). Stomach infections with H. Pylori are common and the stomach responds by lowering the acid level. Poor digestion will cause burping, belching, burning of the esophagus. H. Pylori is the #1 cause of stomach ulcers.

    Tumeric (curcumin) is toxic to H. Pylori and is a star ingredient of curry powder. Tumeric is a mild spice, so stomach upset shouldn't be an issue. Indian food is fantastic. Majaraja restaraunt here in Fort Worth is mouth watering good and the funnest way to get tumeric!

    Glutathione is made by the liver, but our diet is often low in cysteine. The stomach digests glutathione very well, so don't take it orally. Chicken broth (bone not meat) is high in cysteine and in capsule form: N-Acetyl Cysteine (NAC) is best.

    Glutathione is a great liver detox agent. If your liver has a dumpster load of toxin, be careful not to empty the dumpster, the first day. Try a little NAC for 3 days, then add a pinch more. "titration" its called. Glutathione is also a great metal detox agent.
  3. richvank

    richvank New Member

    Hi, luminescent.

    What is found in methylation panel tests is that a subset of PWCs have levels of glutathione in the normal range, but a partial block in the methylation cycle is also found in these people.

    For a subset of those who have taken the Sprectracell test, the glutathione function comes out normal, while the total antioxidant function is low.

    In these groups of people, I have hypothesized that there is a problem with the glutathione peroxidase enzyme.

    One possibility is a selenium deficiency, since this enzyme uses selenium as a cofactor. Some of these people do have a selenium deficiency, and some have reported difficulty in correcting it, perhaps because of high body burdens of mercury, since mercury and selenium form a tightly bound complex. However, not all of these people have a selenium deficiency, based on testing.

    Dr. John McLaren Howard in the UK reported a few years ago (in the Biolab Medical Unit newsletter) that he found that some of the people who suffered from oxidative stress but had normal glutathione levels had one of the tetramers missing from their glutathione peroxidase enzyme, i.e. a genetic polymorphism.

    I think Dr. Howard does measure the activity of this enzyme at his current lab, Acumen Lab in the UK. However, I don't know that he evaluates the structure of this enzyme now.

    So in answer to your question, yes, this is part of the hypothesis, but it is based on various pieces of evidence from lab testing. I don't know that commercial genetic polymorphism testing is available for glutathione peroxidase, however.

    Best regards,

  4. krock

    krock Member

    I had the Spectracell test. It showed my glutathione was 54, and my total antioxidant function was 70. Does that suggest I do not have a methylation problem?
  5. krock

    krock Member

    bump for rich
  6. richvank

    richvank New Member

    Hi, krock.

    Please check the reference ranges on your lab test report. I believe that both these numbers are below their reference ranges, which suggests that you have glutathione depletion. If you have CFS and you have glutathione depletion, it is likely that you also have a partial methylation cycle block. To test this, I recommend the Vitamin Diagnostics methylation pathways panel.

    Here's the new contact information for Vitamin Diagnostics:

    Methylation Pathways Panel

    This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel.

    The panel costs $300 and requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on your clinician’s letterhead.

    Available from:

    Vitamin Diagnostics, Inc.
    540 Bordentown Avenue
    South Amboy, NJ 08879
    Phone:+1 (732) 721-1234

    Lab Director: Tapan Audhya, Ph.D.
    (usually at the lab on Tues. and Wed. from 1 to 3 p.m., Eastern time)

    Dr. Audhya is willing to help clinicians with interpretation of the panel by phone.

    Here is information for interpreting the Vitamin Diagnostics panel:

    Interpretation of the Vitamin Diagnostics
    Methylation Pathways Panel

    Rich Van Konynenburg, Ph.D.

    Several people have asked for help in interpreting the results of
    their Vitamin Diagnostics, Inc., methylation pathway panels. Here are my
    suggestions for doing so. They are based on my study of the
    biochemistry involved, on my own experience with interpreting more
    than 120 of these panel results to date, and on discussion of some of
    the issues with Tapan Audhya, Ph.D., who is the director of the
    Vitamin Diagnostics lab.

    The panel consists of measurement of two forms of glutathione
    (reduced and oxidized), adenosine, S-adenosylmethionine (SAM) , S-
    adenosylhomocysteine (SAH), and seven folic acid derivatives or

    According to Dr. Audhya, the reference ranges for each of these
    metabolites was derived from measurements on at least 120 healthy
    male and female volunteer medical students from ages 20 to 40, non-
    smoking, and with no known chronic diseases. The reference ranges
    extend to plus and minus two standard deviations from the mean of
    these measurements.

    Glutathione: This is a measurement of the concentration of the
    reduced (active) form of glutathione (abbreviated GSH) in the blood
    plasma. From what I've seen, most people with chronic fatigue
    syndrome (PWCs) have values below the reference range. This means
    that they are suffering from glutathione depletion. As they undergo
    the simplified treatment approach to lift the methylation cycle
    block, this value usually rises into the normal range over a period
    of months. I believe that this is very important, because if
    glutathione is low, vitamin B12 is likely unprotected and reacts with toxins
    that build up in the absence of sufficient glutathione to take them
    out. Vitamin B12 is thus “hijacked,” and not enough of it is able to
    convert to methylcobalamin, which is what the methylation cycle needs
    in order to function normally. Also, many of the abnormalities and
    symptoms in CFS can be traced to glutathione depletion.

    Glutathione (oxidized): This is a measurement of the concentration
    of the oxidized form of glutathione (abbreviated GSSG) in the blood
    plasma. In many (but not all) PWCs, it is elevated above the normal
    range, and this represents oxidative stress.

    Adenosine: This is a measure of the concentration of adenosine in the
    blood plasma. Adenosine is a product of the reaction that converts
    SAH to homocysteine. In some PWCs it is high, in some it is low, and
    in some it is in the reference range. I don't yet understand what
    controls the adenosine level, and I suspect there is more than one
    factor involved. In most PWCs who started with abnormal values, the
    adenosine level appears to be moving into the reference range with
    methylation cycle treatment, but more data are needed.

    S-adenosymethionine (RBC) (SAM): This is a measure of the
    concentration of SAM in the red blood cells. Most PWCs have values
    below the reference range, and treatment raises the value. S-
    adenosylmethionine is the main supplier of methyl groups in the body,
    and many biochemical reactions depend on it for their methyl
    groups. A low value for SAM represents low methylation capacity, and
    in CFS, it appears to result from a partial block at the enzyme methionine
    synthase. Many of the abnormalities in CFS can be tied to lack of
    sufficient methyation capacity.

    S-adenosylhomocysteine (RBC) (SAH): This is a measure of the
    concentration of SAH in the red blood cells. In CFS, its value
    ranges from below the reference range, to within the reference range,
    to above the reference range. Values appear to be converging toward
    the reference range with treatment. SAH is the product of reactions
    in which SAM donates methyl groups to other molecules.

    Sum of SAM and SAH: When the sum of SAM and SAH is below 268
    micromoles per deciliter, it appears to suggest the presence of
    upregulating polymorphisms in the cystathione beta synthase (CBS)
    enzyme, though this may not be true in every case.

    Ratio of SAM to SAH: A ratio less than about 4.5 also represents low
    methylation capacity. Both the concentration of SAM and the ratio of
    concentrations of SAM to SAH are important in determining the
    methylation capacity.

    5-CH3-THF: This is a measure of the concentration of 5-methyl
    tetrahydrofolate in the blood plasma. It is normally the most
    abundant form of folate in the blood plasma. It is the form that
    serves as a reactant for the enzyme methionine synthase, and is thus
    the most important form for the methylation cycle. Many PWCs have a
    low value, consistent with a partial block in the methylation cycle.
    The simplified treatment approach includes FolaPro, which is
    commercially produced 5-CH3-THF, so that when this treatment is used,
    this value rises in nearly every PWC. If the concentration of 5-CH3-
    THF is within the reference range, but either SAM or the ratio of SAM
    to SAH is below the reference values, it suggests that there is a
    partial methylation cycle block and that it is caused by
    unavailability of sufficient bioactive B12, rather than
    unavailability of sufficient folate. I have seen this frequently,
    and I think it demonstrates that the “hijacking” of B12 is the root
    cause of most cases of partial methylation cycle block. Usually
    glutathione is low in these cases, which is consistent with lack of
    protection for B12, as well as with toxin buildup.

    10-Formyl-THF: This is a measure of the concentration of 10-formyl
    tetrahydrofolate in the blood plasma. It is usually on the low side in PWCs.
    This form of folate is involved in reactions to form purines, which
    form part of RNA and DNA as well as ATP.

    5-Formyl-THF: This is a measure of the concentration of 5-formyl
    tetrahydrofolate (also called folinic acid) in the blood plasma.
    Most but not all PWCs have a value on the low side. This form is not used
    directly as a substrate in one-carbon transfer reactions, but it can
    be converted into other forms of folate. It is one of the
    supplements in the simplified treatment approach, which helps to
    build up various other forms of folate.

    THF: This is a measure of the concentration of tetrahydrofolate in
    the blood plasma. In PWCs it is lower than the mean normal value of 3.7
    nanomoles per liter in most but not all PWCs. This is the
    fundamental chemically reduced form of folate from which several
    other reduced folate forms are made. The supplement folic acid is
    converted into THF by two sequential reactions catalyzed by
    dihydrofolate reductase (DHFR). THF is also a product of the
    reaction of the methionine synthase enzyme, and it is a reactant in
    the reaction that converts formiminoglutamate (figlu) into
    glutamate. If figlu is high in the Genova Diagnostics Metabolic
    Analysis Profile, it indicates that THF is low.

    Folic acid: This is a measure of the concentration of folic acid in
    the blood plasma. Low values suggest folic acid deficiency in the
    current diet. High values are sometimes associated with inability to
    convert folic acid into other forms of folate, such as because of
    polymorphisms in the DHFR enzyme. They may also be due to high
    supplementation of folic acid.

    Folinic acid (WB): This is a measure of the concentration of folinic
    acid in the whole blood. See comments on 5-formyl-THF above. It
    usually tracks with the plasma 5-formyl-THF concentration.

    Folic acid (RBC): This is a measure of the concentration of folic
    acid in the red blood cells. The red blood cells import folic acid
    when they are initially being formed, but during most of their
    approximately four-month life, they do not normally import, export, or use
    it. They simply serve as reservoirs for it, giving it up when they
    are broken down. Many PWCs have low values. This can be
    caused by a low folic acid status in the diet over the previous few
    months, since the population of RBCs at any time has ages ranging
    from zero to about four months. However, in CFS it can also be
    caused by damage to the cell membranes, which allows folic acid to
    leak out of the cells. Dr. Audhya reports that treatment with omega-
    3 fatty acids can raise this value over time.

  7. krock

    krock Member


    Thanks for your reply.
    The reference range for glutathione is >42%. Mine is 54%.
    The reference range for total antioxidant function is >65%. Mine is 70%.

    I have seen many doctors over the past several years that I have been ill, and have not found anyone that is willing to order most of the less conventional testing like the vitamin diagnostics. So I am trying to work with and extrapolate from what lab tests I have been able to get doctors to order for me. So, any interpretation or opinions about the methyation cycle and protocal based on the above results would be great.


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