IACFS/ME Bulletin publishes article on GDMCB Hypothesis

Discussion in 'Fibromyalgia Main Forum' started by richvank, Jun 25, 2008.

  1. richvank

    richvank New Member

    Hi, all.

    I'm happy to note that I was invited a few weeks ago to write an article for the IACFS/ME Bulletin, and the article was published in the Summer 2008 edition today. It's pasted below. The editors asked me not to get too specific in this article about treatment, because there have not yet been controlled clinical trials. Nevertheless, I was able to discuss the main aspects of the hypothesis and implications for treatment.

    It will be interesting to see what sort of response this article stimulates. The IACFS/ME is a pretty conservative organization, composed mostly of mainline-type physicians. As you may know, I am trying to recruit more physicians to try this type of treatment in their practices. I hope this article will help to do that.

    In the same issue of the bulletin there was a review by Rosamund Vallings of the recent conference at Cambridge University in the UK, at which Dr. Enlander gave an invited talk, also discussing methylation cycle treatment.

    In their Editorial in this issue, the Editorial Advisory Board characterized the GD-MCB hypothesis as "a most intriguing hypothesis."

    Best regards,


    June 25, 2008

    The Glutathione Depletion—Methylation Cycle Block Hypothesis for CFS/ME, and Implications for Treatment

    Richard A. Van Konynenburg, Ph.D.
    Independent Researcher and Consultant


    At the January, 2007, IACFS/ME Scientific Conference in Fort Lauderdale, I presented a poster paper describing a new biochemical hypothesis for the etiology, pathogenesis, pathophysiology and symptomatology of CFS/ME, which I call the “Glutathione Depletion—Methylation Cycle Block (GD—MCB)” hypothesis [1]. This hypothesis is able to explain many of the biochemical and symptomatic features of CFS/ME in a straightforward, specific and testable manner.

    Since the conference, I have continued to develop this hypothesis, and a clinical research study using a treatment protocol based on it is currently underway.
    The GD--MCB hypothesis has not yet been described in a peer-reviewed publication, and controlled clinical trials of treatment based on it have not yet been performed. Nevertheless, I believe it is in the best interest of the CFS/ME community for IACFS/ME members to receive an update on this hypothesis and the implications for treatment at this time.

    History of the GD—MCB Hypothesis

    I began studying CFS/ME in 1996. I was initially struck by the large number and the wide variety of the reported symptoms, involving many organs and body systems. I became convinced that in order for all these seemingly disparate symptoms to be present in this disorder, there must be a fundamental anomaly at the biochemical level that affects many cell types.

    In 1999 I obtained recordings of two talks presented by Paul Cheney, M.D., in which he reported that depletion of glutathione was nearly universal in his CFS patients [2,3]. Patricia Salvato, M.D. [4], and Derek Enlander, M.D. [5] had been using glutathione in their CFS treatment protocols for some years at that time.

    I began to study the published evidence for glutathione depletion in CFS and the roles normally played by glutathione in the body, and as I did so, I realized that many of the aspects of CFS could be explained directly by glutathione depletion. I reported this in a poster paper at our 2004 conference in Madison, Wisconsin [6]. By that time, I had also found that direct efforts to raise glutathione levels or to assist the liver to do so by giving amino acids were temporarily beneficial to many people with CFS, but did not produce a cure for it. I suspected that one or more vicious circles were in play that were preventing the reinstatement of normal glutathione levels, and I reported that at the conference as well.

    Two months later, in December of 2004, an important study was published by S. Jill James et al., in autism research [7]. This study found that glutathione was depleted in autism, also. The study further found that there was a partial block in the methylation cycle, which is located earlier in the sulfur metabolism than the synthesis of glutathione. In addition, it was found that treatment with nutritional supplements directed at correcting the partial block in the methylation cycle not only corrected the block, but also restored glutathione to normal levels, suggesting that these two phenomena were linked. It occurred to me that perhaps this same biochemical mechanism is present in CFS/ME.

    Study of the roles normally played in the body by the methylation cycle and its associated cycles and pathways convinced me that a partial block in the methylation cycle could account for additional aspects of CFS/ME that I had not been able to attribute to glutathione depletion alone. That led me to formulate the GD—MCB hypothesis, and I reported on it in a poster paper at our 2007 conference in Fort Lauderdale, Florida [1]. Since the conference, I have continued to develop this hypothesis and have outlined the goals and major components for treatment based upon it.

    Background Information on Glutathione and the Methylation Cycle

    Glutathione and the methylation cycle are present in all cells of the body, and are part of the basic biochemistry of the cells. When one considers the many vital roles played by these parts of the biochemistry, it is not difficult to understand how the presence of abnormalities in them could explain why so many different organs and systems are impacted in CFS/ME. A listing of their normal functions reads like a roll call of the functions that are not being properly performed in CFS/ME.

    Glutathione is a sulfur-containing tripeptide composed of the amino acids glutamic acid, cysteine and glycine. It is the predominant nonprotein thiol (molecule containing an S-H or sulfhydryl group) in cells. The chemically reduced form, abbreviated GSH, is its active form. It also has a chemically oxidized form, abbreviated GSSG, in which two GSH molecules bind together to form a disulfide bond. GSSG is normally recycled to GSH by the enzyme glutathione reductase, which is powered by NADPH, produced in the pentose phosphate shunt of the glycolysis pathway.

    GSH serves as a substrate for glutathione peroxidase and glutathione transferase enzymes. The former control the levels of hydrogen peroxide and other peroxides, making GSH the basis of the antioxidant enzyme system of the cells. The latter are primarily involved in conjugating glutathione to several classes of toxins, including the heavy metals, as part of the process of removing them from the body. Not only is glutathione responsible for this Phase II detox pathway, it also aids in quenching oxidizing free radicals generated by the Phase I cytochrome P450 enzymes.

    Glutathione maintains the proper oxidation-reduction (redox) potential inside cells by the normally high ratio of GSH to GSSG. The redox potential is a fundamental chemical parameter that governs the rates of many reactions in the cells. In particular, the reactions in the mitochondria that are involved in the utilization of energy by the cells are redox reactions.

    Glutathione stores and transports cysteine throughout the body. It regulates the cell cycle and is involved in DNA synthesis and gene expression. It participates in bile production, and it protects thyroid cells from the hydrogen peroxide they generate as part of their synthesis of thyroid hormones.

    Glutathione plays a vital role in the formation and proper folding of proteins that contain cysteine in their synthesis. These include a number of the secretory proteins, two of which are the hormones ACTH and arginine vasopressin (antidiuretic hormone). Perforin, which is crucial to the proper function of natural killer cells and cytotoxic T cells, contains 20 cysteine residues in its structure. The cell-mediated immune response also requires glutathione, as do other immune system functions. The roles played by glutathione are discussed in more detail in my 2004 poster paper [6].

    The methylation cycle (consisting of methionine, S-adenosylmethionine or SAMe, S-adenosylhomocysteine, and homocysteine) normally performs several important functions as well. It supplies methyl (CH3) groups to literally hundreds of reactions in the cells. It also balances the need for methyl groups with the need for glutathione to control oxidative stress, as well as the need for several other sulfur-containing substances, including cysteine, taurine and sulfate, which perform other vital roles. The methylation cycle also coordinates the supply of methyl groups with the production of new DNA via its connection to the folate cycle. The roles of the methylation cycle are discussed in more detail in my 2007 poster paper [1].
    Etiology and Pathogenesis of CFS/ME According to the GD—MCB Hypothesis

    According to this hypothesis, the etiology of CFS/ME is as follows: In order to develop a sporadic case of CFS/ME, a person must have a genetic predisposition, and must also be subjected to some sufficiently intense and long-duration combination of a variety of physical, chemical, biological or psychological/emotional stressors that place demands on glutathione, the particular combination differing for different patients.

    The enzymes and other proteins that have genetic polymorphisms that are found more frequently in CFS/ME than in the general population have yet to be fully explored, but at present, genetic researchers have reported two in the immune system, six in the neurotransmitter system, and four in the hypothalamus-pituitary-adrenal (HPA) axis. These have been reviewed recently by Smith et al. [8]. All of these enzymes and other proteins play roles in the GD-MCB hypothesized pathogenesis, and this is where the genetic predisposition comes into the hypothesis.

    Among the possible physical stressors that place demands on glutathione are extreme overexercise, physical trauma, and surgery. The chemical stressors include exposure to such toxins as organophosphates, organic solvents, and heavy metals. Biological stressors include infections, immunizations, blood transfusions, insect bites, allergic reactions, and eating or sleeping less than normal. The psychological/emotional stressors include the whole variety of stressful life events, continuing difficulties, dilemmas, and problems in childhood. The various stressors are discussed in more detail in my 2004 poster paper [6].

    Note that according to this hypothesis, both the genetic predisposition and the stressors are necessary to produce onset of a sporadic case of CFS/ME. In the epidemic/cluster cases, the genetic factor is probably less important, and a biological stressor, such as a virulent virus, is probably more important, than in the sporadic cases.

    The pathogenesis is then as follows: The initial effect of the stressors is to raise cortisol secretion (which later drops as the HPA axis is blunted by glutathione depletion) and also to raise epinephrine, while (in most CFS cases) lowering intracellular reduced glutathione.

    The lowering of glutathione produces a state of oxidative stress, allows the buildup of toxins, and removes the protection from vitamin B12 that is normally produced by the formation of glutathionylcobalamin. The cobalt ion in the methylcobalamin cofactor of the enzyme methionine synthase becomes oxidized by the oxidative stress, which inhibits the activity of this enzyme. The built-up toxins (probably especially mercury) react with vitamin B12 and lower the availability of methylcobalamin, thus producing a chronic partial block of methionine synthase. This partially blocks both the methylation cycle and the folate cycle, which are linked at methionine synthase. The oxidative stress also shifts cysteine toward cystine (its oxidized state), which lowers the availability of cysteine, the rate-limiting amino acid for the synthesis of glutathione. Sulfur metabolites then drain through the transsulfuration pathway and are eventually converted to taurine, thiosulfate and sulfate, which are excreted. The patient is left with a chronic partial block of the methylation cycle and (in most cases) a chronic depletion of intracellular reduced glutathione.

    This hypothesis is similar to that proposed for autism by R.C. Deth et al. [9], and as noted above, was inspired by the biochemical research of S. Jill James et al. in autism [7,10]. Further details on this hypothesis can be found in my 2007 poster paper [1].

    Aspects of the Pathophysiology and Symptomatology of CFS/ME that are Explained by the GD—MCB Hypothesis

    The depletion of glutathione can explain many features of CFS/ME: the well-established state of oxidative stress in CFS/ME, the observed buildup of toxins, the lowered cytotoxic activity of natural killer cells, part of the failure of cell-mediated immunity leading to persistent activation of the immune system, the persistent elevation of RNase-L, the fragmentation of RNase-L to form the unregulated low-molecular weight form, the mitochondrial dysfunction that leads to the fatigue in skeletal muscles and the diastolic dysfunction and low cardiac output of the heart, the high prevalence of Hashimoto’s thyroiditis, the (usually mild) central diabetes insipidus that produces high daily urine volume and constant thirst, and the blunting of the HPA axis. Glutathione depletion can also explain part of the reasons for reactivation of latent viral and intracellular bacterial infections. Details of the specific biochemical mechanisms by which glutathione depletion would produce these effects in CFS/ME can be found in my 2004 IACFS poster paper [6].

    A block in the methylation and folate cycles can explain a large number of the observed features of CFS/ME, including the inability to proliferate T cells upon stimulation by mitogens, neurotransmitter-related problems, abnormal ratio of choline to creatine in the brain, deficiency of carnitine, overexpression of genes, and inability to repair myelin, possibly leading to the observed slow processing speed in the brain. Details of the specific biochemical mechanisms by which these effects would result from a methylation cycle block in CFS/ME can be found in my 2007 IACFS/ME poster paper [1].


    Testing is available to determine whether a methylation cycle block and glutathione depletion are present in a CFS/ME patient. The methylation panel offered by Vitamin Diagnostics, Inc. [11] measures the levels of reduced and oxidized glutathione, SAMe, S-adenosylhomocysteine, adenosine, and several folate metabolites. The markers for glutathione depletion are a low ratio of reduced to oxidized glutathione, or low reduced glutathione. The best markers for a methylation cycle block are a low ratio of SAMe to S-adenosylhomocysteine, or low SAMe.

    Urine organic acids testing is also helpful to determine indirectly whether there are a methylation cycle block and glutathione depletion. In particular, the simultaneous occurrence of elevated methylmalonate and formiminoglutamate is a strong indicator of a methylation cycle block, and low pyroglutamate combined with a high ratio of citrate to alpha ketoglutarate is strong evidence for glutathione depletion.

    Implications for Treatment

    Based on this hypothesized pathogenesis, the main goal of treatment would be to facilitate normalization of the activity of the enzyme methionine synthase. This enzyme requires two reactants and a coenzyme for its operation. The reactants are homocysteine and 5-methyltetrahydrofolate, and the coenzyme is methylcobalamin. It is likely that sufficient homocysteine is present, but judging from available test results of the types discussed in the previous section above, both 5-methyltetrahydrofolate and methylcobalamin are deficient in many cases of CFS, probably at least partially due to genetic polymorphisms in genes that code for the enzymes that normally convert the dietary forms to the biochemically activated forms of folate and B12. 5-methyltetrahydrofolate is available as a food supplement, as is methylcobalamin. However, methylcobalamin is the only substance known in biochemical systems to be capable of methylating inorganic mercury, which would facilitate its crossing of the blood-brain barrier. Since many CFS/ME patients apparently have significant body burdens of inorganic mercury, perhaps as a result of inhalation of mercury vapor from amalgam fillings in their teeth, I would suggest hydroxocobalamin instead of methylcobalamin for treatment of CFS. The conversion of hydroxocobalamin to methylcobalamin within the cells requires S-adenosylmethionine (SAMe). The levels of SAMe can be elevated by supplying some supplemental betaine to stimulate the betaine homocysteine methyltransferase (BHMT) pathway.

    In addition to the main goal of normalizing the activity of methionine synthase, other goals of treatment would be to support other parts of the blocked folate metabolism (by using folinic acid), and to provide general nutritional support as well as support for the antioxidant system and the sulfur metabolism in general.

    Given the proposed hypothesis, it can be expected that during the period in which a patient has been ill with CFS, the cell-mediated immune response and the detoxification system will not have been functioning normally, since both depend for their operation on the parts of the biochemistry that have been partially blocked. As a result, it can be expected that patients will have been accumulating toxins and infections throughout the course of their illness. When the activity of methionine synthase is restored by a treatment of the type described above, it can be expected that the large resulting backlog of toxins and infections will start to be addressed by the detoxification and immune systems, and that this will produce detox and die-off symptoms.

    Clinical Research Study

    A research study of a treatment protocol for CFS/ME based on the GD-MCB hypothesis and extracted from the full treatment program used by Amy Yasko, Ph.D., N.D., (primarily in autism) [12] is currently underway in the private practice of Neil Nathan, M.D., of Springfield, Missouri. Its objective is to determine the effectiveness of treatment to lift the methylation cycle block in relieving the symptoms of CFS/ME. There are 30 patients in the study, who meet the diagnostic criteria for both CFS/ME and fibromyalgia. The patients have given informed consent. Testing includes the Vitamin Diagnostics, Inc., methylation panel, characterization of certain genetic polymorphisms, and a thyroid panel, including autoantibodies. Questionnaires are used to collect pertinent data and evaluate symptoms and their severity. The patients are keeping logs of their responses. The treatment duration will be six months, and the methylation panel will be repeated at the end of the duration of treatment. This study is not randomized, doubly blinded, or placebo-controlled, but hopefully the results will demonstrate that this type of treatment is worthy of a more controlled study.

    Summary and Conclusions

    A comprehensive biochemical hypothesis (the Glutathione Depletion--Methylation Cycle Block Hypothesis) has been developed to explain the etiology, pathogenesis, pathophysiology and symptomatology of CFS/ME. The key biochemical features of this hypothesis are a chronic partial block of the methylation cycle at methionine synthase and a chronic depletion of glutathione. This hypothesis explains the observed genetic predisposition, observed biochemical abnormalities, and many of the seemingly disparate symptoms of CFS as reported in the peer-reviewed literature and as observed clinically. Lab testing is available to test this hypothesis and to determine whether it applies to a particular patient. A preliminary clinical study of a treatment based on this hypothesis is currently underway.


    1. Van Konynenburg, R.A., “Glutathione Depletion—Methylation Cycle Block, A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome,” poster paper, 8th Intl. IACFS Conf. on CFS, Fibromyalgia, and Other Related Illnesses, Fort Lauderdale, FL, January 10-14, 2007.

    2. Cheney, P.R., “Evidence of glutathione deficiency in chronic fatigue syndrome,” American Biologics 11th International Symposium (1999), Vienna, Austria, Tape no. 07-199, available from Professional Audio Recording, P.O. Box 7455, LaVerne, CA 91750 (phone 1-800-227-4473).

    3. Cheney, P.R., “Chronic fatigue syndrome,” lecture presented to the CFIDS Support Group of Dallas-Fort Worth, Euless, TX, on May 15, 1999. Video tape available from Carol Sieverling, 513 Janann St., Euless, TX 76039.

    4. Salvato, P., CFIDS patients improve with glutathione injections, CFIDS Chronicle (Jan/Feb 1998).

    5. Enlander, D., personal communication, 2007.

    6. Van Konynenburg, R.A., “Is Glutathione Depletion an Important Part of the Pathogenesis of Chronic Fatigue Syndrome?” poster paper, AACFS 7th Intl. Conf., Madison, WI, October 8-10, 2004.

    7. James, S.J., Cutler, P., Melnyk, S., Jernigan, S., Janak, L., Gaylor, D.W., and Neubrander, J.A., Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism, Clin. Nutrit. 2004; 80:1611-1617.

    8. Smith, A.K., Dimulescu, I., Falkenberg, Narasimhan, S., Heim, C., Vernon, S.D., Rajeevan, M.S., Genetic evaluation of the serotonergic system in chronic fatigue syndrome, Psychoneuroendocrinology 2008; 33: 188-197.

    9. Deth, R., Muratore, C., Benzecry, J., Power-Charnitsky, V-A., Waly, M., How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis, NeuroToxicology 2008; 29:190-201.

    10. James, S.J., Melnyk, S., Jernigan, S., Cleves, M.A., Halsted, C.H., Wong, D.H., Cutler, P., Bock, K., Boris, M., Bradstreet, J.J., Baker, S.M., and Gaylor, D.W., Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism, Amer. J. Med. Genetics Part B (Neuropsychiatric Genetics) 2006; 141V: 947-956.

    11. Vitamin Diagnostics, Inc., Rt. 35 & Industrial Drive,
    Cliffwood Beach, NJ 07735 (phone: 732- 583-7773).

    12. Yasko, A. and Gordon, G., The Puzzle of Autism: Putting it All Together, Matrix, Payson, AZ (2006).

    [This Message was Edited on 06/25/2008]
  2. Forebearance

    Forebearance Member

    Congratulations, Rich!!!!

    This is great! I look forward to showing your paper to my physician. She'll be pleased to have something in a peer-reviewed journal about your most intriguing hypothesis.


  3. Slayadragon

    Slayadragon New Member

    Hi Rich,

    This is great. I'm giving it to my doctors as well.

    Best, Lisa
  4. tansy

    tansy New Member

    and as you pointed out this hypothesis aims to connect the seemingly disperate Sx in ME/CFS. In many ways Dr Kerr's research did the same.

    One of the problems patients with ME and CFS face is they present with too many Sx; doctors have been taught this is a sign of a somatisation (psychsomatic) disorder. Even though research has validated the Sx reported it's takes a long time for the more conservative end of mainstream medicine to take new evidence on board.

    Whilst former Tx might have brought about a resolution, or marked improvement, of some long term Sx, the core Sx remained. Worse still attempts to address toxins and infections would frequently backfire on me.

    Slowly I was able to make sense of that through research; your contributions to discussions here, and elsewhere on the net, helped clarify issues that had been difficult for me to understand sufficiently to make informed choices on how I was to move forward.

    I will be printing this out, and sending it to my GP and people I am currently working with. Over time we will be better able to see whether incorporating supps to support the various methylation pathways into other Tx regimes makes them safer and more effective.

    I wonder if Prof Malcolm Hooper has seen this. He is aware of Dr Myhill's work and in his written report on the Gibson Enquiry recommended her supps to support mitochondria, folates, and B12 be made available to patients with ME through the NHS.

    tc, Tansy
    [This Message was Edited on 06/26/2008]
  5. Slayadragon

    Slayadragon New Member

    Hi Rich,

    How do you pronounce your last name?

    It would be good to know this if I'm going to be discussing your work with physicians.

    Best, Lisa
  6. richvank

    richvank New Member

    Hi, Lisa.

    It's pronounced

    van ko NIGH' nen berg

    The Y is pronounced like a long I sound.

  7. richvank

    richvank New Member

    Hi, forebearance.

    Thank you for the encouragement!

    It's true that the IACFS/ME Bulletin is peer-reviewed by a board of editors, but it probably can't be legitimately characterized as a journal, at least in the sense that people think of as a medical journal that is mailed out to subscribers, collected in libraries, and so on. This one is fairly brief, and goes out by email only to the members of the IACFS/ME and "friends," whatever that means.

    By the way, the Journal of CFS is about to go belly-up. The publisher was bought out by another one, and they have decided to shut it down. It was not listed in PubMed, so was unable to attract a lot of very high quality articles, though there were some interesting things in it. For example, the Canadian diagnostic criteria for CFS were published in it.

  8. brainfoggy

    brainfoggy New Member

    I am printing and giving this to my new doc, I believe he uses the Metagenics products and is familiar with the methylation cycle block hypothesis.

    Thank you!
  9. Rafiki

    Rafiki New Member

[ advertisement ]