Documents written by Rich Van Konynenburg
This Wiki page contains a collection of documents written by Rich Van Konynenburg, Ph.D., an independent researcher who has studied ME/CFS since 1996.
Rich has proposed the Glutathione DepletionMethylation Cycle Block hypothesis for the pathogenesis and pathophysiology of ME/CFS and has suggested treatment based on it.
This treatment was tested in a clinical study conducted by Neil Nathan, M.D., and Rich, and was found to produce significant benefit for more than two-thirds of the patients in the study.
The documents on this Wiki page are in the approximate chronological order in which they were written. Since Richs thinking has been modified over time as more has been learned, where there are conflicts the more recent document should be given precedence.
The documents on this page are as follows:
1. Is Glutathione Depletion an Important Part of the Pathogenesis of Chronic Fatigue Syndrome?
This poster paper was presented at the 2004 AACFS conference.
It presents the case for the importance of glutathione depletion in ME/CFS.
2. Chronic Fatigue Syndrome and Autism
This article appeared in the October 2006 issue of the Townsend Letter. It discusses the commonality between autism and ME/CFS with regard to genetics and biochemistry.
3. Glutathione DepletionMethylation Cycle Block: A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome
This poster paper was presented at the 2007 IACFS conference. It is a detailed biochemical presentation of the GD-MCB hypothesis.
4. Why is the Prevalence of Chronic Fatigue Syndrome Higher in Women than in Men?
This poster paper was also presented at the 2007 IACFS conference. It suggests that the higher prevalence in women is due to the presence of polymorphisms in detox enzymes that metabolize the estrogens, resulting in additional oxidative stress.
5. Suggestions for Treatment of Chronic Fatigue Syndrome (CFS) based on the Glutathione DepletionMethylation Cycle Block Hypothesis for the Pathogenesis of CFS
This article was written on January 25, 2007, in response to a request from Dr. David Bell for a treatment based on the GD-MCB hypothesis. It applies the approach of Amy Yasko, Ph.D., N.D., used primarily in autism, to the treatment of ME/CFS, and includes a simplified approach, extracted from her full treatment protocol.
6. Simplified Treatment Approach Based on the Glutathione DepletionMethylation Cycle Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS)
This article was written on July 18, 2007. It reviews the history of the simplified treatment and the first six months of experience with it, including adverse effects that were reported.
7. Simpler Explanation of GD-MCB Hypothesis for CFS
This article was written on December 13, 2008, in response to a request for an easier to understand explanation of the hypothesis.
It is written for a general audience and does not require familiarity with the intricacies of biochemistry.
8. Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia
This poster paper was presented at the 2009 IACFS/ME conference. It was authored by Neil Nathan, M.D. and Rich, and discusses a clinical study of the simplified treatment approach involving 30 women in Dr. Nathans practice.
9. Is There a Link between Lyme Disease and Chronic Fatigue Syndrome?
This poster paper was also presented at the 2009 IACFS/ME conference. It suggests that Lyme disease can lead to onset of ME/CFS in those who are genomically predisposed, as a result of glutathione depletion by Borrelia burgdorferi bacteria.
10. Contact Information for Ordering the Methylation Pathways Panel
This panel will determine whether the methylation cycle is partially blocked, whether glutathione is depleted, and whether folates have drained from the cells. It thus indicates whether the GD-MCB hypothesis is likely to apply to a given case, and whether methylation cycle treatment is likely to be helpful.
11. Interpretation of the Methylation Pathways Panel
This article was written on May 19, 2011, in response to a request from Tapan Audhya, Ph.D. It is intended primarily for physicians, to assist them in interpreting this panel.
12. Simplified Treatment Approach for Lifting the Partial Methylation Cycle Block in Chronic Fatigue Syndrome
This is the most recent version of the protocol for the simplified treatment approach, written on March 30, 2011. It is a protocol designed to lift the partial methylation cycle block. While it has been found to help most patients with this disorder, some have not been helped. Richs recommendation is to try this protocol for three months. If it is not producing observable benefit by that time, consideration should be given to changing the protocol, such as by trying methylcobalamin rather than hydroxocobalamin.
1.
IS GLUTATHIONE DEPLETION
AN IMPORTANT PART OF THE
PATHOGENESIS OF
CHRONIC FATIGUE SYNDROME?
by
Richard A. Van Konynenburg, Ph.D.
(Independent Researcher)
richvank@aol.com
AACFS Seventh International Conference
Madison, Wisconsin
October 8-10, 2004
WHAT IS GLUTATHIONE?
[Refs. 1--5]
A tripeptide composed of the amino acids glutamic acid, cysteine, and glycine. Its molecular weight is 307.33 Da.
Found in all cells in the body, in the bile, in the epithelial lining fluid of the lungs, and, at much smaller concentrations, in the blood.
The predominant nonprotein thiol (molecule containing an S-H or sulfhydryl group) in cells.
Its active form is the chemically reduced form, called "GSH."
GSH is compartmentalized, with concentrations ranging from 0.5 to 10 millimolar in various organs and cell types.
GSH serves as a substrate for enzymes, including the glutathione peroxidases and the glutathione-S-transferases.
When oxidized, two glutathione molecules join together via a disulfide bond to form "oxidized glutathione," or "glutathione disulfide," referred to as "GSSG."
Inside cells, the concentration of GSSG is normally maintained at less than 1% of total glutathione by the enzyme glutathione reductase, which is powered by NADPH, produced by the pentose phosphate shunt, part of normal carbohydrate metabolism.
WHAT ARE SOME OF THE FUNCTIONS OF GLUTATHIONE (GSH)?
[Refs. 1--5]
Maintains proper oxidation-reduction (redox) potential inside cells. Redox affects the oxidation state of sulfur in enzymes, and thus affects the rates of biochemical reactions in cells.
Scavenges peroxides and oxidizing free radicals directly and also serves as the basis for the antioxidant network.
Performs Phase II detoxication of heavy metals (such as mercury), organophosphate pesticides, chlorinated hydrocarbon solvents, estradiol, prostaglandins, leukotrienes, acetaminophen, and other foreign and endogenous toxins.
Stores and transports cysteine throughout the body.
Transports amino acids, especially cystine into kidney cells.
Regulates the cell cycle, DNA and protein synthesis and proteolysis, and gene expression.
Regulates signal transduction.
Participates in bile production.
Protects thyroid cells from self-generated hydrogen peroxide.
In carrying out several of the above functions, GSH plays very important roles in (1) maintaining mitochondrial function and integrity, (2) regulating cell proliferation, and (3) supporting the immune system.
HOW IS GLUTATHIONE (GSH) SYNTHESIZED IN THE BODY?
[Refs. 1--5]
GSH is synthesized inside cells by a two-step process. The first step involves the ATP-powered enzyme glutamate cysteine ligase (formerly called gamma-glutamylcysteine synthetase). This step is normally the rate-limiting reaction, and is controlled by the cellular redox state and feedback inhibition, among other factors. The second step makes use of the ATP-powered enzyme glutathione synthetase.
The necessary substrates are cysteine (which is often the rate-limiting substrate when GSH is depleted), glutamic acid (or glutamine) and glycine. Cysteine and glutamic acid are joined together in the first step, and glycine is added in the second step.
The liver is the main producer and exporter of GSH.
A few epithelial cell types can import GSH molecules intact.
Most cell types use the gamma glutamyl (or GSH scavenging) cycle. This cycle makes use of the plasma-membrane-bound exoenzymes gamma-glutamyl transpeptidase and dipeptidase. This cycle disassembles GSH outside the cell and imports the parts for reassembly inside. It also serves as a transport mechanism to bring other amino acids into the cell, cystine
(di-cysteine) being favored.
IS GLUTATHIONE DEPLETED IN CHRONIC FATIGUE SYNDROME?
There is considerable evidence that GSH is depleted in at least a substantial fraction of CFS patients. Here are the results of all the published studies that bear on this question:
GSH depletion in CFS was first suggested by Droge and Holm [6].
Cheney [7,8] reported that his CFS clinical patients were almost universally low in GSH.
Richards et al. [9] found that patients could be divided statistically into two distinct groups, one having significantly elevated erythrocyte GSH relative to a healthy control group, and the other having significantly lower values.
Fulle et al. [10] found elevated total (reduced plus oxidized) glutathione in muscle biopsy specimens from PWCs relative to healthy controls, but they did not report values for reduced glutathione alone.
Manuel y Keenoy et al. [11] found that a subgroup of fatigued patients with low magnesium, which did not improve with supplementation, had significantly lower GSH.
Manuel y Keenoy et al. [12] did not find a significant difference between CFS patients and fatigued controls in terms of whole-blood GSH, but they did not compare with a healthy control group.
Kennedy et al. [13] found significantly lower red blood cell GSH in PWCs compared to healthy controls (p=0.05).
Kurup and Kurup [14] found significantly lower red blood cell GSH in myalgic encephalomyelitis patients compared to healthy controls (p<0.01).
IN THE GENERAL POPULATION, WHAT FACTORS OR CONDITIONS ARE KNOWN TO CAUSE DECREASES IN INTRACELLULAR GLUTATHIONE CONCENTRATIONS?
These factors and conditions can be divided into three groups:
The first group is made up of those that (1) lower the rate of GSH synthesis or the rate of reduction of GSSG to GSH, or (2) raise the rate of export of GSH from cells, or (3) lead to loss of GSH from the scavenging pathway. This group includes the following: genetic defects [15], elevated adrenaline secretion [16-20] due to various types of stress, deficient diet [1] or fasting [21], surgical trauma [21,22], burns [23], and morphine [24].
The second group is comprised of toxins that conjugate GSH and remove it from the body [25], such as organophosphate pesticides, halogenated solvents, tung oil (used on furniture), acetaminophen and some types of inhalation anesthesia.
The third group is comprised of conditions that raise the production rates of reactive oxygen species high enough to produce oxidative stress, causing cells to export GSSG. These include strenuous or extended exercise [26], infections (producing leukocyte activation) [21], toxins that produce oxidizing free radicals during Phase I detoxication by cytochrome P450 enzymes [21], ionizing radiation [27], iron overload [28], and ischemia--reperfusion events (such as stroke, cardiac arrest, subarachnoid hemorrhage, and head trauma) [29].
STRESS, DISTRESS, AND STRESSORS
For purposes of this presentation, stressors are defined in the broad sense as events, circumstances or conditions that place demands on a person and tend to move his or her body out of allostatic balance. Allostasis is similar to homeostasis, but allows for changes in the set-point over time to match life circumstances [30]. Stressors can be classified as physical, chemical, biological, or psychological/emotional.
Stress is the state that results from the presentation of such demands. Selye [31] defined stress as "the state manifested by a specific syndrome which consists of all the nonspecifically-induced changes within a biologic system." Although Selye emphasized the nonspecifically-induced responses, the body also exhibits specific responses that depend on the type of stress [32].
Stress can be of a beneficial or a destructive nature. Distress is the destructive type of stress [31].
The perceived stress that people experience depends not only on the stressors to which they are subjected, but also on "their appraisals of the situation and cognitive and emotional responses to it." [33]
A person's history of both the occurrence of stressors and of the degree of perceived stress can be evaluated by structured interviews, and this has been done in a number of studies of CFS risk factors [34-45].
IS THERE EVIDENCE FOR HIGHER OCCURRENCE OF STRESSORS IN CFS PATIENTS PRIOR TO ONSET THAN IN HEALTHY NORMAL CONTROLS?
YES. The types of stressors found to have higher occurrence in one or more CFS risk factor studies [34-45] include the following:
Physical: Aerobic exercise (especially of long duration), physical trauma (especially motor vehicle accidents) and surgery (including anesthesia).
Chemical: Exposure to toxins such as organophosphate pesticides, solvents and ciguatoxin.
Biological: Infections, immunizations, blood transfusions, insect bites, allergic reactions, and eating or sleeping less.
Emotional/Psychological:
Stressful life events, including death of a spouse, close family member or close friend; recent marriage; troubled or failing marriage, separation, or divorce; serious illness in immediate family; job loss, starting new job, or increased responsibility at work; and residential move.
Difficulties, including ongoing problems with relationships, persistent work problems or financial problems, mental or physical violence, overwork, extreme sustained activity, or "busyness."
Dilemmas "A dilemma is a situation in which a person is challenged to choose between two equally undesirable alternatives."[45] Choosing inaction in response to a dilemma leads to further negative consequences.
Problems in childhood, including significant depression or anxiety, alcohol or other drug abuse, and/or physical violence in parents or other close family members; physical, sexual or verbal abuse, low self-esteem and chronic tension or fighting in the family.
IS THERE EVIDENCE FOR HIGHER PERCEIVED STRESS IN CFS PATIENTS PRIOR TO ONSET, COMPARED TO HEALTHY CONTROLS?
YES. Three studies [34, 37, 38] found that CFS patients rated their level of perceived stress prior to onset higher than did healthy, normal controls for a similar period of time.
IS IT SURPRISING THAT GLUTATHIONE BECAME DEPLETED IN MANY CFS PATIENTS?
NO. In view of the strong correspondence between the results of the CFS risk factor studies and the known GSH depletors, it is not surprising. It appears that the CFS patients who were studied had undergone a variety of factors and conditions that are known to deplete glutathione, and had also experienced high levels of perceived stress as a result.
HOW DOES THE NEUROENDOCRINE SYSTEM RESPOND TO STRESS?
This system manifests both specifically- and nonspecifically-induced responses to stress [32]. The nonspecifically-induced responses address the combined load of all the various types of stress that are being experienced simultaneously.
The nonspecific responses are mediated by three parts of this sytem: (1) the hypothalamus-pituitary-adrenal (HPA) axis, which produces cortisol and other glucocorticoids, (2) the sympathetic-adrenomedullary system, which produces epinephrine (adrenaline), and (3) the sympathoneural system, which produces norepinephrine (noradrenaline) [32].
Rapid-onset CFS patients report that they had a normal response to stress prior to their onset of CFS. Therefore, it can be surmised that if they experienced a high load of combined long-term stress lasting a few months to several years prior to their onset, they were subject to high levels of both cortisol and adrenaline during this extended period of time.
Note that depleted rather than elevated cortisol levels are frequently observed clinically in CFS patients (Cleare [46]). However, the decrease in cortisol secretion occurs later in the pathogenesis: "the bulk of the data assembled to date is compatible with the view that the disruption in adrenocortical function is a late finding, and that elucidating the status of the central nervous system components which drive the regulation of the HPA axis would be crucial to a more complete understanding of this final event." (Demitrack [47])
WHAT ARE THE EFFECTS OF ELEVATED LEVELS OF CORTISOL AND ADRENALINE ON THE IMMUNE SYSTEM AND ON GLUTATHIONE LEVELS?
Elevation of cortisol is known to suppress the inflammatory response by several mechanisms, including decreasing the expression of cytokines and cell adhesion molecules, and decreasing the production of prostaglandins and leukotrienes [48]. This effect is beneficially used therapeutically in many cases, but it can also have a down side if an infection is present.
Elevation of cortisol is also known to suppress cell-mediated immunity and to cause a shift to the Th2 type of immune response. Several mechanisms are involved, including suppressing the secretion of IL-1 by macrophages, inhibiting the differentiation of monocytes to macrophages, inhibiting the proliferation of T lymphocytes, and increasing the production of endonucleases, which increases the rate of apoptosis of lymphocytes [33,48].
Long-term elevation of adrenaline can be expected to deplete GSH, because adrenaline decreases the rate of synthesis of glutathione by the liver (Estrela et al. [18]), increases its rate of export from the liver (Sies and Graf [16]; Haussinger et al. [17]; Estrela et al. [18]), and decreases the rate of reduction (recycling) of oxidized glutathione (Toleikis and Godin [19]).
HOW DO VIRAL INFECTIONS ARISE AT THE ONSET OF CHRONIC FATIGUE SYNDROME?
I propose that glutathione depletion is the trigger for reactivation of endogenous latent viruses in CFS (hypothesis).
Here's the support for this hypothesis:
Most of the evidence points to reactivation of latent endogenous viruses at the onset of CFS, rather than new, primary infections (Komaroff and Buchwald [49])
Infections by members of the Herpes family of viruses, such as Epstein-Barr virus and HHV-6 are commonly found in CFS patients [49].
GSH depletion is associated with the activation of several types of viruses [50-53], including Herpes simplex type 1 (HSV-1) [54]. Raising the GSH concentration inhibits replication of HSV-1 by blocking the formation of disulfide bonds in glycoprotein B, a protein that is necessary for proliferation of the virus [54].
Glycoprotein B is also found in all other Herpes family viruses studied, including EBV and CMV [55], and very likely is present also in HHV-6 and performs the same vital function there (hypothesis).
It thus appears very likely that GSH depletion is the trigger for the reactivation of the latent forms of all the Herpes family viruses. Since glutathione likely becomes depleted prior to the onset of CFS, and since infections by these viruses are commonly found in CFS, it seems likely that glutathione depletion initiates the viral infections at the onset of CFS (hypothesis).
CAN ELEVATED CORTISOL AND DEPLETED GLUTATHIONE EXPLAIN THE IMMUNE DYSFUNCTIONS?
YES.
The shift to the Th2 immune response, as observed in CFS [56], is a known effect of both elevated cortisol [57] and of depleted GSH [58, 59]. I suggest that elevated cortisol produces the shift initially, and that GSH depletion maintains it later, after the cortisol level drops due to later blunting of the HPA axis.
The following dysfunctions seen in CFS [60] are known effects of depleted GSH: lowered natural killer cell and cytotoxic T cell cytotoxicity; inability of T cells to proliferate, as seen in decreased mitogen-induced proliferative response of lymphocytes and decrease in delayed-type hypersensitivity [61].
In addition, I hypothesize the following:
The observed chronic immune activation [60] and the observed continuous activation of the RNase-L pathway in CFS [60] result from the failure of cell-mediated immunity to defeat detected infections, owing to the above effects of GSH depletion.
The observed low molecular weight RNase-L [62] results from lack of inhibition of caspases because of thiol (GSH) depletion, and they cleave the RNase-L.
The observed elevated numbers of immune complexes [60] result from the shift to the Th2 response, which produces elevated levels of antibodies.
The observed elevation in antinuclear antibodies [60] results from the observed higher rate of apoptosis [63-66], which is caused by GSH depletion [67].
HOW DOES PHYSICAL FATIGUE ARISE AT THE ONSET OF CFS?
(HYPOTHESIS)
When the immune system detects the viral infection, it becomes activated.
In attempting to proliferate, the lymphocytes draw upon the already depleted supplies of GSH and its precursor, cysteine (or cystine).
Being in the blood, the lymphocytes have earlier access to GSH and cysteine than do the skeletal muscles.
Competition in CFS between the immune system and the skeletal muscles for these substances has already been hypothesized by Bounous and Molson [68], and I agree with their hypothesis.
The skeletal muscles become more depleted in GSH.
This produces a rise in their concentrations of peroxynitrite. (Peroxynitrite forms from superoxide and nitric oxide. Superoxide becomes elevated because the depletion of GSH causes a rise in hydrogen peroxide, and this exerts product inhibition on the superoxide dismutase reaction, causing superoxide levels to rise.)
As Pall [69] has stated, "Peroxynitrite reacts with and inactivates several of the enzymes in mitochondria so that mitochondrial and energy metabolism dysfunction is one of the most important consequences of elevated peroxynitrite."
The resulting partial blockades in the Krebs cycles and the respiratory chains in the red, slow-twitch skeletal muscle cells decrease their rate of production of ATP. Since ATP is what powers muscle contractions, the lack of it produces physical fatigue. It becomes chronic because GSH remains depleted.
SINCE GLUTATHIONE IS AT THE BASIS OF THE BODY'S ANTIOXIDANT SYSTEM, ITS DEPLETION CAN BE EXPECTED TO PRODUCE OXIDATIVE STRESS. HAS THIS BEEN OBSERVED IN CFS?
YES. Oxidative stress is now well-established in CFS.
The following researchers have presented evidence for oxidative stress in CFS:
Ali [70,71]
Cheney [7,8]
Richards et al. [9,72]
Fulle et al. [10]
Manuel y Keenoy et al. [11,12]
Vecchiet et al. [73]
Kennedy et al. [13]
Smirnova and Pall [74]
WHAT EFFECTS DO ELEVATED CORTISOL AND DEPLETED GLUTATHIONE HAVE ON BRAIN FUNCTION, AND ARE THEY OBSERVED IN CFS?
Long-term cortisol elevation is known to damage the hippocampus, and GSH depletion is involved [75].
Additional depletion of GSH would likely exacerbate the effects of elevated cortisol on the hippocampus.
The hippocampus is involved with memory, sleep, and control of the HPA axis.
Deficits in all these areas are seen in CFS.
Examination of the hippocampus in CFS by magnetic resonance spectroscopy suggested significantly lower metabolism in the right hippocampus [76].
It seems likely that elevated cortisol and depleted GSH account for at least some of the CFS brain function deficits.
SINCE GLUTATHIONE NORMALLY REMOVES MERCURY FROM THE BODY, ITS DEPLETION CAN BE EXPECTED TO ALLOW BUILDUP OF MERCURY IN CFS PATIENTS. IS THIS OBSERVED?
YES. While there are no published controlled studies of mercury level testing in CFS patients, several clinicians who specialize in treating CFS have reported that many of their patients have high mercury levels:
Ali [77]
Godfrey [78]
Conley [79]
Poesnecker [80]
Teitelbaum [81]
Corsello [82]
Goldberg [83]
In addition, immune testing has shown significantly elevated hypersensitivity to mercury in many CFS patients (Stejskal et al., [84]; Sterzl et al., [85]; and Marcusson, [86]). This suggests that the immune system has responded to elevated mercury levels.
(Note that there have been epidemiological studies that showed no evidence that dental amalgams are associated with CFS as a causal factor [87,88]. However, this does not constitute evidence that amalgams do not give rise to elevated mercury levels after CFS onset in people who have amalgams and who may have developed CFS as a result of other causes.)
CAN GLUTATHIONE DEPLETION EXPLAIN AUTOIMMUNE THYROIDITIS IN CHRONIC FATIGUE SYNDROME?
YES.
It is known that thyroid cells normally produce hydrogen peroxide to oxidize iodide ions as part of the pathway for producing thyroid hormones. Normally, this oxidation occurs outside the cell membrane, and the interior of the cell is protected from the hydrogen peroxide by intracellular GSH [89].
It has been shown by Duthoit et al., [90] that if hydrogen peroxide is allowed to enter thyroid cells, it will attack and cleave thyroglobulin, producing C-terminal fragments that can diffuse into other cells and are recognized by autoantibodies from patients with autoimmune thyroid disease. This suggests that hydrogen peroxide entry into thyroid cells may be the cause of this disease.
It has been shown by Wikland et al. [91], using fine needle aspiration cytology, that about 40% of patients suffering from chronic fatigue show evidence of chronic autoimmune thyroiditis, even though TSH levels were in the normal range in many of them.
HYPOTHESIS: It seems likely that GSH depletion accounts for the high prevalence of autoimmune (Hashimoto's) thyroiditis in CFS.
WHY IS CFS MORE PREVALENT IN WOMEN THAN IN MEN?
It has been found recently that the monthly menstrual cycle in women presents an additional demand on GSH that does not occur in men. 17-beta estradiol is elevated in women from the late follicular phase through the early luteal phase of the cycle. This hormone stimulates the activity of the enzyme glutathione peroxidase [92].
Perhaps this occurs to protect against elevated production of reactive oxygen species generated during the rapid growth of the endometrium.
The resulting reactions depress the endometrial GSH level during the time the estradiol level is high [92].
HYPOTHESIS: I propose that this additional estradiol-driven demand for GSH in women exacerbates the GSH depletion that occurs as a result of other causes, and that this makes women more vulnerable to developing CFS, accounting for the higher observed prevalence of CFS in women than in men.
WHAT APPROACHES HAVE BEEN USED TO BUILD GLUTATHIONE?
Diet high in sulfur-containing amino acids (as in animal-based protein, such as milk, eggs and meat) and antioxidants (as in fresh fruits and vegetables) [93].
Diet high in GSH, e.g. fresh fruits and vegetables and meats [94].
Curcumin [95].
N-acetylcysteine together with glutamic acid (or glutamine) and glycine [96], or NAC together with dietary protein [97].
Non-denatured whey protein [98]
Oral reduced glutathione [4]
Intravenous reduced glutathione [99]
Intramuscular reduced glutathione [100]
Transdermal reduced glutathione skin cream or lotion [101]
Sublingual reduced glutathione troches [102]
Reduced glutathione rectal suppositories [103]
Reduced glutathione aerosol [104]
Reduced glutathione nasal spray [105]
HAS GLUTATHIONE REPLETION BEEN USED CLINICALLY IN CFS, AND IF SO, WHAT HAVE BEEN THE RESULTS?
YES.
Patricia Salvato, M.D. [100] has used intramuscular injections of GSH combined with ATP clinically for several years. In 1998 she reported on a study of 276 CFS patients, using 100 mg of GSH and 1 mg of ATP weekly. After 6 months of treatment, 82% experienced improvement in fatigue, 71% experienced improvement in memory and concentration, and 62% experienced improvement in levels of pain.
Paul Cheney, M.D. reported in 1999 [7,8] on his clinical use of oral undenatured whey protein in CFS patients. The dosage varied with different patients, up to 40 grams per day. He reported that several of his patients improved on this treatment, and some who had had active infections with herpes family viruses, mycoplasma, or chlamydia were cleared of them by this treatment.
John S. Foster, M.D. and his colleagues reported in 2002 [99] on their use of GSH in an intravenous fast push (over 2 to 3 minutes). Dosage ranged up to 2,500 mg, 1 or 2 times weekly, as part of a detoxification protocol used on a variety of patients, including some with CFS. They reported that the treatment "has been promising in addressing neurodegenerative and neurotoxic disorders."
CONCLUSION
Glutathione depletion indeed appears to be an important aspect of the pathogenesis of chronic fatigue syndrome for at least a substantial fraction of patients.
Is repletion of glutathione likely to be the complete answer for treating CFS?
No. GSH depletion occurs near the beginning of the complex pathogenesis of CFS. There are likely to be many interactions and vicious circles as the pathogenesis develops into the pathophysiology, and there may also be damage that is difficult to correct. The mediators of such damage would likely be infections, toxins and reactive oxygen species, all of which are able to build up because of the depletion of GSH. It is likely that a multifaceted treatment protocol will be necessary.
There are also some cautions that should be exercised:
When GSH repletion is begun in patients who have been GSH-depleted for extended periods of time, their immune and detoxication systems can begin to function at higher levels of performance. If their bodies have accumulated elevated levels of toxins (especially mercury) and infections, glutathione repletion can cause significant Herxheimer-type reactions as pathogens are killed and toxins are mobilized. Care should be taken to proceed slowly and cautiously in such cases in order to avoid moving toxins into the central nervous system or exacerbating symptoms to a level that is intolerable to the patient.
Plasma cysteine level should be monitored periodically when repleting glutathione, to ensure that it does not rise to levels that could be neurotoxic [106].
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64. See, D.M., Cimoch, P., Chou, S., Chang, J., and Tilles, J., The in vitro immunomodulatory effects of glyconutrients on peripheral blood mononuclear cells of patients with chronic fatigue syndrome, Integr. Physiol. Behav. Sci. (1998) 33(3):280-287.
65. Krueger, G.R., Koch, B., Hoffmann, A., Roho, J., Brandt, M.E., Wang, G., and Buja, L.M., Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling, In Vivo (2001) 15(6):461-465.
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73. Vecchiet, J., Cipollone, F., Falasca, K., Mezzetti, A., Pizzigallo, E., Bucciarelli, T., De Laurentis, S., Affaitati, G., De Cesare, D., Giamberardino, M.A., Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome, Neuroscience Letters (2003) 335:151-154.
74. Smirnova, I.V., and Pall, M.L., Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients, Molecular and Cellular Biochemistry (2003) 248:93-95.
75. Patel, R., McIntosh, L., McLaughlin, J., Brooke, S., Nimon, V., and Sapolsky, R., Disruptive effects of glucocorticoids on glutathione peroxidase biochemistry in hippocampal cultures, J. Neurochem. (2002) 82:118-125.
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82. Corsello, S., Review of the multiple factors (loading theory) in the pathogenesis of chronic fatigue syndrome: theoretical review and treatment, conference syllabus, Latest 21st Century Medical Advances in the Diagnosis and Treatment of Fibromyalgia, Chronic Fatigue Syndrome and Related Illnesses, Sept. 19-21, 2002, Los Angeles, CA, Advanced Medical Conferences International, Chicago (info@AdMedCon.com).
83. Goldberg, B., and Trivieri, L., Jr., eds., Chronic Fatigue, Fibromyalgia, and Lyme Disease, second edition (2004) Celestial Arts, Berkeley, CA, p. 175.
84. Stejskal, V.D., Danersund, A., Lindvall, A., Hudecek, R., Nordman, V., Yaqob, A., Mayer, W., Bieger, W, and Lindh, U., Metal-specific lymphocytes: biomarkers of sensitivity in man, Neuroendocrinol. Lett. (1999) 20(5):289-298.
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86. Marcusson, J.A., The frequency of mercury intolerance in patients with chronic fatigue syndrome and healthy controls, Contact Dermatitis (1999) 41(1):60-61.
87. Yip, H.K., Li, D.K., and Yau, D.C., Int. Dent. J. (2003) 53(6):464-8.
88. Bates, M.N., Fawcett, J., Garrett, N., Cutress, T., and Kjellstrom, T., Health effects of dental amalgam exposure: a retrospective cohort study, Int. J. Epidemiol. (2004) 33:1-9.
89. Ekholm, R., and Bjorkman, U., Glutathione peroxidase degrades intracellular hydrogen peroxide and thereby inhibits intracellular protein iodination in thyroid epithelium, Endocrinology (1997) 138:2871-2878.
90. Duthoit, C., Estienne, V., Giraud, A., Durand-Gorde, J.M., Rasmussen, A.K., Feldt-Rasmussen, U., Carayon, P., Ruf, J., Hydrogen peroxide-induced production of a 40 kDa immunoreactive thyroglobulin fragment in human thyroid cells: the onset of thyroid autoimmunity?, Biochem. J. (2001) 360(Pt 3):557-562.
91. Wikland, B., Lowhagen, T., and Sandberg, P.O., Fine-needle aspiration cytology of the thyroid in chronic fatigue, Lancet (2001) 357(9260):956-7.
92. Serviddio, G., Loverro, G., Vicino, M., Prigigallo, F., Grattagliano, I., Altomare, E., and Vendemiale, G., Modulation of endometrial redox balance during the menstrual cycle: relation with sex hormones, J. Clin. Endocrinol. Metab. (2002) 87(6):2843-2848.
93. Van Konynenburg, R.A., Nutritional approaches, chapter 27 in Handbook of Chronic Fatigue Syndrome (2003), L.A. Jason, P.A. Fennell, and R.R. Taylor, eds., Wiley, Hoboken, NJ, pp. 580-653.
94. Jones, D.P., Coates, R.J., Flagg, E.W., Eley, J.W., Block, G., Greenberg, R.S., Gunter, E.W., and Jackson, B., Glutathione in foods listed in the National Cancer Institute's health habits and history food frequency questionnaire, Nutrition and Cancer (1992) 17:57-75.
95. Dickinson, D.A., Iles, K.E., Zhang, H., Blank, V., and Forman, H.J., Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression, FASEB J. (2003) 17(3):473-475.
96. Clark, J. at www.cfsn.com is a proponent and supplier of this combination (for information only, not an endorsement).
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101. Two suppliers are http://www.kirkmanlabs.com and http://www.leesilsby.com (for information only, not an endorsement)
102. Schaller, J., M.D. (http://www.personalconsult.com).
103. One supplier is Hopewell Pharmacy in New Jersey (for information only, not an endorsement).
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2.
February 21, 2006
Chronic Fatigue Syndrome and Autism
by
Richard A. Van Konynenburg, Ph.D.
(richvank@aol.com)
For the past ten years I have been studying chronic fatigue syndrome as an independent researcher. Over the course of several years I developed a hypothesis for the pathogenesis of this disorder that prominently featured the depletion of glutathione. I presented a poster paper on this hypothesis at the AACFS (now the International Association for Chronic Fatigue Syndrome) meeting in October, 2004, in Madison, Wisconsin. This paper can be found at the following url:
http://www.cfsresearch.org/cfs/research/treatment/15.htm
Anecdotal experience of people with CFS who acted upon my hypothesis suggested that while some were able to raise their glutathione levels by various means and experienced benefit from doing so, others were not able to do so. At the time I wrote my poster paper, I was aware of this, and I acknowledged in the conclusions of the paper that there appeared to be factors that were blocking the raising of glutathione in CFS. At that time, I was not sure specifically what they were. I also knew that there was evidence for a genetic predisposition in CFS, but I did not know the details of the genetic variations involved.
Shortly after that, I became aware of the work of S. Jill James et al. in autism (American Journal of Clinical Nutrition 2004 Dec; 80(6):1611-7). They found that glutathione was also depleted in autistic children, that this was associated with a partial block in the methylation cycle (also called the methionine cycle), that this partial block was associated with genetic variations in the genes for certain enzymes and other proteins associated with the sulfur metabolism, and that it interfered with the synthesis of glutathione. They also found that by using certain supplements (methylcobalamin, folinic acid and trimethylglycine) they could lift the block in the methylation cycle and restore the glutathione level.
Upon learning of this work, I became very interested in possible parallels between chronic fatigue syndrome and autism. I attended the conference of the Defeat Autism Now! (DAN!) project in Long Beach, California in October, 2005, sponsored by the Autism Research Institute, headed by Dr. Bernard Rimland. As a result I became convinced that the genetic predisposition found in autism must be the same or similar to that in a major subset of chronic fatigue syndrome, and that the resulting biochemical abnormalities were also the same or similar. As far as I know, the genetic variations in people with chronic fatigue syndrome have not yet been studied in detail or published, but I am optimistic that this will occur soon, because of the rapid advances in the technology for doing so, and because of the current active interest of at least three groups in the U.S. and the U.K. in genomic aspects of CFS.
There are obviously major differences between chronic fatigue syndrome and autism. I believe that these result primarily from the different ages of onset. Autistic children experience onset early in life, before their brains are fully developed. I believe that this gives rise to the very different brain-related symptoms seen in autistic children from those seen in adults with CFS. However, there are many similarities in the biochemistry and symptoms of these two disorders as well, including oxidative stress, buildup of toxins, immune response shift to Th2, and gut problems, for examples.
The triggering factors for autism and chronic fatigue syndrome are also largely different. Although this subject remains controversial, there appears to be substantial evidence that vaccinations (containing either a mercury-based preservative or live viruses, many given within a short period of time) were responsible for triggering many of the cases of autism in genetically-susceptible children (D. Geier and M.R. Geier, International Journal of Toxicology 2004 Nov-Dec; 23(6):369-76; and A.J. Wakefield, several publications beginning in 1997).
In CFS, a variety of triggering factors (physical, chemical, biological, or psychological/emotional) have been found to be involved in various cases, as reviewed in my poster paper, cited above. All these factors have in common that they place a demand on glutathione.
It appears that genetically susceptible persons are unable to maintain normal glutathione levels when the total demand for it is high, and that once glutathione drops sufficiently in a genetically susceptible person, the sulfur metabolism becomes disrupted. In many cases the methylation cycle (part of the sulfur metabolism) becomes partially blocked, and the result can be a depletion of some or all of several important sulfur-containing metabolites, including S-adenosylmethionine (SAMe), cysteine, glutathione, taurine and sulfate. A vicious circle is thus formed, and the depletion in these metabolites causes an avalanche of pathogenesis, since they all have very important functions in the body. I think that much of this pathogenesis is common between autism and CFS. In autism, the loss of methylation capacity because of the drop in SAMe appears to be responsible for much of the interference with normal brain development.
There is also a major difference in the sex ratio between autism and
CFS. In the book mentioned below, Dr. Jon Pangborn discusses possible
reasons why autism is more prevalent in boys. In my poster paper, cited
above, I suggested a hypothesis to explain the female dominance in the
prevalence of CFS in adults.
I think that the reason why the people who have developed CFS as adults did not develop autism as children (even though I suspect that they have the same or a similar genetic predisposition) is that when they were children, not as many vaccinations were required. The schedule of vaccinations required for children in the U.S. has grown substantially over the past two or three decades, as has the incidence of autism. This is also true in the U.K.
Shortly after attending the DAN! conference, I also learned of the work of Dr. Amy Yasko, primarily in autism, but extending to a number of other disorders as well. Working independently of the DAN! project, Dr. Yasko develops her treatment recommendations by analyzing the specific gene variations in each patient. In addition to studying effects on the methylation cycle, Dr. Yasko has gone on to consider the effects on associated biochemistry, including folate metabolism, biopterin, the urea cycle and the synthesis of neurotransmitters.
My main message is that a great deal has already been worked out in autism by the researchers and clinicians associated with the Defeat Autism Now! project, and also by Dr. Yasko, and that I believe that the CFS community would benefit greatly by looking carefully at what they have already done. The doctors associated with the DAN! project treat autism by the use of nutritional supplements that compensate for genetic mutations in the sulfur metabolism. These include such supplements as magnesium sulfate, taurine, molybdenum, vitamin B6 and its active form P5P, magnesium, methylcobalamin, folinic acid, trimethylglycine, and dimethylglycine. They also use certain diets, and they perform chelation treatments to remove heavy metals. The results in many autistic children have been astounding, as can be seen in the webcast cited below, where several are interviewed.
Dr. Yasko, in cooperation with Dr. Garry Gordon, uses many of the same supplements as are used by the DAN! project doctors as well as some additional ones, including RNA supplements, and she is also reporting great success.
So I want to encourage everyone who has an interest in CFS to look at the results of the DAN! project and of Dr. Amy Yasko in autism.
To view videos of the talks given at the latest two DAN! conferences on the internet at no cost (unless you are paying for the internet time!), go to this site:
http://www.danwebcast.com
You can choose the more recent Long Beach conference or the earlier Boston conference. They cover much of the same material, but both are worthwhile to watch. If you want to see and hear a good explanation of the methylation cycle research, go to the Boston meeting first, so you will be able to view the talk by Jill James, who did not attend the Long Beach meeting.
After selecting one of the conferences, go to the lower left and register. This is free. They will email a password to you right away, and then you can choose a talk to watch.
Beyond this, I also want to recommend a book entitled Autism: Effective Biomedical Treatments. This is a new book (Sept. 2005). It is by Jon Pangborn, Ph.D. and Sydney Baker, M.D., a biochemist and an autism clinician, respectively. It is available on Amazon for people within the U.S. For people outside the U.S., it can be obtained from the following website by means of PayPal:
http://www.autismresearchinstitute.com
The cost for the book is $30 U.S.
This is an excellent book. It is a reference book, full of good information and good science, explained clearly. This book deals very practically with developing a treatment program for an individual child. I think that most of it will turn out to apply directly to adults with CFS as well.
In addition, I want to recommend the book by Amy Yasko entitled Genetic ByPass. It is available from the website
http://www.longevityplus-rna.com/store/product.php?productid=49
as part of the "Nutrigenomics Educational Starter Packet." The price is $49.95. This is also an excellent book. It discusses treatments specifically tailored to the particular combinations of genetic variations found in different patients.
I think these two books complement each other. I would recommend reading the Pangborn and Baker book first, as it provides a good basis for understanding the technical aspects of the genetics found in the Yasko book.
Although I have been suggesting consideration of the DAN! treatments and the Yasko testing to people with CFS for only a short time, and it is too soon to draw conclusions, early feedback is very encouraging. While I am going out on a limb to some extent in announcing this now, I don't want to wait any longer, because I think this could help a lot of people. Of course, we should all keep in mind that with the current case definition of CFS we have a very heterogeneous population, and the autism treatments will very likely not help everyone who has CFS, but I am convinced that they will help a substantial subset. So I want to encourage those who have CFS and those who treat it to look into this in the strongest way I can. It could be the answer for many of you.
[Disclaimer: I have no financial interest in anything recommended in this article.]
This Wiki page contains a collection of documents written by Rich Van Konynenburg, Ph.D., an independent researcher who has studied ME/CFS since 1996.
Rich has proposed the Glutathione DepletionMethylation Cycle Block hypothesis for the pathogenesis and pathophysiology of ME/CFS and has suggested treatment based on it.
This treatment was tested in a clinical study conducted by Neil Nathan, M.D., and Rich, and was found to produce significant benefit for more than two-thirds of the patients in the study.
The documents on this Wiki page are in the approximate chronological order in which they were written. Since Richs thinking has been modified over time as more has been learned, where there are conflicts the more recent document should be given precedence.
The documents on this page are as follows:
1. Is Glutathione Depletion an Important Part of the Pathogenesis of Chronic Fatigue Syndrome?
This poster paper was presented at the 2004 AACFS conference.
It presents the case for the importance of glutathione depletion in ME/CFS.
2. Chronic Fatigue Syndrome and Autism
This article appeared in the October 2006 issue of the Townsend Letter. It discusses the commonality between autism and ME/CFS with regard to genetics and biochemistry.
3. Glutathione DepletionMethylation Cycle Block: A Hypothesis for the Pathogenesis of Chronic Fatigue Syndrome
This poster paper was presented at the 2007 IACFS conference. It is a detailed biochemical presentation of the GD-MCB hypothesis.
4. Why is the Prevalence of Chronic Fatigue Syndrome Higher in Women than in Men?
This poster paper was also presented at the 2007 IACFS conference. It suggests that the higher prevalence in women is due to the presence of polymorphisms in detox enzymes that metabolize the estrogens, resulting in additional oxidative stress.
5. Suggestions for Treatment of Chronic Fatigue Syndrome (CFS) based on the Glutathione DepletionMethylation Cycle Block Hypothesis for the Pathogenesis of CFS
This article was written on January 25, 2007, in response to a request from Dr. David Bell for a treatment based on the GD-MCB hypothesis. It applies the approach of Amy Yasko, Ph.D., N.D., used primarily in autism, to the treatment of ME/CFS, and includes a simplified approach, extracted from her full treatment protocol.
6. Simplified Treatment Approach Based on the Glutathione DepletionMethylation Cycle Block Pathogenesis Hypothesis for Chronic Fatigue Syndrome (CFS)
This article was written on July 18, 2007. It reviews the history of the simplified treatment and the first six months of experience with it, including adverse effects that were reported.
7. Simpler Explanation of GD-MCB Hypothesis for CFS
This article was written on December 13, 2008, in response to a request for an easier to understand explanation of the hypothesis.
It is written for a general audience and does not require familiarity with the intricacies of biochemistry.
8. Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia
This poster paper was presented at the 2009 IACFS/ME conference. It was authored by Neil Nathan, M.D. and Rich, and discusses a clinical study of the simplified treatment approach involving 30 women in Dr. Nathans practice.
9. Is There a Link between Lyme Disease and Chronic Fatigue Syndrome?
This poster paper was also presented at the 2009 IACFS/ME conference. It suggests that Lyme disease can lead to onset of ME/CFS in those who are genomically predisposed, as a result of glutathione depletion by Borrelia burgdorferi bacteria.
10. Contact Information for Ordering the Methylation Pathways Panel
This panel will determine whether the methylation cycle is partially blocked, whether glutathione is depleted, and whether folates have drained from the cells. It thus indicates whether the GD-MCB hypothesis is likely to apply to a given case, and whether methylation cycle treatment is likely to be helpful.
11. Interpretation of the Methylation Pathways Panel
This article was written on May 19, 2011, in response to a request from Tapan Audhya, Ph.D. It is intended primarily for physicians, to assist them in interpreting this panel.
12. Simplified Treatment Approach for Lifting the Partial Methylation Cycle Block in Chronic Fatigue Syndrome
This is the most recent version of the protocol for the simplified treatment approach, written on March 30, 2011. It is a protocol designed to lift the partial methylation cycle block. While it has been found to help most patients with this disorder, some have not been helped. Richs recommendation is to try this protocol for three months. If it is not producing observable benefit by that time, consideration should be given to changing the protocol, such as by trying methylcobalamin rather than hydroxocobalamin.
1.
IS GLUTATHIONE DEPLETION
AN IMPORTANT PART OF THE
PATHOGENESIS OF
CHRONIC FATIGUE SYNDROME?
by
Richard A. Van Konynenburg, Ph.D.
(Independent Researcher)
richvank@aol.com
AACFS Seventh International Conference
Madison, Wisconsin
October 8-10, 2004
WHAT IS GLUTATHIONE?
[Refs. 1--5]
A tripeptide composed of the amino acids glutamic acid, cysteine, and glycine. Its molecular weight is 307.33 Da.
Found in all cells in the body, in the bile, in the epithelial lining fluid of the lungs, and, at much smaller concentrations, in the blood.
The predominant nonprotein thiol (molecule containing an S-H or sulfhydryl group) in cells.
Its active form is the chemically reduced form, called "GSH."
GSH is compartmentalized, with concentrations ranging from 0.5 to 10 millimolar in various organs and cell types.
GSH serves as a substrate for enzymes, including the glutathione peroxidases and the glutathione-S-transferases.
When oxidized, two glutathione molecules join together via a disulfide bond to form "oxidized glutathione," or "glutathione disulfide," referred to as "GSSG."
Inside cells, the concentration of GSSG is normally maintained at less than 1% of total glutathione by the enzyme glutathione reductase, which is powered by NADPH, produced by the pentose phosphate shunt, part of normal carbohydrate metabolism.
WHAT ARE SOME OF THE FUNCTIONS OF GLUTATHIONE (GSH)?
[Refs. 1--5]
Maintains proper oxidation-reduction (redox) potential inside cells. Redox affects the oxidation state of sulfur in enzymes, and thus affects the rates of biochemical reactions in cells.
Scavenges peroxides and oxidizing free radicals directly and also serves as the basis for the antioxidant network.
Performs Phase II detoxication of heavy metals (such as mercury), organophosphate pesticides, chlorinated hydrocarbon solvents, estradiol, prostaglandins, leukotrienes, acetaminophen, and other foreign and endogenous toxins.
Stores and transports cysteine throughout the body.
Transports amino acids, especially cystine into kidney cells.
Regulates the cell cycle, DNA and protein synthesis and proteolysis, and gene expression.
Regulates signal transduction.
Participates in bile production.
Protects thyroid cells from self-generated hydrogen peroxide.
In carrying out several of the above functions, GSH plays very important roles in (1) maintaining mitochondrial function and integrity, (2) regulating cell proliferation, and (3) supporting the immune system.
HOW IS GLUTATHIONE (GSH) SYNTHESIZED IN THE BODY?
[Refs. 1--5]
GSH is synthesized inside cells by a two-step process. The first step involves the ATP-powered enzyme glutamate cysteine ligase (formerly called gamma-glutamylcysteine synthetase). This step is normally the rate-limiting reaction, and is controlled by the cellular redox state and feedback inhibition, among other factors. The second step makes use of the ATP-powered enzyme glutathione synthetase.
The necessary substrates are cysteine (which is often the rate-limiting substrate when GSH is depleted), glutamic acid (or glutamine) and glycine. Cysteine and glutamic acid are joined together in the first step, and glycine is added in the second step.
The liver is the main producer and exporter of GSH.
A few epithelial cell types can import GSH molecules intact.
Most cell types use the gamma glutamyl (or GSH scavenging) cycle. This cycle makes use of the plasma-membrane-bound exoenzymes gamma-glutamyl transpeptidase and dipeptidase. This cycle disassembles GSH outside the cell and imports the parts for reassembly inside. It also serves as a transport mechanism to bring other amino acids into the cell, cystine
(di-cysteine) being favored.
IS GLUTATHIONE DEPLETED IN CHRONIC FATIGUE SYNDROME?
There is considerable evidence that GSH is depleted in at least a substantial fraction of CFS patients. Here are the results of all the published studies that bear on this question:
GSH depletion in CFS was first suggested by Droge and Holm [6].
Cheney [7,8] reported that his CFS clinical patients were almost universally low in GSH.
Richards et al. [9] found that patients could be divided statistically into two distinct groups, one having significantly elevated erythrocyte GSH relative to a healthy control group, and the other having significantly lower values.
Fulle et al. [10] found elevated total (reduced plus oxidized) glutathione in muscle biopsy specimens from PWCs relative to healthy controls, but they did not report values for reduced glutathione alone.
Manuel y Keenoy et al. [11] found that a subgroup of fatigued patients with low magnesium, which did not improve with supplementation, had significantly lower GSH.
Manuel y Keenoy et al. [12] did not find a significant difference between CFS patients and fatigued controls in terms of whole-blood GSH, but they did not compare with a healthy control group.
Kennedy et al. [13] found significantly lower red blood cell GSH in PWCs compared to healthy controls (p=0.05).
Kurup and Kurup [14] found significantly lower red blood cell GSH in myalgic encephalomyelitis patients compared to healthy controls (p<0.01).
IN THE GENERAL POPULATION, WHAT FACTORS OR CONDITIONS ARE KNOWN TO CAUSE DECREASES IN INTRACELLULAR GLUTATHIONE CONCENTRATIONS?
These factors and conditions can be divided into three groups:
The first group is made up of those that (1) lower the rate of GSH synthesis or the rate of reduction of GSSG to GSH, or (2) raise the rate of export of GSH from cells, or (3) lead to loss of GSH from the scavenging pathway. This group includes the following: genetic defects [15], elevated adrenaline secretion [16-20] due to various types of stress, deficient diet [1] or fasting [21], surgical trauma [21,22], burns [23], and morphine [24].
The second group is comprised of toxins that conjugate GSH and remove it from the body [25], such as organophosphate pesticides, halogenated solvents, tung oil (used on furniture), acetaminophen and some types of inhalation anesthesia.
The third group is comprised of conditions that raise the production rates of reactive oxygen species high enough to produce oxidative stress, causing cells to export GSSG. These include strenuous or extended exercise [26], infections (producing leukocyte activation) [21], toxins that produce oxidizing free radicals during Phase I detoxication by cytochrome P450 enzymes [21], ionizing radiation [27], iron overload [28], and ischemia--reperfusion events (such as stroke, cardiac arrest, subarachnoid hemorrhage, and head trauma) [29].
STRESS, DISTRESS, AND STRESSORS
For purposes of this presentation, stressors are defined in the broad sense as events, circumstances or conditions that place demands on a person and tend to move his or her body out of allostatic balance. Allostasis is similar to homeostasis, but allows for changes in the set-point over time to match life circumstances [30]. Stressors can be classified as physical, chemical, biological, or psychological/emotional.
Stress is the state that results from the presentation of such demands. Selye [31] defined stress as "the state manifested by a specific syndrome which consists of all the nonspecifically-induced changes within a biologic system." Although Selye emphasized the nonspecifically-induced responses, the body also exhibits specific responses that depend on the type of stress [32].
Stress can be of a beneficial or a destructive nature. Distress is the destructive type of stress [31].
The perceived stress that people experience depends not only on the stressors to which they are subjected, but also on "their appraisals of the situation and cognitive and emotional responses to it." [33]
A person's history of both the occurrence of stressors and of the degree of perceived stress can be evaluated by structured interviews, and this has been done in a number of studies of CFS risk factors [34-45].
IS THERE EVIDENCE FOR HIGHER OCCURRENCE OF STRESSORS IN CFS PATIENTS PRIOR TO ONSET THAN IN HEALTHY NORMAL CONTROLS?
YES. The types of stressors found to have higher occurrence in one or more CFS risk factor studies [34-45] include the following:
Physical: Aerobic exercise (especially of long duration), physical trauma (especially motor vehicle accidents) and surgery (including anesthesia).
Chemical: Exposure to toxins such as organophosphate pesticides, solvents and ciguatoxin.
Biological: Infections, immunizations, blood transfusions, insect bites, allergic reactions, and eating or sleeping less.
Emotional/Psychological:
Stressful life events, including death of a spouse, close family member or close friend; recent marriage; troubled or failing marriage, separation, or divorce; serious illness in immediate family; job loss, starting new job, or increased responsibility at work; and residential move.
Difficulties, including ongoing problems with relationships, persistent work problems or financial problems, mental or physical violence, overwork, extreme sustained activity, or "busyness."
Dilemmas "A dilemma is a situation in which a person is challenged to choose between two equally undesirable alternatives."[45] Choosing inaction in response to a dilemma leads to further negative consequences.
Problems in childhood, including significant depression or anxiety, alcohol or other drug abuse, and/or physical violence in parents or other close family members; physical, sexual or verbal abuse, low self-esteem and chronic tension or fighting in the family.
IS THERE EVIDENCE FOR HIGHER PERCEIVED STRESS IN CFS PATIENTS PRIOR TO ONSET, COMPARED TO HEALTHY CONTROLS?
YES. Three studies [34, 37, 38] found that CFS patients rated their level of perceived stress prior to onset higher than did healthy, normal controls for a similar period of time.
IS IT SURPRISING THAT GLUTATHIONE BECAME DEPLETED IN MANY CFS PATIENTS?
NO. In view of the strong correspondence between the results of the CFS risk factor studies and the known GSH depletors, it is not surprising. It appears that the CFS patients who were studied had undergone a variety of factors and conditions that are known to deplete glutathione, and had also experienced high levels of perceived stress as a result.
HOW DOES THE NEUROENDOCRINE SYSTEM RESPOND TO STRESS?
This system manifests both specifically- and nonspecifically-induced responses to stress [32]. The nonspecifically-induced responses address the combined load of all the various types of stress that are being experienced simultaneously.
The nonspecific responses are mediated by three parts of this sytem: (1) the hypothalamus-pituitary-adrenal (HPA) axis, which produces cortisol and other glucocorticoids, (2) the sympathetic-adrenomedullary system, which produces epinephrine (adrenaline), and (3) the sympathoneural system, which produces norepinephrine (noradrenaline) [32].
Rapid-onset CFS patients report that they had a normal response to stress prior to their onset of CFS. Therefore, it can be surmised that if they experienced a high load of combined long-term stress lasting a few months to several years prior to their onset, they were subject to high levels of both cortisol and adrenaline during this extended period of time.
Note that depleted rather than elevated cortisol levels are frequently observed clinically in CFS patients (Cleare [46]). However, the decrease in cortisol secretion occurs later in the pathogenesis: "the bulk of the data assembled to date is compatible with the view that the disruption in adrenocortical function is a late finding, and that elucidating the status of the central nervous system components which drive the regulation of the HPA axis would be crucial to a more complete understanding of this final event." (Demitrack [47])
WHAT ARE THE EFFECTS OF ELEVATED LEVELS OF CORTISOL AND ADRENALINE ON THE IMMUNE SYSTEM AND ON GLUTATHIONE LEVELS?
Elevation of cortisol is known to suppress the inflammatory response by several mechanisms, including decreasing the expression of cytokines and cell adhesion molecules, and decreasing the production of prostaglandins and leukotrienes [48]. This effect is beneficially used therapeutically in many cases, but it can also have a down side if an infection is present.
Elevation of cortisol is also known to suppress cell-mediated immunity and to cause a shift to the Th2 type of immune response. Several mechanisms are involved, including suppressing the secretion of IL-1 by macrophages, inhibiting the differentiation of monocytes to macrophages, inhibiting the proliferation of T lymphocytes, and increasing the production of endonucleases, which increases the rate of apoptosis of lymphocytes [33,48].
Long-term elevation of adrenaline can be expected to deplete GSH, because adrenaline decreases the rate of synthesis of glutathione by the liver (Estrela et al. [18]), increases its rate of export from the liver (Sies and Graf [16]; Haussinger et al. [17]; Estrela et al. [18]), and decreases the rate of reduction (recycling) of oxidized glutathione (Toleikis and Godin [19]).
HOW DO VIRAL INFECTIONS ARISE AT THE ONSET OF CHRONIC FATIGUE SYNDROME?
I propose that glutathione depletion is the trigger for reactivation of endogenous latent viruses in CFS (hypothesis).
Here's the support for this hypothesis:
Most of the evidence points to reactivation of latent endogenous viruses at the onset of CFS, rather than new, primary infections (Komaroff and Buchwald [49])
Infections by members of the Herpes family of viruses, such as Epstein-Barr virus and HHV-6 are commonly found in CFS patients [49].
GSH depletion is associated with the activation of several types of viruses [50-53], including Herpes simplex type 1 (HSV-1) [54]. Raising the GSH concentration inhibits replication of HSV-1 by blocking the formation of disulfide bonds in glycoprotein B, a protein that is necessary for proliferation of the virus [54].
Glycoprotein B is also found in all other Herpes family viruses studied, including EBV and CMV [55], and very likely is present also in HHV-6 and performs the same vital function there (hypothesis).
It thus appears very likely that GSH depletion is the trigger for the reactivation of the latent forms of all the Herpes family viruses. Since glutathione likely becomes depleted prior to the onset of CFS, and since infections by these viruses are commonly found in CFS, it seems likely that glutathione depletion initiates the viral infections at the onset of CFS (hypothesis).
CAN ELEVATED CORTISOL AND DEPLETED GLUTATHIONE EXPLAIN THE IMMUNE DYSFUNCTIONS?
YES.
The shift to the Th2 immune response, as observed in CFS [56], is a known effect of both elevated cortisol [57] and of depleted GSH [58, 59]. I suggest that elevated cortisol produces the shift initially, and that GSH depletion maintains it later, after the cortisol level drops due to later blunting of the HPA axis.
The following dysfunctions seen in CFS [60] are known effects of depleted GSH: lowered natural killer cell and cytotoxic T cell cytotoxicity; inability of T cells to proliferate, as seen in decreased mitogen-induced proliferative response of lymphocytes and decrease in delayed-type hypersensitivity [61].
In addition, I hypothesize the following:
The observed chronic immune activation [60] and the observed continuous activation of the RNase-L pathway in CFS [60] result from the failure of cell-mediated immunity to defeat detected infections, owing to the above effects of GSH depletion.
The observed low molecular weight RNase-L [62] results from lack of inhibition of caspases because of thiol (GSH) depletion, and they cleave the RNase-L.
The observed elevated numbers of immune complexes [60] result from the shift to the Th2 response, which produces elevated levels of antibodies.
The observed elevation in antinuclear antibodies [60] results from the observed higher rate of apoptosis [63-66], which is caused by GSH depletion [67].
HOW DOES PHYSICAL FATIGUE ARISE AT THE ONSET OF CFS?
(HYPOTHESIS)
When the immune system detects the viral infection, it becomes activated.
In attempting to proliferate, the lymphocytes draw upon the already depleted supplies of GSH and its precursor, cysteine (or cystine).
Being in the blood, the lymphocytes have earlier access to GSH and cysteine than do the skeletal muscles.
Competition in CFS between the immune system and the skeletal muscles for these substances has already been hypothesized by Bounous and Molson [68], and I agree with their hypothesis.
The skeletal muscles become more depleted in GSH.
This produces a rise in their concentrations of peroxynitrite. (Peroxynitrite forms from superoxide and nitric oxide. Superoxide becomes elevated because the depletion of GSH causes a rise in hydrogen peroxide, and this exerts product inhibition on the superoxide dismutase reaction, causing superoxide levels to rise.)
As Pall [69] has stated, "Peroxynitrite reacts with and inactivates several of the enzymes in mitochondria so that mitochondrial and energy metabolism dysfunction is one of the most important consequences of elevated peroxynitrite."
The resulting partial blockades in the Krebs cycles and the respiratory chains in the red, slow-twitch skeletal muscle cells decrease their rate of production of ATP. Since ATP is what powers muscle contractions, the lack of it produces physical fatigue. It becomes chronic because GSH remains depleted.
SINCE GLUTATHIONE IS AT THE BASIS OF THE BODY'S ANTIOXIDANT SYSTEM, ITS DEPLETION CAN BE EXPECTED TO PRODUCE OXIDATIVE STRESS. HAS THIS BEEN OBSERVED IN CFS?
YES. Oxidative stress is now well-established in CFS.
The following researchers have presented evidence for oxidative stress in CFS:
Ali [70,71]
Cheney [7,8]
Richards et al. [9,72]
Fulle et al. [10]
Manuel y Keenoy et al. [11,12]
Vecchiet et al. [73]
Kennedy et al. [13]
Smirnova and Pall [74]
WHAT EFFECTS DO ELEVATED CORTISOL AND DEPLETED GLUTATHIONE HAVE ON BRAIN FUNCTION, AND ARE THEY OBSERVED IN CFS?
Long-term cortisol elevation is known to damage the hippocampus, and GSH depletion is involved [75].
Additional depletion of GSH would likely exacerbate the effects of elevated cortisol on the hippocampus.
The hippocampus is involved with memory, sleep, and control of the HPA axis.
Deficits in all these areas are seen in CFS.
Examination of the hippocampus in CFS by magnetic resonance spectroscopy suggested significantly lower metabolism in the right hippocampus [76].
It seems likely that elevated cortisol and depleted GSH account for at least some of the CFS brain function deficits.
SINCE GLUTATHIONE NORMALLY REMOVES MERCURY FROM THE BODY, ITS DEPLETION CAN BE EXPECTED TO ALLOW BUILDUP OF MERCURY IN CFS PATIENTS. IS THIS OBSERVED?
YES. While there are no published controlled studies of mercury level testing in CFS patients, several clinicians who specialize in treating CFS have reported that many of their patients have high mercury levels:
Ali [77]
Godfrey [78]
Conley [79]
Poesnecker [80]
Teitelbaum [81]
Corsello [82]
Goldberg [83]
In addition, immune testing has shown significantly elevated hypersensitivity to mercury in many CFS patients (Stejskal et al., [84]; Sterzl et al., [85]; and Marcusson, [86]). This suggests that the immune system has responded to elevated mercury levels.
(Note that there have been epidemiological studies that showed no evidence that dental amalgams are associated with CFS as a causal factor [87,88]. However, this does not constitute evidence that amalgams do not give rise to elevated mercury levels after CFS onset in people who have amalgams and who may have developed CFS as a result of other causes.)
CAN GLUTATHIONE DEPLETION EXPLAIN AUTOIMMUNE THYROIDITIS IN CHRONIC FATIGUE SYNDROME?
YES.
It is known that thyroid cells normally produce hydrogen peroxide to oxidize iodide ions as part of the pathway for producing thyroid hormones. Normally, this oxidation occurs outside the cell membrane, and the interior of the cell is protected from the hydrogen peroxide by intracellular GSH [89].
It has been shown by Duthoit et al., [90] that if hydrogen peroxide is allowed to enter thyroid cells, it will attack and cleave thyroglobulin, producing C-terminal fragments that can diffuse into other cells and are recognized by autoantibodies from patients with autoimmune thyroid disease. This suggests that hydrogen peroxide entry into thyroid cells may be the cause of this disease.
It has been shown by Wikland et al. [91], using fine needle aspiration cytology, that about 40% of patients suffering from chronic fatigue show evidence of chronic autoimmune thyroiditis, even though TSH levels were in the normal range in many of them.
HYPOTHESIS: It seems likely that GSH depletion accounts for the high prevalence of autoimmune (Hashimoto's) thyroiditis in CFS.
WHY IS CFS MORE PREVALENT IN WOMEN THAN IN MEN?
It has been found recently that the monthly menstrual cycle in women presents an additional demand on GSH that does not occur in men. 17-beta estradiol is elevated in women from the late follicular phase through the early luteal phase of the cycle. This hormone stimulates the activity of the enzyme glutathione peroxidase [92].
Perhaps this occurs to protect against elevated production of reactive oxygen species generated during the rapid growth of the endometrium.
The resulting reactions depress the endometrial GSH level during the time the estradiol level is high [92].
HYPOTHESIS: I propose that this additional estradiol-driven demand for GSH in women exacerbates the GSH depletion that occurs as a result of other causes, and that this makes women more vulnerable to developing CFS, accounting for the higher observed prevalence of CFS in women than in men.
WHAT APPROACHES HAVE BEEN USED TO BUILD GLUTATHIONE?
Diet high in sulfur-containing amino acids (as in animal-based protein, such as milk, eggs and meat) and antioxidants (as in fresh fruits and vegetables) [93].
Diet high in GSH, e.g. fresh fruits and vegetables and meats [94].
Curcumin [95].
N-acetylcysteine together with glutamic acid (or glutamine) and glycine [96], or NAC together with dietary protein [97].
Non-denatured whey protein [98]
Oral reduced glutathione [4]
Intravenous reduced glutathione [99]
Intramuscular reduced glutathione [100]
Transdermal reduced glutathione skin cream or lotion [101]
Sublingual reduced glutathione troches [102]
Reduced glutathione rectal suppositories [103]
Reduced glutathione aerosol [104]
Reduced glutathione nasal spray [105]
HAS GLUTATHIONE REPLETION BEEN USED CLINICALLY IN CFS, AND IF SO, WHAT HAVE BEEN THE RESULTS?
YES.
Patricia Salvato, M.D. [100] has used intramuscular injections of GSH combined with ATP clinically for several years. In 1998 she reported on a study of 276 CFS patients, using 100 mg of GSH and 1 mg of ATP weekly. After 6 months of treatment, 82% experienced improvement in fatigue, 71% experienced improvement in memory and concentration, and 62% experienced improvement in levels of pain.
Paul Cheney, M.D. reported in 1999 [7,8] on his clinical use of oral undenatured whey protein in CFS patients. The dosage varied with different patients, up to 40 grams per day. He reported that several of his patients improved on this treatment, and some who had had active infections with herpes family viruses, mycoplasma, or chlamydia were cleared of them by this treatment.
John S. Foster, M.D. and his colleagues reported in 2002 [99] on their use of GSH in an intravenous fast push (over 2 to 3 minutes). Dosage ranged up to 2,500 mg, 1 or 2 times weekly, as part of a detoxification protocol used on a variety of patients, including some with CFS. They reported that the treatment "has been promising in addressing neurodegenerative and neurotoxic disorders."
CONCLUSION
Glutathione depletion indeed appears to be an important aspect of the pathogenesis of chronic fatigue syndrome for at least a substantial fraction of patients.
Is repletion of glutathione likely to be the complete answer for treating CFS?
No. GSH depletion occurs near the beginning of the complex pathogenesis of CFS. There are likely to be many interactions and vicious circles as the pathogenesis develops into the pathophysiology, and there may also be damage that is difficult to correct. The mediators of such damage would likely be infections, toxins and reactive oxygen species, all of which are able to build up because of the depletion of GSH. It is likely that a multifaceted treatment protocol will be necessary.
There are also some cautions that should be exercised:
When GSH repletion is begun in patients who have been GSH-depleted for extended periods of time, their immune and detoxication systems can begin to function at higher levels of performance. If their bodies have accumulated elevated levels of toxins (especially mercury) and infections, glutathione repletion can cause significant Herxheimer-type reactions as pathogens are killed and toxins are mobilized. Care should be taken to proceed slowly and cautiously in such cases in order to avoid moving toxins into the central nervous system or exacerbating symptoms to a level that is intolerable to the patient.
Plasma cysteine level should be monitored periodically when repleting glutathione, to ensure that it does not rise to levels that could be neurotoxic [106].
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65. Krueger, G.R., Koch, B., Hoffmann, A., Roho, J., Brandt, M.E., Wang, G., and Buja, L.M., Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling, In Vivo (2001) 15(6):461-465.
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73. Vecchiet, J., Cipollone, F., Falasca, K., Mezzetti, A., Pizzigallo, E., Bucciarelli, T., De Laurentis, S., Affaitati, G., De Cesare, D., Giamberardino, M.A., Relationship between musculoskeletal symptoms and blood markers of oxidative stress in patients with chronic fatigue syndrome, Neuroscience Letters (2003) 335:151-154.
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82. Corsello, S., Review of the multiple factors (loading theory) in the pathogenesis of chronic fatigue syndrome: theoretical review and treatment, conference syllabus, Latest 21st Century Medical Advances in the Diagnosis and Treatment of Fibromyalgia, Chronic Fatigue Syndrome and Related Illnesses, Sept. 19-21, 2002, Los Angeles, CA, Advanced Medical Conferences International, Chicago (info@AdMedCon.com).
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86. Marcusson, J.A., The frequency of mercury intolerance in patients with chronic fatigue syndrome and healthy controls, Contact Dermatitis (1999) 41(1):60-61.
87. Yip, H.K., Li, D.K., and Yau, D.C., Int. Dent. J. (2003) 53(6):464-8.
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89. Ekholm, R., and Bjorkman, U., Glutathione peroxidase degrades intracellular hydrogen peroxide and thereby inhibits intracellular protein iodination in thyroid epithelium, Endocrinology (1997) 138:2871-2878.
90. Duthoit, C., Estienne, V., Giraud, A., Durand-Gorde, J.M., Rasmussen, A.K., Feldt-Rasmussen, U., Carayon, P., Ruf, J., Hydrogen peroxide-induced production of a 40 kDa immunoreactive thyroglobulin fragment in human thyroid cells: the onset of thyroid autoimmunity?, Biochem. J. (2001) 360(Pt 3):557-562.
91. Wikland, B., Lowhagen, T., and Sandberg, P.O., Fine-needle aspiration cytology of the thyroid in chronic fatigue, Lancet (2001) 357(9260):956-7.
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94. Jones, D.P., Coates, R.J., Flagg, E.W., Eley, J.W., Block, G., Greenberg, R.S., Gunter, E.W., and Jackson, B., Glutathione in foods listed in the National Cancer Institute's health habits and history food frequency questionnaire, Nutrition and Cancer (1992) 17:57-75.
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96. Clark, J. at www.cfsn.com is a proponent and supplier of this combination (for information only, not an endorsement).
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2.
February 21, 2006
Chronic Fatigue Syndrome and Autism
by
Richard A. Van Konynenburg, Ph.D.
(richvank@aol.com)
For the past ten years I have been studying chronic fatigue syndrome as an independent researcher. Over the course of several years I developed a hypothesis for the pathogenesis of this disorder that prominently featured the depletion of glutathione. I presented a poster paper on this hypothesis at the AACFS (now the International Association for Chronic Fatigue Syndrome) meeting in October, 2004, in Madison, Wisconsin. This paper can be found at the following url:
http://www.cfsresearch.org/cfs/research/treatment/15.htm
Anecdotal experience of people with CFS who acted upon my hypothesis suggested that while some were able to raise their glutathione levels by various means and experienced benefit from doing so, others were not able to do so. At the time I wrote my poster paper, I was aware of this, and I acknowledged in the conclusions of the paper that there appeared to be factors that were blocking the raising of glutathione in CFS. At that time, I was not sure specifically what they were. I also knew that there was evidence for a genetic predisposition in CFS, but I did not know the details of the genetic variations involved.
Shortly after that, I became aware of the work of S. Jill James et al. in autism (American Journal of Clinical Nutrition 2004 Dec; 80(6):1611-7). They found that glutathione was also depleted in autistic children, that this was associated with a partial block in the methylation cycle (also called the methionine cycle), that this partial block was associated with genetic variations in the genes for certain enzymes and other proteins associated with the sulfur metabolism, and that it interfered with the synthesis of glutathione. They also found that by using certain supplements (methylcobalamin, folinic acid and trimethylglycine) they could lift the block in the methylation cycle and restore the glutathione level.
Upon learning of this work, I became very interested in possible parallels between chronic fatigue syndrome and autism. I attended the conference of the Defeat Autism Now! (DAN!) project in Long Beach, California in October, 2005, sponsored by the Autism Research Institute, headed by Dr. Bernard Rimland. As a result I became convinced that the genetic predisposition found in autism must be the same or similar to that in a major subset of chronic fatigue syndrome, and that the resulting biochemical abnormalities were also the same or similar. As far as I know, the genetic variations in people with chronic fatigue syndrome have not yet been studied in detail or published, but I am optimistic that this will occur soon, because of the rapid advances in the technology for doing so, and because of the current active interest of at least three groups in the U.S. and the U.K. in genomic aspects of CFS.
There are obviously major differences between chronic fatigue syndrome and autism. I believe that these result primarily from the different ages of onset. Autistic children experience onset early in life, before their brains are fully developed. I believe that this gives rise to the very different brain-related symptoms seen in autistic children from those seen in adults with CFS. However, there are many similarities in the biochemistry and symptoms of these two disorders as well, including oxidative stress, buildup of toxins, immune response shift to Th2, and gut problems, for examples.
The triggering factors for autism and chronic fatigue syndrome are also largely different. Although this subject remains controversial, there appears to be substantial evidence that vaccinations (containing either a mercury-based preservative or live viruses, many given within a short period of time) were responsible for triggering many of the cases of autism in genetically-susceptible children (D. Geier and M.R. Geier, International Journal of Toxicology 2004 Nov-Dec; 23(6):369-76; and A.J. Wakefield, several publications beginning in 1997).
In CFS, a variety of triggering factors (physical, chemical, biological, or psychological/emotional) have been found to be involved in various cases, as reviewed in my poster paper, cited above. All these factors have in common that they place a demand on glutathione.
It appears that genetically susceptible persons are unable to maintain normal glutathione levels when the total demand for it is high, and that once glutathione drops sufficiently in a genetically susceptible person, the sulfur metabolism becomes disrupted. In many cases the methylation cycle (part of the sulfur metabolism) becomes partially blocked, and the result can be a depletion of some or all of several important sulfur-containing metabolites, including S-adenosylmethionine (SAMe), cysteine, glutathione, taurine and sulfate. A vicious circle is thus formed, and the depletion in these metabolites causes an avalanche of pathogenesis, since they all have very important functions in the body. I think that much of this pathogenesis is common between autism and CFS. In autism, the loss of methylation capacity because of the drop in SAMe appears to be responsible for much of the interference with normal brain development.
There is also a major difference in the sex ratio between autism and
CFS. In the book mentioned below, Dr. Jon Pangborn discusses possible
reasons why autism is more prevalent in boys. In my poster paper, cited
above, I suggested a hypothesis to explain the female dominance in the
prevalence of CFS in adults.
I think that the reason why the people who have developed CFS as adults did not develop autism as children (even though I suspect that they have the same or a similar genetic predisposition) is that when they were children, not as many vaccinations were required. The schedule of vaccinations required for children in the U.S. has grown substantially over the past two or three decades, as has the incidence of autism. This is also true in the U.K.
Shortly after attending the DAN! conference, I also learned of the work of Dr. Amy Yasko, primarily in autism, but extending to a number of other disorders as well. Working independently of the DAN! project, Dr. Yasko develops her treatment recommendations by analyzing the specific gene variations in each patient. In addition to studying effects on the methylation cycle, Dr. Yasko has gone on to consider the effects on associated biochemistry, including folate metabolism, biopterin, the urea cycle and the synthesis of neurotransmitters.
My main message is that a great deal has already been worked out in autism by the researchers and clinicians associated with the Defeat Autism Now! project, and also by Dr. Yasko, and that I believe that the CFS community would benefit greatly by looking carefully at what they have already done. The doctors associated with the DAN! project treat autism by the use of nutritional supplements that compensate for genetic mutations in the sulfur metabolism. These include such supplements as magnesium sulfate, taurine, molybdenum, vitamin B6 and its active form P5P, magnesium, methylcobalamin, folinic acid, trimethylglycine, and dimethylglycine. They also use certain diets, and they perform chelation treatments to remove heavy metals. The results in many autistic children have been astounding, as can be seen in the webcast cited below, where several are interviewed.
Dr. Yasko, in cooperation with Dr. Garry Gordon, uses many of the same supplements as are used by the DAN! project doctors as well as some additional ones, including RNA supplements, and she is also reporting great success.
So I want to encourage everyone who has an interest in CFS to look at the results of the DAN! project and of Dr. Amy Yasko in autism.
To view videos of the talks given at the latest two DAN! conferences on the internet at no cost (unless you are paying for the internet time!), go to this site:
http://www.danwebcast.com
You can choose the more recent Long Beach conference or the earlier Boston conference. They cover much of the same material, but both are worthwhile to watch. If you want to see and hear a good explanation of the methylation cycle research, go to the Boston meeting first, so you will be able to view the talk by Jill James, who did not attend the Long Beach meeting.
After selecting one of the conferences, go to the lower left and register. This is free. They will email a password to you right away, and then you can choose a talk to watch.
Beyond this, I also want to recommend a book entitled Autism: Effective Biomedical Treatments. This is a new book (Sept. 2005). It is by Jon Pangborn, Ph.D. and Sydney Baker, M.D., a biochemist and an autism clinician, respectively. It is available on Amazon for people within the U.S. For people outside the U.S., it can be obtained from the following website by means of PayPal:
http://www.autismresearchinstitute.com
The cost for the book is $30 U.S.
This is an excellent book. It is a reference book, full of good information and good science, explained clearly. This book deals very practically with developing a treatment program for an individual child. I think that most of it will turn out to apply directly to adults with CFS as well.
In addition, I want to recommend the book by Amy Yasko entitled Genetic ByPass. It is available from the website
http://www.longevityplus-rna.com/store/product.php?productid=49
as part of the "Nutrigenomics Educational Starter Packet." The price is $49.95. This is also an excellent book. It discusses treatments specifically tailored to the particular combinations of genetic variations found in different patients.
I think these two books complement each other. I would recommend reading the Pangborn and Baker book first, as it provides a good basis for understanding the technical aspects of the genetics found in the Yasko book.
Although I have been suggesting consideration of the DAN! treatments and the Yasko testing to people with CFS for only a short time, and it is too soon to draw conclusions, early feedback is very encouraging. While I am going out on a limb to some extent in announcing this now, I don't want to wait any longer, because I think this could help a lot of people. Of course, we should all keep in mind that with the current case definition of CFS we have a very heterogeneous population, and the autism treatments will very likely not help everyone who has CFS, but I am convinced that they will help a substantial subset. So I want to encourage those who have CFS and those who treat it to look into this in the strongest way I can. It could be the answer for many of you.
[Disclaimer: I have no financial interest in anything recommended in this article.]