Rich Van Konynenburg, Ph.D.
Neil Nathan, M.D.
Gordon Medical Associates
Santa Rosa, CA
Yasko Protocol Conference – Boston
July 30-August 1, 2010
1. People undergoing treatment for chronic fatigue syndrome as discussed in this talk must be under the care of a licensed physician.
2. Some of what will be discussed in this talk is hypothesis—unproven theory. I will try to distinguish between what is hypothesis and what is well established and considered to be scientifically true at this time.
3. The authors have no financial interest in the tests or supplements discussed in this paper.
The Bottom Line
• A hypothesis has been developed to explain chronic fatigue syndrome (CFS).
• Key features: a chronic partial block of the methylation cycle, significant draining of folate from the cells, and a chronic depletion of glutathione.
• Explains: genetic predisposition, biochemical abnormalities, and many seemingly unconnected symptoms of CFS.
• Tested in a clinical study using a simplified treatment extracted from the full treatment program of Dr. Amy Yasko, and results are found to be consistent with the hypothesis.
• Lab testing is available to determine whether the hypothesis applies to a particular patient. So far it appears to apply to most CFS patients.
• This simplified Yasko treatment is currently producing significant benefits in most patients who use it, and it has resulted in apparently complete recovery in a small number of patients.
Topics to be covered in this talk
• What is chronic fatigue syndrome (CFS) ?
• What is the history of CFS ?
• Who has CFS ?
• What is glutathione, and what does it do ?
• What is the methylation cycle, and what does it do ?
• What is the Glutathione Depletion—Methylation Cycle Block hypothesis for CFS ?
• Why doesn’t everyone get CFS ?
• Why do more women than men get CFS ?
• How does the GD-MCB hypothesis account for the features of CFS ?
• Why and how has the Yasko protocol been applied to treating CFS ?
• What clinical testing has been done and what were the results ?
• What testing is available to find out if the GD-MBC hypothesis applies to a given case of CFS ?
What is chronic fatigue syndrome?
• Defined in terms of a set of symptoms, and diagnosed when other possible causes for them have been ruled out.
• Symptoms: Severe chronic lack of energy, post-exertional exhaustion, difficulties in thinking and memory, pain especially in the muscles, sleep problems, immune system problems, endocrine problems, and many, many more.
• Case definitions: Fukuda et al.(1994): CDC-sponsored international research definition, Carruthers et al.(2003): Canadian consensus diagnostic definition
• Many people are unhappy with the name or with the definitions, or both. They believe that the name trivializes a very serious illness, and that the definitions in terms of symptoms are not specific enough. There is no diagnostic biomarker, and the cause (or causes) are not known/agreed upon. The definitions produce a heterogeneous population.
• How is fibromyalgia related to CFS? – The original diagnostic definition for fibromyalgia from the American College of Rheumatology focused on pain and pain sensitivity. Many people satisfied the definitions for both CFS and fibromyalgia, but others did not. The proposed new definition moves fibromyalgia closer to overlapping with CFS. The cause of fibromyalgia is likewise not known.
• Is it the same disorder as myalgic encephalomyelitis (M.E.), which originated in the UK? There is disgreement about this.
• Does CFS have a sudden or a gradual onset? There are some cases of each.
• Does CFS occur in epidemics or clusters, or does it occur sporadically ? Some of each.
• What’s the severity of CFS ? – Some people with CFS are able to continue working full time, some carry on a few normal activities, some are housebound, some are bedridden, and a few even die from it, though the cause of death may be assigned to something more immediate. Most people who develop CFS are chronically ill for many years
What is the history of CFS?
• First defined in the U.S. by the CDC in 1989, after clusters of cases appeared at a few locations, the best-known being near Incline Village on Lake Tahoe in Nevada.
• CFS had probably existed for much longer, but under different names.
• It seems that the prevalence has been much higher starting in the 1980s, but this is difficult to prove.
• Cause or causes have not been found (or agreed upon). The most recent suspect is the XMRV retrovirus.
Who has chronic fatigue syndrome?
• A million or more people in the U.S., and several million more worldwide.
• More women than men.
• Some children, but mostly adults.
• Minorities have higher prevalences than the non-minority population.
• Only about 15% of those in the U.S. who have CFS are believed to have been diagnosed.
Glutathione—What is it and what does it do?
• A tripeptide, composed of glutamate, cysteine and glycine
• Found in all cells, blood, bile and epithelial lining fluid of the lung
• Synthesized by cells, particularly liver and red blood cells
• The most abundant thiol (sulfhydryl)-containing substance in cells
• Has reduced and oxidized forms, GSH and GSSG
• Ratio of GSH to GSSG controls the redox potential in cells
• Serves as basis for the antioxidant system, quenching reactive oxygen species
• Conjugates several classes of toxins for removal from the body in Phase II detox, and quenches free radicals generated in Phase I detox in general
• Supports immune system, especially cell-mediated immunity
• Plays important role in synthesis of proteins that contain cysteine
• Participates in bile production
• Protects vitamin B12 inside the cells
What does the methylation cycle do?
• Supplies methyl (CH3) groups for a large number of biochemical reactions in the body.
• Controls the overall sulfur metabolism, balancing the needs for methyl groups, for GSH to control oxidative stress, and for other sulfur metabolites, including cysteine, taurine and sulfate.
• Coordinates the production of new DNA with the supply of methyl groups, which are used to methylate DNA, among many other roles.
What causes most cases CFS, according to this hypothesis ?
Genetic predisposition together with : Stressors
(Some combination of a variety of physical, chemical, biological and or psychological/emotional stressors, the particular combination differing from one case to another).
This combination initially raises cortisol and epinephrine, and it depletes intracellular reduced glutathione (GSH).
Pathogenesis (disease development) of most cases of CFS, according to this hypothesis
1. Stressors deplete glutathione (GSH), which produces oxidative stress, allows toxins to accumulate, and removes protection from vitamin B12.
2. Oxidative stress partially blocks methionine synthase in the methylation cycle.
3. Accumulated toxins (probably especially mercury) react with much of the vitamin B12.µ
4. The partial block of methionine synthase (MTR) becomes chronic, and the sulfur metabolism therefore becomes dysregulated
5. Sulfur metabolites drain down the transsulfuration pathway and are eventually excreted, depleting methionine.
6. Intracellular cysteine levels become too low to restore glutathione levels to normal.
7. Glutathione depletion and the partial block in methionine synthase form a vicious circle, and this vicious circle becomes chronic, producing CFS.
8. The symptoms of CFS result from this vicious circle.
Why doesn’t everyone get CFS?
• A major reason is likely to be differences in the combinations of inherited genetic polymorphisms.
• There has not yet been a complete genome study of the polymorphisms that are more frequent in CFS than in the general population.
• However, there is evidence from family and twin studies as well as from limited polymorphism studies that there is a genetic component in the development of CFS.
What are some things that might be expected if glutathione were depleted, and are they observed in CFS?
• Oxidative stress—observed.
• Mitochondrial dysfunction and low ATP output, leading, for examples, to physical fatigue in skeletal muscles—observed; and diastolic dysfunction in the heart, leading to low cardiac output—observed.
• Buildup of toxins, including heavy metals—observed.
• Immune response shift to Th2—observed.
• Inability of T cells to proliferate in response to mitogens—observed.
• Reactivation of herpes family viral infections—observed.
• Thyroid problems—observed.
• Low secretion and dysregulation of certain cysteine-containing secretory proteins, including ACTH, antidiuretic hormone, and perforin.
Low ACTH leads to blunting of the HPA axis—observed, low antidiuretic hormone leads to high daily urine volumes and constant thirst—observed, and low perforin leads to low cytotoxic activity of the natural killer cells and the CD8 (“killer”) T cells—observed.
What are some things that might be expected if the methylation capacity were diminished, and are they observed in CFS?
• Overexpression of many genes because of lack of gene silencing by methylation—observed.
• Lowered synthesis of choline and creatine—abnormal ratio of choline to creatine observed in brain.
• Lowered synthesis of carnitine—deficit observed.
• Lowered synthesis of coenzyme Q-10—supplementation observed to be beneficial.
• Lowered synthesis of three component of myelin—slow brain processing speed observed.
How does this hypothesis account for the higher prevalence of CFS in women than in men?
• During their potentially reproductive years, estrogens are produced in larger amounts in women, and must be metabolized.
• Some people (both men and women) inherit polymorphisms in the genes that code for some of the detox enzymes involved in the metabolism of the estrogens (CYP1B1, COMT and GST enzymes).
• In women, these polymorphisms can lead to redox cycling when metabolizing estrogens. This adds an additional bias toward depletion of glutathione and development of oxidative stress.
• Oxidative stress initiates the pathogenesis of CFS.
Why was the Yasko protocol applied to CFS?
• CFS involves glutathione depletion, as was found in autism, and it appeared that this depletion could not be corrected by direct boosting of glutathione.
• It seemed that there was a good chance that CFS also involved a partial block in the methylation cycle, as was found in autism.
• If so, treatments that were effective for treating the methylation cycle issues in autism might also be effective for CFS.
• The Yasko protocol was directed toward treating the methylation cycle and was being successfully applied to autism.
How was the Yasko protocol applied to CFS?
• Two ways: the complete treatment protocol was tried initially and is still used by some patients, and a “simplified treatment approach” was introduced later.
• What is the simplified treatment approach?
Five supplements extracted from Step 2 of the complete Yasko treatment protocol: Perque Activated B12 Guard (hydroxocobalamin), FolaPro (5-methyl tetrahydrofolate), Intrinsi B12/folate: (Combination of [folic acid, 5-methyl tetrahydrofolate, and folinic acid], cyanocobalamin, calcium, phosphorus, and intrinsic factor), phosphatidyl serine complex, and General Vitamin Neurological Health Formula. [Note that Intrinsi/B12/folate has since been replaced by Actifolate.]
• Why was this simplified approach used? To decrease the cost and the complexity, which are problems for many CFS patients, who are unable to work, and have cognitive problems as a result of this disorder. Many were not able to use the full treatment protocol.
• Were there disadvantages to simplifying the treatment? Yes, it was a compromise.
Who influenced the history of applying the Yasko protocol to the treatment of CFS?
• Paul Cheney, M.D., Patricia Salvato, M.D., Derek Enlander, M.D.
• Michael Goldberg, M.D., Prof. Malcolm Hooper
• Bernard Rimland, Ph.D.
• S. Jill James, Ph.D.
• Prof. Richard Deth
• S.R. (patient)
• Amy Yasko, Ph.D., N.D.
• S.T. (patient)
• David Bell, M.D.
• K.T. (patient)
• L.D. (patient)
• Tapan Audhya, Ph.D.
• Ratna Ling Working Group
• Neil Nathan, M.D.