To Kurt re: Oxidative Stress and the GD--MCB hypothesis
Hi Rich,
I have some questions for you.
***Hi, Kurt.
***Sorry to be so slow getting back to you. Ive just been swamped with emails, and am pretty far behind in trying to answer them all.
Clearly oxidative stress is an important part of the CFS pathology. But would reducing oxidative stress alone resolve enough of the disease to extend life? What about the other co-morbid CFS pathologies? Shouldn't those also be treated, particularly those that make a major contribution to the oxidative stress, such as the many documented co-infections, as well as HPA malfunction, environmental toxins, even life stress and anxiety, all of which can deplete GSH.
***If the partial methylation cycle block is lifted and glutathione is thus allowed to come back up to normal, some of these issues will automatically be taken care of, according to my hypothesis, and according to some of the clinical evidence so far. Both the immune system and the detox system begin operating more normally when the partial methylation cycle block and glutathione are normalized, and they are able to take care of some of the infections and toxins. However, it appears that they may need some help when certain infections or too large a body burden of toxins are present. For examples, mold illness and Lyme disease appear to need to be treated specifically, because both can hold down glutathione. Too high levels of heavy metal toxins can block the enzymes in the methylation cycle and related pathways, so that they cannot recover without special detox efforts. If KPU is present, there will need to be supplementation of things like B6 and zinc, which are needed as cofactors, but are depleted in KPU. And yes, if the person continues under high stress, that can also impede recovery, because the elevated epinephrine can auto-oxidize to adrenochrome, and that can deplete glutathione. According to my hypothesis, the HPA axis will normalize when glutathione comes up to normal, and one person has reported this.
Next, have you considered ALL of the genetic problems found in PWC, which include stress and hormone management system deletions, immune system problems (RNasL and probably others), as well as problems in the mitochondrial system, the WBCs, along with the methylation and detox system problems? I would think a full protocol should address all these factors.
***The entire genome has not been studied to measure frequencies of all the possible polymorphisms in CFS. However, it isnt clear that this needs to be done in order to have effective treatment. In our clinical study on 30 women, which can be read about here:
http://aboutmecfs.org/Trt/TrtMethylStudy09.pdf
we ignored genomics and treated them all the same, using the Simplified Treatment Approach. At least two-thirds of them showed improvement, and on the average, the improvement was statistically significant for the entire group. We found that having the main CBS polymorphism did make a difference in how fast they recovered, but even those who were homozygous for this SNP showed improvement over the 6-month period.
I do find this idea fascinating that MB-GD contributes to premature aging. The idea that we are in some type of accelerated aging process makes some sense. Although it is a strange type of aging, almost like aging stops and at the same time we deteriorate. I can pass for 10-20 years younger than my age, so some aging process is actually not working, and I know other PWC like this (there has been a thread on this topic), but inside I feel 90 years old.
***Yes, that is strange. I wonder if lower exposure to the sun can be involved, at least in some cases. Sun exposure does take its toll on the skin, and on how old a person appears to be. But there is probably more to it than that.
Next question, aside from methylation/glutathione support, do you think we should we could benefit from standard life extension therapies as CFS treatments? Such as Gary Gordon's protocols? I am thinking in particular of his daily use of EDTA, among other things.
***I think EDTA can certainly help to take out some of the toxic metals. Its part of Amy Yaskos protocol for detoxing aluminum, for example. I guess I would suggest that fixing the partial methylation cycle block and raising glutathione are the initial things that should be done. After these are restored, other things could certainly be considered. But they are so foundational to the overall metabolism that normalizing them needs to have high priority, I think. I can link essentially all the features of CFS to these basic metabolic abnormalities by specific and detailed biochemical mechanisms.
A 'systems biology' perspective, which I think is the most rational medical paradigm for CFS, suggests that we look at relationships between co-morbid pathologies.
***I agree. And some of the cases Ive studied have some very unusual comorbidities. They do have the symptoms of CFS, but other things have led to it, or have developed later because of immune dysfunction or detox dysfunction, for example. Just to give a partial list of things that have come up as comorbidities in cases Ive consulted on, here are some things I have found: PANDAS in an adult, the Lorenzos oil disease, Wilsons disease, cyanide toxicity, autonomous multinodular goiter, a variety of autoimmune diseases, mold illness, Lyme disease and its coinfections, a very tenacious fungal infection in one of the sinuses, genetic abnormality in vitamin B2 utilization, major exposures to toxins, traumatic brain injury, traumatic spinal injury, vitiligo, drug reactions, congenital heart disease, major diabetes insipidus, major gut problems involving serious malabsorption, and alcoholic liver disease.
Methylation blocks are the ultimate systems failure, affecting so many processes. I know you have a lot of expertise there. So a question, isn't this always only a partial block? Because I assume if methylation were really blocked we would be dead. So would not 'sluggish methylation' or 'poor methylation' be more appropriate terminology?
***Thats right. We couldnt live with zero methylation capacity or zero glutathione. These things are vital. I try to remember to write and say partial methylation cycle block, but I dont always remember. If I were naming the hypothesis today, I would include partial in it, but the cat is already out of the bag at this point.
Also, glutathione depletion would seem to have many causes, more co-factors than poor methylation alone.
***Thats right. You may not have understood the first part of my hypothesis. In the hypothesis, the initial causes of the glutathione depletion can be a wide variety of physical, chemical, biological and psychological/emotional stressors, the combination being different for each case. But when glutathione goes low enough in a person with the predisposing genomics, a partial block occurs in the methylation cycle because B12 loses its protection by glutathione. The partial block in the methylation cycle then"locks" in the glutathione depletion by a vicious circle mechanism, and CFS becomes chronic. So the partial methylation cycle block is usually not the first cause of the glutathione depletion, but it stabilizes it and prevents glutathione from coming back up.
I guess what I am saying is that your theory does make sense here, considering the early mortality of PWC who succomb to cancer and heart disease, but I would like to see that placed in the larger context of the entire CFS pathology. And I want to know how to integrate your approach with everything else we know about CFS now, how to construct a 'systems biology' approach to CFS treatment.
***Well, I actually did that three years ago. I invite you to take a close look at my 2007 IACFS poster paper, which can be found on Corts website:
http://aboutmecfs.org/Rsrch/GSHMethylation.aspx
***Thanks for your interest.
***Best regards,
***Rich
-)
