Re: How does the vicious circle form?

November 6, 2006

Rich,

In my case I am faced with the probability of some other vicious

circle mechanism besides mercury becasue one of my daughters has CFS

nearly identical to my own case, and she has had little or no mercury

exposure. She has never had a mercury filling, and did not start to

contract CFS until she was about 18 years old, a long time after any

Thimerisol vaccinations. And we eat very little fish, and have no

other known mercury exposure. I do have amalgams, but she does not.

I had CFS for about 6 years prior to her contracting CFS, so it was

not an acute type of contagion, or if it was, it was very slow. And

we both have classic cases, fit all criterion.

Here is what my daughter and I do share. Some genetics of course.

And we both have Lyme and both have mycoplasma titers. But I have

other family members positive for Lyme who are asymptomatic or have

only mild symptoms. The entire family (8 people) has the mycoplasma

titers, and only the two of us are sick, although my wife has a light

case of MCS.

I believe that some other factor is depleting the GSH, along with the

Cortisol and other similar hormones. I suspect we must consider ALL

of the genetic issues being uncovered as a composite whole. Systemic

thinking. After all, PWC have a pattern of SNPs related to several

very different biochemical processes, not just those related to GSH.

So what happens when we combine them all in our model of the

pathology? RnasL, Hypercoag, HLA-DR, the 16 WBC SNPs, the CDC

findings, etc. That might provide insights into additional vicious

cycle mechanisms involved in the CFS stalemate.

Additionally, I beleive there are some structural neurological

patterns in the brain involved in CFS, and probably the genes behind

those patterns are unexplored. I suspect the structural genetics

because of the findings related to brain structure abnormalities in

CFS, and also due to my observation that my daughter with CFS has a

similar personality and 'brain type' to myself and many other PWC.

(speaking of brain type in the sense used by www.braintypes.com, which

is postulated to include structural variations).

--Kurt

>

> Hi, all.

>

> I realize that I have not responded to quite a few posts, both on

> and off the list, that have been directed to me in the past few

> weeks, and I'm sorry about that. We've gotten through quite a bit

> of family and household related things around here, but now I'm

> facing the possible prospect of having to put together one or two

> papers for the IACFS conference coming up in January. I still

> haven't heard from the committee as to whether my abstracts have

> been accepted, and I can't wait or I will run out of time to work on

> the papers. So now I'm trying to put together a coherent story on

> the chance that they give me the go-ahead to present my glutathione

> depletion--methylation cycle block hypothesis for the pathogenesis

> of CFS.

>

> In connection with that, I have a new idea I'm kicking around and

> wonder if any of you have any thoughts on it.

>

> As most of you will no doubt recall, for a long time I focused on

> glutathione depletion as a major factor in the pathogenesis of CFS

> for at least a substantial subset of PWCs.

>

> You will also probably recall that for several years I encouraged

> PWCs to try to build their glutathione by various methods, such as

> ingesting nondenatured whey proteins or putting glutathione per se

> into the body by various routes.

>

> And as you will probably also recall, this worked for a few PWCs,

> but for many others, it didn't work, either because they could not

> tolerate these treatments or because, while they helped temporarily

> in quite a few cases, the effects were not permanent if the

> treatment was stopped.

>

> So over the course of time I began to suspect that there was one or

> more vicious circle mechanism blocking the restoration of normal

> levels of glutathione. That's where I was at the time of the last

> AACFS conference in Oct. 2004, when I presented my glutathione

> poster paper.

>

> When I became aware of the work of S. Jill and coworkers in

> autism in early 2005, it dawned on me that one possibility for a

> vicious circle mechanism in CFS might be the one apparently observed

> to be active in many cases of autism, i.e. that glutathione

> depletion was associated with a block earlier in the sulfur

> metabolism, namely in the methylation cycle. I began to pursue the

> parallels between CFS and autism, and learned that there are

> actually quite a few, so this seemed promising.

>

> Initially, I encouraged PWCs to try the three treatments that had

> been found to restore the glutathione level and the methylation

> cycle in the study, namely methylcobalamin, folinic acid and

> trimethylglycine (aka betaine). This didn't work out too well for

> those who tried it, so it appeared that the situation was somewhat

> more complex. After learning from the work of the DAN! project in

> autism, I went on to study Dr. Amy Yasko's treatment approach

> (sorry, Ken, I won't dwell on this too long, but it's important as

> background here). Dr. Yasko's approach seemed to be able to account

> for differences between PWCs based on their individual genetic

> makeup, so this made more sense to me. Also, her approach was more

> ordered in terms of the sequence of doing things, and it also seemed

> more gentle in terms of using smaller amounts of a larger number of

> treatments. So I encouraged PWCs to try Dr. Yasko's approach, and

> quite a few are doing so now, I think at least twenty. I think we

> are seeing that the genetic variations found in CFS are similar to

> those found in autism, and I think we now also understand why

> different PWCs responded differently to the glutathione-building

> efforts, and why hitting PWCs with treatments directed at the

> methylation cycle right away did not work out well, in the light of

> Dr. Yasko's work. I think it will still be a while before we can

> give a very confident evaluation of this treatment for CFS, but I

> continue to be optimistic, based on the few comments that people

> have made so far about their experiences with it.

>

> O.K., now back to the vicious circle mechanism. How does that

> work? The hypothesis as it currently stands is that a load of some

> combination of long term physical, chemical, biological, and/or

> psychological/emotional stressors (differrnt combinations for

> different PWCs, some not involving psychological/emotional stress,

> but others definitely involving it) raises cortisol and epinephrine

> levels, and lowers glutathione levels. When glutathione becomes

> depleted, it impacts the methylation cycle in a couple of ways. One

> is that low glutathione causes the redox conditions to become more

> oxidizing inside the cells, since glutathione is responsible for

> maintaining the usual reducing conditions there. Some of the

> enzymes in the methylation cycle are redox-sensitive, because they

> have cysteine residues, and these have sulfur atoms that can either

> be in the sulfhydryl (reduced) state, or in the disulfide (oxidized)

> state. If they become oxidized, the activity of the enzyme is

> diminished. There is a 10-year-old paper in the literature that

> demonstrates that when glutathione is forced down, methylation

> suffers, so this is pretty well established.

>

> Another way in which glutathione depletion could suppress the

> methylation cycle is by interfering with the conversion of other

> forms of B12 to methylcobalamin, which is the form needed by

> methionine synthase to convert homocysteine to methionine.

> Glutathione is needed to make these conversions.

>

> So I think I can explain why the methylation cycle gets suppressed

> if glutathione goes low. And if the methylation cycle is

> suppressed, the production of cysteine from methionine will slow

> down. Cysteine is normally the rate-limiting amino acid for

> synthesizing glutathione, so now we have the makings of a vicious

> circle.

>

> O.K., that's all history. Now I'm finally getting to the issue at

> hand. When I was in Boston for the Yasko conference in early

> October, I was able to get together for coffee with a couple of

> longstanding CFS internet friends, Lillian Greeley and Sheila

> Statlender. After I explained the above to them, Sheila posed a

> question to me, which was, " O.K., how come you can't break the

> vicious circle just by raising glutathione with supplements? " or

> something to that effect. I told her that some people seemed to be

> able to do that, but most could not, and I didn't know why.

>

> Well, this question has continued to bug me since then. But

> yesterday I think I might have come up with an answer to it, and

> that's what I want to bounce off you. Here's what I suggest: We

> know that one of the jobs that glutathione normally has is to bind

> to toxic heavy metals, such as mercury, and escort them out of the

> body. When glutathione becomes depleted, this is one of the jobs

> that does not get done, and if there is ongoing exposure to heavy

> metals, the body burdens of these metals will rise. It's known in

> chemistry that mercury binds preferentially to sulfur atoms, because

> of the strength of their bond. Sulfur is present in enzymes in the

> methylation cycle. It seems reasonable to believe that as the

> amount of mercury in the body rises, some of it could bind to these

> enzymes. Prof. Deth has shown that the enzyme methionine

> synthase is particularly sensitive to very small concentrations of

> mercury, and that mercury inhibits its operation. So I suggest that

> this is the mousetrap that prevents setting things right for most

> PWCs simply by raising glutathione. The lowering of glutathione thus

> does two things here: it inhibits the activity of enzymes in the

> methylation cycle by allowing the redox to become more oxidizing,

> and then over time it allows mercury to build up, and that compounds

> this inhibition in a more irreversible manner. You may recall that

> there is published work showing that adding supplementary

> glutathione does not very effectively remove mercury that is already

> bound to enzymes in the body.

>

> So I suggest that that is why one has to give direct support to the

> methylation cycle enzymes in order to break the vicious circle, get

> the methylation cycle operating normally again, and restore the

> levels of glutathione on a permanent basis.

>

> There are still some aspects I haven't figured out about this.

> Like, how does the direct support to these enzymes (in the form of

> various forms of folate and cobalamin or B12) get them operating

> again, when they still have mercury bound to them? Maybe it's a

> matter of the cells making new copies of them, and working with

> those, and the others are eventually disassembled and recycled. I'm

> not sure. But anyway, I think this mercury binding concept may

> answer the question that Sheila posed.

>

> If anybody has any thoughts about this, I would be interested.

>

> Rich

>

November 6, 2006

I don't know why... but your question reminds me of a comment someone else on

this list made.

They were paraphrasing Jill St. and the comment was to the efffect that

viruses have some affinity for mercury. Get rid of the viruses and you would get

rid of the mercury...

So I'm wondering if viruses mess with the methylation cycle by means other

than glutathione depletion.. and the chain reaction you have outlined here.

I have no idea if this makes any sense. Just thought I would throw it out

there ...

In any event, I am very glad you reprised your thoughts here because I am one

of those people who seem to be doing well at raising glutathione directly, and

now I will add in support for the methylation cycle.

Question: (for Rich, or those who have been on the list longer than I ), what

tests can one do if one is doing this glutathione/ methylation cycle approach?

Is it sufficient to track intracellular glutathione and are there ways to

measure the performance of the methylation process?

thanks

Louella

---------------------------------

Sponsored Link

Get an Online or Campus degree - Associate's, Bachelor's, or Master's - in less

than one year.

November 6, 2006

Hi Rich,

I have long suspected that mercury is a big player in my illness. It

just seemed that whenever I would have major work done on my teeth, my

health would worsen. I probably had more amalgam put in and taken out

of my mouth, over and over again, than any person on the planet.

I have no idea when I was bitten and developed Lyme and Babesia.

According to LaVoie (sp?), who was one of the earliest MDs to be

involved in Lyme treatment, a person can be infected many years before

symptoms surface. Dr LaVoie unfortunately passed away in 1993.

So, I'm not really clear on what your question is, but in my own case,

mercury is certainly suspect. I also have many SNPs, according to the

Yasko testing.

Thanks for all you are doing to unravel the puzzle that is CFIDS.

Best,

Michele G