CFS/ME Once Again Confirmed As A Metabolic Disorder

[haidut]

I posted previously about recent research indicating that CFS/ME is likely due to hypometabolism caused by environmental stress.
CFS Is Likely Hypometabolism Triggered By Environmental Stress
The earlier studies found lower activity of the enzyme PDH, which is the rate-limiting step for entrance of energetic substrate into the Krebs (citric acid) cycle.
The Ability To Metabolize Glucose Is Impaired In CFS/ME Patients

This newer study found lower levels of Krebs cycle metabolites, which is consistent with the results of the first study - i.e. lower activity of PDH means less pyruvate gets converted in AcetylCoA and enters the Krebs cycle. Ultimately, this results in lower ATP levels and possibly increased levels of lactic acid - i.e. basically the cancer/diabetes metabolism. The study found that simply increasing ATP levels restored proper functioning of cells from patients with CFS/ME. Other interventions should also work include inosine (as an alternative precursor to ATP), thiamine, biotin, niacinamide, and of course thyroid. In addition, pregnenolone may also help as it was found to regulate a crucial receptor (TRPM3) involved in CFS/ME.
Pregnenolone As A Possible Treatment Of CFS/ME
Another important finding of the study is that the metabolic dysfunction in CFS/ME is likely not due to genetic causes as some recent news articles in JAMA tried to claim.

Stanford team announces update on ME/CFS research
"...The team’s metabolomics tests on severely-ill patients revealed problems with the citric acid cycle. Participants’ blood work showed that some of the chemicals involved in the citric acid cycle are very low, making it difficult for the patient to generate the chemicals we use for energy. Several chemicals were found to be two standard deviations away from those of healthy controls, which is serious, according to Davis. The problems found in the citric acid cycle of ME/CFS patients does not look like the result of a typical genetic defect in the mitochondrial metabolism, Davis noted. Recent research by Fluge and Mella has also suggested that pyruvate dehydrogenase, the enzyme that helps glycolysis transition into the citric acid cycle, may be blocked."

"...Davis said that the next step is to use the device to test the effects of various drugs on the cells and serum of ME/CFS patients. For example, Davis’ team found that adding ATP to unhealthy ME/CFS cells and serum made the cells respond normally. The team also plans to test drugs that many ME/CFS patients have reported helpful using this device, such as Valcyte and Rituximab."


Finally, a a bit of side but important note. As the article says, government funding agencies (like NIH) are apparently NOT interested in funding new hypothesis discovered independently. NIH is only interested in handing over hypothesis the NIH considers worthy and then directing the grant recipients to perform research on those "convenient" hypothesis. How can we have innovation and discoveries that cure a disease if a new hypothesis never gets funded!?
"...Davis and his team applied for federal funding from the National Institute of Health (NIH) for the research that led to the data showing the dysfunctional citric acid cycle in people with ME/CFS. The NIH turned down both of his grants “because we were trying to do discovery, and they wanted us to only do hypothesis testing,” Davis said. “I said to them: the scientific method is first observation, then hypothesis. And if you have virtually no observations you can’t generate a good hypothesis. I think one of the big problems we have is that we do not know enough at the molecular level to generate hypotheses.”

 

[SB4]

Here's how I understand it so far. There is chronic oxidative stress from virus / bacteria / other factors. This chronic oxidation causes cells to inhibit glucose oxidation (PDH-- PDK++ Pyruvate kinase--) in favor of producing reducing agents (NADPH Glutathione). The reducing agents aren't enough however so oxidation still occurs.

This oxidation leads to methaemoglobin being produced from Fe^2+ being oxidised to Fe^3+. This means blood carries less O2, is a darker color, and the heart needs to work harder to oxygenate tissues. The decreased O2 leads to bigger and quicker breathes blowing out CO2. Furthermore the platelets are also overwhelmed with peroxynitrite causing mitochondrial to be shut down, reduced ATP, increased Lactate. These sick platelets generate less electric and magnetic charges/field and so clump together, leading to poor blood flow, and decreased CO2. This causes tachycardia and heart pounding. The decrease of CO2, increase of lactate, decrease of O2, and oxidative stress lead to increased cortisol, adrenaline, estrogen (?), and in general stress hormones, with a reduction in thyroid (?).

Now the muscle, brain, gut, liver, etc cells of the body are being supplied with less O2, less CO2, more stress hormones, inflammatory proteins, and oxidation. Faced with this the cell shuts of glucose oxidation. It needs to make more reducing agents so doesn't want to send glucose toward respiration, instead deflecting it to NADPH by phosphatasing PDH and pyruvate kinase.
The increased stress hormones means more fatty acids and less glucose oxidation (Randle cycle) so glucose gets shunted to lactate. The Lactic Acid causes increases in NO which further block respiration.
Now even beta oxidation is struggling as fats require more O2 per ATP than carbs. In a desperate bid to make energy, the cell produces lots of lactic acid. Which causes more stress hormones, NO, lactic acid and less CO2, O2, respiration. This is the vicious circle we appear to be stuck in.

So you could say the solution would be to get rid of the stressor. This is difficult as the stressor is unknown. General antivirals etc only work in some people.
Well, perhaps you can break out of the vicious cycle with B1/B3/B7/Mg/Preg/Thyroid/CoQ10? It appears that most people with CFS seem to get a benefit from these things but it is no solution. Tolerating high doses of these brings side effects.

I think this train of thought is on the right track, but pieces are still missing.

 

[energyandstruct]

I posted previously about recent research indicating that CFS/ME is likely due to hypometabolism caused by environmental stress.
CFS Is Likely Hypometabolism Triggered By Environmental Stress
The earlier studies found lower activity of the enzyme PDH, which is the rate-limiting step for entrance of energetic substrate into the Krebs (citric acid) cycle.
The Ability To Metabolize Glucose Is Impaired In CFS/ME Patients

This newer study found lower levels of Krebs cycle metabolites, which is consistent with the results of the first study - i.e. lower activity of PDH means less pyruvate gets converted in AcetylCoA and enters the Krebs cycle. Ultimately, this results in lower ATP levels and possibly increased levels of lactic acid - i.e. basically the cancer/diabetes metabolism. The study found that simply increasing ATP levels restored proper functioning of cells from patients with CFS/ME. Other interventions should also work include inosine (as an alternative precursor to ATP), thiamine, biotin, niacinamide, and of course thyroid. In addition, pregnenolone may also help as it was found to regulate a crucial receptor (TRPM3) involved in CFS/ME.
Pregnenolone As A Possible Treatment Of CFS/ME
Another important finding of the study is that the metabolic dysfunction in CFS/ME is likely not due to genetic causes as some recent news articles in JAMA tried to claim.

http://www.meaction.net/2017/02/22/stanford-team-announces-breakthrough-in-mecfs-research/
"...The team’s metabolomics tests on severely-ill patients revealed problems with the citric acid cycle. Participants’ blood work showed that some of the chemicals involved in the citric acid cycle are very low, making it difficult for the patient to generate the chemicals we use for energy. Several chemicals were found to be two standard deviations away from those of healthy controls, which is serious, according to Davis. The problems found in the citric acid cycle of ME/CFS patients does not look like the result of a typical genetic defect in the mitochondrial metabolism, Davis noted. Recent research by Fluge and Mella has also suggested that pyruvate dehydrogenase, the enzyme that helps glycolysis transition into the citric acid cycle, may be blocked."

"...Davis said that the next step is to use the device to test the effects of various drugs on the cells and serum of ME/CFS patients. For example, Davis’ team found that adding ATP to unhealthy ME/CFS cells and serum made the cells respond normally. The team also plans to test drugs that many ME/CFS patients have reported helpful using this device, such as Valcyte and Rituximab."


Finally, a a bit of side but important note. As the article says, government funding agencies (like NIH) are apparently NOT interested in funding new hypothesis discovered independently. NIH is only interested in handing over hypothesis the NIH considers worthy and then directing the grant recipients to perform research on those "convenient" hypothesis. How can we have innovation and discoveries that cure a disease if a new hypothesis never gets funded!?
"...Davis and his team applied for federal funding from the National Institute of Health (NIH) for the research that led to the data showing the dysfunctional citric acid cycle in people with ME/CFS. The NIH turned down both of his grants “because we were trying to do discovery, and they wanted us to only do hypothesis testing,” Davis said. “I said to them: the scientific method is first observation, then hypothesis. And if you have virtually no observations you can’t generate a good hypothesis. I think one of the big problems we have is that we do not know enough at the molecular level to generate hypotheses.”

Update, apparently Davis has gotten a grant from NIH finally. Not sure if big or small one though.

 

[haidut]

Update, apparently Davis has gotten a grant from NIH finally. Not sure if big or small one though.

Great, hopefully more research will come out soon.

 

[energyandstruct]

Couple of things that I'm thinking about:

Short QT interval is a finding in CFS, but ray thinks prolonged QT interval is part of hypothyroidism

Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome. - PubMed - NCBI


https://l-i-g-h-t.com/transcript-369

"
. RAY PEAT: You can see it in an electrocardiogram or if you kneel and have someone thump your Achilles tendon, so your toes twitch away from your body. The relaxation – if your thyroid function is good, the relaxation will be instantaneous and your foot will relax with a floppy, instantaneous, complete relaxation. If your thyroid is low, it will comeback slowly to exactly where it started. And the heart is doing the same thing,

00:19:39 > with a prolongation of the QT interval. The T wave represents repolarization or relaxation. So you can see it in either thumping your Achilles tendon or looking at the electrocardiogram. And when that is slow, that means that the cell is retaining water and calcium. And in that swollen state, it is permeable. It absorbs things that it shouldn’t and it leaks some of the enzymes that it shouldn’t leak. So you can see those in the blood during fatigue or hypothyroidism. "

Is CFS different than classical hypothyroidism?

 

[energyandstruct]

The Adenosine - Phosphatidic Acid Hypothesis

This is a layperson's theory on CFS based on the most recent high quality metabolomics studies. It's pretty detailed. I have trouble parsing it atm but thought some may be interested in it

 

[energyandstruct]

Here's how I understand it so far. There is chronic oxidative stress from virus / bacteria / other factors. This chronic oxidation causes cells to inhibit glucose oxidation (PDH-- PDK++ Pyruvate kinase--) in favor of producing reducing agents (NADPH Glutathione). The reducing agents aren't enough however so oxidation still occurs.

This oxidation leads to methaemoglobin being produced from Fe^2+ being oxidised to Fe^3+. This means blood carries less O2, is a darker color, and the heart needs to work harder to oxygenate tissues. The decreased O2 leads to bigger and quicker breathes blowing out CO2. Furthermore the platelets are also overwhelmed with peroxynitrite causing mitochondrial to be shut down, reduced ATP, increased Lactate. These sick platelets generate less electric and magnetic charges/field and so clump together, leading to poor blood flow, and decreased CO2. This causes tachycardia and heart pounding. The decrease of CO2, increase of lactate, decrease of O2, and oxidative stress lead to increased cortisol, adrenaline, estrogen (?), and in general stress hormones, with a reduction in thyroid (?).

Now the muscle, brain, gut, liver, etc cells of the body are being supplied with less O2, less CO2, more stress hormones, inflammatory proteins, and oxidation. Faced with this the cell shuts of glucose oxidation. It needs to make more reducing agents so doesn't want to send glucose toward respiration, instead deflecting it to NADPH by phosphatasing PDH and pyruvate kinase.
The increased stress hormones means more fatty acids and less glucose oxidation (Randle cycle) so glucose gets shunted to lactate. The Lactic Acid causes increases in NO which further block respiration.
Now even beta oxidation is struggling as fats require more O2 per ATP than carbs. In a desperate bid to make energy, the cell produces lots of lactic acid. Which causes more stress hormones, NO, lactic acid and less CO2, O2, respiration. This is the vicious circle we appear to be stuck in.

So you could say the solution would be to get rid of the stressor. This is difficult as the stressor is unknown. General antivirals etc only work in some people.
Well, perhaps you can break out of the vicious cycle with B1/B3/B7/Mg/Preg/Thyroid/CoQ10? It appears that most people with CFS seem to get a benefit from these things but it is no solution. Tolerating high doses of these brings side effects.

I think this train of thought is on the right track, but pieces are still missing.

the "something" which causes the oxidative stress could be mycotoxins, nanoparticles (this is very speculative), or a virus but I think biotoxins more likely upstream of virus

 

[SB4]

the "something" which causes the oxidative stress could be mycotoxins, nanoparticles (this is very speculative), or a virus but I think biotoxins more likely upstream of virus

Yeah, it could be any of the above but for my case I lean more to undetected virus. Since the onset appears to be from tonsillitis /freshers week.

There used to be a guy post on here called @tyw , I have been reading his posts ever since the Jack Kruse days. He is a smart guy and I respect his opinion. He found his life long IBS symptoms to be caused by a virus using TCM I think. If I am right, I also think that he said something to the effect of there being more virus problems than mainstream medicine recognises, yet TCM does. I think this point of view fits in quite well with CFS, etc.

Another almost completely unrelated thing is the entire time I have been in hospital all the doctors have ranged from dismissive to, in some cases, quite hostile, except for one old Chinese doctor doing the rounds. He said he knows young people that this has happened to and it's very sad. He was the only doc to show genuine sympathy and understanding out of over a dozen. Just kind of interesting I thought.

 

[energyandstruct]

Yeah, it could be any of the above but for my case I lean more to undetected virus. Since the onset appears to be from tonsillitis /freshers week.

There used to be a guy post on here called @tyw , I have been reading his posts ever since the Jack Kruse days. He is a smart guy and I respect his opinion. He found his life long IBS symptoms to be caused by a virus using TCM I think. If I am right, I also think that he said something to the effect of there being more virus problems than mainstream medicine recognises, yet TCM does. I think this point of view fits in quite well with CFS, etc.

Another almost completely unrelated thing is the entire time I have been in hospital all the doctors have ranged from dismissive to, in some cases, quite hostile, except for one old Chinese doctor doing the rounds. He said he knows young people that this has happened to and it's very sad. He was the only doc to show genuine sympathy and understanding out of over a dozen. Just kind of interesting I thought.

what hip describes as the dual-factor hypothesis interests me the most though--would explain odd geographical pattern of outbreaks. biotoxins suppressing immunity + virus...

 

[SB4]

what hip describes as the dual-factor hypothesis interests me the most though--would explain odd geographical pattern of outbreaks. biotoxins suppressing immunity + virus...

Not heard this one, you got a link?

 

[energyandstruct]

Not heard this one, you got a link?

ME is not mould intolerance; mould intolerance is not ME

 

[energyandstruct]

Dual-factor theory of ME/CFS

One argument that may link mold, biotoxins and other chemical toxins to triggering ME/CFS is the fact that ME/CFS can appear in severe yet very localized infectious epidemic outbreaks.

The London 1955 Royal Free Hospital ME/CFS outbreak is one example of a very localized epidemic which afflicted 1 in 10 of the hospital staff, but affected very few people outside the hospital, in spite of the virus being pretty contagious; and the 1984 Lake Tahoe outbreak is another localized outbreak that was severe, but did not spread to the rest of the country.

I always found it very perplexing that infectious epidemic outbreaks of ME/CFS could cause such severe disease, and yet not spread much further than the localized environment, apart from perhaps some sporadic appearing as the virus spreads outwards. To me, that makes it impossible that epidemic ME/CFS is caused by a virus alone, because if it were just a virus, then that virus would have spread to the whole region or country, and caused the same devastation throughout.

But it seems that as these viruses leave the vicinity of these outbreaks, they lose most of their ability to cause ME/CFS.

To my mind, that means there must have been some local cofactor (such as a toxin) present only in the vicinity of the outbreak — a cofactor which in combination with the virus then causes ME/CFS. And as soon as the virus spreads further than the local area containing the toxic cofactor, the virus loses most of its ability to trigger ME/CFS.

So this argument presents the logical requirement for such a cofactor, and this then makes us consider the possibility of mold, biotoxin or toxic chemical cofactors being present only in the vicinity of the outbreak, acting in tandem with the virus to trigger ME/CFS.


In the case of Royal Free Hospital, there were investigations into possible toxic chemicals in the hospital environment (including investigations into the use of pesticides, chemicals used in the kitchen and catering, and the paints and materials used during renovations; ref: 1). These investigations came back negative.

However, I think back in 1955, nobody would have been aware of toxic mold (as there was no knowledge about mold toxicity then), and so would not have looked for it. Thus it is conceivable that there may have been water damage and a toxic mold growth in communal staff rooms in one or more of the hospital buildings, which in combination with the virus, caused the Royal Free outbreak. If the mold infested rooms were used by staff only, that could also explain why it was mostly only the hospital staff who contracted ME/CFS, with very few hospital patients being affected.


Likewise, in the case of the Lake Tahoe outbreak, Lake Tahoe survivor @Erik Johnson points out that in the year of the epidemic, a bright green cyanobacteria (toxic algae) started growing all over the beach of Lake Tahoe, which he found made him a little sick. Erik says that a toxic cyanobacteria called Microcystis which periodically grows in the Boca Reservoir (located just north of Lake Tahoe) sometimes results in contamination of the water supplies of both Reno and Lake Tahoe. So this Microcystis toxic cyanobacteria may have been one of the biotoxins present during the outbreak.

Erik also points out that people who were living or working in buildings he knew to be moldy were more likely to get ME/CFS during the Lake Tahoe outbreak (Erik had had a lifelong mold allergy, so was familiar with which buildings in the area had a mold problem).

Erik Johnson has been championing the theory that toxic mold and biotoxins were the cofactors behind the Lake Tahoe outbreak ever since that outbreak occurred.

For Erik, it was mold avoidance that was key to recovering from his Lake Tahoe ME/CFS (but remember that Erik was mold sensitive anyway, so this treatment may not work for other ME/CFS patients).

Erik sometimes posts on this forum (see his posts here).


So I think the localized nature of the above ME/CFS outbreaks suggests a dual-factor theory for ME/CFS, where a virus may only cause ME/CFS in combination with some immune suppressing factor, such as a toxin.

One fact that tends to corroborate this dual causal factor theory is Dr John Chia's discovery that an acute viral infection + corticosteroids often triggers ME/CFS (see this post for details of Chia's corticosteroid discovery).

Dr Chia investigated thousands of ME/CFS patients' case histories, and noted that ME/CFS was often triggered in these patients when corticosteroids were prescribed during the course of an acute infection. Corticosteroids weaken the immune response, so it seem that when the immune response is weakened during the time of an acute infection when you first catch a virus linked to ME/CFS, that creates the conditions necessary for the virus to trigger ME/CFS.

So with acute viral infection + corticosteroids, we see another example of the dual causal factor theory of ME/CFS.

I think to toxic algae or mold may have analogous immunosuppressive effects to corticosteroids, weakening the immune response in such a way that allows the virus to trigger ME/CFS.

 

[SB4]

@debored13 Thanks, yeah that seems pretty legit.

Makes me think back, I had a number of things that could have been cofactors in my illness. My slow decent started around the time I got tonsillitis in September 2011. It was my final year of university, I had just moved into new student flat that week, I got tonsillitis from freshers (clubbing) so could have got some other pathogens along for the ride, I took lots of NSAIDs to get rid of tonsillitis and gave myself a stomach ulcer, and I then took some meds (proton pump inhibitors, antibiotics?) to get rid of ulcer.

NSAIDs might be immunosupressive or cause lack of appropriate inflammatory response. Higher cortisol from moving to new place and final year of uni. Ulcer and potential other pathogens could have caused extra assault on system. Don't think there way any mold though.

Very interesting theory though not sure how useful it is yet in terms of treatments. I suppose it indicates it could really be a virus that's causal.

 

[Whataboutbob]

http://aplaceof.info/chronic_wellness/1 Hypoth Feb 98.rtf
ACTMECFS Nov 98 paper