Pyruvate dehydrogenase deficiency does not lead to fatigue: Fluge & Mella's PDH impairment revisited

Messages
124
Likes
287
Everyone is toxic. .
I know that many hold strong beliefs on the 'toxins in CFS' theory. I dont want to totally dismiss the theory. But I think it might be useful to discuss why such a theory has such wide intuitive appeal despite significant contrary clinical evidence.

The possibility that toxins in our environment/foods may somehow build up in our bodies and poison our mitochondria leading to decreased ATP production and fatigue certainly sounds like a plausible and attractive model for CFS. A quick google search shows that the internet is full of Business Models that work on basis that i) You have been poisoned by your Westernized life-style and ii) You can be treated (and cured) using Our Detox program/products/supplements/etc/etc. The arsenic example suggested above is clearly is a mitochondrial poison that is highly toxic. But the current restricted use of arsenic together with its known historical use combined with the known epidemiology of CFS make it highly unlikely be a causal (or even a contributing) factor to mitochondrial toxicity in CFS patients.

In my opinion, the 'everyone is toxic' concept, is an 'easy sell' that lacks adequate scientific evidence. Most often, the toxin argument lacks any specific claims that can be independently verified by high quality clinical evidence. Which toxins? From where? What organelles can they be found in? What are the consequences to cell biochemistry?

Even if we accept that we are exposed to more 'toxins' today compared to 60 years ago, what is the clear solid scientific evidence that shows the 'toxins bombarding and poisoning our our bodies' are causative of increased disease rates. Just to take one example. Benzene is a nasty chemical. Highly toxic. Exposure to benzene has been clearly shown to increase the likelihood of acute myeloid leukemia (AML). But the age-adjusted incidence rate for AML has changed very little over the last 60 years. Surely the toxin argument should mean that with benzene-derivatives being used so widely in our Westernized lifestyles, the age-adjusted incidence for AML should sky-rocket. But it hasnt. There are many other examples where a specific chemical has been shown to have a causative role in a specific cancer but the age-adjusted incidence rate has changed very little over the last 60 years.

Now of course, we should avoid as many toxins in our environment/diet as possible, particularly with CFS. But apart from some obvious exceptions (asbestos and mesothelioma, or cigarettes and lung cancer just to name a couple), the actual epidemiological data suggests that, in general, we are not succumbing to an overload of toxins which results in (or contributes to) CFS.

Also, to state the obvious, some individuals have diagnosed chemical sensitivities that can cause a whole range of serious heath issues. Clearly, such individuals need to be vigilant in avoiding chemicals and toxins. But it is not really valid to try and extrapolate observations from disease groups with diagnosed chemical sensitivities to a widespread chemical toxicity being responsible for significant numbers of CFS patients.

What is perplexing to me is that simply declaring 'toxins' to be the culprit is often seen as a 'QED moment'. 'Toxins' seem to be a self-validating argument where critical analysis and evaluation of the data is not necessary. "Of course its the toxins, right?" A 'practitioner' will tell a patient that they have a 'build up of toxins' and they need to embark on a whole range of 'detox treatments' in order to cure themselves. The uncomfortable truth that toxins may not be responsible is often countered by 'practitioners' ordering in-house non-accredited tests for 'toxins' and heavy metals such as mercury, arsenic, cadmium, and lead (which very often come back positive). And a positive toxin report is all that is required to re-assure the patient that they need to embark on a detox program. Some detox programs advertised on the internet dont even make sense medically with claims that include 'inadvertently mobilizing toxins', 'detoxify in order to adapt and rebuild', 'timing detox to coincide with liver diurnal cycles', 'entering super detox mode' and so on. Rarely are such advertising descriptions backed by any sensible scientific description or publications.

Again, there are some important exceptions. For example, NAC is used clinically to detox overdose patients. The ability of NAC to increase Glutathione in the liver and reduce free radical damage may have important therapeutic benefits in at least some CFS patients.

But, I do agree: There is something intuitively appealing about the 'detox model'. For many the idea that we could take some natural herbs to gently help the liver to detox and free our bodies of toxic burdens..... well........ it just seems to make sense. But, in assessing different treatments, perhaps one consideration might be to recognize that while some 'pre-packaged concepts' might satisfy our intuitive beliefs, they may not make much scientific sense.

Anyway, I guess no matter what our theories, we all know that the nature of the 'CFS beast' involves many treatment failures and very few treatment successes.

Food for thought

Rodger
 

Hip

Senior Member
Messages
16,224
Likes
34,257
So it has been found that translocator proteins are blocked but it has also been found that ME CFS cells begin working again when they are given the serum from healthy people?

This must mean therefore that the translocator proteins can unblock pretty easily?
That's a very good point. Whatever the factor causing the energy metabolism blockage , it must "unstick" itself pretty easily from whatever part of the energy metabolism mechanism it is blocking.
 
Last edited:

alex3619

Senior Member
Messages
13,810
Likes
37,681
Location
Logan, Queensland, Australia
One of the big issues with thinking about toxins is about combinatorial impact. Traditionally, for toxin A, X amount of toxin is safe, and X+Y amount is unsafe. Yet what about impact from toxin A+B+C? There is little research on this. Furthermore our food and water is almost universally contaminated with huge numbers of substances that do not occur in nature in any quantity. We keep adding more and more to the environment, much faster than it degrades. We literally have no idea what it is all doing. When we do investigate we also typically look at single toxins, not combinations.

Now I think the argument that there is no proof that most of these substances do harm is both accurate and highly misleading. Sure, most probably do no harm. Most. Yet the ones that do are unidentified and might do catastrophic harm.

Now when it comes to non-toxic issues, how much do we know about the combination of bacterial or viral infections and a range of toxins? I suspect we know close to nothing. Similar arguments apply to genetic and dietary and other problems.
 

alex3619

Senior Member
Messages
13,810
Likes
37,681
Location
Logan, Queensland, Australia
I don't have the knowledge to answer this question, but I imagine that an ANT autoantibody might bind reasonably tightly to its ANT protein target inside the cell
I doubt it. Its more likely to be a weak binding, and easily dislodged. The only way it would be a strong binding is if there were a specific autoimmune response targeting that protein, and specifically that part of the protein outside the mitochondrial wall. I suspect its more likely to be weak specificity as to target ... but we lack good data in any case. Almost anything is possible without better data.

Yet if its inside the cell then action outside the cell should not dislodge it. What might is a substantive change in pH, either low or high.
 

Hip

Senior Member
Messages
16,224
Likes
34,257
The only way it would be a strong binding is if there were a specific autoimmune response targeting that protein, and specifically that part of the protein outside the mitochondrial wall.
In the case of the ANT autoantibody found in coxsackievirus B myocarditis, the autoantibody that targets the ANT protein is thought to arise due to the fact that antibodies to the coxsackievirus B capsid protein are cross-reactive to ANT protein.

So I guess that the strength by which this capsid protein antibody binds to the ANT protein will depend on how similar the capsid protein antigen is to the ANT protein antigen.
 

alex3619

Senior Member
Messages
13,810
Likes
37,681
Location
Logan, Queensland, Australia
So I guess that the strength by which this capsid protein antibody binds to the ANT protein will depend on how similar the capsid protein antigen is to the ANT protein antigen.
... and how similar to that particular 3D conformation of the exposed protein. So its likely to be weak. pH can greatly modify that binding. Cross reactivity has little to do with protein sequence, its about conformation and charge.
 

Learner1

Senior Member
Messages
5,605
Likes
10,023
Location
Pacific Northwest
@Learner1 is an inability to tolerate any of the methyl supplements a sign of toxicity? Eg methylcobalamin?
Yes, its very likely. You need several other cofactors, adequate water and fiber consumption, and good elimination capability or whatever you've mobilized can't get out of your body and produces symptoms before being redeposited in your fat, bones, brain, mitochondria, etc.
 

Learner1

Senior Member
Messages
5,605
Likes
10,023
Location
Pacific Northwest
I would definitely be interested in the link between mitochondrial membrane (dys)function and how it relates to different kind if toxins that might build up inside cells. Are there, for instance, any ME recovery or remission stories from people that went through detox regimes?
I can only speak for myself. 18 months ago, I was sleeping 16 hours a day, I got rid of arsenic and lead that were measurable in both blood and urine under a competent doctor's supervision, and got down to sleeping 10 hours a day with improved cognitive function. I also have immunecsnd infection problems, so I wasn't cured, Working on these has removed my brain fog and got me sleeping 8-9 hours a day.

I suspect most people have more than one problem to solve which is why this disease is so vexing. "I tried X and it didn't work..."

The exception seems to be people with mold exposure, who seem to get well after treating just that.
What are typical toxins found by the Acumen test for ppl with ME, and what can be done to “remove” them from mitochondria? Is the Acumen test avail for ppl from abroad?
I don't know what is typical, but I live in the US and my doctor ordered the test (looking for possible causes of my cancer), which showed a couple of concerning chemicals as DNA adducts.

Avoiding toxins is best. Being nutritionally replete helps avoid kicking up toxins as your body has the ability to run its detox processes in a continual basis.

Mitochondria recycle every 6-8 weeks or so, so toxins are released and picked up again by the new ones, so having your detox processes running well will help them be eliminated rather than being picked up.

In my case, as I was very toxic, I used an alpha lipoic acid polymer, PolyMVA, which greatly reduced my toxicity, along with curcumin and a comprehensive methylation protocol. I also used NT Factor to repair mitochondrial membranes.

This process was doctor supervised and measurable on my labs and led to dramatically positive changes in my function.
@Learner1 you mentioned toxicity and methylation supplements, could you please elaborate on that? I get very ill if I try to supplement 5-MTHF, but do you see a connection with mitochondrial (or cell) toxicity related to such supps?
Yes, as described above. You need to have adequate cofactors for not just the folate cycle, but also the methionine cycle, glutathione production, and the trsnssulfuration pathway.

These include B1, B2, B3, B6, B12, magnesium, potassium, selenium, molybdenum, trimethylglycine, glutamine, cysteine, glycine, and methionine, and antioxidants.

If you just supplement 5-MTHF, but don't have adequate amounts of the other nutrients, you will run into trouble.
 

Learner1

Senior Member
Messages
5,605
Likes
10,023
Location
Pacific Northwest
Just noticed that the newspaper also provides its own English translation:
https://tidsskriftet.no/en/2017/12/...yndrome-and-pyruvate-dehydrogenase-deficiency
Thank you for providing the translation. I'm not sure it adds much value however. It's one guy's opinion and, while some of his points are well taken, not all of his assumptions are correct. For instance, he seems to think that all patients with ME/CFS are inactive, which is not true.

But, he does mention that There was no care taken to see if patients were fasted or not, which could make a difference in the results. He also mentions that patients with PDH deficiencies would have high lactate and high alanine, yet most ME/CFS patients have low alanine. And though some ME/CFS patients have high lactate, I have seen several people's test results who, like me, have low lactate and low pyruvate.

I've never found the PDH deficiency to make much sense to me, and I I agree that Fluge and Mellas findings don't seem to match genetic PDH patients. But, when the paper came out, I was struck by the fact that the pattern of amino acids I had on a fasting plasma amino acid test, as well as a urine amino test seem to match what Fluge and Mella found in the patients they studied.
 
Messages
3,587
Likes
4,303
Location
Vermont, school in Western MA
Fluge and Mella's results, and points out that:
Dr Bliksrud says the fact that patients with genetic PDH deficiency diseases do not generally experience fatigue suggests that the PDH impairment found by Fluge and Mella may not be the cause of ME/CFS.
I feel like all of us probably read 5he wikipedia page of Pdh deficiency after thr fluge and mella study. First of all, I'm pretty damn sure people with that experience fatigability and something like PEM or weakness...

This may be a semantic argument ? Like how one defines fatigue? But high lactate certainly would cause muscle pain on minimal exertion and, I imagine, weakness.

Idk if any of us think that pdh deficiency would cause every single me/cfs symptom, so this supposed refutation may be a strawman. Sorry for not citing primary source and going on memory, I just got dropped on my head by the doorman lifting my wheelchair to a non accessible doctor's office, and then many whipladh/concussion/stroke symptoms on top of my usual cci sx , and I am sicker than ever ... btw if anyone has any post tbi /concussion treatments besides "xenon " I would love some.
 
Messages
3,587
Likes
4,303
Location
Vermont, school in Western MA
Okay , back to topic at hand. So , the comparison of a partial pdh problem or blockage in me/cfs to the disorder pdh complex deficiency is just an analogy, not a homology.

However , fatigue and ataxia are among the problems listed under symptoms!s of pdh complex deficiency. But it should be noted that in most cases me/cfs is not congenital and pdh complex deficiency is. Which means that a great many symptoms of pdh complex deficiency are caused by a fetal brain developing in an environment of toxic lactic acidosis far higher than the levels we might imagine in me/cfs. And also one has to consider the question of adaptation . regardless , it is sort of a simple disorder it seems like , the main damage is caused by lactic acidosis in the brain and other organs, over years and years and years. But the toxicology rule "dose makes the poison " isn't just applicable to exogenous drugs , it is applicable to those chemicals inside the body like lactate, that we are discussing here .

Various forms of painful muscle dysfunction are also noted in this disorder, along with lesions in the brain and corpus callosum. A) maybe a small overdose of lactic acid causes "fatigue " or "PEM" and a large dose causes "spasticity" or the more extreme muscle symptoms seen in this disorder. Also hyper intensities in the brain that are not quite lesions have been noted. See the Paul Cheney seminar I have posted for more details. And in that seminar, he also notes fluoroscopy or spectroscopy?? (I always b forget the difference ) studies that were able to detect lactate in me/cfs patients brains non invasively. I believe these have been replicated.

I also think we need to consider some sort of semantic barriers and reporting bias from the cognitive difficulties of this population. To put it bluntly they are severely mentally disabled... I know we are mentally disabled in a way, in that we. Can't use much cognitive energy, but not in the way that this population is... Its hard to explain without using the stigmatizing "r word" that you know. So how thoroughly are they going to report all of their symptoms ? But also you can see similar arguments or problems in the tethered cord literature or cci literature where there's no record of PEM or whatever, and that is without the population being predominantly mentally disabled people who die extremely young. Simply put, some symptoms are hard to put into words, doctors aren't great listeners, and so they may not enter the lexicon until some patient coins them. Combine that with mentally disabled adults who die young and its not hard to believe that the researchers or doctors are not getting a rich interior picture of those peoples life.

And like I said earlier , maybe it is still quite different from me/cfs but that could be dose response curve. Many of us have said when we are wired-tired we feel spasticity, ataxia is sometimes present , hyperreflexia is too , and we feel on the verge of seizures even if we dont have them. Our fatigue is different from the conventional notion of fatigue and exists on a continuum with things like seizures from excitotoxicity, or even death , even if its at lower end of that continnuum.

Gimme feedback on if this post was at All making sense or helpful

Oh PS, a better comparison would be an adult that gets some form of milder or moderate lactic acidosis after a relatively normal developmental stage. Or ThE symptoms of sepsis with high lactate but milder ... That is a better model for what adult onset of partial pdh deficiency would be like
 
Messages
7,441
Likes
17,714
A myriad of other toxins can contribute to fatigue by impacting mitochondria, biochemistry and physiological functioning.
in a recent experiment, N=1....I resumed taking a half dose of some chinese herbal tea I use to aid my digestion and IBS-d. I've been on a break, have not taken in a few months.

One hour after taking the tea, I felt a detox effect set in quickly, something likely came out of the liver channel...(one of the herbs targets the liver). I developed a unique odd dull throbbing neck/brain stem head ache, and got incredibly "sleepy"...just literally passing out erect in my chair at 2 pm. Whatever "was released there" caused an incredibly sleepiness.

Similar effect today. I'm going to hang in there with it....

There definately are: toxins- this is not the result of physical activity, its not PEM.
 
Messages
3,587
Likes
4,303
Location
Vermont, school in Western MA
And though some ME/CFS patients have high lactate, I have seen several people's test results who, like me, have low lactate and low pyruvate
I mean, lactate in the blood and lactate in the brain or muscles is two different things. Obviously if we had pdh complex deficiency u would expect lactate in the blood too, but maybe lower levels could just be in the tissues or cells