A Metabolic Trap for ME/CFS?

[pamojja]

- Accutane / isotretinoin. This is an oral acne drug that is nothing more than ultra-high dose Vitamin A,

I may add that is a synthetic ultra-high dose form of vitamin A:

The recommended dosage range for Accutane is 0.5 to 1.0 mg/kg/day given in two divided doses with food for 15 to 20 weeks.

So for a average 70kg human at the smallest dose that's at least 70 mg of Accutane. If it had any resemblance to natural Retinol, it would amount to 233.000 IUs vitamin A per day! That would be an insane daily dose for up to 5 month, even if would be only natural vitamin A.

https://en.wikipedia.org/wiki/Vitamin_A#Side_effects

In general, acute toxicity occurs at doses of 25,000IU/kg of body weight, with chronic toxicity occurring at 4,000IU/kg of body weight daily for 6–15 months.[38] However, liver toxicities can occur at levels as low as 15,000IU (4500micrograms) per day to 1.4 million IU per day, with an average daily toxic dose of 120,000IU, particularly with excessive consumption of alcohol.[citation needed] In people with renal failure, 4000IU can cause substantial damage. Signs of toxicity may occur with long-term consumption of vitamin A at doses of 25,000–33,000IU per day.[1]

Personally I've following Linus Pauling therapy recommendation, except for vitamin A where he recommends 25.000 IU daily. Took my time and gradually increased while periodically testing serum retinol and retinol binding protein. Took my about 8 year till I reached his recommended dose, and to my surprise from there onward never experienced any of my before infrequent psoriasis outbreaks. Further, my serum level hasn't risen much more than still below the mean of normal.

So I would clearly distinct between these insane doses of a synthetic analog from vitamin A, an essential beneficial nutrient. Which this day probably many are deficient in, since an other study found that up to 50% of females can't convert to active vitamin A from beta-cartene.

How Much is Too Much? : Appendix B: Vitamin and Mineral Deficiencies in the U.S.

Nutrient from food alone, ranked by the occurrence of dietary inadequacy among adults | Percentage of dietary intakes below the estimated average requirement for a specific population* | Naturally occurring sources of nutrient**

2-to-8-year-old children | 14-to-18-year-old girls | Adults 19 and older

Vitamin D | 81% | 98% | 95% | Fatty fish, mushrooms [vitamin D is naturally formed in the body when skin is exposed to sunlight; vitamin D is added to fortified milk]

Vitamin E | 65% | 99% | 94% | Nuts, seeds, vegetable oils, green leafy vegetables

Magnesium | 2% | 90% | 61% | Whole grains, wheat bran and wheat germ, green leafy vegetables, legumes, nuts, seeds

Vitamin A | 6% | 57% | 51% | Preformed vitamin A: liver, fatty fish, milk, eggs; provitamin A carotenoids: carrots, pumpkins, tomatoes, leafy green vegetables

Calcium | 23% | 81% | 49% | Milk, yogurt, cheese, kale, broccoli

Vitamin C | 2% | 45% | 43% | All fruits and vegetables, particularly citrus fruits and tomatoes

Vitamin B6 | 0.1% | 18% | 15% | Many foods; highest levels in fish, beef, poultry, potatoes and other starchy vegetables, and fruit other than citrus

Folate | 0.2% | 19% | 13% | Many foods; highest levels in spinach, liver, asparagus, Brussels sprouts [mandatory, standardized addition to enriched flour and flour products]

Zinc | 0.2% | 24% | 12% | Red meat, poultry, beans, nuts, some seafood, whole grains

Iron | 0.7% | 12% | 8% | Highest amounts in meat and seafood; lower levels in nuts and beans [mandatory, standardized addition to enriched flour and flour products]

Thiamin | 0.1% | 10% | 7% | Whole grain products [mandatory, standardized addition to enriched flour and flour products]

Copper | 0% | 16% | 5% | Shellfish, whole grains, beans, nuts, potatoes, organ meats (kidneys, liver)

Vitamin B12 | 0% | 7% | 4% | Animal products: fish, meat, poultry, eggs, milk

Riboflavin | 0% | 5% | 2% | Milk and dairy products, eggs, meat, green leafy vegetables, legumes [mandatory, standardized addition to enriched flour and flour products]

Niacin | 0.1% | 4% | 2% | Meat, fish, seeds and nuts, whole grains [mandatory, standardized addition to enriched flour and flour products]

Selenium | 0% | 2% | 1% | Found in different plant and animal foods; highest levels in seafood and organ meats (kidneys, liver)

 

[J.G]

So I would clearly distinct between these insane doses of a synthetic analog from vitamin A, an essential beneficial nutrient.

You would. The question is whether ordinary Vitamin A and the synthetic variant, isotretinoin, are also functionally distinct when it comes to mitochondrial toxicity and storage by the liver. I would not personally assume that just because a vitamin is taken in its natural form, it can't do any harm in doses of 25.000IU daily, which is still absurdly high.

 

[pamojja]

The question is whether ordinary Vitamin A and the synthetic variant, isotretinoin, are also functionally distinct when it comes to mitochondrial toxicity and storage by the liver.

Not even considering the synthetic distinction, alone that insane concentration and doses in vitro and mice liver explain mitochondrial toxicity sufficiently. Beyond such theoretical concerns:

http://lpi.oregonstate.edu/mic/vitamins/vitamin-A#deficiency

Vitamin A deficiency-related disorders
Disease of the eye and blindness
With an estimated 250,000 to 500,000 children becoming blind annually, vitamin A deficiency constitutes the leading preventable cause of blindness in low- and middle-income nations (35)...

 

[J.G]

Not even considering the synthetic distinction, alone that insane concentration and doses in vitro and mice liver explain mitochondrial toxicity sufficiently.

Fully agree with you there. Isotretinoin is nasty, nasty stuff. Acute VitA toxicity takes weeks to recover from fully. Let alone taking astronomically high doses of (synthetic) VitA over the course of several months that will inevitably cause chronic toxicity. How long will it take for the body to use that all up, even if any and all VitA consumption is halted afterwards? (Assuming the body can put it to use in the first place, since we're talking a synthetic analogue.) Rhetorical question of course; I don't think an answer is out there.

But I'm gonna rest the Accutane talk here - we're derailing the topic a little bit.

 

[mariovitali]

@J.G

Just saw your blog. Very very interesting.

Perhaps we are not derailing the Thread since it is quite possible that Post-Accutane, Post-Finasteride Syndrome, Gulf War Syndrome and ME/CFS may have the same Biological Basis, namely the Liver (hypothesis)

And here is my main concern with the Metabolic Trap Hypothesis. It disregards all possible Liver Issues (including Fibrosis, Hemochromatosis and many more) that an individual may have.

Shouldn't we make absolutely certain that the main Metabolic Organ is not responsible for a Hypometabolic State?

 

[J.G]

@J.G
And here is my main concern with the Metabolic Trap Hypothesis. It disregards all possible Liver Issues (including Fibrosis, Hemochromatosis and many more) that an individual may have.

Yes, that is my concern as well. The chronic cell-danger response may in some cases be legitimate. This is why I assume that the Davis team, even though their working hypothesis is one of an erroneous "altered state", is also looking for latent / persistent pathogens as a possible perpetuating mechanism. (In which case forcefully removing the metabolic blockade, insofar as chronic CDR indeed leads to that, could be dangerous.)

 

[JES]

The main reason to suspect a metabolic trap or something of that sort is from the fact that ME/CFS patients in many cases have a sudden onset, i.e. some initial viral infection or whatever triggers the disease in a matter of days or weeks. And some experience temporary remissions only to fall back ill later again after a new trigger. Some people also experience very rapid and sometimes permanent relapses after exercise. And some people equally describe rapid temporary remissions. For example whenever I get sick with a cold or flu, which unfortunately happens rarely, I experience none of the typical symptoms and I feel temporarily more or less cured for a day or two.

 

[shoponl]

And some people equally describe rapid temporary remissions. For example whenever I get sick with a cold or flu, which unfortunately happens rarely, I experience none of the typical symptoms and I feel temporarily more or less cured for a day or two.

The same thing happens sometimes in autism; it's called the fever effect. Interesting. https://iancommunity.org/ssc/fever-effect-curious-phenomenon-autism

 

[babeng]

Isotretinoin is nasty, nasty stuff.

Unfortunately I have first hand experience with this "nasty stuff", and I believe this is what caused my CFS many years ago. After reading what @mariovitali has said about the liver, I'm going to ask my doctor for a fibroscan the next time I see him.

 

[jpcv]

The main reason to suspect a metabolic trap or something of that sort is from the fact that ME/CFS patients in many cases have a sudden onset, i.e. some initial viral infection or whatever triggers the disease in a matter of days or weeks. And some experience temporary remissions only to fall back ill later again after a new trigger. Some people also experience very rapid and sometimes permanent relapses after exercise. And some people equally describe rapid temporary remissions. For example whenever I get sick with a cold or flu, which unfortunately happens rarely, I experience none of the typical symptoms and I feel temporarily more or less cured for a day or two.

I have contact with a patient with ME who had a chicunkunya infection, she said that her ME symptoms changed radically during some weeks- disorganized, she said- and that after 2-3 months she was back to her basal ME state.

 

[FMMM1]

Can somebody explain what a kinetic model is? Is it a computer simulation, or something literally built out of cells, or something else?

I've copied a bit from the OMF site below (Google some of the text and you should find it). PDK enzyme was the subject of discussion; lets say it converts X to Y. I guess what they'd do is label the substrate "X" (i.e.label with carbon 14 or similar - stable isotope - mass spectrometer), add this labelled substrate to live cells from someone with ME/CFS, and look at look at what happens to the labelled substrate (carbon 14 or similar). If it isn't converted in the usual way (to Y), or if the rate of conversion is low, then you'd suspect a problem.

Interesting (from memory) a study in the UK, focused on members of the Asian community in the UK who marry close relatives, found that people often seem to be able to function normally even if they have 2 copies of a mutant gene. So having a mutation doesn't necessarily give a negative outcome; often the body has a work around.

It's a long time since I worked as a science technician and (even then) my knowledge was pretty basic. Alex was a professional lead scientist and has a very good understanding; there are many others on this site (and elsewhere) who in my view have a very good understanding of science regarding ME/CFS. Also try looking at reviews on Health Rising, they tend to be user friendly.

Option - Forget the science and lobby for funding for research?


Extract from OMF site:
"The new OMF-funded work will test this hypothesis using stable isotope metabolic tracer experiments on cells from ME/CFS patients and healthy controls (managed and carried out by a senior life science professional at Stanford, Julie Wilhelmy), and expert mass spectrometry at the Stanford Metabolic Chemistry Analysis Center headed by another collaborator, Curt R. Fischer, PhD. Everyone involved is already working hard on experimental tests."

 

[ljimbo423]

I've copied a bit from the OMF site below (Google some of the text and you should find it). PDK enzyme was the subject of discussion; lets say it converts X to Y.

Hi FMMM1- Do you mean PDH enzyme not PDK?

Jim

 

[FMMM1]

Hi FMMM1- Do you mean PDH enzyme not PDK?

Jim

You are of course correct.

These extracts are from the web:
"A reduction in PDH enzymatic activity may lead to accumulation of pyruvate and ...... Øystein Fluge and Olav Mella are named as inventor".

I'm not sure about this but based on a few minutes on the web:
1) Glucose is converted to pyruvate (glycolisis)?
2) Pyruvate is converted by PDH to Acetyl Co-A?
3) "A reduction in PDH enzymatic activity may lead to accumulation of pyruvate".

So for healthy cells (controls) adding labelled Pyruvate results in labelled Acetyl Co-A. If PDH activity is impaired in ME/CFS cells then adding labelled Pyruvate results in lower levels of labelled Acetyl Co-A i.e. compared to healthy controls.

Possibly these scientists will work through each stage looking at what's happening in ME/CFS compared to controls.

 

[ljimbo423]

@FMMM1 - That sounds like a fairly straight forward way to test the PDH activity.

My feeling is, at least a subset of people with ME/CFS will have impaired PDH activity.

Jim

 

[FMMM1]

@FMMM1 - That sounds like a fairly straight forward way to test the PDH activity.

My feeling is, at least a subset of people with ME/CFS will have impaired PDH activity.

Jim

Think of the upstream cause. Neil McGregor (omf symposium september 2017) found genetic mutations; I had thought that this was in mast cells but I've checked and it was Langerhans cells:
"Langerhans cells and mast cells are both resident in large numbers in the skin and act as sentinel cells in host defense. ...".
This is from Simmaron Research - Montreal ME/CFS conference
"Unutmaz found that a high percentage of MAIT cells had been repeatedly activated in ME/CFS patients".

Also, check out Mark Davis's talk on activation of T-cells in ME/CFS - OMF Community Symposium.

So possibly these finding may point to a problem with the activation of the immune system and this results in the metabolic effects.


"Activation May Underlie 'Chronic ...

https://twitter.com/i/web/status/974387033543139328

15 Mar 2018 - Filmmaker @unrestfilm, fighting for #pwme #pwd @MEActNet Wife of @owasow http://unrest.film/watch #mecfs #mcas #pots #IIH @harvard @".

Sorry for the rushed reply.

 

[ljimbo423]

So possibly these finding may point to a problem with the activation of the immune system and this results in the metabolic effects.

This is my understanding as well. It seems to me that the immune activation sets off a domino effect.

One of the biggest problems it causes, if not the biggest, is the mitochondrial dysfunction.

I also feel like there is low grade brain inflammation from the immune activation, which causes many disabling symptoms too.

I think researchers are zeroing in on the core issues!

Thanks for the informative post!

Jim

 

[Sushi]

I also feel like there is low grade brain inflammation from the immune activation, which causes many disabling symptoms too.

Have you followed Dr. Jarred Younger's research on elevated brain temperature in ME/CFS patients. It is interesting.

 

[ljimbo423]

Have you followed Dr. Jarred Younger's research on elevated brain temperature in ME/CFS patients. It is interesting.

I have read a little of Jarred Younger's work. Although the elevated brain temperature sounds new to me. It does sound interesting. Thanks!

Jim

 

[raghav]

In his interview to Cort Robert Phair said they are looking at 5 variants of a gene which is involved in the metabolic trap. So will the treatment be different for the 5 variants and if so will it mean we will have to get our dna tested ? Or is the solution the same for all the 5 variants ? Hope somebody from OMF can clarify.

 

[FMMM1]

In his interview to Cort Robert Phair said they are looking at 5 variants of a gene which is involved in the metabolic trap. So will the treatment be different for the 5 variants and if so will it mean we will have to get our dna tested ? Or is the solution the same for all the 5 variants ? Hope somebody from OMF can clarify.

Could you direct me to the interview?

I wonder if these mutations relate to the KIR locus. In one of his talks Ron Davis talks about the KIR locus. From a little bit of internet research the KIR locus has been implicated in (transplanted) organ rejection; i.e. along with the HLA locus. If so then this may fit with the immune problems found by Unutmaz (Montreal ME/CFS Conference), Mark Davis (omf community symposium 2017) etc.