Houston, we have a problem.
The mystery cause of ME/CFS is shutting down production of CoA - turning that back on again is the route to more energy. Restricting vitamin A and carotenoids could be the route.
The fatigue of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) could be explained by the fact that production of CoA is inhibited. (5) Stopping the inhibition would increase energy levels throughout the body. Retinoic acid excess could be a reason that CoA production is blocked in mitochondria. (1, 2) Lack of retinol, inactive vitamin A, could be a reason that oxidative phosphorylation and the Citric Acid Cycle isn’t happening in ME/CFS. (8)
Retinol itself has regulatory roles for mitochondria independent of Retinoic acid.
“Here we show that retinol is essential for the metabolic fitness of mitochondria. When cells were deprived of retinol, respiration and ATP synthesis defaulted to basal levels. They recovered to significantly higher energy output as soon as retinol was restored to physiological concentration, without the need for metabolic conversion to other retinoids. Retinol emerged as an essential cofactor of protein kinase Cδ (PKCδ), without which this enzyme failed to be activated in mitochondria. […] The data provide a mechanistic explanation to the nearly 100-yr-old question of why vitamin A deficiency causes so many pathologies that are independent of retinoic acid action.” (Acin-Perez, 2010) (8)
If you have a factory that turns A’s into B’s, at a moderate pace, then you always have some A’s and some B’s. If the factory is in over-drive, at an all-night-long pace with an endless supply of conversion factors, then all inputs of A’s would quickly be turned into B’s and at any one time the factory would be full of B’s and there wouldn’t be many A’s except for any new shipments.
In this scenario, Vitamin A / retinol, (or beta-carotene - two retinols joined together), are the A’s, and Retinoic Acid/retinoids are the B’s. If something did cause the enzyme in the liver to over activate retinol to Retinoic Acid, (6), then the moderating balance is lost. The factory would be producing B’s non-stop with as many units of A as it can get.
Quails were deprived of vitamin A in their diet but were supplemented with Retinoic Acid in order to see the effects on melatonin production. Retinoic acid alone was insufficient to promote normal function in the birds.
“We next deprived Japanese quail of vitamin A by feeding them a vitamin A-free diet supplemented with retinoic acid, and examined the effects of vitamin A deficiency on the expression of AANAT mRNA in the pineal gland and the retina. Vitamin A deficiency reduced both the expression of AANAT mRNA and melatonin content in the pineal gland. Retinal AANAT mRNA rhythm disappeared in vitamin A-deficient quails. Moreover, the responsiveness of the pineal gland and the retina to light was reduced by vitamin A deficiency when compared with the control group.” (7)
“Moreover, the responsiveness of the pineal gland and the retina to light was reduced by vitamin A deficiency when compared with the control group.” (7) *That would likely be due to the loss of rhodopsin which uses retinol as a subunit.
What is Acetyl CoA?
What is Acetyl CoA - an ancient molecule essential for life. It is a coenzyme that turns carbon dioxide into usable carbon for building other molecules, or for use in the Citric Acid Cycle. See Figure 1 and Figure 2. (2) We need it for our energy level. We have to make our own, we can’t take a supplement of it.
“Of the six known pathways of CO 2 fixation in nature 4, 5, the acetyl-CoA (AcCoA; or Wood–Ljungdahl) pathway is the most ancient 6, 7, 8. It reduces CO 2 to acetyl and then pyruvate—the ubiquitous C 2 and C 3 building blocks for life.” (3)
(C 2, C 3 - very short carbon chains with 2 or 3 carbons, instead of longer fatty acid carbon chains or more complex sugar molecules).
Low CoA would then lead to lower production of melatonin which has a protective role in mitochondria as an antioxidant and other ways. (5) The loss of melatonin would likely also lead to depression like mood changes due to effects on our endogenous opioid system. (5) That is an additional topic, which I have not covered further in this post.
Over-simplification of metabolism is an Achilles Heel of non-functional medical care.
The other Problem: Non-functional health specialists over-simplify nutrition and tend to see anything related to a nutrient as a need to just give more of the nutrient without realizing that it might be a missing cofactor or mineral or protein transport carriers rather than a dietary lack of the nutrient. Giving more wouldn’t help much. The missing cofactor, mineral and adequate protein is needed (unless it is a gene difference in which case GcMAF, Vitamin D Binding Protein, has been helpful for some conditions that tend towards low vitamin D levels (Bovine Colostrum supplements may be a source of GcMAF - check that, I am not referencing it right now *No, it is not. It is a source of lactoferrin which has antiviral benefits (gcmafplus.com).
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The problem (Houston - we have a problem) is that the research focus currently is on very early stages of recognizing that vitamin A has a role in ME/CFS, or fibromyalgia, or other conditions; and the approach tends towards - Let’s supplement just in case vitamin A does have a role to play. What if the role is excess though? The supplement would ultimately be adding to the person’s inflammation and long-term risks of chronic degeneration.
Lack of vitamin A can be a problem in underdeveloped nations where food variety is limited or scarce. But it is fairly uncommon in the U.S. where it is relatively easy to get the recommended intake (700-900 mcg/day females-males). (4)
Hypervitaminosis A - usually seen with excess use of retinol/vitamin A supplements (not carotenoids).
Excess may be more common than expected if over-conversion is happening. (6) In normal health carotenoids are not a risk of toxicity; the risk is a temporary orange skin-tone, just cut back of orange/green produce. Only the active form of vitamin A is considered a risk for hypervitaminosis A which is generally seen with high dose supplements, (4), not with liver curry. Food has the advantage of taste and satiety, and our taste buds can be smarter than we realize. Supplements in a capsule bypass our taste bud’s role in satiety - we had enough of that flavor, let’s stop eating.
Symptoms of excess vitamin A chronically may include:
“The most common side effects of chronic vitamin A toxicity — often referred to as hypervitaminosis A — are:
dry skin [&/or chapped lips, with non-healing sores at the corners of the lips]
nausea and vomiting
delayed growth [children with hypervitaminosis A may be stunted, shorter than their potential, (6)]
joint and bone pain
The symptoms would vary with severity of the excess intake and duration of use. Excess Retinoic acid is a serious problem that is likely not being recognized and instead is being called a variety of conditions with other labels.
Retinoic Acid is involved in fighting intracellular viral infections, or inflammation.
Retinoic acid in excess tells the genes to activate for an infection and turns off others that would be used for normal mitochondrial function with the Citric Acid Cycle. (5) The tone of the review article (5) on ME/CFS suggests a belief that the patients are having relapses due to flare-ups of Epstein Barr Virus - which is present in about 90% of us and most people don’t get sick to it. Is that the right premise to proceed from?
The issues caused by vitamin A and D excess are more complex than other nutrients because they can affect gene transcription. The active forms can activate receptors which tell cells to make proteins from certain genes. Both nutrients are so potent that the body generally won’t allow an excess of the active forms to be present. They are held inactive and ready to be used for an infection or other need on a carrier protein within the bloodstream. Free activated molecules of vitamin D (*it is a seco-steroid hormone) or Retinoic acid are deactivated fairly soon during normal health.
Pathogens have had many generations to figure out ways to bypass our immune defense systems. Both vitamin A and D are critically involved in immune function and some pathogen types have evolved ways to affect vitamin A or D metabolism.
On average, people and medical professionals tend to know the basic message about a nutrient - vitamin D helps make strong bones (but it needs magnesium and vitamin K2 and calcium to be able to do so). Vitamin A helps us defend against measles severity - true. Lack of vitamin A can cause an Acquired Immune Deficiency syndrome without any HIV virus or CoV jab to lead the way there.
The problem is not everyone is average and not everyone has low vitamin A or D intake. Neither are typically low in a standard diet if dairy products are used.
For some people, too much activation may be occurring, or too little removal of the activated form of vitamin A or D. Either way, more intake of the nutrients would be adding to the excess of the active form. Gene differences may make the receptors more or less active, or the transport carrier proteins may be dysfunctional. Malnutrition with lack of protein could be a factor. Magnesium and other trace minerals may be needed. Nutrients are a team that may not function with some missing or too many of others present. Minerals compete for similar transport proteins.
Schizophrenia symptoms can be caused by either too little vitamin A or too much Retinoic Acid. How to tell the difference? Blood tests require a doctor’s order and a lab and money to pay for it - and the results may be inconclusive. When we don’t know enough about a problem, then we can’t really know if a screening test is able to identify a problem consistently - or do we really know that it is even the problem?
Fluctuating lab values, could suggest a fluctuating dietary intake is involved.
Inconsistency in lab values was mentioned as a problem within ME/CFS research, (5), how to tell what labs are typical of the condition if the values aren’t consistent? Is that in itself a clue?
If someone had peaches or liver curry some days but not every day and they don’t take a one-a-day vitamin with a steady daily amount of vitamin A, then the excess Retinoic acid problem would fluctuate. The day or two after the liver curry might be a “flare-up” of the mystery condition, and then improvement would slowly occur as the liver curry influx slowly cleared out. Other people might be using a one-a-day supplement and having kale and mango smoothies most days and their symptoms and lab values might be elevated every day. Tomato and meat sauce with spinach pasta, parmesan, with peaches and yogurt for dessert - big vitamin A and carotenoid load. It would be easy, even expected, to have fluctuating symptoms and lab values if the problem is a dietary factor that is in many common foods.
Elimination diets aren’t easy, but hard things can be achieved! Motivation may need to be from within. No one is going to tell you, or me, at this stage of research that this should be done. Early Adopter stage of marketing the consumer has to seek out the specialty product (knowledge in this case).
Continuing over two hundred times (amyloid reducing drug trials) with the same approach may be trying the wrong thing though. The focus on Alzheimer’s dementia treatment and research has been on the misfolded protein accumulation and how to reduce it. It turned out to not make much difference for patients - possibly amyloid beta protein build up is a side effect being caused by something else (like histamine excess leading to hyperinflammation) rather than it being the initial cause of dementia.
Too much Retinoic acid or too little vitamin A can cause similar symptoms of schizophrenia. The retinoid metabolism is complex and impacts much of physical and mental health.
The amyloid build up would be more like the hot coals left after a campfire. It can also occur without severe symptoms. So, what does cause the severe symptoms? Based on my n = 2 field trial - histamine excess causes severe mood symptoms, and would leave inflammatory damage over time, that targets the hippocampus.
Multifactorial Conditions - many causes → similar symptom set.
When we label a “condition” and have an expectation that the “condition has these symptoms”, then we have built ourselves a thought cage. What if there is a cluster of symptoms that has a variety of causes? Some patients might have a few causes wrong with their lives, or only one, but the factors all present with a similar cluster of symptoms because the same root pathway is being affected similarly but for the varied reasons. The one condition mentality expects all patients to have the same underlying dysfunction in the root pathway.
With varied causal factors, each person would need to have their own reasons figured out and repaired/mitigated for before the cluster of symptoms would be improved. I call these types of problem multifactorial, with many possible causal factors and only some, one, or all, may be present to produce the cluster of symptoms - “the condition”. And to “cure” “the condition”, then some, one, or all, would need to be corrected.
The complexity of our inflammatory response is a big problem. Anything that causes inflammation would also be adding to mast cell degranulation and a histamine excess concern. A few examples of causal factors for ME/CFS like symptoms or histamin excess/hyperinflammation:
Radiation for astronauts causes similar symptoms as ME/CFS (5) and sleeping with strong EMF may cause similar problems. Radiation or EMF opens TRP channels and allows calcium entry into cells which is excitatory - inflammatory.
Flickering strobe-like lights degranulates mast cells leading to histamine and inflammatory cytokines.
Low methyl folate or low DOA enzyme to break down histamine could be causal.
A diet high in histamine triggers or allergens would be causing mast cell degranulation or adding to the histamine load with preformed dietary histamine.
Glyphosate is inflammatory and may add to the risk for low vitamin D which can increase allergy or autoimmune risks.
Microbiome dysbiosis is involved and reduced butyrate is seen in ME/CFS and adds to the immune dysfunction. (5)
There are many inflammatory aspects to modern life. (Hyperinflammation post)
In ME/CFS specifically, there has been a link to a history of viral infection - leading to the expectation that the ongoing illness is a latent infection with flare-ups. (5) However, if the history of infection led to a change in the liver enzyme (6), that leads to constant activation of vitamin A and carotenoids to Retinoic acid (RA), then the dietary and supplements of those nutrients would be causing inflammation by activating the anti-viral Retinoid pathways. The body would think and act like it was fighting infection, but it is just reacting to the excess RA.
And to help explain the confusion over Is Vitamin A good for us but bad in this case? the fluctuating lab values was a good clue. Vitamin A, retinol, is also a signaling chemical as well as being needed for rod cells and dim light vision. Retinol promotes mitochondrial use of the Citric Acid Cycle (8) which makes it easy to see why a medical team might want more retinol for ME/CFS. But if after you give retinol to a patient whose liver over converts it to Retinoic acid and sends it out into the body that night, then you are only going to have a temporary improvement based on a temporary increase in retinol.
The next day the patient will be more inflamed from the increased load of Retinoic Acid - which can activate PPAR receptors which inhibit mitochondria from using the Citric Acid Cycle. It switches the mitochondria to burning fat for energy without oxidative phosphorylation, (1, 2), which produces less energy for each molecule of glucose = fatiguing ~ ME/CFS. (5)
Fluctuating would occur based on dietary fluctuation - ate salmon and broccoli or didn’t, and also by the timelapse between intake of vitamin A and the later conversion by the liver that night and next day. The person would then be low in retinol/vitamin A and have excess Retinoic acid. There might be a temporary improvement in mood or energy on the same day as the use of the retinol providing food or supplement, (8), but that temporary improvement would turn into the inflammatory symptoms the next day after the retinol had been converted to active Retinoic acid. See graphic below “Reduced serum retinol.” (6)
There are a few slightly different forms of activated RA which may be why the term retinoids was used in the graphic below.
Figure 1. Retinoid toxicity hypothesis of vaccine injury. (6)
PPAR beta/delta receptors activate fat burning in mitochondria instead of Citric Acid Cyle oxidation and are activated by Retinoic Acid.
“Three classes of nuclear receptors exist for which retinoic acid acts as a ligand: retinoic acid receptors (RAR), retinoid X receptors (RXR), and the peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) [39,40,41].” (114)
The ability to use the Citric Acid Cycle can be turned off by Retinoic acid activating PPAR beta/delta receptors; which then prevents production of Acetyl CoA; which is needed for the cycle to occur within mitochondria. In order to ever be healthy again the body would need to switch back to production of CoA and use of the Citric Acid Cycle by mitochondria - and that would require not having excess Retinoic Acid present.
Added complexity: and also, not having a high saturated fat diet, which is what would normally cause the PPAR beta/delta inhibition of PDK and the Citric Acid Cycle by limiting CoA production . . . which blocks the Citric Acid Cycle from functioning, and the mitochondria switch to using fat for energy. (1, 2)
“The administration of a diet high in saturated fats for 4 weeks to rats significantly increased PDK2 and PDK4 protein expression in both fast-twitch white muscle fiber sub-types (anterior tibialis) and slow-twitch red muscle fiber sub-types (soleus) in rats .” (2)
Using fat for energy production is more inefficient for energy needs though, and it produces more waste and lactate build up from the accumulating pyruvate, which is seen in ME/CFS. (5)
If the body is flooded with excess Retinoic Acid, many things might be happening as the receptors transcribe inflammatory and other proteins. The trend would be fight infection or inflammation because that is what Retinoic acid Receptors do for adults more than the developmental roles seen in infants. It could be damaging the DNA of developing cells such as sperm.
The mystery cause of ME/CFS is shutting down production of CoA - turning that back on again is the route to more energy - Retinol promotes the Citric Acid Cycle (8) but Retinoic Acid could be blocking it. Retinoic acid excess could be a reason that CoA production is blocked. (1, 2) We are not going to be healthy without the ability to make Acetyl CoA. We can’t just take a supplement of it. We have to assemble it within the mitochondria. CoA production is stopped in ME/CFS. The big question should be is Why? and How do we start it again? Maybe if we stopped inhibiting it with Retinoic acid activating PPAR which leads to inhibition of CoA production, then it would start again.
If we are over-converting Vitamin A and carotenoids to Retinoic Acid, then we may need to thoroughly restrict all dietary sources of vitamin A and carotenoids and active Retinoic Acid (in foods like liver). There would always be some intake from dark green veggies, but as long as it isn’t full servings of dark green veg, I seem to maintain my energy level and normal health. The bigger switch for many people might be the animal product sources of vitamin A. I had already stopped all animal products due to an autoimmune like condition that seemed to be albumin autoimmune antibodies. Avoiding albumin containing foods automatically is also avoiding vitamin A containing foods.
If we are over-converting Vitamin A and carotenoids to Retinoic Acid, then we need to stop riding the hamster wheel of fluctuating, feel-good retinol that turns into too much inflammatory Retinoic Acid. Balance is health. Roller coasters are exciting and inflammatory.
If your diet is making you feel like you have the flu every single day, wouldn’t you rather know that so you could choose a different menu?
Your doctor is not going to order or prepare your meals for you. There is sadly not a three-week resort where your needs and meals will be catered to while you work through figuring this out (that would be really nice though - a carefully designed clinic with prepared meals for you). Diet is not taught in detail in medical school. If PDK is being inhibited by PPAR beta/delta, then that is a root problem and excess Retinoic Acid could be causal.
Lab screening trials designed to check for fluctuation might be the way to prove it. Take before and after measurements of retinol and Retinoic acid/retinoids every few hours after providing a food or supplement source to the ME/CFS patients for two or three days. See if there is a drop in retinol and an increase in retinoids and how long the phases last.
Elimination Diet - not easy, but can be very effective, (and easier than some things, like chemotherapy or surgery).
To exclude histamine triggers and vitamin A and carotenoid foods, it might be easier to give a list of what can be used rather than giving a list of all the things to avoid. If overactivation of Retinoic Acid is a problem, then in my personal experience the retinoid sources have to be very restricted in order to maintain a Not-fighting-an-imaginary-viral-infection state within the body.
An elimination diet for just vitamin A sources wouldn’t rule out histamine sensitivity issues. And an elimination diet for histamine would include vitamin A and carotenoid foods so it would not rule out Retinoic acid excess. Which if present would leave the person with histamine excess symptoms even though they were trying to exclude histamine foods. It would be confusing - What did I eat wrong? (carrots, oh). Once the gut is inflamed and there are leaky membranes, then other food components can also add to inflammation or allergy and autoimmune risk. The more varied problems, the more the person would have to work to identify and stop using triggering foods.
Complete resolution of all symptoms may not be possible if chronic changes had occurred like bone spurs. However, as a person improves, it becomes easier to identify what food eaten yesterday might have added to today’s inflammatory reaction. When everyday isn’t inflamed, and a routine has been established, then it is easier to tell if the luncheon out yesterday left today feeling unwell or feeling fine. Keeping records and keeping foods simple and not processed makes it easier also. Processed foods, even “organic” may contain mystery ingredients that don’t need to be included on the label like Neotame which is an excitotoxin and can add to migraine or other cognitive symptoms.
So - I am not saying following an Elimination diet is easy - I am saying that it can work with some tweaking at the individual basis (what are particular sensitivities?). AND that it would be the treatment if it worked. It hurts when you bang your thumb with a hammer? Stop banging your thumb with a hammer.
What is inflammatory for people on average has patterns, but problem foods can also be unique to what the individual tended to eat frequently. Rotation diets with more variety and a few days between suspect foods sometimes can help with tolerating it. Eliminating inflammatory foods or nutrients may be the only thing that really would work as a prevention for worsening health, if Retinoic acid over-conversion is happening. The excess Retinoic acid causes the viral infection-like response. It can also cause liver and kidney disease or may lead to Alzheimer’s dementia or other neurologic conditions.
If deficiency of retinoids was a common underlying reason for Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fatigue and chronic pain and/or mental illness conditions, then it seems like these people would already have been trying one-a-day supplements and those haven’t been helping, or not enough to resolve the symptoms. If it doesn’t work, then why keep trying the same solution?
The over-conversion of carotenoids and retinol/vitamin A, to Retinoic acid, leads to a twofold problem for patients - an excess of the gene transcribing Retinoids - AND - a deficiency of the inactive retinol/vitamin A which the body needs for other important jobs too. If deficiency alone was the problem than I would think we would have seen more success with food sources and supplements than we have for ME/CFS.
***And/or glyphosate residue is affecting both vitamin A and D metabolism, which may make a person low in active forms, even if dietary sources are available. I had to exclude glyphosate sources from my diet to reduce chronic inflammation and improve my health.
Disclaimer: Opinions are my own and the information is provided for educational purposes within the guidelines of fair use. While I am a Registered Dietitian this information is not intended to provide individual health guidance. Please see a health professional for individual health care purposes.
From Retinoids in Schizophrenia: 114) Reay, W.R., Cairns, M.J. The role of the retinoids in schizophrenia: genomic and clinical perspectives. Mol Psychiatry 25, 706–718 (2020). https://doi.org/10.1038/s41380-019-0566-2 https://www.nature.com/articles/s41380-019-0566-2
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https://www.sciencedirect.com/science/article/pii/S027858462030292X Full text pdf: https://www.dropbox.com/s/vofaipxk1tknxu0/1-s2.0-S027858462030292X-main.pdf?dl=0 *carried over from the last post.
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