note* - PWC means person with chronic fatigue/fibromyalgia


Posted to Co-Cure Mon, 3 Apr 2000 14:26:50 -0400 by Rich Van Konynenburg

Metabolic Pathogenesis Hypothesis for CFS/FM

I would like to propose a metabolic hypothesis for the pathogenesis of CFS/FM that I believe fits many of the observations.

The essential idea is that the onset of CFS/FM occurs when a chronic partial blockade is inserted somewhere in the chain of reactions that make up the intermediary metabolism, i.e. the pathway involved in burning fuel and making ATP. Intermediary metabolism includes glycolysis, the pyruvate dehydrogenase complex, the Krebs cycle, and the respiratory chain.

There are several subsets of PWCs, and each subset has a different etiology, but all the etiologies have in common the fact that they impact intermediary metabolism by inserting a chronic partial blockade somewhere within it.

Different etiologies insert the partial blockade at different places in the intermediary metabolism. This explains why subsets of PWCs differ in terms of their history of triggering factors, speed of onset, biochemical indicators, and response to various treatments, while at the same time they generally share a more or less common set of symptoms.

The symptoms arise from the common pathogenesis and pathophysiology, which flow from the various etiologies, but the etiologies are different.

One major etiology appears to be the depletion of reduced glutathione, as suggested by Dr. Cheney and Dr. Bounous. Most of the known "triggering factors" for CFS/FM are known to use reduced glutathione.

These include infections, physical trauma, surgery, lack of sleep, excessive physical exercise, emotional stress, exposure to toxins or oxidants, excessive use of alcohol, diet deficient in antioxidants and sources of the amino acids that are precursors for making glutathione, such as cysteine, etc.

If the inventory of reduced glutathione gets too low in the liver, it hoards what it needs to preserve life. The muscle cells then become deficient in reduced glutathione. This allows the peroxynitrite, an oxidizing free radical, to build up. Peroxynitrite attacks the enzyme cis-aconitase in the Krebs cycle of the muscle cells, producing a partial blockade. This causes a drop in ATP production, which robs the calcium pumps of the energy needed to pump Ca ions back into the sarcoplasmic reticulum, and it also robs the myosin heads of the ATP needed to detach them from the actin fibers.

This leads to the observed fatigue, weakness, and contractions in the muscles. Meanwhile, back in the Krebs cycle, citrate builds up (as observed by the U. of Newcastle group), because it is just upstream of the partial blockade. Citrate is transported into the Sarcoplasm, and it downregulates phosphofructokinase in the glycolysis chain, further lowering the ATP production.

This latter effect causes a glucose backlog in the blood, and the pancreas is forced to raise the insulin level to push it into the liver and fat cells, where it is converted to stored fat. This accounts for the weight gain in many PWCs. The overshoot in the control system then produces hypoglycemia in many PWCs. They consume carbohydrates again, and the cycle is repeated. (This is why a low carbohydrate diet is helpful for many PWCs. It stops this cycle.)

The resulting high average insulin level causes the fatty acids to be sequestered in the fat cells, and thus not available to be burned for fuel by the muscle cells. This accounts for the stubbornness of the weight gain in many PWCs.

Since the muscle cells cannot use glucose efficiently because of the downregulation of glycolysis by citrate, and since they cannot get fatty acids because of the high insulin, they burn amino acids for fuel, using what's left of the Krebs cycle, by anapleurosis. This causes the amino acid levels in the blood to drop (which is observed).

The shortage of amino acids in the blood then causes other problems: The lymphocytes are unable to get enough glutamine and other amino acids, so cell-mediated immunity becomes dysfunctional. Since this is the type of immunity needed to counter viruses, intracellular bacteria, and yeasts, they begin to thrive. The result is infections that spread systemically and do their damage on tissues, including the brain. This leads to cognitive problems, etc.

Another problem is that the cells of the small intestine are unable to get enough glutamine also, which is their main substrate. This leads to irritable bowel syndrome and to leaky gut syndrome. The latter produces food allergies.

There is also a shortage of tryptophan in the blood, and this leads to depletion of serotonin and melatonin, affecting mood and sleep. Etc., etc.

Another etiology is the hypercoagulability theory of Dr. David Berg. This etiology interferes with oxygen getting to cytochrome oxidase, and thus produces a partial blockade at the end of the intermediary metabolism chain. ATP production drops, and the same syndrome ensues.

A third etiology is the excess phosphate reabsorption etiology of Dr. R. Paul St. Amand. In my opinion (not his, at least yet) the excess phosphate ties up magnesium ions in the mitochondria, and this leads to downregulation of pyruvate dehydrogenase and/or isocitrate dehydrogenase, which are very magnesium dependent, thus putting partial blockades at one or both of these sites. Again, the same symptom set occurs.

I suspect that there are probably several more etiologies, based on my observations of the range of PWC subsets, but I suggest that all of them somehow impact the intermediary metabolism, and that's what brings on CFS/FM.

I have focussed here on the muscle cells, but other kinds of cells are probably also affected, including cells in the nervous system. In the case of neurons, the major use of ATP is to drive the sodium-potassium ATPase ion pumps. When these are short of ATP, they are unable to maintain the intracellular ion concentrations at the proper values.

This leads to a change in the osmotic potential inside the cells, because the pumps normally move three sodium ions out when they bring two potassium ions in. The result is increased concentration of ions inside, and this causes the cells to absorb water and swell. This may be the origin of the need to perform Chiari surgergy in some PWCs. Their brains have swollen too much for the available space allowed by the bones of the head and neck.

Another effect of the lack of ATP for the ion pumps is that the membrane potential drops, and this reduces the threshold for firing action potentials (nerve impulses). This may be one of the origins of the increased sensation of pain in FM. (The other appears to be spinal in location, and appears to be associated with lowered serotonin.)

Comments are welcome. Please mail them to: vankonynenburg1~llnl.gov

Doreen, I take glutamine which cuts back on the stomach problems.....I'm wondering about glutathione.....this was a dizzying piece to read and I don't understand it, could you bring it down to laymans terms for me? Thank you so much!!!!Shelly.......................

the book "The Amino Revolution" by Robert Erdmann, PHD? It is a great book. I took the aminos for my allergies, they were cured by taking a group of amino acids together, one being glutamine. A friend of mine has my book, but I am anxious to get it back, because after reading your post, I'll bet there will be a good formula in there for Fibro/CFS.

It is a great read, I would recommend it to everyone. My DH takes aminos, and his acid reflux is GONE!! No more Prevacid!!


Thanks for all the info, an interesting theory, food for thought. The more I read lately, the more I am convinced that all health problems are related to nutrition.

-Jess

...for a mere structures engineer whose dearly beloved daughter came down with ME/CFS last Christmas after 3 years of chronic recurrent glandular fever (EBV). Her doctor said there was nothing she could prescribe for it, but she could take supplements "if she wanted".

So, out with my trusty Dr Atkins Vitanutrient book and endless hours of internet study, and so far I've managed to cobble up the following protocol, the hard core of which I present below. I wonder what you think of it? It has certainly proved beneficial.

Dr Cheney notes that the blood does not get oxygenated. Solution: First squalene, then later switched to Ge-132 (oxygenators), which latter seemed more powerful in its effects.

Dr Cheney also notes that even if the blood does get oxygenated, it is not carried to the extremities where it is needed. Solution: Niacin (a vasodilator) in the form of inositol hexanicotinate.

Dr Cheney finally notes that even if the blood is oxygenated and then carried to where it needs to go, the oxygen will not be absorbed where it is needed due to a lack of glutathione as part of the condition. Solution: NAC, which dumps glutathione into the body, probably better than anything else.

Dr Atkins extols the virtues of Calcium AEP (colamine phosphate) as an autoimmune saviour which has helped a large number of his MS patients (a related condition, it seemed to me). Trouble is, it has to be injected and we know of no-one who is both qualified and willing to do so. Solution: Take the AEP orally along with piperine, a pepper extract which increases bio-availability between 5 to 30 times.

All of the above went down very well, especially when combined with ginkgo biloba, which carries its cargo faithfully to the brain.

But oh dear, between long plateaus of happy normality, the relapses and fatigue would still occur.

My daughter has always had a very sweet tooth, to the disgruntlement of her low-carb (5 years now) father... However, I noticed something strange. She would get massive cravings for sugar, which only ever occurred during spells of fatigue. She assured me it was not her sweet tooth getting the better of her, she really DID need the sugar (she knows her body well). In addition, she passed out briefly one day, which cried "diabetes!" to me. Further study though indicated hypoglycaemia (notice my English spelling? ; we're English) wherein the insulin, combined with haywire hormones, shoved all the glucose into the muscles, starving the brain inter alia. From the muscles, it was stored as fat. So that explained her weight gain, and also how I arrived at this website

Back to Dr Atkins, we came up with Chromium picolinate, a wonderful balancer of blood sugar, but which takes several weeks to take effect. Also noted was that with any large intake of sugar, the body's Chromium becomes depleted as it is used in metabloising the sugar. A double-edged sword. We added glutamine, which is a much faster acting balancer, taken daily in small amounts, but to be taken by the teaspoonful whenever the sugar craving arose. It's been only about ten days so far, but it seems successful (gasp of relief...).

So that's where we are so far, what think you? The haywire hormones remain for future study which will include (iceblock on my head) your hypothesis. I hope my humble dictionary plus the internet will help me translate it into laymanese (Krebs cycle? WOW!).

Oh, BIG WARNING for any who want to try this at home. DO NOT take piperine if you are on ANY medication whatsoever, even aspirin or whatever. I don't want to kill you by causing overdose of the med.

SO now you know why I'm called,

Supp King.

This is a really useful and fascinating post.
I'm an analyst and have been trying to analyse what's going on in my body, but I've a maths degree, not any sort of biological background. This really helps.
I've already started taking NAC and glutamine, probably at much lower doses than I need.

In particular Supp King, I sound very similar to your daughter - I have hypoglycaemia and the cravings for sugar correlate. Since I've been on a low carb diet my blood sugars are much more stable, but when I have sugar I get terrible terrible reactions - the sugar really exacerbates the fatigue the following day(s), with recently very bad crashes the following day.
But I find it hard to stay away from the sugar when my body is crying out for it. My willpower has to be stronger, and I'm going to try the glutamine too.

Best of luck to you all