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Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases, 2019, McGregor et al.

Inara

Senior Member
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Some folks with hyperadrenergic POTS may have high norepinephrine, but their other catecholamines may still be low.
But only when standing is norepinephrine high, not necessarily when supine. I think in fact that's the normal scenario - norepinephrine has to rise in a certain amount in order to call it hyperadrenergic POTS. It's an "emergency reaction" of the body.

The psychiatrists would like us to believe that. For most of us, this is a medical disease,.
This whole stress-response-overactive-HPA has no factual ground in case of ME (I'm not even sure if it can be viewed as proven for any case, which doesn't mean that stress - e.g. infections, high-performance sports, toxins, too much work - doesn't have bad consequences for the body). I am lowish in cortisol (and norepinephrine when supine), too, and in fact, things that are supposed to "activate" the parasympathicus (esp. the vagus nerve) make many things worse in me.
 

pattismith

Senior Member
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interestingly, therapy with purine blockers like mercaptopurine produce fatigue as side effect.

Thiopurines, a previously unrecognised cause for fatigue in patients with inflammatory bowel disease
Thomas W.T. LeeDepartment of Gastroenterology and Monash University Department of Medicine, Box Hill Hospital, Box Hill Victoria, AustraliaSearch for other works by this author on:Oxford AcademicPubMedGoogle
2008
Abstract
Background: Active inflammatory bowel disease, anaemia, iron deficiency and depression, alone or in combination, are known contributing factors of fatigue in inflammatory bowel disease. However, in some patients, fatigue cannot be attributed to known causes.
Thiopurines are not a recognized cause.

AIM: To describe the clinical scenario of a series of patients where thiopurines were the likely cause of fatigue.

Method: The clinical scenario of 5 patients was examined with specific reference to the temporal association of thiopurine therapy with fatigue, the effect of its withdrawal and rechallenge, and drug specificity.

Results: The onset of severe fatigue was related to the introduction of azathioprine or 6-mercaptopurine, rapid relief was experienced on its withdrawal in all patients, and fatigue rapidly occurred on rechallenge. The speed of onset was rapid in two patients and in the context of gradual withdrawal of moderate steroid dose, but recurred rapidly on rechallenge when not on steroids.

Conclusions: Marked fatigue is a previously unrecognized adverse effect of thiopurines. It does not appear to be drug-specific. Its onset might be masked by concurrent steroid therapy.


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This is a great study. I became an enthusiastic student of biochemistry after my ME diagnosis, but I'll have to learn some new stuff to fully understand the implications.

Please forgive me for asking a dumb question, but it does seem that we have problems metabolizing glucose. But I'm not sure that this is the reason for PENE/PEM. I feel less fatigued since going on a ketogenic diet, but PENE hasn't changed at all unfortunately. Those numbers look like they come mainly from glucose metabolism -- since my PENE persists glucose metabolism can't be the reason for PENE, can it?

Seems to me that the study made no attempt to account for dietary differences, I wonder if they should have checked participants for their insulin levels (insulin resistence/hyperinsulinemia)? Maybe the numbers would look different for people on ketogenic diets?
 
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Can't say I have a good grasp of this but I wonder if allopurinol might be beneficial here. It has protective properties in intestinal/ischemia reperfusion injury and intestinal mucosal ischemia is one way to alter the gastrointestinal barrier function and allopurinol also enhances purine salvage.
Most of uric acid comes from fructose or from glucose being converted to fructose via the poliol pathway (video from Gary Fettke) in people with hyperinsulinemia (which would be most of us according to Joseph Kraft), and then via AMP to IMP to uric acid (Robert Lustig). IIRC Allopurinol just blocks the creation of uric acid from hypoxantin (purines).

I have no detailed insight here, but I distinctly remember that we tend to convert ADP to AMP a lot more than healthy people. Assuming that uric acid can be converted to hypoxanthine (most of these conversions work both ways), the rise in hypoxanthine might just be a manifestation of this fact: more AMP means more uric acid, hence more hypoxanthine. PENE may be due to the fact that we have to refill our ADP/ATP reserves as AMP can't be converted easily to ADP (wish I had a reference for that, I read it in some book who knows when).
 

Marylib

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@Murph Sorry you lost your doc Donald Lewis. I had heard of him and I am sure it is a blow to his patients and to those relying on him for well-diagnosed research subjects.