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Organic Acid Test (OAT) results – do we ALL show the Warburg effect?

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I’m interested to see if all members who’ve had their Urine Organic Acids test to look back to see if their test results resemble a metabolite profile typical of the Warburg effect. For those of you not familiar, the Warburg effect is upregulated glycolysis despite available oxygen and is not unique to cancer, but is also a property of activated inflammatory immune cells as seen in sepsis and burns patients. Metabolic studies of ME/CFS have determined the disease closely resembles systemic inflammatory response syndrome (SIRS), sepsis is essentially SIRS secondary to bacterial infection, SIRS is secondary to non-bacterial infection.
If your test shows very low or undetected Pyruvate, low to normal Lactate, high Citrate and Succinate, and low or undetectable Fumarate, this is a typical profile of the Warburg effect. My understanding is ME/CFS patients have low pyruvate without raised lactate indicating impaired glycolysis, this is very irregular. In fact, low pyruvate doesn’t even get mentioned in the OAT interpretive guide let alone the other metabolites in concert. My GP never picked up on these anomalies with my test. I doubt a cancer patient would reveal this profile, but a sepsis or burns patient probably would due to the systemic metabolic alteration. It begs the question, could this be an adequate biomarker for ME/CFS in the obvious absence of burns or sepsis? Hence, I seek members test results to compare with mine.

My pyruvate was undetectable, lactate low-normal (2nd quintile), citrate and succinate both very high (4th/5th quintile), and fumarate undetectable. I did my test 2 years after ME/CFS onset, at the time I was moderate on the severity scale.

Metabolic studies of ME/CFS indicate pyruvate dehydrogenase inhibition limiting transport of pyruvate into the mitochondria. The remaining fate for pyruvate is lactate, but with lactate also reduced this means glycolytic production of pyruvate must be inhibited. In oncology, this is referred to as “cancer-specific metabolic budgeting system” in which the final step of glycolysis to form pyruvate is downregulated in favour of producing glycolytic intermediates for cellular proliferation. Pyruvate Kinase is the key enzyme in this last step of glycolysis, and it’s M2 isoform (PKM2) is exclusively expressed to help regulate the balance between upstream glycolytic intermediates for proliferation and pyruvate for energy. PK hasn’t been studied in ME/CFS, but I’d bet the house PKM2 is over-expressed to the usual M1 isoform, as is ubiquitous in most cancers and sepsis. Without pyruvate for energy, the cell must resort to fats or amino acids to fuel OXPHOS which is why many of us do better on keto or amino acids. In sepsis, Krebs cycle intermediates citrate is increased for synthesis of lipids and succinate increased to stabilise hypoxia-inducible-factor to maintain aerobic glycolysis and inflammation, though perhaps longer-term or more severe patients may not exhibit this. As I say, I tested mine two years in. The intermediate fumarate is low due to the break in the krebs cycle to sustain high succinate. The same occurs after isocitrate, where alpha-ketoglutarate is supplemented by glutaminolysis.

McGregor believes impaired glycolysis is at the root of ME/CFS and I think he’s bang on the money. Emerging evidence suggests a correlation between increased PKM2 and a pro-inflammatory state. Do we just need to suppress PKM2? Pyruvate is an inhibitor of PKM2, and Davis found pyruvate worked with his nanometer test. Interestingly, pure T3 also suppresses PKM2, is this the reason high dose Pure T3 helped some patients? Shikonin is an inhibitor of PKM2 and could also be tested.

A caveat to this theory is PKM2 overexpression promotes mitochondrial fusion, so what about Prusty’s findings on mitochondrial fragmentation under stress? Interestingly, PKM2 trans-locates to mitochondria under oxidative stress and has been demonstrated to affect mitochondrial fission/fusion mediators. In sepsis, the fission/fusion balance shifts toward fission by upregulation or downregulation of these mediators. This is a field of current research. Is PKM2 trying to compensate a stress-induced fission mediator in ME/CFS? This could be a feedback trap.

Getting back to impaired glycolysis then, do we all show it and is OAT a reasonable diagnostic tool? Please advise how soon after onset you did the test, and how severe you are. It is apparent that more severe patients and maybe more long term patients also have mitochondrial impairment and the krebs cycle intermediates may therefore yield different results.
 

sb4

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I am quite interesting in pyruvate as I think it is significant in my case. Indeed my post meal symptoms are much less when low carb.

For my OAT I have:
Pyruvic 2.0 (0.28-6.7)
Lactic 8 (.74-19)
Succinic 2,2 (<5.3)
Fumaric .34 (<.49)
Citric 36 (2.2-260)

This was when I was eating fairly low carb. My results don't quite line up with your idea of warburg. Although the pyruvic is at the bottom end of the "normal" range (they have 2 seperate ranges) and lactic is low -normal.
 
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Thanks @godlovesatrier you seem to fit the profile. :thumbsup: I did Genova Diagnostics test, they use slightly different metabolites and measures to your test, who was yours done through? I might read up on their guide to compare the measures with what Genova uses (mcg/mg creatinine). While your citric wasn't high, your aconitic was low suggesting a slight 'break' in the cycle. Can I ask what severity you were when you did the test and were you a fast or slow ME/CFS onset? I'm wondering if a sudden onset might show in these results compared to a slow onset. This is all rather intriguing.

Thanks your results @sb4 - what brand test was yours? What severity were you when you did the test? And were you a slow of sudden onset? Your pyruvate isn't that low so I'm curious how that compares with your functionality at the time of the test.

Out of interest, I've created a rough illustration of this warburg effect showing the krebs-cycle breaks and why Citrate and succinate are elevated, and where PKM2 is and why pyruvate/lactate is likely low.

1594850120323.png
 
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Wouldn't this just as likely be another indication we are fighting an infection?
Thanks @deeterm - yep, you fit the profile too! :thumbsup: Your question really deserves an answer which I'd like to know too. Would a 'healthy' person infected with the flu show this profile or is it reserved to just those who've suffered an exaggerated systemic immune response like SIRS or burns patients? It's probably never been tested, but I'm inclined to think it wouldn't show anywhere near to this extent, and certainly not remain two years after infection! Impaired glycolysis is a pretty major dysfunction to sustain and burns patients have been known to suffer this a few years, it can be quite a challenge for hospitals to address.

Just looking into where I can get an OA test in NZ.
Hi @anne_likes_red I'm from NZ too, you can order through Nutripath, their agent Nutrisearch in NZ. It gets sent to Australia. Don't even think you need a practitioners order. I'm trying to remember, it was around $400 I think.


I thought I'd better post my results (had to twink out the comments so a bit messy). My pyruvate wasn't detected at all, nor fumurate, within Genova's range.

1594868136821.png
 

sb4

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@WantedAlive Mine says "Great Plains Laboratory" at the top. At the time I was moderate-severe. I am shocked to see your pyruvate not even registering, and others being so low. I should say that I don't experience PEM however I do heavily suspect my glucose metabolism is messed up by this illness. Perhaps being low carb at the time had something to do with it. What was your diet like when you did the test?
 
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Hi there,

I got mine done with the London clinic of nutrition. I was in a very bad way when I got these done. Struggling to walk up the stairs. Breathless. Fatigue. Etc. Even so until interested my Siberian ginseng I felt just like this in May of this year. Currently got a nasty bacterial infection though. I wish our immune systems were not utter garbage.

I was sudden onset. Went to bed at 1.30am woke up about 7 or 8am the next day with full blown ME. This was 2 or 3 weeks after recovering from a horrible viral infection.

So what does this all mean? What can we take to correct the issue?
 
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What was your diet like when you did the test?
I wasn't on low-carb diet when tested. If anything, being on low carb might lower your pyruvate not raise it, it is after all the end product of glucose metabolism.
So what does this all mean? What can we take to correct the issue?
Well, ain't that the million dollar question! As I describe in this thread introduction, ME research has good evidence to suggest glycolytic impairment. I'm proposing enzyme PKM2 is implicated here, it always is in warburg effect, why would it be different in ME/CFS? If it was as simple as suppressing PKM2, in theory bypassing glycolysis, and fueling OXPHOS with a Keto diet should work. It does for some and did for me. Transitioning into ketosis over 3 days I went from moderate ME to near remission. It was truly transformational, and felt exactly like I'd unloaded 80kg off my back. HOWEVER, two days later, I went for a storming 300m walk across a car park with a slight incline, and by 250m it all started to fall apart. The next day I was back down to moderate-severe and I've never recovered since, on any diet. Today I'm still semi-Keto, wheelchair-bound grade-2 severe, I can't walk 5m. So what did I 'break' on that walk? Looking at Fisher's research on impaired complex V and Prusty's fragmentation when mitochondria are subjected to stress tests, maybe that's what happened. It was a sudden and catastrophic failure of energy production, of keto fueled mitochondria and not of glycolysis. Maybe therefore, over-expressed PKM2 which is thought to be pro-fusion, is actually a consequence of stress induced mitochondrial fragmentation, and what's "in the plasma" of ME patients might be driving that. Exosomes have been suggested as one possibility, which could be packages say from mitochondrial fragmentation, and I have sighted recent Alzheimer's research using exosomes on mitochondria which induce not dissimilar results to Fishers ME/CFS findings. All still wild speculation of course. Simple answer, we need more quality research!
 
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I guess the point being that we could be fighting an infection like coxsakie, mycoplasma or CMV thus keeps us in an inflamed state.
Absolutely valid, and maybe why some recover using antivirals. Yet what I don't understand is, the research to date seems to be turning up less active viral load in ME patients than healthy people. I've tried antivirals and while they didn't work for me, I did feel a slight improvement within half hour of first dosing - that was really strange. So I researched Valcyte and it happens to be an inhibitor of Deoxyadenosine triphosphate (dATP). High dATP can be toxic and impair immune function, is associated with adenosine-deaminase-deficiency and immunodeficiency. High dATP levels can be found in red blood cells of AMA patients. I've always wondered about adenosine, as high adenosine causes a hot-burning feeling much like what I feel after exertion. Could it be possible ME patients on high dose antivirals for a year or more are accidentally addressing a different problem from viruses? That said, I'm trialing oxymatrine presently, suspecting enterovirus.
 

ljimbo423

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Yet what I don't understand is, the research to date seems to be turning up less active viral load in ME patients than healthy people.
My research has found the same things. As many or more active viruses in healthy people than in ME/CFS.

So I researched Valcyte and it happens to be an inhibitor of Deoxyadenosine triphosphate (dATP). High dATP can be toxic and impair immune function, is associated with adenosine-deaminase-deficiency and immunodeficiency.
That's an interesting finding, that I hadn't heard of. I think the way antivirals are helping some people is also through some kind of immune modulation/anti-inflammatory action, although I haven't looked into that very deeply.

That said, I'm trialing oxymatrine presently, suspecting enterovirus.
I tried oxymatrine at 900-1,200 mg a day for a year or so with no benefits. I hope you have better luck with it than I did.
 

Hip

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@WantedAlive you might like to break up your text in to paragraphs of not more than around 4 or 5 lines, with a blank line in between paragraphs, as lots of ME/CFS patients have cognitive difficulties when it comes to reading large blocks of text.
 

Learner1

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Agreed. Hard to read runon blocks of text.

I'm not at all convinced of your findings it interpretation for all ME/CFS patients...
your test shows very low or undetected Pyruvate, low to normal Lactate, high Citrate and Succinate, and low or undetectable Fumarate, this is a typical profile of the Warburg effect.
My pyruvate was undetectable, lactate low-normal (2nd quintile), citrate and succinate both very high (4th/5th quintile), and fumarate undetectable. I did my test 2 years after ME/CFS onset, at the time I was moderate on the severity scale.
This was 4/18, Paleo diet with 50% calories from fat, 25% protein and carbs... Level of functionality was maybe 70% of normal, improved from 40% of normal.

Screenshot_20200717-171501.png




Screenshot_20200717-171426.png


This colorful one is 3/20, same dietary macros, 95% of normal.

However, the next section shows a big problem which match the results of recent metabolic testing. Note that glutaric metabolites are high, my guitaric acid is sky-high elsewhere. Seems that I am not burning fatty acids, I am burning glucose laying on the table and with any effort in exercise. I've had two experts look at it and they agreed. So, the experience I'm having with hitting a wall with aerobic exercise is that I'm blowing through my glycogen stores too fast. I don't know whether this is a problem with glycolysis or glucogenolysis or glyconeogenesis, or what. But, I'm definitely not burning sugar to make energy which is what the Warburg effect says. And I'm a stage 3 cancer survivor...

My understanding is ME/CFS patients have low pyruvate without raised lactate indicating impaired glycolysis, this is very irregular. In fact, low pyruvate doesn’t even get mentioned in the OAT interpretive guide let alone the other metabolites in concert.
The Genova Diagnostics guide has it. This is what it says:

Low Levels: The rate-limiting problems for glycolysis can be:

• Insulin deficiency, which reduces activity of glucokinase

• Insulin/glucagon dysregulation, which impairs both glycogenesis and glycogenolysis

• Deficiency of magnesium, the activator of phosphokinase enzymes needed for glycolysis and gluconeogenesis

• Excessive aluminum, which binds phosphate and inhibits phosphokinase enzymes

• Excessive antimony, which inhibits phosphofructokinase

• Excessive iodine, which may inhibit glyceraldehyde dehydrogenase

• Excessive fluorine or fluoride, which inhibits enolase (forms phosphoenol pyruvate)

Glycogenolysis, to free up stored glucose, can be inhibited by insufficient glucagon or epinephrine, both of which stimulate the phosphorylase enzyme that controls glycogenolysis. This is particularly important in the morning, upon arising; thus if pyruvic acid is low in first-morning urine, low blood sugar due to impaired glycogenolysis is likely. This could be due to insufficient glucagon secretion (such as in pancreatic insuffi-
ciency) or to inadequate catecholamines (resulting from inadequate nutrient precursors such as phenylalanine and tyrosine, adrenal medullary insufficiency, or impaired ability of platelets to carry the catecholamines, as in platelet clumping.)

Gluconeogenesis is an unlikely reason for low pyruvate in first morning urine. This process usually becomes critical in
activities requiring extended periods of physical exercise and
endurance.
So, it's sifting through these possibilities to look at what's happening. I have several ideas I'm exploring with my doctors, but definitely not the Warburg effect.
Getting back to impaired glycolysis then, do we all show it and is OAT a reasonable diagnostic tool? Please advise how soon after onset you did the test, and how severe you are. It is apparent that more severe patients and maybe more long term patients also have mitochondrial impairment and the krebs cycle intermediates may therefore yield different results.
The OAT is a very useful diagnostic tool for many things. However, it's important to have it interpreted properly. And, there can be many explanations. For instance, my doctors and I had attributed my high glutaric acid to being B2 deficient and I kept ramping my dose up, and found that no matter how high I erased it I always seem to be off the charts. So, now we are looking into the more esoteric possibilities which are more serious in nature.
 
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But, I'm definitely not burning sugar to make energy which is what the Warburg effect says.
@Learner1 From your results you're correct in that your pyruvate, the end product of glycolysis, is low. That doesn't mean you're not burning glucose though, but as you say it's just not for energy. The Warburg Effect is not only about upregulated glycolysis for energy production.

This was explained in my thread post where I referred to the 'cancer specific metabolic budgeting system', whereby in the Warburg Effect the conversion to pyruvate is throttled back by enzyme PKM2 so that glycolytic intermediates before this end stage of glycolysis are backed up for neucleotide synthesis and cellular proliferation (see diagram). This is what happens in systemic inflammation, sepsis, etc.

Thanks for your two tests, your first one does fit my theory somewhat. My understanding is it's thought early or less severe patients have impaired glycolysis, whereas longer or more severe patients have impaired glycolysis and mitochondrial impairment. This mitochondrial impairment would likely affect the krebs-cycle intermediates citric and succinate and produce different results (ie lower measures). I should test myself again too, as I'm much worse than my first test, and see the difference.

The Genova Diagnostics guide has it. This is what it says:
I never saw that in my 2017 GD guide, low pyruvate just wasn't an option. They must've updated it. Thanks I'll take a look.
 

Learner1

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@Learner1 From your results you're correct in that your pyruvate, the end product of glycolysis, is low. That doesn't mean you're not burning glucose though, but as you say it's just not for energy.
My metabolomic test showed I'm pretty much only burning glucose, and not fat. This is a problem I'm discussing with experts.
Thanks for your two tests, your first one does fit my theory somewhat.
I disagree. It MIGHT fit your theory but there are other reasons for those results. Again, from the Genova Interpretive Guide:
Screenshot_20200718-072723.png
Screenshot_20200718-072801.png

My understanding is it's thought early or less severe patients have impaired glycolysis, whereas longer or more severe patients have impaired glycolysis and mitochondrial impairment. This mitochondrial impairment would likely affect the krebs-cycle intermediates citric and succinate and produce different results (ie lower measures).
I have had ME/CFS for 5 years. It was triggered by carboplatin and paclitaxel chemotherapy, both of which are known to damage mitochondria. I was treated between 18 months and 3 years ago for HHV6, which is known to cause mitochondrial fragmentation. My mitochondrial function has improved over time with significant nutrient intervention, but are still impacted by the chemo.

And, while I agree that my mitochondrial impairment could be a reason for abnormal Krebs values, other things like intestinal dysbiosis, malabsorption, nutrient deficiencies, and toxicity can also be behind them.

It's just a lot more complicated than one simplistic theory.
 

bread.

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I totally agree with you on that comment! And I'm more than happy to accept I may be barking up the wrong tree here. I really only want to explore if a common pattern emerges. Hopefully we'll get some more results. I appreciate you posting the extracts from the guide too, very helpful.
where can i do that test, i am in europe and very severe, do you have a link that gets me there directly? ty
 
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@bread. I'm not sure where in Europe you are but I found World Health Laboratories do OAT tests. I'm from the opposite side of the world, so I wouldn't know if they can be recommended, but they appear to have many locations globally - they appear to be competent. Maybe other PR members can recommend one in europe, or you seek advice from your physician. There are a few laboratories in UK too you could use. Just search 'Organic Acid Tests' in your region. Good luck.
https://www.worldhealthlaboratories.com/organic-acid