Naviaux et. al.: Metabolic features of chronic fatigue syndrome

Leopardtail

Leopardtail

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Jonathan Edwards said:
I am uncertain abut this study. If it has identified a particular metabolic profile shift for ME/CFS then it may well be groundbreaking. However, despite the claim that they found a consistent signature they also say that most of the out of line findings were individual or idiosyncratic. I cannot quite follow that. What also worrisome is that if there is a consistent pattern you do not need multiple regression analysis - you just look at the scatter plots. In the past disease mechanisms have not been found this way. You may need to look at three variables, like calcium,phosphate and alkaline phosphatase to identify hyperparathyroidism, but three is about the most and there are obvious reasons for the triad. I am inherently cautious about big data fishing trips. The other issue is whether this is just a reflection of inactivity - as several people have said.

There are various aspects of context like confident statements about ME/CFS being treatable with supplements that look out of line for a rigorous scientific approach when so far we have no hint of mechanism for the metabolic profile.

Autoimmune disease can set in motion just about any mechanism or sequence of events you like because the autoantibody can bind to any of 40,000 proteins, each responsible for a different function. So yes, an autoimmune process could lead to a shifted metabolic state just as in Addison's disease or Hashimoto's disease.

So Rituximab could be working by removing B cells that generate antibodies that drive the hypo metabolic state although these would seem not to be alarm signals in the usual sense. But the proposal about rituximab working via lipid rafts is a misunderstanding of the biology. The killing mechanism is quite irrelevant to the effect of having no B cells, whether in autoimmunity or cancer. It has nothing to do with any relation of ME to cancer if there is one. I think that can be disregarded.
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I read it differently Johnathon. They tested a fair number of metabolites of which some reasonably consistent patterns were found across patients. In addition to those some metabolites were markedly different in separate patients (to be expected in any group).
 
Gingergrrl

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Leopardtail said:
They tested a fair number of metabolites of which some reasonably consistent patterns were found across patients. In addition to those some metabolites were markedly different in separate patients (to be expected in any group).
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I did the Metabolon test (not for ANY research study and completely for my own knowledge) and I think my results matched with the overall research that maybe 25% matched with ME/CFS but 75% was unique to me and my situation. I made up the percents and they are just a guess. I don't think any two patients would have the same Metabolon results, even if they lived in the same house, but I could be wrong.
 
CFS_for_19_years

CFS_for_19_years

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Leopardtail said:
I find that side effects build up over time. When I came off fluoxetine it took six weeks for its effect to dissipate. I'm inclined to think we are slow to metabolise and eliminate drugs hence the side effects at higher doses.
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Fluoxetine and its metabolite, norfluoxetine, both have very long half-lives:
http://www.rxlist.com/prozac-drug/clinical-pharmacology.htm
Accumulation And Slow Elimination
The relatively slow elimination of fluoxetine (elimination halflife of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. [......] Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine's metabolism is not proportional to dose.

Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks.

The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation).
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A

ash0787

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I guess if you include lots of 'mild' CFS patients that can still walk freely it will rule out deconditioning as a cause for the metabolic signature, and presumably just being extremely tired e.g. after a marathon / staying up for 36 hours
wouldn't cause such a shift in certain nutrients that are only used in a particular way.

I do believe in this research, I think it will become the main diagnostic tool, but at the same time I am becoming a bit skeptical about whether the disease is primarily caused by a change in behavior of the mitochondria for various reasons ( some studies not finding mitochondrial dysfunction or lack of ATP, only effective drugs so far target the immune system )
 
Leopardtail

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F

FMMM1

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Jonathan Edwards said:
I am uncertain abut this study. If it has identified a particular metabolic profile shift for ME/CFS then it may well be groundbreaking. However, despite the claim that they found a consistent signature they also say that most of the out of line findings were individual or idiosyncratic. I cannot quite follow that. What also worrisome is that if there is a consistent pattern you do not need multiple regression analysis - you just look at the scatter plots. In the past disease mechanisms have not been found this way. You may need to look at three variables, like calcium,phosphate and alkaline phosphatase to identify hyperparathyroidism, but three is about the most and there are obvious reasons for the triad. I am inherently cautious about big data fishing trips. The other issue is whether this is just a reflection of inactivity - as several people have said.

There are various aspects of context like confident statements about ME/CFS being treatable with supplements that look out of line for a rigorous scientific approach when so far we have no hint of mechanism for the metabolic profile.

Autoimmune disease can set in motion just about any mechanism or sequence of events you like because the autoantibody can bind to any of 40,000 proteins, each responsible for a different function. So yes, an autoimmune process could lead to a shifted metabolic state just as in Addison's disease or Hashimoto's disease.

So Rituximab could be working by removing B cells that generate antibodies that drive the hypo metabolic state although these would seem not to be alarm signals in the usual sense. But the proposal about rituximab working via lipid rafts is a misunderstanding of the biology. The killing mechanism is quite irrelevant to the effect of having no B cells, whether in autoimmunity or cancer. It has nothing to do with any relation of ME to cancer if there is one. I think that can be disregarded.
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First of all I recall folks running statistics training pointing out the risks re "big data fishing trips" and advising that you should have a theory to test. If you check out Chris Armstrong's webinar I think that he's proposing that this is a response to low grade ongoing sepsis reaction and pointing out "evidence" in the form of Hornig/Lipkin's cytokine paper and Hanson's recent metabolmics paper (looking at evidence of translocation across gut into bloodstream); also other papers re chronic encephalitis (inflamation) come to mind. So if I understand this correctly there is a theory re what's maintaining the condition.

I think the theory that proteins are being used as fuel when glucose is available is interesting. If this is an objective change in metabolism, and it can be measured, then presumably it can assist doctors in diagnosing the condition.

Also, the increased allantoin in urine (and plasma?), presumably indicating oxidative stress, may provide the basis for a diagnostic test. However, something to enable a correction for the dilution factor in urine is needed.

In terms of autoantibodies, I'm strongly in favour of maintaining that line of research. If I understand this correctly Chris Armstrong reckons that this is a heterogeneous condition i.e. more than one biochemical condition. Therefore, there may be an autoantibody form in a portion of those with the condition. It may be that metabolmics testing is a way of separating out groups of people with different metabolic conditions and assisting in identifying the underlying cause be it autoimmune or other.

As for Sphingolipids, TRIP receptors (Griffiths University), and much else, it's all extremely complicated but they may help to explain some/all of the ME/CFS spectrum.
 
Kati

Kati

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There was a question/comment by Vogt et all on the naviaux et al paper:
http://www.pnas.org/content/early/2016/11/02/1615143113.extract
Full text viewable here

In a recent paper in PNAS by Naviaux et al. (1) on metabolomics in chronic fatigue syndrome (CFS), the authors claim to have discovered an objective, diagnostically useful “chemical signature” of the condition, and that this signature corresponds to a “hypometabolic response to environmental stress similar to dauer.” Although we salute the authors’ methodological efforts and interesting findings, we have serious concerns regarding their interpretation

First, by stating that CFS has a chemical “signature,” the authors suggest that they have discovered something very specific. However, findings of metabolic differences between patients with CFS and healthy controls do not automatically yield a test that can single out a specific disease. The authors have …
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Naviaux et al. team's answer was just published here is a preview:
http://www.pnas.org/content/early/2016/11/02/1616261113.extract.html?etoc
Full text

We thank Vogt et al. for their comments (1). We respond to their three points in order. First, we are aware of the need to extend future metabolomics studies to include other disease groups. We stated this fact in the discussion of ref. 2 and are validating the results in independent cohorts. The detailed biochemical phenotype or signature that we found provides a first glimpse at a previously hidden biology. For example, disturbances in sphingolipid metabolism have important implications for immunobiology and neuroendocrine regulation relevant to myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) (3). Sphingolipids are important mediators of the cell danger response (CDR) (4), and the CDR is an important regulator of the behavioral and functional changes produced by infection, and associated with sickness behavior...
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Woolie

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Kati said:
There was a question/comment by Vogt et all on the naviaux et al paper:
http://www.pnas.org/content/early/2016/11/02/1615143113.extract
Full text viewable here : http://sci-hub.cc/doi/10.1073/pnas.1615143113
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Wow, this comment is a great example of "do as I say and not as I do". They set out all the very high standards that biomed research should meet, that are of course never met by psychosocial research.

I have to laugh at them saying Naviaux et al need to compare their CFS cohort with a dozen other cohorts, including depression, PTSD, fibromyalgia. Again and again, I've seen psychosocial research that fails to do this - which, when it comes to claims about psychosocial causation, would be to compare the CFS cohort with another with similar impairment of known aetiology (e.g., MS).

Actually, I can't think of a single psychosocial study of CFS that does this at all. I expect this is because such comparisons would not work in their favour.

And the big punchline of this commentary is that even if there were a biological signature, this wouldn't necessary mean we've found a cause, which could still be psychological/psychosocial!

They neglect of course, to point out that the argument for CFS being psychological/psycholosocial is founded entirely on the absence of a biological signature in the first place. Therefore, if we are to find one, the remaining arguments in favour of a psychological model become almost nonexistent.

I am so sick and tired of these double standards being applied, where biomed research has to be flawless, but psychological research can be loose, free and generally sloppy. Clean up your own house first! :mad::mad::mad::mad::mad:
 
Woolie

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PS you'll notice that biomed researchers never criticise the psychosocial research like this, even though they could have a field day is they so desired. I suspect that's because they think it beneath them. But there's also a general feeling that this psycho stuff is probably useless but also harmless. I wish we could show that it isn't!
 
Snow Leopard

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Vogt et al. said:
Although this reference may not be irrelevant, the authors missed the opportunity to contextualize their findings in relation to clinical CFS research and stress theories (6–8). In humans, stress responses necessarily involve orchestrated neuroendocrine signaling, which, in turn, is influenced by mental states, such as conscious and unconscious interpretation of the surroundings (8).
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The fact is the HPA axis his one of the few areas of CFS research that has extensive attention. No specific HPA axis abnormality has been found. Likewise Wyller's pet "sustained arousal" theory was disproven by his failed Clonidine trial - so the authors of the letter should stop applying a double standard to what they believe is evidence and what they believe isn't evidence.
 
paolo

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TrixieStix said:
Anyone have any thoughts on the difference in opinion between Dr. Naviaux and Dr. Fluge? In the video of his October presentation in Stockholm I believe Dr. Fluge states that he does not believe it is a "dauer like state".
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Fluge and Mella think that the alteration of the metabolism in ME/CFS is due to the immune response (maybe to an autoantibody) and that several compensatory mechanisms are active in order to produce energy and bypass the blockage produced by the immune system on the energetic metabolism.

Naviaux thinks that the origin of the shut off of mitochondria is an evolutionary conserved response to stress (whether it is an infection or any other trigger) which is manteined by some sort of signalling.

In other words, while Fluge and Mella describe a damage of the energy metabolism produced by an abnormal response of the immune system, Naviaux describe an orchestrated response to a trigger, which has evolved to defend the host against several stressors.
 
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Snow Leopard

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TrixieStix said:
Anyone have any thoughts on the difference in opinion between Dr. Naviaux and Dr. Fluge? In the video of his October presentation in Stockholm I believe Dr. Fluge states that he does not believe it is a "dauer like state".
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I think calling it a "dauer" like state was inappropriate and doesn't quite describe the illness in humans...
 
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