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The Metabolic ME/CFS Subset Outlined

Discussion in 'Latest ME/CFS Research' started by Cort, Sep 20, 2009.

  1. Cort

    Cort Phoenix Rising Founder

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    From the latest Phoenix Rising newsletter: The first outlined my horror at the possibility that the Pacific Fatigue Lab's work was not being replicated; :eek: the second my relief that it actually was! :cool:

    Thus far it looks like about half of the ME/CFS patients tested show a very unusual inability to generate the same amount of energy in a repeat exercise test; ie they seem to have some sort of metabolic defect that keeps them from being able to exercise.

    Why the CDC doesn't pick up on stuff like this is just unreal to me. :mad:
    http://aboutmecfs.org/Conf/IACFS09Exercise.aspx


    NOOOOOOO! It’s Happening Again! (Or is it?) - Tolerance to Repeated Maximal Exercise in ME/CFS. E Taub. E. Stein and B. MacIntosh.

    I came across this poster before Dr. Van Ness gave his presentation (see below) and shot Dr. Stein a rather angry look. How could you, I thought? How could you debunk this great theory? How dare you? Objectivity was definitely thrown to the winds. Five females with ME/CFS bicycle to exhaustion two days in a row and their VO2 Max results don’t budge…at all. They were as strong metabolically the second day as they were the first day. This looked to set a record for hopes dashed - just in the last month I’d sent out a newsletter suggesting that the repeat exercise studies could be ‘IT’ in this disease - and now this….

    After talking to Dr. Stein, though, it was hard to get upset with her. She, herself has had ME/CFS for many years. She’d done the study hoping and expecting that the results would be different. She assured me that all the participants had had strong post-exertional fatigue but that they just didn’t have ‘metabolic dysfunction’.

    This means that post-exertional fatigue is not necessarily synonymous with metabolic dysfunction - you could be wiped out by exercise and still not have ‘metabolic dysfunction’. (One wonders if the opposite is true as well - I know of one patient who was able to exercise even when his VO2 levels were quite low.) When I asked Staci Stevens about the study, she said the participants had had pretty high VO2 maxes to start off with – and that could have made a difference.

    The Metabolic Subset - A Diagnostic Test for the Identification of Metabolic Dysfunction. J. VanNess, Staci Stevens, K. Kumasaka, H. Singh, et. al.

    The title says it all; ‘A Diagnostic Test for the Identification of Metabolic Dysfunction' – not chronic fatigue syndrome. Despite the CDC's effort to expand the parameters of this disease (‘unwellness syndrome’?) we are slowly seeing the beginning of the end of chronic fatigue syndrome name and the breaking up of the disease. The research community appears to sense that the era of ’subsets’ is upon us.

    In his opening remarks HYPERLINK Dr. Peterson stated that the search for A biomarker is over, that it’s all about subsets now. The Whittemore-Peterson Institute believes they’ve found immune biomarkers for a subset of patients. If they have, they’ve cut a whole chunk of ME/CFS patients free from the chronic fatigue syndrome label. Both Staci Stevens and Dr. Klimas implored the CDC to go after subsets at the public review of the CDC’s draft strategic plan.

    The Pacific Fatigue Lab’s presentation was about nailing down that metabolic dysfunction subset, those patients whose metabolic tests undergo inexplicable declines during a second exercise test. The Pacific Fatigue Lab presented data from a broad range of results from their studies and disability evaluations, the Montoya Valcyte Study and some patients from a practitioner in Ithaca, New York. About 40% of their group, 40% of patients from Ithaca (7 patients), 55% of Dr. Montoya’s patients and about 70% of people doing disability evaluations at the PFL met the threshold for ‘metabolic dysfunction’. At this point it appears that somewhere around half the patients thus far tested have this problem.

    The percentages may be higher. Dr. Van Ness remarked on the possibility that a ‘physiological floor’ could be obscuring some of the results. Apparently some people who have very low VO2 max scores the first day had similar scores the next day as well. This could mean there’s a floor you can’t get lower than (and still be alive?).

    The tests are not necessarily representative of the population at large; the PFL won’t do tests if you’re too ill and there are presumably a lot of healthier patients who have considerable fatigue and impaired functioning who don’t fit into the high EBV or disability group.

    Unfortunately the Pacific Fatigue Lab has been another casualty in the NIH Grant meat grinder; they spent six months or so putting together a several hundred page grant application and were denied - in no small part because they weren’t allied with a major institution. Staci Steven suggested they probably won’t undergo that process soon again.

    Dig Deeper: Check out ‘Cracking the Foundation’ for more on the Pacific Fatigue Lab’s Work
  2. acer2000

    acer2000 Senior Member

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    Whats always been weird about the PFL work is this discrepancy between people who's scores drop the second day and people whos scores are the same the second day. How do they explain this? It would seem the people who's scores don't drop the second day (but are still low on both days) don't have PEM? Do they then not have "ME/CFS" and should be looking for other (more static) causes of metabolic dysfunction?

    It would behoove them to look at other markers in these two groups to figure out what is different. ie. Do these people show the same inflamitory cytokines, test positive for the same bugs, have the same/different onset or history? Endodrine problems? etc..
  3. caledonia

    caledonia

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    I read the article but I still don't understand what they mean by metabolic dysfunction? What are they measuring? Thyroid, adrenals, pancreas, krebs cycle?

    If they don't have PEM, how can they have CFS? On the other hand, my PEM shows up the worst 2 days after exertion, although some dropoff could probably be measured on the first day after exertion.
  4. Cort

    Cort Phoenix Rising Founder

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    Metabolic dysfunction refers to the inability of some patients to duplicate their results on to exercise tests one done the day after the other. They bicycle to exhaustion each time but during the second test they get exhausted much more quickly and tests indicate that they're not able to produce as much energy.

    Basically they cannot manage to reach the same amount of VO2 max (or oxygen intake); apparently the maximum amount of oxygen intake during exercise is analogous to the maximum amount of energy the body can produce. So their bodies cannot produce the same amount of energy on the second exercise test; somehow that first bout of exercise damaged their ability to produce energy.

    You might say 'well sure' - they were tired from the first bout - but apparently even patients who are very very ill with other disorders can still that same VO2 max the second time. So far as we know right now this is something unique to chronic fatigue syndrome.

    Everybody had PEM but about half of those people were able to produce the same amount of energy the next day as they did the first day; their PEM appears to derive from something else.
  5. Dolphin

    Dolphin Senior Member

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    At the 2007 IACFS/ME conference, there was at least one research group that did three exercise tests as I recall.
  6. shiso

    shiso Senior Member

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    I think limiting the metabolic dysfunction subset (if there turns out to be one) to those who have lower VO2 according to the narrow parameters of the PFL 2 day exercise test protocol has the danger of excluding people who actually have metabolic dysfunction, but for many conceivable reasons (like having relatively high VO2 to start with) do not show decreased VO2 on the second day. I'm not a scientist, and would probably be easily convinced otherwise, but I think it's dangerous to simply conclude that if they don't show decreased VO2 on the second day under the PFL protocol, they don't have metabolic dysfunction.

    As I mentioned, my doctor told me after a single exercise test that measured a lot more than VO2 that I had metabolic dysfunction unusual to people who take the test, looking at more than just the VO2 number.

    Examining results of a three day exercise test would be interesting - e.g., some people might be able to produce the same or similar amount of energy after day 1 of exercise, but might show a dramatic VO2 decrease after day 2. Seems to me they would be in the metabolic dysfunction "subset", no?

    I am encouraged that progress is being made to define subsets (hopefully, because they will define different etiological mechanisms among different ME/CFS patients and hopefully lead to effective treatments); however, I would hope the methods of identifying such subsets would be as refined as possible and able to account for discrepancies - and that the subsets are meaningful in terms of leading to effective treatment (one can hope). :)
  7. caledonia

    caledonia

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    Ok, so the test is differentiating between PEM and metabolic dysfunction (MD). PEM means you feel crappy, but MD means you can't produce as much energy. You may feel crappy (sore muscles, extra tired?) but you may be able to produce the same energy despite that.

    I always took PEM to include MD.
  8. acer2000

    acer2000 Senior Member

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    I think the issue with the group of people who's V02 doesn't drop the second day isn't that its "normal" both tests. I think its low both tests. Presumably the people who's values dropped were low and then dropped lower.
  9. Cort

    Cort Phoenix Rising Founder

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    Yes, one of the researchers said he thought there was a floor beneath which patients may not be able to drop; they were still too low but they didn't drop further. Given Shiso's results there's obviously alot more to learn about this subject - too bad the PFL didn't get the NIH grant they tried for!

    There was a three day repeat exercise study at Reno (as well). The results were quite surprising; they did, as a group, show metabolic dysfunction as defined by the PFL- but they did show something else: - from the latest newsletter.

    http://aboutmecfs.org/Conf/IACFS09Exercise.aspx

    Exercise and Hormones in Spain - Suarez, A, Javierre, C. Alegre, J. etc. al. Hormonal Evaluation in the Chronic Fatigue Syndrome

  10. Dolphin

    Dolphin Senior Member

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    Very interesting, Cort.

    Two studies of non-pharmacological interventions (Jason, 2007 and Roberts, 2009) found that people with low or abnormal cortisol (e.g. flattened across the day) didn't respond as well as the people who had normal cortisol.
  11. kolowesi

    kolowesi Senior Member

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    hormones and PEM

    Great thread, very good info.

    I just flunked out of physical therapy. This is my fifth major exercise attempt in 11 years. Every time, I've had a relapse (viral, bacterial, fungal).

    This time, I think I almost made it past some sort of invisible barrier. I had been on testosterone and hydrocortisone for 10 months or more (plus estradiol, progesterone, vit D, CoQ10, etc). I had reached nearly 60% functioning: though I could not have worked part time yet because my brain was still gone, I could stay upright most of the day.

    Because a Lyme treatment guideline recommends physical therapy (not, mind you, discriminating those of us who have viral heart infections or whatever the heck it is that causes PEM), I decided to try non-aerobic exercise.

    I might have gotten away with it, if I hadn't let them boost my weights and reps too fast. By the 4th week, I had not recovered in 4 days between sessions. The hallmark of the pre-crash state has always been my pushing through unusual fatigue to exercise. My heart rate was going much higher, much faster, too. PEM is cumulative for me.

    So I'm thinking that the hormones are a key difference, and that people's levels should be tested in this type of experiment. The hydrocortisone has given me so much more endurance.

    I've not had the VO2max test, but was normal on Dr. Lerner's bicycle ergometer test. I'm thinking I would have passed the 2 day test. But PEM is my most dastardly enemy.

    Kelly
  12. Cort

    Cort Phoenix Rising Founder

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    Hi Tom - yes, such interesting cortisol findings! There is no getting away from cortisol. The CDC has been all over cortisol; they associated their sexual abuse findings with low cortisol levels, they've found unusual genetic polymorphisms in ME/CFS patients that would appear to exacerbate or trigger cortisol problems.

    Dr. Vernon has developed a model that suggests that if you could just drain ME/CFS patients of much of the cortisol in their body (mop it up actually) the system would reset itself. Now we have the Spanish study showing that exercise further depletes cortisol levels (Could this be why I really can't exercise early in the day - when cortisol levels in ME/CFS patients are so low?). And as you say two studies have found that patients with low cortisol just don't as much from any kind of behavioral/meditative/mindfulness therapies. There is alot of there there in cortisol and ME/CFS.

    But why is the CDC not finding or investigating safe ways to increase cortisol levels? Its strange; their research into cortisol has paid off - now they need to concentrate on how to bring it up but they're not yet.
  13. Cort

    Cort Phoenix Rising Founder

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    Yes Kelly - it was interesting to seen that a good percentage of people with PEM do not have metabolic dysfunction as defined by the PFL. I think hormones are very important for some people - you must at least in part be the HPA axis subset; it did help signficantly but there's much more to go.

    I wish we could get all these subsets figured out. What we need I think is a huge study with several hundred patients and throw every test in the book at them and see what pops out. All I need to do is find that winning lotto ticket....:rolleyes:
  14. Finch

    Finch Down With the Sickness

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    Subsets

    The approach of the subset area is, of course, good news, but for me it's also just a bit worrisome for my poor psyche. That's because, after all these years of my PCP telling me of my wonderful lab results, I'm afraid I'd "fail" all the tests showing biomarkers for subsets as well. What will we have to go through to find out what subset we're under? How many attempts?

    Of course, I'm just being reactive to all I went through at the beginning, before I was finally diagnosed. The doctors would say, "I think I know what's causing your problems," and they'd test me for it, then they'd say the test was just normal. Then they'd think of something else, etc. Of course, they did have to rule out everything else they could think of, as CFS was not a diagnosis they wanted to give. In those days, it meant they were helpless to "fix" me.

    Don't get me wrong, I'm looking forward to all this research on subsets coming together so that appropriate treatments can be found for each of us. It's really exciting, actually! I guess it just can't happen fast enough!
  15. shiso

    shiso Senior Member

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    Agreed Cort, that a well-funded, large-scale study involving lots of patients and testing from multiple angles would go a long way in pulling together all the disparate findings that research has revealed so far. If only!!

    Interesting about all the findings on cortisol. Consistent with the Spain study you mentioned, Martin Pall explains in his book "Explaining 'Unexplained Illnesses'" his belief that the obvious place to look for potential specific biomarker(s) for illnesses like CFS is "to look at consequences directly related to the most characteristic symptom or symptoms of each illness," which in the case of CFS he believes is PEM. He discussed this with Dr. Cheney and Cheney told him that he had already consistently found that "when normal controls exercise their cortisol levels increase substantially," but cortisol levels decrease when his CFS patients exercise. Dr. Pall suggests a hypothesis, based on the Cheney discussion and various studies, that that there might be "a specific region of the brain that is impacted in CFS which is responsible for the control of the hypothalamus in response to exercise. The consequent hypothamalic dysfunction after exercise produces HPA axis dysfunction and therefore lowered cortisol production after exercise." (M. Pall, Explaining Unexplained Illnesses, p. 98-101.)

    As much as I am excited about the progress being made to address subsets, I relate to Finch's wariness about subsets. The identified subsets would have to be meaningful in terms of searching for answers and treatments in an individual patient. I guess the aim with identifying subsets is to differentiate among the different disease processes going on among such a heterogeneous patient population (leaving aside the delay caused by studying people who don't have ME/CFS but qualify as having it under certain over-inclusive case definitions) so that research into treatment for as many subsets as possible can be furthered, WPI style. From all that I've read of patient accounts of their version of ME/CFS on blogs and forums just in the past year, I can almost automatically identify others who have the same symptom set I have; conversely, I often read someone's story and think to myself "this person meets the Fukuda definition but it doesn't sound like the same disease I have."

    If more rigorous research could be funded and the work to identify subsets could proceed at a faster pace and researchers collaborated on their findings, I think it would likely reveal that many or most patients would fall under multiple "subsets" and treatments could be explored accordingly. Now only if it would happen! Yesterday! (Sorry if I've repeated myself on this thread :rolleyes:)
  16. kolowesi

    kolowesi Senior Member

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    Which subset

    As others have said, I'm a little worried that I wouldn't fit neatly into a subset.

    I fit the Incline Village cohort, as a research lab tested me in 2006 and found very high antibodies to HHV-6a (GS strain). I donated extra sera for their repository, as my antibody levels were off the scale. I had very low B and T cells while EBV was reactivated.

    The HPA axis fits me, as I have pituitary dysfunction and adrenal insufficiency. Growth hormone appears to be OK though, which is unusual.

    I have high BP and passed the tilt table test. These two things eliminate me altogether according to Dr. Cheney's older model. However, 3 different research tests show I have active CMV, and CMV can raise one's blood pressure.

    I can't stay upright for long without what feels like brain swelling. Concurrent with this is extreme fatigue and sensory overload. Depression is an early indicator.

    I have enterovirus, along with CMV, in my stomach tissues. I am one band short of CDC positive on the Ignenex Western Blot for Lyme, even after being on antibiotics for years.

    I'm sure I have ME because I have all the symptoms except for spots on the MRI. I was diagnosed with CFIDS, not ME. It may have developed after Lyme Bb infection.

    Could the HPA dysfunction be a result of inflammatory cytokine damage? Dr. Vernon's research paper, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2613527 talks about several feedback loops, but what came first? I suspect pathogens, in my case. HPA axis is secondary.

    As for mitochondrial damage, I tested positive for ciguatera epitope. Richvank explained that this is thought to be pieces of the mitochondrial wall. (I hope I remember correctly, I couldn't understand the Hokama study.) So maybe there is mitochondrial dysfunction, and there is mitochondrial explosion?

    I love the idea of coming up with a database of tests. You are right, a person would need all of them, so data-mining wouldn't work. Any interest in being a researcher, Cort?

    Sorry to be all about me, but I've been trying to figure out why I don't fit for a while.

    Kelly
  17. bertiedog

    bertiedog Senior Member

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    Hi Cort
    You might be interested to know that this is the best year I have had since crashing completely in 2000. I should add that I am now 61 so would expect to be worse not better. But there is a definite reason as to why I have been able to do so much more this year and that is to do with cortisol and fludrocortisone.

    I had mercury poisoning and still have high nickel. In 2002 tests indicated I had a bad adrenal problem and also my thyroid was affected. A knowledgeable doctor put me on originally hydrocortisone about 25 mg daily and also Armour. For the first time in years I started to feel a lot better but would still crash and wasn't able to exercise too much.

    I still caught many viruses very easily but did have all 13 large amalgams removed and chelated as per Cutler. No improvement though until this year. I crashed badly last December and couldn't get better. I worked out I needed fludrocortisone because of a severe postural orthostatic tachycardia problem but it turns out I only need 1/2 a tablet daily to do the trick for me as it regulates my sodium/potassium which must have been completely wrong. I was aware I was a salt waster cos if I licked my skin it tastes of salt which isn't normal. I also take extra potassium having had low red blood cell potassium (along with magnesium).

    My CFS doctor (Dr Myhill) advised me to give myself magnesium injections and I have been doing this for a couple of years and now have a good level of magnesium and for the past year only doing one every other day.

    Once on the Fludro I noticed I didn't keep getting the heart racing I used to have. Often it was a nightmare going to bed cos my heart would just race and then the adrenaline would kick in causing horrible symptoms of anxiety and panic plus muscle pain. Since the fludro this has virtually ceased and I have been sleeping the best for 30 years. I think the effort of going up stairs to bed was too much for me and my cortisol would also have been at a very low level around 11pm, hence the effect on my heart.

    The icing on the cake so to speak was when I decided to try splitting my dose of Prednisolone in 2 so that I take 2.5mg on waking plus 2.5mg hydrocortisone and then 2.5mg Pred around 2 pm with another 2.5mg h/c around 6 pm.

    Doing this has meant that I have been able to run 2 local charities which involves lots of meetings and organisation but the best thing of all is that at last I can really enjoy my walks. Usually its around 25 to 30 minutes at a very good pace and not be half dead like before. Also my blood sugar doesn't run out the way it had for years. I have a bs monitor and I can see the difference, it just doesn't ever go low like it used to and hence I can now exercise so much more than before.

    I still notice that if I have had a lot of pressure with meetings then my energy is affected and I won't be able to walk so well or so far and I have to take 2.5mg h/c before I try and walk otherwise I would be too exhausted.

    So its not a cure but I have really got my life back. I think the poisoning issues are what stops me producing ATP properly but I am going to do a retest of the Mitochondria Translactor test that Dr Myhill can organise. I had this done in 2005 and it showed up high DNA/RNA stuck to the mitochondria which McClaren Howard thought was probably viral. I will be interested to see if it still shows up or whether I have been able to clear it cos I don't get anything like the viruses I used to. I think that the nickel might show up instead because only this year I still had too high levels in my rbc and its also sitting in some enzyme receptors where manganese should be. Dr McClaren Howard commented also that I had a low number of metal binding enzymes but I don't know why this might be, maybe genetic?

    Finally I would like to add that I got a Diploma in Nutrition since getting sick and have been able order many Genova Adrenal Stress tests for people with ME/CFS. They have ALL come back showing very reduced cortisol levels, some with ridiculously low levels whereby the person couldn't function and it would explain why they were housebound. One lady started on h/c and within days felt a new person and this has been maintained so there is no question in my mind that cortisol plays a massive role in this illness and its a good idea to get a Genova test done through the internet to at least see what one's saliva cortisol looks like in the range.

    It worries me a bit that so many researchers mention nothing but viruses but from personal experience of many CFS patients they have demonstrated problems with heavy metals and/or organophosphates but this just doesn't seem to be mentioned so much, just viruses. Perhaps its just the subset thing?

    Pam
  18. acer2000

    acer2000 Senior Member

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    Well the findings re: normal ACTH production but diminishing cortisol production would argue in favor of the "adrenal fatigue" hypothesis. It kind of also fits with the idea that many people who get cfs do so after or during prolonged life stress - their adrenal reserves would be depleted at that point setting them up for a crash.
  19. kolowesi

    kolowesi Senior Member

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    HPA damage

    Not to argue with stress at the time of onset, I definitely had that.

    I have low ACTH along with low cortisol. I don't know how long my ACTH was low cause no one looked at it the first 11 years. So now I have "pituitary dysfunction" and "adrenal insufficiency."

    The mathematical model paper suggests boosting ACTH and lowering cortisol in order to reset cortisol at a higher steady-state. Why not fix the ACTH and let that fix the cortisol??

    Many docs reacted to me as if I just couldn't handle stress. I was told to meditate, do the relaxation response exercises, etc. and I did do that and much more. None of those guys checked my ACTH to see if the problem was higher up the axis.

    It's ironic that I am worse at handling stress now, far worse, than I was at onset. Fighting a bunch of infections for a bunch of years stresses the adrenals too. And inflammation could have damaged the HPA axis, there is a sentence somewhere in the paper hinting at that (could not find it again).

    Kelly
  20. Dolphin

    Dolphin Senior Member

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    I've a math background and understood the paper when I read it (although my memory is not the best now - but I do have notes with it but too tired to look). It is pure speculation whether it would work or not. I think it is saidy only 5-10% of drugs get to stage-3 FDA trials - but on paper they could work.

    I'm not sure I'd call it a CDC paper now - it was written by Suzanne Vernon (not in the CDC now) and Broderick (never in the CDC). Given all the discussions about the CDC, I think it's useful to make distinctions. It's not something Reeves or Jones refer to from what I recall.

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