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What is wrong with our bodies

Discussion in 'General ME/CFS Discussion' started by Dr.Patient, Jun 24, 2015.

  1. Dr.Patient

    Dr.Patient There is no kinship like the one we share!

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    Posted elsewhere, but here now for putting it together:

    I think the core problem is acute or chronic mitochondrial dysfunction, citric acid cycle, etc hence the inability to produce energy.

    The neurological part exists in all patients, if not cognitively, definitely in theautonomic nervous system, as seen by orthostatic intolerance. I don't think it is a primary central or peripheral nervous system problem.

    When I have a good day, my gut is fine. On bad days, the gut starts acting up, with constipation. I still have no strength to digest chicken. The gut problems I attribute to low energy and autonomic dysfunction. I haven't messed around with gut microbes, etc, because I believe that microbes here are not the problem.

    The immune part comes in in that a lot of these are caused by flu viruses that hit and run, something deranged with the immune system. The damage is already done. There is nothing great that immune modulators can do, as seen by the lack of consistent response to rituxan, for eg.

    It is also not a persistent bacterial or Lyme either, hence the failure of antibiotics. Antiviral drugs help, by suppressing herpes and other viruses, since infection and relapses of viruses themselves can cause fatigue even in those without cfs.

    There is no primary inflammation problem. Hence, the lack of response to anti inflammatory drugs.

    For some reason, aggressive resting is the only thing that works (except in the really "gone" cases) somewhat, to some extent.

    Until we crack this exertion-PEM link, there is no real treatment for this condition.

    I'd like to call it Mitochondrial Neuro Immune Disease to reflect the components that are affected.

    I have understood this illness as a physician, and feel it and live it everyday as a patient.

    That's why I stuck to just rest and antiviral, other than other drugs for symptoms.

    Now, the factor of Time comes in. Some people have gotten better after a decade, so that's what I'm hoping for.

    If I weren't a physician, I would have probably tried all the treatments that people do.

    I cannot imagine how I would have dealt with this illness if I hadn't had the medical knowledge and understanding and judgement.
     
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  2. Dr.Patient

    Dr.Patient There is no kinship like the one we share!

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    Hence the term "myalgic encephalomyelitis" is clinically inaccurate and inadequate.
     
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  3. Dr.Patient

    Dr.Patient There is no kinship like the one we share!

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    I'm beginning to understand that autonomic dysfunction is the second biggest abnormality in mecfs after mitochondrial dysfunction, if not the first.

    This is what prevents the body from giving us signals when we overexerted in the first place. The response of the autonomic nervous system is delayed and inadequate, so we keep exerting ourselves.

    Then that response becomes overcorrected, with fast and abnormal responses to activities, preventing us from doing even basic ADLs.

    There is a major screwup here. Physicians can see the dysfunction eventually, which eventually becomes manifest in heart rate or bp abnormalities.

    But fixing that autonomic dysfunction is not possible at this time, hence the prolonged suffering.

    The only recoveries here are spontaneous, in the lucky ones.
     
  4. Chriswolf

    Chriswolf Senior Member

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    I'm currently having a lovely bout of dysautonomia, feeling tired and weak does not help at all.

    I definitely think there are medications that doctors can prescribe to ameliorate the impact of it, but many of them in my experience don't want to.
     
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  5. anciendaze

    anciendaze Senior Member

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    I'm going through a bout of PEM following an episode where I had to change a flat tire. Blame that if you find any lapses in my reasoning.

    I don't question a lack of energy, which has to have some connection with mitochondria, but I do wonder how most of us got to this point in life without exhibiting profound weakness. I know some former jocks are on this forum. Myself, I never was much of an athlete, though there was a time when I took 50-mile bike rides.

    We seem to have an acquired mitochondrial defect, or a defect in some biochemical precursor required by mitochondria and provided by cells. There may be some of us with inherited mitochondrial disease that was exposed by physiological stress, but I can't make that explanation work for the majority.

    Some simple problems with mitochondria would respond to supplements, which don't seem to do as much good as we would like. The benefits we gain are nothing like a cure. There has to be some on-going pathology.

    What I'm now betting on is immune dysfunction as the root cause. I could be wrong, and I'm sure by the standards of current immunologists I would be considered wrong. What is going on in us is more subtle than having most of your CD4+ T-cells die, as happens in AIDS. Considering the professional battle that took place before that grossly abnormal pathology was accepted as valid I'm not at all surprised that current standards don't find much wrong with us.

    I've read quite a number of research papers on illnesses that were not considered CFS. I was particularly interested in those "of unknown etiology" because these described research frontiers where current paradigms had yet to succeed.

    Where there was damage to nerves, I regularly discovered there was some evidence of invasion by T-cells, generally those which cope with viral infections. The same thing showed up in damage to endocrine organs. When I looked at cardiovascular problems I came across reference to "endothelial dysfunction", and this too showed evidence of invasion by cytotoxic T-cells. There is substantial work on endothelial dysfunction as a possible precursor to atherosclerosis. If episodic hypoperfusion is behind tissue damage it would explain a lot. There is also feedback in localized immune problems: when the bloodstream is slow to transport immune cells and remove wastes a great deal goes wrong.

    I don't have "The Answer"(tm), but I can think of some good questions.
     
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  6. anciendaze

    anciendaze Senior Member

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    One more thought related to mitochondrial dysfunction. A very straightforward indication of autoimmune response against mitochondria would be the presence of antibodies to cardiolipin (ACA), which forms a substantial fraction of the inner membrane of mitochondria. Cardiolipin is also found in the membranes of common bacteria like e. coli. This would make onset of chronic illness following an acute flu-like illness which disturbed gastrointestinal mucosa. and allowed bacteria to penetrate some tissues, plausible.

    One study using a research assay for ACA found a surprisingly high percentage of their cohort of ME/CFS patients, and all their GWI patients, positive for ACA. Since there are clinical tests for ACA, I wondered why this had not been seen as a marker before. The answer was that, once the early tests for ACA had overcome limitations in sensitivity, doctors started seeing positive assay results which did not match their clinical diagnoses. The result was that thresholds for positive results were set high, and there was no point in developing more sensitive assays. Hokama's assay was developed to detect ciguaterra toxin poisoning, which turned out to be causing mitochondrial damage. That assay was using an antibody to an antibody to cardiolipin. The original discovery was largely serendipity, but it happened to researchers who followed up.

    The story continues to resurface.

    I doubt this disease will fit the classical model of autoimmune diseases. There has to be more to the story than we currently understand. This doesn't bother me, because I have not been impressed with results from treatment of several cases of identified autoimmune disease I've known. Medicine still does not understand the causes of RA, MS or SLE. Many times treatments have been as bad as the disease.

    I want better treatment options.
     
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  7. JPV

    JPV ɹǝqɯǝɯ ɹoıuǝs

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    That's not really correct. Numerous forum members have gotten better with various regimens that took time.
     
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  8. alex3619

    alex3619 Senior Member

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    There is no question the mitochondria are not producing the energy we need, but there is still substantive doubt its a mitochondrial problem. Something appears to be impacting the transfer of essential substances into and maybe out of the mitochondria. A few studies have hinted at that. In other words, the TCA and ETC may be OK (if you ignore the CoQ10 deficiency) but analogously having a working engine is no good without a battery and gas., or with faulty spark plugs

    Low energy impacts nerves much more severely than other cell types.

    However proper autonomic function is essential to proper mitochondrial function. These are all interacting deficits with circular causation. Its makes it very hard to identify the underlying cause. What we do know though is that isolated muscle cells, which are not impacted by autonomic issues, are still defective. (This also kills the psychobabble arguments.)
     
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  9. halcyon

    halcyon Senior Member

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    Excessive production of ROS (and probably other reactive species) (1 2 3 4) coupled with poor redox capacity perhaps. It would explain a lot, including some of the immune system findings.

    I'm starting to think that any autoimmunity that shows up in this disease is actually a symptom instead of the cause.
     
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  10. Gingergrrl

    Gingergrrl Senior Member

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    @Dr.Patient I know you refer to this a lot but was wondering where you got this statistic or info? I have not really seen spontaneous remissions on PR but someone is doing a poll on this now so I could be wrong!

    In my own case, I have tried all kinds of things but am about to try a LOT more and also revisit some things that I have already tried now that I am no longer living in a home with severe toxic mold.

    But if I get better (any percent better) it will be b/c of massive effort on my part, seeing many specialists, lots of tests and treatments, and even moving.

    I guess I am curious re: all the spontaneous remissions and if you could explain more?
     
  11. JPV

    JPV ɹǝqɯǝɯ ɹoıuǝs

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    @zzz made a post about a spontaneous remission he had from taking isosorbide dinitrate (nitroglycerin) that lasted for 8 years...

    Dr Jay Goldstein's Instant Remission ME/CFS Treatments

    I'm sure that there's others but that's the most memorable one that I've read about.
     
  12. Gingergrrl

    Gingergrrl Senior Member

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    @JPV that is true and I can't believe I forgot that (sorry zzz!) but in general they still seem very rare and not common IMO. Although I wish I was wrong.
     
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  13. Effi

    Effi Senior Member

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    totally agree! If we fit into the classical model of autoimmune disease it wouldn't be so hard to find a biomarker. I feel like this is going to be a totally new kind of illness umbrella, with lots of subsets.
    I know a couple of people with 'classic' autoimmune diseases and I sometimes wonder what is worse: the symptoms of their disease, or the side effects of their agressive treatment. A rock and a hard place. But at least they have a choice...
     
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  14. gregh286

    gregh286 Senior Member

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    Still think its auto immune inflammation in cytokines due to underlying bacteria/virus
    Add me to the list (il-8 @ 1600 Ref. 0-15 pg/ml) and its 13/13 with high IL-8:
    http://forums.phoenixrising.me/index.php?entries/high-il-8-as-a-marker-for-cfs.1690/&page=2

    I had days when a crash comes on real fast and you just need to get horizontal ASAP. I think this is a cytokine storm of sorts. A perpetual cycle of inflammatory boom and bust.

    Had a mito function test done and was 100%. Mito function tests low correlation of results V patient state,
     
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  15. anciendaze

    anciendaze Senior Member

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    Traditional "autoimmune disease" is strictly limited to problems caused by antibodies to "self". Specialists who recognize this is not the whole story now talk about "autoinflammatory" conditions, which fits us better.

    On the subject of ROS, I want people to understand that these have a natural role in the degradation of foreign or misfolded proteins. This process consumes substantial energy. In illnesses producing a fever nobody is very surprised that you feel bad, suffer cognitive impairment and exhibit symptoms of weakness until the foreign material is out of your system.

    I've thought a lot about the current lack of biomarkers. Some problems are due to diagnostic confusion, but not all. On the one hand we now have objective evidence of low anaerobic threshold dropping even lower after exercise. One case where I saw results showed a threshold at 50 watts power output which dropped to 40 watts on retest. In talking about the biochemical sources of power I conclude this shows disturbances amounting to grams of material, not the picograms researchers keep seeking. My inference here is that this material is simply lumped in with normal biochemical waste.

    Due to work like the Light's we have seen evidence of slow clearance of lactates, plus cytokine patterns typical of response to foreign molecules. We don't yet know if this is due to defects in specific cellular machinery, or to a pathological process which keeps overloading normal mechanisms with a steady stream of waste products. I'm guessing the reason we have trouble distinguishing material resulting from a pathological process is that this material is thoroughly degraded by the time it leaves the cell. We are like investigators sifting ashes to find out if these were once records of criminal activity.

    ---

    A side note on my statement above about those changes in assay thresholds for ACA: I want to make it clear that medical doctors are not complete idiots. Should a patient be tested after a weekend bout of some kind of gastrointestinal "bug" it is very likely they will show some antibodies to common bacteria normally confined to the gut, and cardiolipin is a component of many bacterial membranes. This normally goes away soon after the illness resolves.

    To avoid giving false alarms for autoimmune disease based on isolated ACA readings test thresholds are set high. This is part of the standard practice of treating stable values as "real", and variation as random. The unstated assumption behind this is that living organisms exhibit homeostasis. We are unable to find problems in maintaining homeostasis until something measurable goes seriously wrong, often causing permanent damage. We have few tests that tell us how well biological feedback is working to maintain equilibrium, or how close patients are to losing this in response to predictable perturbations.

    A standard maxim taught in medical schools runs something like this: "85% of your patients will get better no matter what you do." (This makes optimistic assumptions about what interventions a doctor might try.) The take-home message is that most of a doctor's activity is simply watching and waiting until clear clinical signs of illness become apparent before attempting any significant intervention. (I sometimes speculate about what evidence-based medicine could show about the benefits of nihilotherapy.)

    The truth of the matter is that most of the time a doctor has no real idea what is taking place inside the particular patient in front of him/her, and makes treatment decisions based on knowledge of generic patients. There is an initiative to change this right now going by the name of "precision medicine". This sounds a lot better than my description.
     
  16. GONZ0hunter

    GONZ0hunter

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    Is auto immune the right term or immune dysfunction?
     
  17. Crux

    Crux Senior Member

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    I'm believing more and more that gut microbes are surely involved with ME/CFS.

    With OI,POTS, etc., lowered catecholamines, such as acetylcholine, are associated.
    Choline is needed to produce ACh.
    There are microbes that can interfere with choline metabolism.

    http://www.ncbi.nlm.nih.gov/pubmed/25466896

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535645/

    There are all sorts of microbes that can induce IBS, when overgrown, or deficient. I'll bring up the case of IBS-C, since it's been my bane, and the OP has brought it up.

    An overgrowth of methanogens is a possible cause of constipation. The consideration of methanogens as pathogenic is relatively recent. Dr. Mark Pimentel has been instrumental in this research.

    http://www.nature.com/ajgsup/journal/v1/n1/full/ajgsup20126a.html

    Here's a paper that is interesting because it describes how microbes utilize catecholamines for growth. Maybe that's why we tend to crash with any sort of stimulation, whether from activity, stressors, supplements, or meds. ?

    http://www.hindawi.com/journals/scientifica/2013/361073/

    With PEM, the term includes exertion, and of course it's true, we know that.

    Strangely though, I accidentally induced it when I took a lactic acid producing probiotic.
    I hadn't been overactive that day, but the additional lactate felt the same as PEM.

    I suspect that certain microbial overgrowths and their products are a large factor in ME/CFS, but that future treatments will have to be much more specific and inter-individual than past ones.
     
  18. waiting

    waiting Senior Member

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    This is so well put, @anciendaze! A very intriguing thought.
     
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  19. halcyon

    halcyon Senior Member

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    Perhaps. Those two words get thrown around a lot but it seems like they are often misused or misattributed. Ask any doctor or layman for an example of an autoimmune disease and almost everyone will probably say MS. The problem is that there's no agreement that MS is even autoimmune and there's evidence that it isn't.

    Very true.
     
  20. anciendaze

    anciendaze Senior Member

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    "Autoimmune" has become a label for a limited version of a hypothesis: that the immune system is acting against the body's interests. The simplified early version was that the humoral immune system, which was about the only thing understood at the time, was producing antibodies against "self". Researchers now recognize this is inadequate, and are starting to investigate more complicated immune malfunctions under the rubric "autoinflammatory".

    In this regard I find a recent publication about recruitment of T-cells to damaged tissues very interesting. Notice that this is not a simple matter of producing autoantibodies. B-cells produce a peptide which is transmitted locally to memory T-cells which in turn stop signalling for more cytotoxic T-cells. You will not find such things by investigating isolated immune cells of a single type. This is an example of what I mean about making the term "immune system" refer to an actual system, not a collection of disparate parts.

    That peptide had been overlooked partly because it was a subunit of a known protein which performed an entirely different function. Biological researchers tend to suffer from "functional fixedness" which Nature doesn't even consider. Evolution will use anything that comes to hand for any purpose. Unique purpose is the exception to the general rule.

    Another example of this phenomenon takes place when we discuss ATP, which everyone here knows is there for the purpose of supplying energy to cells. This meant that researchers tended to overlook purinergic signalling in which ATP played a very different role. What seems to me to have been found is that cells often use purinergic signals to decide if other cells near them are actually acting on different signals that are less localized. In a sense the cloud of ATP molecules leaving a cell serves to confirm that some cell near it is not just aware something is wrong, but is actually taking action on the signals it has received. One possible cellular action which consumes or disperses ATP is tagging by ligands and degradation by proteasomes of foreign or misfolded proteins within the cell. This process is important in clearing infections.

    Both of these examples tended to get overlooked because the biochemicals involved were not part of general circulation. If you didn't find them in the right context, and disregarded them because you "knew" they served a different purpose, you would never understand what was going on.

    If forced to sum everything up at present, when solid data for hypotheses remain sparse, I would say we suffer from a problem with our immune systems which is causing trouble in many different places without producing the conspicuous lesions or other signs on which standard clinical practice routinely depends. We have any number of symptoms, but doctors have been trained to ignore symptoms that only the patient perceives.

    (One bone I'd like to pick with those who train psychiatrists is the exhortation to "think sphincter" in diagnosing mental illness. Don't they understand the role the autonomic nervous system plays in control of those sphincters? Ask any specialist in MS if loss of urinary continence is a significant sign.)

    What I don't have right now is a single cause that is easy to test. I'm convinced some antibodies are involved, and that polyclonal expansion of B-cells is taking place, as might happen in bacterial infections. I'm convinced cytotoxic T-cells are invading healthy tissues, and that the types of these are typical of response to viral infections. What do these conflicting clues suggest? To me it looks like another pathogen is misdirecting immune response to protect itself, and the body's defenses are blaming common viruses or bacteria already present, and generally under control. One problem we have is that a great deal of the action is taking place in the intracellular environment. It would be easier to investigate if it produced convenient biochemical signals in peripheral blood.

    We have repeatedly crossed viruses and bacteria off the list of suspects because "everybody has them". It looks to me like there are many such most people can control most of the time, but not always. (Almost everyone has EBV, but few have Burkitt's lymphoma.) What is more I feel that the defects that cause these problems to show up fairly early in adult life are not quite as unusual as claimed. We tend to suddenly behave as if we were many years older. Other people reach a similar state by a longer route.

    These are not problems of a negligible minority.
     
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