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Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency (2017) Bliksrud

Discussion in 'ME/CFS research' started by hixxy, Dec 14, 2017.

  1. hixxy

    hixxy Senior Member (Voting Rights)


    More at the links below.

    English: http://tidsskriftet.no/en/2017/12/d...yndrome-and-pyruvate-dehydrogenase-deficiency
    Norwegian: http://tidsskriftet.no/2017/11/deba...ttelsessyndrom-og-pyruvat-dehydrogenasemangel

    There is a reply by Karl Johan Tronstad, Øystein Fluge and Olav Mella in the comments under the English article.
    merylg, Barry, Kalliope and 4 others like this.
  2. Dolphin

    Dolphin Senior Member (Voting Rights)


    Chronic fatigue syndrome and pyruvate dehydrogenase function

    Karl Johan Tronstad, Øystein Fluge, Olav Mella

    We appreciate the comments, but wonder why this kind of debate is raised in Tidsskriftet (The Journal of the Norwegian Medical Association) rather than the journal which published the original

    article. Bliksrud gives an inaccurate image of the findings, with partially uncritical use of sources and an incomplete description of a complex research field.

    We have suggested the hypothesis that impaired pyruvate dehydrogenase function may play a role in chronic fatigue syndrome. We have not made any statements “without reservations”. The hypothesis is based on scientific arguments and will be tested thoroughly through further research. We have stressed that there is no indication of a structural defect in, nor a lack of, the pyruvate dehydrogenase enzyme in patients with chronic fatigue syndrome. We argue that our results may imply a dysregulation of the enzyme function. We have repeatedly emphasized that these findings at present do not justify new methods for treatment or diagnostics. How the media chose to report on the findings was evidently difficult to control.

    We have made every effort to describe our results in a clear and precise manner in order to avoid misunderstandings. Terms like “pyruvate dehydrogenase deficiency” are misleading in this context, and it is unfortunate that Bliksrud applies this particular term in his comment, and even in the title. There is no indication of an enzyme deficiency. Rather, we have explained why we believe the results to be consistent with a partial impairment of the enzyme function, as a result of changes in the underlying regulatory mechanisms.

    Pyruvate dehydrogenase is an essential enzyme in energy metabolism, and is carefully regulated both allosterically, post-translationally and through gene transcription, partly via energy-sensitive signaling pathways (1, 2). When Bliksrud narrows the enzyme’s role in disease mechanisms to what is seen in genetic primary pyruvate dehydrogenase deficiency, the basis for comparison is limited. It is not obvious that that such a systemic, permanent condition should be comparable to a more fluctuating, perhaps local and context dependent impairment of the enzyme function. In a number of conditions, pyruvate dehydrogenase is associated with other potentially pathogenic mechanisms. One example is primary biliary cirrhosis, which involves autoantibodies against components of the pyruvate dehydrogenase complex, and where fatigue is a characteristic symptom (3). It is also relevant to look at other conditions involving glucose metabolism and regulation of pyruvate dehydrogenase, such as diabetes and cancer (2), and also normal adaptation to variable metabolic and physiological circumstances (4). In the article, we have elaborated on how these mechanisms may play a part in chronic fatigue syndrome.

    There are no published systematic studies suggesting increased blood lactate at rest in chronic fatigue syndrome, but many patients describe a sensation of rapid accumulation of lactate upon activity. The accumulation of lactate may occur at a considerably lower muscular effort than among healthy. Alanine levels normally increase in plasma as a result of muscular work, in parallel with lactate (1), but we anticipate such an increase to be considerably more permanent in genetic primary pyruvate dehydrogenase deficiency than in chronic fatigue syndrome, where the effects are context dependent and triggered by activity. Since alanine plays a specific role in transporting amino groups to the liver, from amino acid catabolism in the muscles, the serum level is expected to vary independently of changes in glucose catabolism. In order to limit possible misinterpretations, we therefore chose not to include alanine in the statistical analyses of the amino acid categories. Studies of both lactate and alanine in chronic fatigue syndrome should preferentially be performed using standardized protocols for physical exercise testing. We would also like to point out that measurements of citric acid cycle substrate consumption are used in laboratory investigations to detect mitochondrial pyruvate oxidation defects (5).

    Direct measurement of pyruvate dehydrogenase activity would of course be relevant, but is complicated. A method developed to detect genetic primary dehydrogenase deficiency would not necessarily be suitable for measurement of reversible and contextual enzyme inhibition, which may be caused by altered phosphorylation state. Therefore, as shown in the article, we are working with living cell cultures exposed to serum from either patients with chronic fatigue syndrome or healthy controls, to assess central parameters of energy metabolism.

    Although individual patients describe avoidance of certain foods, there are no systematic studies which show that patients with chronic fatigue syndrome, with a body mass index equivalent to that of the general population, have a significantly different diet compared to healthy controls. Surprisingly, Bliksrud refers to a case series describing four patients with known eating disorder who developed chronic fatigue syndrome. Needless to say, this article does not constitute relevant evidence of the dietary habits of this patient population in general, nor of our study sample. Nevertheless, as we have not performed a detailed dietary anamnesis, we cannot categorically rule out that dietary factors could play a role. However, as there are no known or expected systematic differences in dietary habits, the number of included patients (153) and controls (102) will counteract significant bias in the analyses.

    We observed that overnight fasting led to reduced levels of several amino acids, and therefore included only non-fasting patients in the comparison (see supplementary tables in the article). The altered amino acid profile was primarily observed in non-fasting women with chronic fatigue syndrome as compared to healthy women. Some changes were highly significant, of moderate effect sizes, with differences in mean values of approximately 15%. Yet the values were within the normal ranges. Thus, there are no amino acid deficiencies, but the data rather reflect compensation mechanisms for an altered metabolism. In the same samples, we observed no differences in triglyceride levels which increase after meals, or free fatty acids which increase upon fasting (1). We therefore find it unlikely that differences in fasting state should explain the findings. Also, our results are consistent with other reports, including studies where only fasting individuals were included (see references in article).

    Our study included more patients than previous metabolism reports. The changes in amino acid profiles could not be explained by disease severity or duration, age, BMI or physical activity level (see supplementary tables in article). Bliksrud mentions, without further specification, that immobilization leads to metabolic changes, and refers to a study of mRNA analysis of muscle biopsies after limb immobilization. There are more relevant and comparable studies of serum metabolites after immobilization, where the results do not correspond to our findings in patients with chronic fatigue syndrome (6, 7).

    We have not found reports showing an amino acid pattern equivalent to what we observed in patients with chronic fatigue syndrome, in healthy subjects after exercise, inactivity or dietary changes, nor in other patient groups. That does not signify that the observed changes are exclusive for patients with chronic fatigue syndrome. We have not maintained that these changes are specific to chronic fatigue syndrome, and we entirely agree with Bliksrud that it would be interesting to investigate whether similar changes take place in other groups suffering substantial fatigue.

    We hope we have conveyed a more nuanced image than reflected in Bliksrud’s comments, and we confirm that our hypothesis still stands.

    1. Berg JM, Tymoczko JL, Gatto GJ, Stryer L. Biochemistry. 8. utgave. New York: W.H. Freeman & Company, 2015.
    2. Gray LR, Tompkins SC, Taylor EB. Regulation of pyruvate metabolism and human disease. Cell Mol Life Sci. 2014;71(14):2577-604.
    3. Bjorkland A, Loof L, Mendel-Hartvig I, Totterman TH. Primary biliary cirrhosis. High proportions of B cells in blood and liver tissue produce anti-mitochondrial antibodies of several Ig classes. J Immunol. 1994;153(6):2750-7.
    4. Zhang S, Hulver MW, McMillan RP et al. The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutr Metab (Lond). 2014;11(1):10.
    5. Sperl W, Fleuren L, Freisinger P et al. The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders. J Inherit Metab Dis. 2015;38(3):391-403.
    6. Glover EI, Yasuda N, Tarnopolsky MA et al. Little change in markers of protein breakdown and oxidative stress in humans in immobilization-induced skeletal muscle atrophy. Appl Physiol Nutr Metab. 2010;35(2):125-33.
    7. Kujala UM, Makinen VP, Heinonen I et al. Long-term leisure-time physical activity and serum metabolome. Circulation. 2013;127(3):340-8.
    Sing, merylg, Marit @memhj and 16 others like this.
  3. Andy

    Andy Committee Member

    Hampshire, UK
    BurnA, Trish, Valentijn and 1 other person like this.
  4. Kalliope

    Kalliope Senior Member (Voting Rights)

    This debate in the Journal for the Norwegian Medical Association has escalated, and deserves its own thread.
    I therefore copy a previous post of mine from the thread News from Scandinavia into this thread, as I was quite shocked by today's contribution to the debate by prof. Wyller:

    Professor Vegard Bruun Wyller joins the debate. He is an ME-researcher with a bio-psycho-social approach to ME and one of the editors of the Journal for the Norwegian Medical Association.

    Ukritisk medieopptreden av ME-forskere
    google translation: Uncritical media performance by ME researchers

    This tabloid message was rapidly spread in social media, and may have influenced both public opinion, bureaucratic decisions (including research funding) and patient self-perception. The latter may cause patients to fail to receive effective treatment. A recent intervention study shows the effect of the "Lightning Process" method (4), which is a variant of cognitive behavioral therapy. Patients with chronic fatigue syndrome should of course be encouraged to try such methods, but many will probably say no if they believe in the (incorrect) message that the disease is "in the blood". Thus, they miss an opportunity to improve their level of functioning and, at best, become completely healthy.

    Inara, Barry, Lidia and 6 others like this.
  5. Londinium

    Londinium Senior Member (Voting Rights)

    The first response should be to ask for a citation that LP is 'a variant of CBT'. Is that the new selling point for LP now that neurolinguistic programming is considered to be nonsense?

    Funny how certain BPS proponents are happy to jump on alleged methodological flaws of biomedical studies whilst remaining blind to the glaring shortcomings (e.g. A vs A+B, FFS) of their own field's trials.

    Going back to the original criticisms, the only one that seemed to have at least half a point was the one around comparing patients to fully healthy controls, thereby introducing a confounding factor of immobility. This is a often a difficulty with ME/CFS studies, and the idea that one could use controls who have otherwise been immobilised isn't necessarily a bad one, but you might be swapping one confounding factor for another. However, even then it seems unfair to use the Su et al study to criticise as 'tenuous' the finding around serum inhibiting ATP production when that study itself is using serum not only from patients with muscle wastage but also chronic renal failure. Seems Tronstad/Fluge/Mella were right to bat that one back by finding far more relevant studies that, taken in conjunction with the Su study, suggest it's probably kidney failure that causes serum to inhibit ATP production that muscle wastage.
    Inara, Snow Leopard, Barry and 5 others like this.
  6. Daisybell

    Daisybell Senior Member (Voting Rights)

    New Zealand
    Bliksrud just sounds annoyed that he is receiving blood samples for metabolic testing.
    Those pesky patients - why won’t they just accept that they have a psychological illness and keep out of my way....

    I wonder if he has actually done the metabolic testing on any of the samples??
    Manganus, Inara, Barry and 3 others like this.
  7. Esther12

    Esther12 Senior Member (Voting Rights)

    The Norwegian biopsychosocial lot seem keener to tie themselves to LP than their UK colleagues. I doubt that's going to work out well for them in the long-run.

    Is there a way to post a link to Tuller's new piece?
    Inara, Snow Leopard, Barry and 8 others like this.
  8. Kalliope

    Kalliope Senior Member (Voting Rights)

    There is a national center of expertise for ME/CFS in Norway, Oslo. The doctor leading the center used to work in prof. Wyller's team (he works with children and adolescents, the center of expertise with people over 18 years).

    She seems stuck in a bio-psycho-social approach to ME. It is a tragedy, because with the right people in a center like that, things could really have moved forwards for ME-patients.

    Recently, the Norwegian Consumer Ombudsman had a campaign against alternative medicine. The rules concerning advertising have become very strict. You can among other no longer share "recovery-stories" if you are selling the remedy/undocumented approach.

    An LP-coach, who has become a multimillionaire from selling LP in Norway and is considered an expert on ME by some health personnel, was one of the recipients of a letter from the Consumer Ombudsman about the new rules. All her recovery-stories on her Facebookpage and website were quickly deleted.

    A few days later a new patient-organisation (sic) surfaced called Recovery Norge. It consists of people having cured themselves by their own efforts. Quite a few from ME by LP. Of course this LP-coach is a central person but the face outwards is actually a doctor (who, guess what? Has written a debate article together with prof. Wyller on how we should no longer divide between what is "psychological" and what is "physiological" and of course using ME as the main example).

    Yesterday Recovery Norge shared the "happy" news that they had been invited to the national center of expertise for ME/CFS to give a lecture.

    The Consumer Ombudsman will do nothing, as this is a patient organisation now, not sellers of alternative approaches.

    And this new patient organisation is just sharing hope, according to themselves. You CAN get better, you see, if you're just willing to make the effort. :facepalm::banghead::arghh:
    Last edited: Dec 15, 2017
    Inara, Viola, Barry and 11 others like this.
  9. Kalliope

    Kalliope Senior Member (Voting Rights)

    New addition to the debate about PDH-enzyme and ME in the Journal for the Norwegian Medical Association.

    It is written by a research supervisor (I hope I have translated the job title correctly) in a hospital.

    He describes the function to the PDH-enzyme and says the PDH-complex contains several groups of sulphur and thus can be a point of attack by chronic exposure to mercury. He has been contacted by several people with background within dentistry and with symptoms of chronic fatigue syndrome who claim to have improved with supplements of lipoid acid.

    Kronisk utmattelse og pyruvat dehydregonase komplekset
    google translation Chronic fatigue syndrome and pyruvate dehydregonase complex
    Last edited: Dec 15, 2017
    Inara, merylg, Viola and 6 others like this.
  10. Esther12

    Esther12 Senior Member (Voting Rights)

    I was just reading, via google translate, this silly paper on CFS [unsure whether this should be a new thread, I thought probably not worth it but others may disagree]:

    Chronic fatigue syndrome in general practice
    By Kirsti Malterud and Hanne Hollnagel


    Maybe this helps explain the soft-spot for the Lightning Process we see from some in Norway's medical profession?:

    Some more fun bits:

    They go beyond uncritical citing of PACE:

  11. Barry

    Barry Senior Member (Voting Rights)

    Exactly ... medical research would be great if it weren't for people getting ill all the time.
  12. Marit @memhj

    Marit @memhj Established Member (Voting Rights)

    In my deliriumishy-frustration search over the outcome measures in supra-efficient Psych-based Therapy/Treatment interventions nowadays (SMILE/PACE etc), I read Powell 2001 and ya!! One point is the text itself,next and bestpoint: that patient-cohort became more healthier than norwegian healthy teens..... Powell 2001 .

    magical, better than LP even!!!

    so when mentions Wyllers comment in this tread, here is more:

    What exactly is myalgic encephalomyelitis? 20oct2015 http://tidsskriftet.no/en/2015/10/what-exactly-myalgic-encephalomyelitis

    Chronic fatigue syndrome/myalgic encephalomyelitis – pathophysiology, diagnosis and treatment
    Wyller, Reme 1dec2015 http://tidsskriftet.no/en/2015/12/c...litis-pathophysiology-diagnosis-and-treatment

    Chronic fatigue syndrome and experience with the Lightning Process Live Landmark et al 15mar2016 (want RCT)

    ;) so Tuller & the paceman crew is wellcome, you guys did not catch the LP-plague
  13. Kalliope

    Kalliope Senior Member (Voting Rights)

    New addition to the debate.
    This time by Michael Ottlinger - medical scientist and care giver.
    His contribution is in English.

    We need more true metabolists looking at CFS

    I hope this subject will enter the Genetic and Metabolic Diseases practice for whatever knowledge can be gained. This is a desperate situation for so many people who have lingered, are lingering, with these debilitating diseases.
    Manganus, Barry, Inara and 4 others like this.
  14. deleder2k

    deleder2k Established Member

    Do we know what tests he is referring to?

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