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Fibromyalgia and CFS: The Underlying Biology & Related Theoretical Issues (King's/IoP)

Discussion in 'Latest ME/CFS Research' started by Simon, Apr 21, 2015.

  1. Simon

    Simon

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    Book chapter, published March 2015, from "Clinical Challenges in the Biopsychosocial Interface"

    Fibromyalgia and Chronic Fatigue: The Underlying Biology and Related Theoretical Issues

    Romano G.F.a · Tomassi S.b · Russell A.a · Mondelli V.a · Pariante C.M.a aStress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London, UK

    Note the senior author is Prof Carmine Pariente from King's/IoP, which generally champions a biopsychosocial view of mecfs. Pariente is also the lead researcher of a £370k MRC study looking at fatigue following interferon-alpha treatment of Hepatitis C as a model of mecfs, discussed here, lay summaries from here.

    Abstract
    There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS). Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging.

    This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined.

    Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM.

    Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes.

    However, to what extent these systems' abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified.

    Paywalled, 48-hour access for $12.50 inc UK taxes. You can read some of it at Google books

    The articel cites 141 studies, many straight-up biomedical ones. It also explores changes to the HPA,a nd cortisol in particular - and a possible link to childhood trauma. This is a favourire theme at King's. Still, an interesting review. More comments as I have energy (and before my access runs out).
     
    Last edited: Apr 22, 2015
  2. Simon

    Simon

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    Commentary (in stages)
    note I've only covered the CFS elements of this review, not Fibro

    Case definitions
    Interestingly, their definition focuses on fatigue of 6 months+, and the additional symptoms quoted does not include PEM; which suggests an Oxford Criteria perpsective. That said, they don't actually cite the Oxford criteria, but do include Fukuda, as well as the suspect CDC 'Empiric' criteria. Note, though, that they also focus on mitochondrial problems which arguably are linked to PEM.

    Biomed and BPS perspective (both covered in intro)
    On biomed research
    The paper rightly notes lots of methodological issues with research to date including small sample size, different case definitions, questionable diagnostic procedures and lack of replication but adds that "some replicated findings are emerging, and the increasing number of studies in the field is encouraging"

    Inflammation
    They go on to talk about the effect of interferon-alpha treatment on Hepatitis C patients produciing similar symptoms to mecfs - the basis of their MRC study above.

    A long review of the evidence of inflammation is summarised as:
    • Pro-Inflammatory cytokines ↑ IL-1β, TNF-α, IL-6
    • Anti-inflammatory/ immunosuppressive cytokines ↑ IL-10, TGF-β1
    • C-Reactive Protein ↑ CRP
    • T and B cells ↑ CD8+, CD38+, CD4+, CD19+, CD20+, CD21+
    • Antibodies Anti: 5-HTR1A, DRD2, CHRM1, OPRM1, 5HT, ↓ IgG1, IgG3
    • Number and activity of NK cells
    • Pro-inflammatory Cytokines induced Tryptophan Metabolism ↑ Quinolinic acid ↓ Serotonin [Dr Mady Hornig is very interested in the possible role of Tryptophan in mecfs]
    next post: Oxidative stress -> mitochondrial problems -> mecfs symptoms
     
    Last edited: Apr 22, 2015
  3. Simon

    Simon

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    comments continued

    Oxidative stress -> mitochondrial problems -> mecfs symptoms
    The paper notes that oxidative stress is often linked with activation of the immune systme and implies that immune activation drives the oxidative stress, though a summary diagram implies a two-way relationship. It's not clear to me what would set off the oxidative stress in the first place, if not the immune inflammation. It then argues that the oxidative stress leads to mitochondrial damage and so energy production problems that could be behind mecfs:
    The review says that many of the symptoms of mecfs inc muscle pain, memory problems, fatigue, exercise intolerance are symptoms of mitochondrial disease too.
    [However, I've read papers on CPET/maximal exercise studies commenting that the results of these tests in mecfs patients look very different to those for patients with mitochondrial disease. And while this review cites several studies that show increased production of lactic acid, a hallmark of mitochondrial disease, not all mecfs studies find this]

    A long review of the evidence for oxidtive stress mitochondrial dysfunction markers is summarised as:
    I'm sorry these comments aren't a bit 'listy' and not well digested, but my 48 hour paid access will soon expire. More to follow.
     
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  4. Never Give Up

    Never Give Up Collecting improvements, until there's a cure.

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    Very interesting. Thanks for posting. They seem to be doubting the party line, but not willing to reject it altogether.

    It would be interesting to compare this to what the authors say about the biological mechanisms underpinning depression.
     
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  5. worldbackwards

    worldbackwards A unique snowflake

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    I imagine that we'll be seeing more of this post-IOM as everyone starts hedging their bets and preparing to jump between bandwagons if necessary. It's quite amusing that King's have suddenly just found all this out now!
     
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  6. A.B.

    A.B. Senior Member

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    If the Rituximab trial confirms the pilot study findings, the situation will change over night.
     
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  7. Esther12

    Esther12 Senior Member

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  8. Simon

    Simon

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    Hypothalamic-Pituitary-Adrenal Axis Abnormalities (especially re cortisol/stress)

    To kick off, a good description of the HPA axis:
    Very short video about the HPA axis, covering hormone secretion, the critical starting point of HPA activation:



    Basically, the Hypothalamus gland in the brain releases a hormone called CRH which acts on the Pituitary gland next door, which in turn secretes adrenocorticotropic hormone (ACTH) into the bloodstream. ACTH then reaches the Adrenal glands (sitting on top of the kidneys), inducing the release of glucocorticoids, such as cortisol.

    [​IMG]

    Relevance of HPA
    This review focuses on the release of cortisol but there are other measurable affects of HPA problems, including POTS and neurally mediated hypotension (studied by Prof Julia Newton), heart rate variablilty (Newton and others), and cerebral blood flow (Prof Julian Stewart).

    A key feature of the HPA is the 'awakening response' where cortisol level rise markedly as we come out of sleep and start the day. There's quite a lot of evidence this response is blunted in mecfs, along with reduced average daily cortisol levels [though only compared with healthy controls; it's not clear how deconditioned controls do, or those with other illnesses. Then again, that's true for most mecfs findings - the IoM report highlighted the lack of use of sick controls that would help show if abnormalities are specific to mecfs or are more markers of ill-health].

    As the authors say:
    On the link with childhood trauma
    However, a couple of studies that probably came out after this chapter went to press suggest otherwise. A large population study (n=1,000), measuring cortisol and heart-rate variability (another HPA measure) at two time points found no link between difficult childhood (or adult) experiences and either of these measures. And another new study looked at mecfs adolescents and found no link between childhood trauma and the Cortisol Awakening Reponse (CAR). The authors of this study pointed out that previous research measured CAR just once which is unreliable as it varies a lot day to day, and childhood trauma would be expected to have a more general affect. They looked at CAR over 7 days, and found no link with childhood trauma.

    Other ways of testing the HPA are so-called provocation tests, both the insulin tolerance test (injecting insulin causes a release of the stress hormone cortisol) or a 'social stress test' which again causes cortisol to rise. Cortisol response in mecfs patients was reduced to both tests. Similar blunted cortisol response was seen in CRH and ACTH testing (remember, these are the hormones that kick off HPA activity).

    Summary of findings:
    to come: chapter conclusions
     
    Last edited: Apr 23, 2015
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  9. Simon

    Simon

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    Summary and conclusions

    Overall, the authors say there are "some common themes underlying a plethora of less consistent findings", themes they identify as:
    • Some evidence of immune activation (nb this would have been written before the large Hornig/Lipkin 'immune signatures' paper) qualified by "Whether or not the inflammatory profile might be different in different forms of fatigue (i.e., in milder or short- er syndromes) has yet to be studied [140] "
    • Some evidence of abonmal oxidative stress and mitochondrial dysfunction
    • Some evidence of a role of the HPA axis, with typically blunted responses. "However, again it is unclear whether the HPA axis is involved as a primary causal factor or as a secondary, maintaining factor, prolonging fatigue or worsening the outcome."
    • the childhood trauma aspect didn't feature in the summary.
    They finish off with:
    Overall, I thought it was a useful piece. Though I ran out of access before I'd had time to read it all properly: 48-hour access isn't very useful to patients with cognitve fatigue.
     
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  10. Sidereal

    Sidereal Senior Member

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    Can you not just take screenshots of the whole article?
     
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  11. Tired of being sick

    Tired of being sick Senior Member

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    Why only a 48-hour access?
     
  12. Tired of being sick

    Tired of being sick Senior Member

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    I knew it had to be $$$$$!
     
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  13. Tired of being sick

    Tired of being sick Senior Member

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    Lol........

    Rent/Cloud

    • Rent for 48h to view
    • Buy Cloud Access for unlimited viewing via different devices
    • Synchronizing in the ReadCube Cloud
    • Printing and saving restrictions apply
     
  14. Simon

    Simon

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    You use the handy gizmos, not to mention copy and paste.
    Yeah: no printing, no saving; some neat features such as pop-up inline references (as opposed to scrolling to the end of the docc), while it lasts.

    To be fair, King's have been doing cortisol work for a good decade, and Parient must have applied for the MRC grant for his interferon study at least four years ago (that study is looking for links between psychosocial factors and post-interferon-treatment fatigue too).
     
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  15. wastwater

    wastwater Senior Member

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    I don't think I have very much pituitary gland left as seen in my Scan.might be adenoma or empty sellar syndrome
     
    Last edited: Apr 23, 2015
  16. debored13

    debored13 Senior Member

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    it's possible that cfs is because of "reductive stress", an opposite mechanism to oxidative stress. this distinction is important as reducing agents would make it worse, whereas oxidizing agents would make it better
     
  17. wastwater

    wastwater Senior Member

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    Primary ESS most likely in reply to my earlier post
     
  18. Mithriel

    Mithriel Senior Member

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    I realise I am too cynical, but I worry that all this abnormal biology is seen as a consequence of our disease being perpetuated because our "sickness response" is kept switched on. And it is kept switched on because of our behaviour.

    So, of course, we need intensive CBT and GET to fix it.

    Please let me be wrong.
     

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