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

[Simon]

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).

 

[Simon]

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)

it has been proposed that such similar disorders be considered on a continuum, as opposed to distinct diagnoses: that is, to be viewed according to a dimensional approach, as opposed to a categorical approach [6][this reference basically argues that there are a range of somatic disorders with common causes, not distinct IBS, CFS etc]

Biological, psychological, and social factors have been implicated in the pathogenesis and the maintenance of these disorders, although the degree to which each of these factors contributes to these processes has been a source of debate, with more debate arising in recent years as further biological evidence has mounted [7, 8: these are the Simon Wessely 'Zebras' paper emphpasising the BPS perspective, and the Michael Maes/Frank Twisk pro-biomedical riposte].

also note:
The current paucity of treatment options has contributed to the increased level of disability, and without a medical explanation for their symptoms, patients feel increasingly stigmatised..

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

Interestingly, the increased production of pro- inflammatory cytokines can contribute to the de- velopment of a range of symptoms and behav- ioural changes that both humans and animals ex- perience when affected by physical illnesses and that resemble those in CFS/FM. These changes and symptoms are often referred to as ‘sickness behaviour’ [some prefer the phrase "sickness response"] and include symptoms such as fatigue, pain, low mood, and cognitive impairment. While this is an evolutionary adaptive response during infection because it facilitates the body’s fight against virus or bacteria, more recently, it has been suggested that when such changes occur in the absence of infection, they may contribute to pathology [11]

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

 

[Simon]

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:

Under normal circumstances, ROS [reactive oxygenn species] in mitochondria are generated through the progression of reductive and oxidative reactions but are neutralised by the scavenger activity of antioxidants. However, if the equilibrium between antioxidants and the oxidative status is compromised, the accumulation of ROS may damage the structure of the mitochondria, leading to dysfunction in the production of O 2 and ATP, which leads to cell death (apoptosis). Muscle and nerve cells are especially sensitive to mitochondrial defects because they need so much ATP and O 2 to function normally

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:

Table 2. Oxidative and nitrosative stress and mitochondrial dysfunction markers

• Oxidative stress products ↑ Ox-LDL, 8-isoprostaglandin, F2α-isoprostane, peroxides, Met-Hb, TBARS
• Anti-oxidants ↓ CoQ10, glutathione
• Antibodies vs. oxidative and nitrosative stress products. Anti: Oxidised fatty acids, MDA, nitro-tyrosine, nitro- phenylalanine, nitro-arginine, nitro-tryptophan, nitro-cysteine
• Enzymes ↑ COX-2, iNOS
• Transcription factors ↑ NF-kB (nuclear factor-kB), ↓ p53
• Mitochondrial dysfunction ↑ Lactic acid, ↓ ATP, mitochondrial DNA

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.

 

[Never Give Up]

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.

 

[worldbackwards]

They seem to be doubting the party line, but not willing to reject it altogether.

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!

 

[A.B.]

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!

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

 

[Esther12]

The next chapter in that book is about how patients should be treated and looks dire (although I could only get access to about 2/3 of the pages):

http://forums.phoenixrising.me/inde...pace-trial-protocol.3928/page-127#post-586931

 

[Simon]

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

To kick off, a good description of the HPA axis:

Another biological system extensively studied in CFS/FM is the neuroendocrine system [94] , and the hypothalamic-pituitary-adrenal (HPA) axis in particular. Broadly, the endocrine system coordinates functions among different organs through hormones (peptides, steroids, or amino acid derivatives) released into the bloodstream from the endocrine glands. Hormones determine the maintenance of homeostasis and affect target tis- sues’ functions by binding selectively to receptors located inside or on the surface of cells. The HPA axis is one of the main neuroendocrine axes and is directly relevant to the biological responses to stress.

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.

Relevance of HPA

the HPA axis is involved in controlling responses to stress; inducing behavioural changes [96] ; and affecting many fundamental bodily functions, including immune system activity, mood and energy storage, and energy/fatigue [21, 97, 98] . The relevance of cortisol levels to CFS/FM was first considered based on the observation that conditions characterised by altered levels of glucocorticoids, such as Addi- son’s and Cushing’s diseases, have similar core symptoms, including fatigue, arthralgia, myalgia, sleep problems, and mood disturbances [99] .

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:

4] . Whether these abnormalities are a cause, a consequence, or a maintaining factor is, however, still under debate.

On the link with childhood trauma

Two recent studies found a reduced CAR in a large group of adolescents with CFS and in subjects with CFS and a history of childhood traumatic experience, with CFS patients without such a history showing normal cortisol levels [108, 109] . This seems to suggest a significant role for childhood trauma in influencing and shaping the individual stress response in the context of CFS [110] .

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:

Table 3. HPA axis abnormalities

• Basal cortisol levels ↓ Cortisol Awakening Response ↓ Cortisol profile
• Stimulation tests ↓ Cortisol after Insulin tolerance test and TSST (Trier Social Stress Test) ↓ Cortisol after ACTH and CRH test (hypo-responsiveness)
• Suppression test ↓ Cortisol after DST and PST (hyper-responsiveness)

DST = dexamethasone suppression test; PST = prednisolone suppression test.

to come: chapter conclusions

 

[Simon]

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:

Perhaps more in CFS/FM than in any other area, more biological research is truly needed in order to identify new targetable mechanisms that could be used a biomarkers for outcome prediction and for the discovery of new therapeutic interventions.

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.

 

[Sidereal]

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.

Can you not just take screenshots of the whole article?

 

[Tired of being sick]

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.

Why only a 48-hour access?

 

[Tired of being sick]

I knew it had to be $$$$$!

 

[Tired of being sick]

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

 

[Simon]

Can you not just take screenshots of the whole article?

You use the handy gizmos, not to mention copy and paste.

Printing and saving restrictions apply

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.

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!

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).

 

[wastwater]

I don't think I have very much pituitary gland left as seen in my Scan.might be adenoma or empty sellar syndrome

 

[frozenborderline]

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.

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

 

[wastwater]

Primary ESS most likely in reply to my earlier post

 

[Mithriel]

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.