Adrenergic dysfunction in patients with [ME/CFS] and fibromyalgia: A systematic review and meta-analysis, 2024, Hendrix et al

[SNT Gatchaman]

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis
Jolien Hendrix; Lara Fanning; Arne Wyns; Ishtiaq Ahmed; Madhura Shekhar Patil; Emma Richter; Jente Van Campenhout; Kelly Ickmans; Rembert Mertens; Jo Nijs; Lode Godderis; Andrea Polli

BACKGROUND
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms.

METHODS
A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software.

RESULTS
This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31–.67]; Z = 5.29, p < .01) and β1 adrenergic receptor expression (SMD = .79 [.06–1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18–.97]; Z = 2.85, p < .01), β2 AR (SMD = .41 [.02–.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03–.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [−.47 to −.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = −.79 [−1.27 to −.30]; Z = −3.14; p < .01).

CONCLUSIONS
This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

Link | PDF (European Journal of Clinical Investigation)

 

[Creekside]

Another study that should have used inactive, unhealthy controls. I would expect a difference in adrenaline functions between active an inactive people.

 

[mango]

 

[Mij]

Doesn't high adrenaline slow down the thyroid? I have this issue since menopause started but not M.E.

 

[Dolphin]

The lead author has just written this:

Wanneer sporten je gezondheid in gevaar brengt
https://www.eoswetenschap.eu/psyche-brein/wanneer-sporten-je-gezondheid-gevaar-brengt

Automated English translation:
When exercise puts your health at risk
https://www-eoswetenschap-eu.transl...uto&_x_tr_tl=en&_x_tr_hl=en-US&_x_tr_pto=wapp

https://www-eoswetenschap-eu.transl...uto&_x_tr_tl=en&_x_tr_hl=en-US&_x_tr_pto=wapp
Jolien Hendrix
Jolien Hendrix is a PhD researcher at the Vrije Universiteit Brussel and KU Leuven. Her research focuses on the role of epigenetics and the autonomic nervous system in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia. She compares patients with healthy individuals to investigate which biological abnormalities could explain their symptoms. The research is supervised by professor Jo Nijs, professor Lode Godderis and dr. Andrea Polli and is funded by FWO.

https://twitter.com/user/status/1841126055874019791

 

[DigitalDrifter]

Would anybody care to speculate upon why this was found? Also Jarred Younger Says ME & Fibromyalgia are different manifestations of the same illness, do we agree or disagree?

 

[Ash]

Would anybody care to speculate upon why this was found? Also Jarred Younger Says ME & Fibromyalgia are different manifestations of the same illness, do we agree or disagree?

Yes.

I think he said they (him and his colleagues I guess) were tending to think of them as different manifestations of the same thing, rather than that they’d made a firm conclusion that this is the case. I think he did a video on this a while back?

I think at the milder end FM and ME present very differently, but people who’re severely affected by both have more overlap.

I’ve always thought of them as two overlapping circles and not two sides of the same coin or whatever.

But I think its complicated by the fact that the very worst people in UK BPSery and as well as all the doctors who call ME “your chronic fatigue” and use this as a reason not to investigate even unrelated symptoms and conditions because everything can be explained away via ‘chronic fatigue’ as if that were an explanation for and in itself. Failing this FM call explain all the troubling straggler symptoms also apparently as an explanation all to itself even though we don’t actually know what it is. So this well trodden path of conflation, as a tool of exclusion from medical treatment, both of these conditions are here considered no medical, does bias me against “Lumping”.

I don’t think we benefit people with either or both diagnosis and symptom patterns by assuming that they are one and the same from a research perspective.

I’m a “Splitter”.

I also think probably it’s too early to say either way.

 

[shak8]

I have been diagnosed with both FM and CFS, 28 years ago.

I find the words used for diagnosis (IOM 2015) are imprecise:

non-refreshing sleep, confusion, what exactly do these mean?

Since the etiology of either diagnosis is unknown, whether they are closely related is speculation.


The symptoms I do NOT have:

no headaches, no lymph node enlargement (during PEM).
No OI.
No extreme sleep disturbances (my sleep meds work for the most part)
no exacerbation of exhaustion to the point of needing days in bed

I DO have:

daily moderate-severe muscle pain in several body regions

delayed onset muscle soreness (DOMS) from innocuous or light, repetitive muscle use,

dizziness with gait problems when I've exceeded my limits (more than an hour at a time in public).

social and sensory intolerance, inability to concentrate, distracted

exhaustion from very light activities (one hour upright, in public; extended phone calls, walking 30 min x 2 days in a row)




.

 

[ME/CFS Science Blog]

Had a closer look at this review. The meta-analyses are presented in the supplementary material here:
https://onlinelibrary.wiley.com/act...i.14318&file=eci14318-sup-0001-AppendixS1.pdf

Here's an overview of the main results for the ME/CFS meta-analyses. Most of the findings did not show a significant result.

For adrenaline 3 out of 5 studies (78% of the weights) were from the Wyller group. The reviewers included 91 patients from the Kristiansen et al. 2019 study but those 91 were patients with chronic fatigue following EBV. Only a small minority of 19 met the Canadian criteria.
https://pubmed.ncbi.nlm.nih.gov/31039432/

The response to physical stressor studies sound interesting but I've checked and these are mainly the 3 studies by the Lights and the failed replication attempt by Lloyd et al. For those who don't remember Alan and Kathleen Wright were studying fatigue and reported gene expression changes in ME/CFS patients after exercise including in adrenergic receptors. These were popular studies for a while but when the group of Andrew Lloyd tried to replicate it, they failed to find the same results.
https://pubmed.ncbi.nlm.nih.gov/19647494/
https://pubmed.ncbi.nlm.nih.gov/21615807/
https://pubmed.ncbi.nlm.nih.gov/22210239/
https://pubmed.ncbi.nlm.nih.gov/27713703/

There is also one study, Krupp et al. 2003, that reported extreme effect sizes (SMD of -7.66 for example). Perhaps there is an error there than the authors reported an SE while the reviewers thought it was an SD. Anyway, it does not seem reliable and is best excluded I think.

 

[forestglip]

The response to physical stressor studies sound interesting but I've checked and these are mainly the 3 studies by the Lights and the failed replication attempt by Lloyd et al. For those who don't remember Alan and Kathleen Wright were studying fatigue and reported gene expression changes in ME/CFS patients after exercise including in adrenergic receptors. These were popular studies for a while but when the group of Andrew Lloyd tried to replicate it, they failed to find the same results.

I wonder why Lloyd didn't also test a2a.

 

[Hutan]

So, it's sounding pretty much like a null result across the board then.

I see that Younger made the same point as occurred to me that the measure of adrenalin at rest probably wasn't really 'at rest' for the ME/CFS patients. Getting into the clinic for the test was probably a much bigger deal compared to everyday activity levels for the ME/CFS patients, so it's not surprising that some people with ME/CFS might have a bit more adrenalin when sitting in the clinic.

I'm actually surprised that there wasn't a bigger effect. I'd be open to the idea that something about adrenalin is not working right, given I've observed that novel situations seem to protect a bit against PEM.

Given all of that, the conclusion in the abstract of this paper looks to be reporting what they wanted to report:

This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

 

[fst]

Getting into the clinic for the test was probably a much bigger deal compared to everyday activity levels for the ME/CFS patients, so it's not surprising that some people with ME/CFS might have a bit more adrenalin when sitting in the clinic.

If the effect is due to getting to the clinic, then, in a way, these studies did show a difference in adrenergic function. Just not 'at rest', as claimed, and probably heavily confounded by fitness level and means of getting to the clinic.

Also Adrenaline and Noradrenaline have a short plasma half-life, 2-3 Minutes. So I'd assume that levels return to baseline relatively fast, unless there's sustained stimulus (which might very well be the case).

I'd be open to the idea that something about adrenalin is not working right, given I've observed that novel situations seem to protect a bit against PEM.

I have experienced the opposite, novel situations are likely to cause PEM and routine stuff is more easy. But maybe it depends on the nature of these novel situations.

Still, I'm also open to the idea, the 'adrenaline dumps' were quite real for me.

I've been wondering, whether it could be increased sensitivity (similar to the buspirone story) instead of adrenaline levels themselves, since all these studies are not really convincing.

 

[ScoutB]

On the novel situation thing -- as far as I know, catecholamines (adrenaline/epinephrine, noradrenaline/norepinephrine, dopamine) are water soluble and don't cross the bbb much. (Though I believe the release of these things as neurotransmitters in the brain is still often going hand in hand with their separate release into the bloodstream as part of a general response to taxing situations, bear attacks etc.)

On the brain side, my skim of studies before left me with the impression that the brain is sort of adjusting the pattern of how it releases noradrenaline vs dopamine in novel situations. E.g. this study of mice exploring virtual reality environments said:

We found that within familiar environments some [dopamine releasing] axons and the vast majority of [noradrenaline releasing] axons showed a correlation with the animals’ running speed. However, as mice approached previously learned rewarded locations, a large majority of [dopamine releasing] axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, [noradrenaline releasing] axons displayed a pre-movement signal predictive of the animal’s transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many [noradrenaline releasing] axons showed large increases in activity that remained elevated for over a minute, while the previously observed [dopamine releasing] axon ramping-to-reward dynamics disappeared during the same period.

So, just to make stuff up for an example, you could imagine maybe if dopamine release isn't working quite right for us under normal conditions, maybe certain novel situations/environments could mask that issue because there the brain is switching over to a different mode of dopamine/noradrenaline use anyway.