A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients with Chronic Fatigue, 2019, Padnekar et al

[Andy]

Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates. The comparison is performed against matched healthy control subjects.

We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously. Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.

Paywall, https://ieeexplore.ieee.org/document/8857427
Sci hub, https://sci-hub.se/10.1109/embc.2019.8857427

 

[Sly Saint]

I thought that generally speaking pwME have lower cortisol levels than 'the norm'?

Findings
Hypocortisolism (a low cortisol level) frequently occurs in patients with ME/CFS, confirmed by studies measuring cortisol levels and in urine[4] and saliva.[8][9] In addition to general hypocortisolism, ME/CFS patients have a decreased cortisol awakening response, ie, morning cortisol levels peak later compared to healthy controls.[10] In 2018, Roerink, et al, studied hair cortisol concentrations in CFS patients to assess if hypocortisolism was a prolonged phenomenon. They found that there was a trend of lower hair cortisol concentrations in CFS patients, thus suggesting that hypocortisolism was long-term in ME/CFS.[10] As people with ME/CFS improved, their hypocortisolism improved.[9]

https://www.me-pedia.org/wiki/Cortisol

eta: this research seems to suggest the opposite or have i misunderstood.

 

[Amw66]

I thought that generally speaking pwME have lower cortisol levels than 'the norm'?

https://www.me-pedia.org/wiki/Cortisol

eta: this research seems to suggest the opposite or have i misunderstood.

Urine , saliva and hair, but not serum.
My daughter had slightly low cortisol serum levels a couple of years ago, which prompted endocrinologist to try hydrocortisone. . Not tested since then .

 

[MeSci]

Haven't read it, but am put off by the use of 'chronic fatigue' instead of 'chronic fatigue syndrome'.

 

[rvallee]

The authors' understanding of FM and ME is laughably bad but they could have stumbled on something interesting nonetheless.

The liver seems to come up a lot. It's also the main organ in clearing up lactate.

So this is an interesting angle, one not of overproduction of certain hormones and metabolic byproducts but of an impaired ability to clear them up. Does that make sense, @mariovitali?

Question would remain what triggers this impairment and whether it's a dysfunction or the normal operation of an upstream process. I wonder if that is also a factor in the sickness response.

 

[FMMM1]

This is an extract from the paper:
"The serum cortisol level is only a marker. If the principal issue is lower clearance rate, we should understand it with respect to a key tissue and investigate which of the biological mechanisms that breakdown cortisol are affected".

Interesting to know if they could resolve what is lowering the clearance rate and, if so, whether this would be a biomarker?

 

[mariovitali]

Interesting work in the sense that they use a novel method to analyse cortisol patterns. To be honest i've never heard the algorithm they used and i have no idea how it works. Unfortunately, i will not be able to spend time to get to know the algorithm in detail.

@rvallee Yes what you say makes sense. And it is probably the same reason on why severely ill patients cannot tolerate medications and/or supplements.I hypothesise that this happens because the liver cannot detoxify the substances that are contained in supplements/medications.

Here are some references regarding the Liver and ME/CFS:



___________________________________________________________________


Possible Inflammation of the Liver ? : ME/CFS Study
Title : Changes in the transcriptome of circulating immune cells of a NZ cohort with ME/CFS (2019) Sweetman et al :



From supplemental material :

https://journals.sagepub.com/doi/su...8820402/suppl_file/Supplementary_Material.pdf

___________________________________________________________________



NIH Presentation - Dr. Mark Davis

Dr Mark Davis, presentation at NIH, mentions FGF21 which is associated with Liver / Gall bladder function:

___________________________________________________________________



Fibromyalgia Symptoms and Liver Disease

“Consistent with prior investigations of patients with HCV [4], we identified a high prevalence of fibromyalgia in patients with cirrhosis, affecting nearly one-third of our large patient cohort. However, our data also provide new and important insights. First, widespread chronic pain meeting criteria for fibromyalgia was not limited to HCV, but also affected patients with other underlying causes of liver disease. Second, in HCV-infected individuals, viremia was not associated with widespread pain. Third, NASH and HCV had a comparable prevalence of fibromyalgia. Taking together with the fact that mood disorders and sleep disturbances were the best independent predictors of fibromyalgia in our cohort, this suggests that central sensitization rather than inflammatory or viral processes plays a key role in this common comorbidity.”

Link of study :



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688457/







___________________________________________________________________

Fibromyalgia and Liver fibrosis, Johns Hopkins Study :

Title : A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndrome diagnosis from healthy controls


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255277/


Note hepatic fibrosis below :

___________________________________________________________________




Traumatic Brain Injury + ME/CFS


TBI affects the liver through Vagus nerve and cholinergic signalling :

Link of study : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247752/

 

[Amw66]

Low T3 impedes cortisol clearance in liver. A low T3 state ( as opposed to low T3 syndrome) was suggested in a couple of papers- part of body shutting down, like a hibernation " dauer" response.

Liver is key to many processes which are out of whack - bile, lipids, hormones, gut dysbiosis, glucose, detox processes to name but a few.

I don't t know why there has been so little investigation

 

[rvallee]

And it is probably the same reason on why severely ill patients cannot tolerate medications and/or supplements.I hypothesise that this happens because the liver cannot detoxify the substances that are contained in supplements/medications.

Right! I was just thinking earlier about alcohol intolerance and how common it is. Frankly I don't even know what it means but, again, liver. Some level of nausea is also common and that tends to at least have some link with the liver, in cases of indigestion or too much alcohol.

That makes many arrows pointing to the liver. How much "intelligence" does it have? Or is this waste function driven by the nervous system? Endocrine? Wondering what direction that would point to, up- or downstream. Is the ability of the liver to do this work testable? Whether it's universal, or some types of molecules?

If it doesn't get cleared up, basically it stays in the blood. So... something in the blood. Anyhoo, a growing hypothesis that warrants formal tests.

 

[rvallee]

I thought that generally speaking pwME have lower cortisol levels than 'the norm'?

https://www.me-pedia.org/wiki/Cortisol

eta: this research seems to suggest the opposite or have i misunderstood.

That would seem to be consistent since finding low numbers in urine would be expected if the liver is slower than normal to clear it. Although the lower hair concentration would be odd since it should be expected to be higher if it takes longer to clear up. Unless it hair concentration depends on the liver's function to clear it (and use it, I guess), but I'm way out of my league here.

Interesting, especially the correlation noted that symptoms improve along with urine cortisol concentration.

 

[mariovitali]

Right! I was just thinking earlier about alcohol intolerance and how common it is. Frankly I don't even know what it means but, again, liver. Some level of nausea is also common and that tends to at least have some link with the liver, in cases of indigestion or too much alcohol.

That makes many arrows pointing to the liver. How much "intelligence" does it have? Or is this waste function driven by the nervous system? Endocrine? Wondering what direction that would point to, up- or downstream. Is the ability of the liver to do this work testable? Whether it's universal, or some types of molecules?

If it doesn't get cleared up, basically it stays in the blood. So... something in the blood. Anyhoo, a growing hypothesis that warrants formal tests.

The “something in the blood” is not a virus I believe. Bhupesh Prusty believes that a virus is still active. Whereas the Liver injury hypothesis suggests that the problem was always there and it is compensated until a stressor comes in ( viral infection, medication, head injury, etc) that disrupts the compensatory state and a vicious cycle is started. So what is the problem ? I think it is a combination of factors that is at play. I will post more soon about this.

 

[Snow Leopard]

Why did they only base their model on 8 subject pairs when they good results for a total of 36 matched subject pairs? There is no explanation provided (where art thou peer review!?!)

The original study was conducted by Crofford/Demitrack et al, and was published in 2004.
https://www.ncbi.nlm.nih.gov/pubmed/15157948

There were no significant differences between patient and control groups for mean ACTH or cortisol over the entire 24-h period or in any given time period.

The original study showed difference in serum cortisol between CFS (n=15) and CFS&FM (n=12) patients and controls for most of the day (controls had higher cortisol in early morning when most patients were probably asleep).

No clear pattern for ACTH, which was slightly higher at most time points for controls vs FM (n=13), but higher for CFS&FM vs controls and lower for CFS vs controls.

Given the lack of clear differences, why would you then try to claim you have a model of the difference between patients and controls?

Here is the image (from Crofford et al. Brain, Behavior, and Immunity 18 (2004) 314–325)

 

[FMMM1]

Here's a talk by Wenzhong Xiao around 14.55 minutes he shows a slide for Cortisil levels
Basically normal cortisol (healthy controls) starts higher and ends lower compared to the levels in people with ME

Earlier in the talk he discusses sleep.

 

[FMMM1]

Low T3 impedes cortisol clearance in liver. A low T3 state ( as opposed to low T3 syndrome) was suggested in a couple of papers- part of body shutting down, like a hibernation " dauer" response.

Liver is key to many processes which are out of whack - bile, lipids, hormones, gut dysbiosis, glucose, detox processes to name but a few.

I don't t know why there has been so little investigation

Agree i.e. there should be more research into promising areas such as cortisol; however, the problem is funding for research. ME Action are doing a big lobbying push in the US; Solve seem to be doing a lot + OMF ----

If you're in the EU then there is lobbying going on (supported by ME Action) https://www.s4me.info/threads/eu-pe...obby-for-funding-for-me-research.10363/page-6

If you want to get involved in the UK then ME Action are doing a lot there

 

[Snow Leopard]

Here's a talk by Wenzhong Xiao around 14.55 minutes he shows a slide for Cortisil levels
*video removed from quote*
Basically normal cortisol (healthy controls) starts higher and ends lower compared to the levels in people with ME.

The key point that this is not a sensitive (nor specific) finding as shown by Crofford et. al. (and other studies). Many patients have similar diurnal cortisol patterns to controls.

Those that have different patterns almost certainly have different wake-sleep-activity patterns than controls that can explain the difference. Cortisol is primarily a feed-forward metabolic hormone that adjusts based on diurnal energy requirements and anticipated energy demands.