Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie ME/CFS: 2021, Stanculescu, Larsson and Bergquist

I read in the chronic critical illness literature that taking exogenous hormones are not the way to go and can actually make things worse. For example they trialed HGH in critical illness and discovered it did the opposite of what they expected, it significantly increased illness severity and mortality.

Researchers in the chronic critical illness field are pushing for clinical trials of treatment with hypothalamic releasing hormones/factors to restore anterior pituitary function and recover from chronic critical illness. Intervening at this point in the axis doesn’t seem to have the negative effects from feedback loops that treatment with exogenous hormones suffers from.

I see papers going back to early 2000s suggesting this but still trials haven’t been done. What a shame for the medical field to leave CCI patients to suffer like this, especially now with COVID producing so many more ICU cases and therefore many more with coming out of acute ICU with chronic critical illness.

 

Edit: From the Desk of Jonas Bergquist, MD, PhD Uppsala University

https://www.omf.ngo/omf-funded-research-paper-published/

 

I've been told, following an MRI, that my pituitary is squashed and the stalk that attaches it to the rest of me is stretched, although the words "empty sella" haven't been said to me. I think it is unlikely that a pituitary which has been flattened in one plane and stretched in another could be working perfectly. The cause of my pituitary problems is most likely (in my opinion) to be caused by my Normal Pressure Hydrocephalus (NPH) - a condition I've been told I've most likely had since birth, infancy or childhood. And, despite the name, pressure in the head of someone with NPH isn't always normal.

There has been limited research into the HPA axis in people like me, and it seems likely that pituitary function is negatively affected in about a third, according to the following paper.

Title : Pituitary Function in Patients with Normal Pressure Hydrocephalus before and after Neurosurgical Correction

Link : https://academic.oup.com/jcem/article/97/10/3545/2834091

Despite having surgical correction of my NPH I am not aware that anyone has ever checked the output of my pituitary or my hypothalamus before and/or after surgery.

Edit : I wonder if there would be a point in having a poll asking people if they have ever been told their pituitary or their hypothalamus doesn't look normal, or the hormonal secretions of either is abnormal or low.

 

I know this is total speculation, but maybe the people with CCI/AAI and ME had pressure on their hypothalamus or pituitary gland due this condition and surgery possibly relieved this pressure causing ME remission or improvement?

 

Jaime Seltzer [ME Action] mentioned that you could "diagnose" ME from hormone patterns.

 

Does anyone have any ideas of how PEM could be caused by/connected to dysregulation of the endocrine system? Can't see that discussed in the paper.

 

Don't want to be a debbie downer, but this theory sounds way too simplistic to me.

 

Perhaps this endocrine system dysregulation hypothesis could relate to something downstream of a more central pathological mechanism of me/cfs - like hypothalamus inflammation (https://www.healthrising.org/blog/2020/05/27/neuroinflammatory-paradigm-chronic-fatigue-me-cfs/) or problems at the vagus nerve

 

Dominic spent a lot of time working on and seeking feedback for his hypothesis here, so it's cool to see that he has gotten this published alongside the Uppsala group. Really impressive work for an independent researcher. Happy for him.

 

Both Fluge & Mella and Ron Davis do not know if it’s a single factor that’s in the blood causing metabolic dysfunction. I’ve always wondered why they think it’s one thing when they have no evidence yet to show that.

This hypothesis says that multiple aberrant levels of hormones, cytokines, and oxidative stress markers in the blood are shown to contribute to metabolic dysfunction and references the supporting studies showing the metabolic effects of each of these factors.

 

I would encourage people to read up on the functions of the hypothalamus and pituitary gland. This system is central to maintaining homeostasis and directly performs or regulates so many vital bodily functions. To me it’s no surprise that any dysfunction arising from this system would have disastrous effects throughout the body.

Everything the hypothalamus and pituitary gland directly perform or regulate are to me directly linked to ME symptoms, and here is just a subset: fatigue, sleep, circadian rhythms, body temperature, emotions, appetite and thirst, energy maintenance, stress control, blood pressure and heart rate, disgestion, perspiration, and more.

 

And good old Dr. Jacob Teitelbaum, in his book: From Fatigued to Fantastic postulated there was a problem in the hypothalamus and pituitary gland decades and decades ago. But he is an MD, also suffering from ME, and he basically prescribed supplements, which did not help much. But he does in his book talk about this, in the way he does.

 

Oh, is he a member of this forum??

 

I'm not impressed either. I hope the current generation of ME/CFS researchers can come up with better hypotheses than this.

HPA-axis, cortisol, growth hormone, thyroid hormones, cytokines, oxidative stress etc. all these things have been studied in the past 30 years without showing anything remarkable that stands out. So a good hypothesis would try to explain the symptoms of ME/CFS with a mechanism that doesn't create any stark abnormalities in these markers. I'm afraid that the researchers of this paper did just the opposite: they looked at the literature, saw that these markers were frequently studied and then tried to formulate a hypothesis that combines all of them in one big framework.

I also don't understand why ICU patients form a good model for ME/CFS or why the two would be related. Table 1 presents a comparison, but from looking at I would argue at it looks more like an argument against than for the hypothesis. ICU characteristics include ventilator dependence, skin breakdown associated with incontenince, brain dysfunction manifesting as coma or delirium and distress from symptoms such as thirst.

 

I'm disappointed that OMF and Bergquist sent out an email to highlight this paper.

 

The interesting part of ICU patients, is that patients who survive their ICU stay may be developing symptoms similar to ME- and when i say this i have the post-sepsis community in mind.

I am actually interested to hear more from their hypothesis (i will have to read the paper)- for me it brings a flavor of dysregulated ‘main switch’. Whether it represents the chicken, the egg or the pasture remains to be seen.

In my case it was very clear that my hormones changed drastically following onset, which included sex hormones, thyroid and adrenals. But who knows? After so many years, you know, I am not getting too excited.

 

Well, to me it depends how it was framed. Did they acknowledge it is an unproven hypothesis that would need to be tested to prove or disprove its validity?

 

It is always good to thank your funders. It seems like they did just that, also informing about why they reached out to the ICU community. Here is the newsletter article, which links directly to the paper:

 

HPA axis hypotheses have almost been done to death. The main problem is that basal serum cortisol (or the other markers discussed) is neither a sensitive, nor specific predictor of ME/CFS or symptoms.

Yes there is attenuated morning salivary Cortisol concentrations in some patients but this is not a consistent finding, just like serum cortisol. Note that cortisol is a feed-foward metabolic hormone, as it's main function is to stimulate gluconeogenesis. Salivary cortisol itself isn't terribly important and this can be explained by different sleep-wake activity patterns between patients and controls. There may also be a sort of sampling bias, namely participants who normally sleep in are getting up earlier than normal as they were told to collect samples from certain hours in the morning, for example. (and the participants don't want to admit they're actually sleeping at that time)

Or maybe patients simply have too much humor?
"Humor attenuates the cortisol awakening response in healthy older men"
https://www.sciencedirect.com/science/article/abs/pii/S0301051110000840

(this should be a clue that the finding is very non-specific)

Bergquist and colleagues discuss 'pulsatility' of ACTH release, but this has already been studied and the results are equivocal.

While the study of pulsatility of the various hormones in patients might be interesting, I think it is unlikely to lead to any breakthroughs given how much study there has already been of the HPA axis in ME/CFS patients.