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

https://www.frontiersin.org/article...=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland's pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.

 

I hope that one of the centres is able to propose a study protocol that could investigate this once and for all. Scientists have been flagging the endocrine system as potentially important for decades, but the trouble is that they can't study it effectively by poking around the edges with a few blood and urine samples. If researchers agree that it's worth doing at all, it needs to be a well-designed study (probably involving hospital stays), supported by enough money to do it properly.

 

Agreed..

Does this has any relevance to the metabolic trap theory? They mention “alternate steady state”, which reminded me of the systems engineering approach that Phair discusses. Is this related or different system?

from paper:
“However, long, repeated stress—from which the system doesn't have time to recover—leads to a persistent high glucocorticoid receptor concentration, forcing the HPA axis to an alternate steady state. More recent models of the HPA axis have also included non-genomic feedback-controls (71), the endogenous effects of circadian rhythm (72), and interactions with the gonadotropic axis and the immune system (73, 74) to explain how HPA axis suppression is maintained even after the initial stress is gone.”

 

Well, presumably this is something that OMF will be able to fund, given that he's leading one of their collaborative centers.

 

Absolutely – but if the hypothesis is worth testing (and obviously most of us lack the knowledge to assess the merit), it strikes me as one of those that could be appropriate for applications to government-funded programmes. *

If it is thought possible for the endocrine system to fall into a disordered steady state in the way suggested, it's likely to have relevance to more than one chronic disease; that ought to be significant enough to enable a good research case to be made. It would be equally useful to find enough evidence to cast doubt on the possibility, too.

ETA: * Even if a smarter way to do it might be to base the research application on a different disease...

 

The authors already referred to the type of initial study to disprove the hypothesis. It doesn’t require any complex experimental methods or technology. It looks at a key part of the hypothesis by taking direct hormone measurements from blood, unlike for example cytokine, metabolic, and neuroinflammation measurements which are difficult to do, get a consistent and clear picture from, and hard for other labs to replicate.

Do this with a CCC diagnosed ME/CFS cohort. Not complicated, just requires resources for the 24-hr patient stay and blood draws. Acquire the important clinical and demographic data that can affect hormones such as disease severity, duration, age, gender, etc in the study to use it in the analysis.

Even moderate and moderate-severe ME/CFS patients could do this if they could withstand the travel because they wouldn’t have to exert during the study and could stay in a bed.

If OMF thinks this is interesting please make use of the money they have to do the study now. I believe it has way more “bang for the buck” than funding a lot of the expensive experimental research being done because it could be a eureka moment with a simple study whereas much of the experimental research seems to be getting us nowhere even if the results show some clues.

They keep looking at complex areas of pathophysiology such as the immune system, cellular metabolism, and neuroinflammation but, while these are interesting research areas, they could just be looking at wrong place, at the result of what is really driving this and therefore even if they find targetable treatments in these areas they might not work and it will be more wasted time and money.

It could also be a direct path to effective treatment borrowing from the work done in the chronic critical illness field.

 

I don't know enough to judge how good this hypothesis is but testing it asap and thoroughly does seem worthwhile if only because we keep getting all these small and inconclusive studies about hormones in ME. So it would be good to have a really good study on this to sort out if this remains an avenue worth pursuing or if it's a dead end.

Especially since there are quite a few patients experimenting with hormone treatments based on those inconclusive studies, without overwhelming success as far as I can tell. Better evidence one way or the other would be good. And it does sound as though the technology is there, ready to go, since they've used it in the critically ill field already.

 

Dr Bansal had a hypothesis that sounds similar to part of this- that high stress over a prolonged period could cause glucocorticoid receptor resistance which knocked into an ME state.

As far as I know there was no paper published for this part of his research. Tagging @alex3619 who was interested in it.

 

Nancy Klimas has suggested GCR resistance too.

 

So far as I am currently aware Bansal retired without publishing or something like that. If I recall correctly this was about too many glucocorticoid beta receptors, though I might have the details wrong. This is yet another area that needs investigating or replication.

 

It's nice to read a paper that is so well written. Very professional (unlike some other things published recently).

It also reminded me that my pituitary gland is squished. I wonder if that's a risk factor for the "vicious cycle". This cycle is observed in critically ill patients who fail to recover and a similar pattern also exists in ME/CFS (according to this paper).

 

Me too -- empty sella syndrome -- I kept mentioning it to doctors as a possible cause / implication in my symptoms, but was dismissed every time -- it is hard to fathom how having a flattened gland can not have an impact.

 

On the last occasion that my ME was taken semi-seriously by the medical establishment I was told, following a blood test, that my level of growth hormone was lower than would be expected, however this wasn't investigated any further.

 

Here are a couple of extracts
"In sum, the HPA axis dysfunctions in ME/CFS are not unlike the dysfunctions in prolonged critical illness. However, to our knowledge a comprehensive study of the pituitary pulsatile secretions of ACTH in ME/CFS patients—which proved revelatory in understanding prolonged critical illness—does not yet exist. The relationship between the pituitary's pulsatile ACTH secretions, severity of illness, the integrity and function of adrenal glands and resulting physiological alterations in ME/CFS thus remains largely unexplored."
Yea that looks like something which could be studied.

"Hypothalamic endocrine suppression: Researchers have suggested that hypothalamic endocrine suppression could explain ME/CFS (132, 186) and fibromyalgia (187–189). Our thesis upholds this hypothesis and seeks to strengthen it by suggesting that the controversy around the existence of central endocrine suppression in ME/CFS may be resolved by studying the pulsatile secretions of the pituitary—rather than single or average measurements of circulating tropic and non-tropic hormone concentrations, which can fail to discern the dysfunctions of the endocrine axes."

Yes - looks like a potential biomarker study/way to understand disease mechanism.

When I read this I recalled a comment from Jaime Seltzer [ME Action] about much being (in ME) explained by inactivity:
"Significantly, a group of ME/CFS patients were found to have 50% smaller adrenals than controls (68), resembling adrenal atrophy in prolonged critical illness."

Interesting to see what those who have much more knowledge than I do have to say @Snow Leopard @Jonathan Edwards . Also, if this hypothesis is correct then what would you expect to see in a GWAS study @Simon M [don't feel obliged top respond Simon].

 

Our family member has also had evidence of low HGH many times, and even tried injecting it in order to supplement. I note that many other hormones are also all over the place, but supplementation is not helping with the ME symptoms.

( I once had a chat, about 2 or 3 decades ago, with a very old American doctor--, who kept telling me that in his view this nightmare illness was in some way due to dysfunction of hormonal mechanisms. But his speciality was elsewhere; but he was well aware and knowledgeable of the American outbreaks, etc.)

 

Agreed that this definitely seems well worth looking into! Brilliant rationale for me/cfs.

On a personal note, when I was admitted to A&E during what I later realised were PEM crashes (before I knew my symptoms were M.E.), my blood checks all came back normal apart from an imbalance of sodium (hyponatremia) on both occasions.
When I wasn't crashing, my sodium levels were found to be normal.

 

The virologist I saw years ago ordered a CT scan to r/o a pituitary tumor years ago based on my symptoms. Everything was normal.

 

A dysregulation of this sort might also explain a symptom that is rarely discussed in the literature: episodes of hypoglycemia without having (according to usual tests) diabetes, pituitary, adrenal or thyroid disease.

Also changes in water balance during PEM.

 

I experience a feeling of deep dehydration during PEM. It's certainly not the same as normal dehydration from not drinking enough fluids.

 

Seems related to me check out references to signalling problem in Fluge & Mella's 2016 study

"According to this model, ME/CFS is caused by immune interference with an unidentified target, potentially a signaling factor, which ultimately causes metabolic dysfunction and induction of secondary rescue mechanisms."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/

so could the signalling factor be a hormone?