The true nature of an autoimmune disease, Leisk and Nocon 2021

https://pubmed.ncbi.nlm.nih.gov/32149617/

It’d also be expected downstream of POTS and any IgE related annoyances.

 

Well, separate to that study, it’s a common marker I see in my clients.

Either really high cortisol or really low.

 

Serum, urine and saliva. My favourite is the 24h urine cortisol test to show total cortisol, with saliva tests throughout the day to understand the spike patterns. You then need to relate this to the sleep cycle hours, which are usually abnormal.

The expectation is that the issue is first noticed as elevated cortisol until various deficiencies cause insufficiency and it becomes dysregulated.

 

On a "spot check" at some point through the day, they appear to be in normal range? That wouldn't be unexpected at all. Checking at specific times, relative to sleep cycles, etc., would show differences. Also need to factor in the common use of benzodiazapines vs effect on cortisol, for ME.

 

If your clients have such markers, they probably have something else going in addition to, or instead of ME/CFS.

In over 30 years of research, with over 50+ studies on cortisol patterns or related neuroendocrine systems, researchers have only found equivocal results. This should be a clue "nothing to see here, move along". Many patients (myself included) have only ever had normal levels of cortisol in their serum, when tested.

None of the studies have found "very really high or really low" cortisol. Some studies have found a flattened salivary cortisol curve, which is to say lower peaks in the morning (and sometimes evenings). But this is exactly what one should predict a-priori for a highly sedentary individual. Cortisol is a feed-forward metabolic hormone and cortisol secretion patterns adapt to the sleep-wake and daily activity patterns. If individuals are not highly active in the morning, then there is less need for awakening cortisol secretion, else they have glucose levels that are too high in the morning.

 

Thanks for your comments @Snow Leopard they remind me of @Jonathan Edwards comment "When I acted as MRC advisor this recent time around the GWAS project was the one thing that looked worthwhile, apart from maybe some actimetry studies." [https://www.s4me.info/threads/georg...dian-article-21-1-21.18562/page-4#post-319043]

So maybe what's needed are actimetry studies in addition to cortisol/rather than cortisol.

 

That's not what I've seen at all. Seems to be a regular pattern.

Cortisol is also a key part of the immune response. Dysregulated mast cell activation and all of the fun that comes along with that, along with the collagen production issues and skin / gut barrier issues will also influence cortisol secretion.
eg.
https://pubmed.ncbi.nlm.nih.gov/24809845/
https://pubmed.ncbi.nlm.nih.gov/30028389/

 

Well.. I’m more interested in the evidence in front of me than someone else’s evidence on this.

I’m not sure what someone else has looked at - eg.

Did they do a 24h urine sample?
Did they perform multiple saliva checks throughout the day and relate that to the total urine amounts?
Did they relate that to sleep cycles?
Did they relate that to carbohydrate and protein intakes?
Did they control for benzodiazepine use?
Did they control for 11HSD1i use or other supplements?

ME patients appear to be one of the biggest users of supplements. Unless you’re controlling for all of these factors, it’s hard to interpret meaningful results.

 

Here’s the follow up paper -

https://www.researchgate.net/public...d_enzymatic_cofactors_in_the_HASD_CFSME_model

 

One thing I'd like to point out is that inhibition of α-ketoglutarate dehydrogenase inhibits ROS production, thus preventing this particular step in the cycle leading to a feedback loop involving excessive ROS.
https://www.jneurosci.org/content/24/36/7779.short

 

Yes, that was reference 165 in my paper.

Also see Ref 36, 39, 45, 46, 47, 60, 94, 135, 156, 166, 167.

167 is particularly good. 156, also.

 

This thread is a bit heated in spots so I just want to say that I'm not intending any hostility or unpoliteness whatsoever.

In this paper it says the following: "increased use of Branched-Chain Amino Acids (BCAAs)[10], as observed in CFS/ME by Missailidis et al., 2020"

1) This is jumping the gun. I saw elevated expression of enzymes that catabolise BCAAs as a source of substrate for the TCA cycle, in immortalised lymphocytes. Expression levels alone don't give the whole picture here. One cell type (that possesses other variables as mentioned above by Jonathan) also does not give the whole picture, nor tell us with any certainty what is occurring in vivo or in other tissues. I have not yet tested BCAA utilisation rates and have not yet tested other tissue/cell types (we can thank the pandemic for that... ). My work is too early to be used in even the vaguest sense to guide treatments. I would never want it going near the word "treatment". It's a hypothesis that's still very much going to be tested and presumably adjusted after new observations.

When interpreting these kinds of results it's important to hone in on the details. Scanning through papers for the overall thrust and then using it to guide an idea can be misleading.

2) Wrong paper cited, should be this one: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921983/

Hi Jonathan. I'm sure this is a general comment and while I can only speak for myself, I would happily publish a negative result and move on to whatever it tells me is worth looking at instead. Whether mitochondrial or otherwise.

 

Each step in the HASD model can be tested and demonstrated reliably.

The BCAA use is explained by aggressive transamination via glutaminolysis. It’s required to manage the vast amounts of aKG being generated by mitochondrial activity.

My second paper explains it in more detail. It also shows how the gut microbiome is involved and why it normally should be preventing this state, instead of contributing to it.

 

This looks like a Cortisol 101 to me and we need and deserve at this stage something better. I have had alternative medical practitioners take an interest in mine and their other patients cortisol and your approach looks familiar in the above

The problem with supplements did feel worse to me living in Australia and NZ. I met patients there spending a large proportion of their income on supplements as they tried one approach after another in desperation with little in the way to show for it.

They were, in my experience, a lot of snake oil salesman in both countries. There wasn't the equivalent of this forum. Nothing seemed to change at a grassroots level over 30 years and the lessons learned by older patients rarely discussed.