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

Hutan said:
Joshua, you seem to be suggesting people with HASD CFS/ME have chronically elevated cortisol levels. The reference you give doesn't relate to the elevated cortisol part of the sentence. What makes you think people with ME/CFS have elevated cortisol? Looking at cortisol in ME/CFS studies broadly, there's little evidence for abnormal levels, especially high levels.

You also seem to be suggesting low oestrogen levels as a result of high cortisol levels. What evidence is there for that?


I've made a thread to discuss this study:
Spironolactone as a treatment for CFS in patients with positive Epstein Barr virus serology, 2020, Campo and Taylor
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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.
 
There are numerous studies of cortisol in ME/CFS, as many researchers seem to think 'ah, ME/CFS, caused by stress, therefore there must be a cortisol marker'. Looking at the various studies, there is no evidence that people with ME/CFS, as a group, have abnormal cortisol levels. Typically, distributions of cortisol look very similar to the distributions of cortisol in healthy controls. How many clients with ME/CFS have you seen? How did you measure their cortisol levels?

joshua leisk said:
Either really high cortisol or really low.
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But your paper seemed to be suggesting that people with ME/CFS have elevated cortisol. It looks as though a number of your assumptions about what treatment might be appropriate flow from that assumption.
 
Hutan said:
There are numerous studies of cortisol in ME/CFS, as many researchers seem to think 'ah, ME/CFS, caused by stress, therefore there must be a cortisol marker'. Looking at the various studies, there is no evidence that people with ME/CFS, as a group, have abnormal cortisol levels. Typically, distributions of cortisol look very similar to the distributions of cortisol in healthy controls. How many clients with ME/CFS have you seen? How did you measure their cortisol levels?


But your paper seemed to be suggesting that people with ME/CFS have elevated cortisol. It looks as though a number of your assumptions about what treatment might be appropriate flow from that assumption.
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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.
 
joshua leisk said:
The expectation is that the issue is first noticed as elevated cortisol until various deficiencies cause insufficiency and it becomes dysregulated.
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So you are saying that people who develop ME/CFS initially have high cortisol, but then, due to deficiencies in the substances needed to make it, develop low cortisol, and then, after a while, it could be anything, but it isn't normal? Do you have any evidence for this, or does it just seem likely? How many people have you observed this change over time in?

Again, I have to come back to the fact that studies on quite large numbers of people with ME/CFS find the distribution of levels of cortisol look essentially the same as in healthy controls - most in both groups are within normal range.
 
Hutan said:
So you are saying that people who develop ME/CFS initially have high cortisol, but then, due to deficiencies in the substances needed to make it, develop low cortisol, and then, after a while, it could be anything, but it isn't normal? Do you have any evidence for this, or does it just seem likely? How many people have you observed this change over time in?

Again, I have to come back to the fact that studies on quite large numbers of people with ME/CFS find the distribution of levels of cortisol look essentially the same as in healthy controls - most in both groups are within normal range.
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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.
 
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There have been a range of approaches to cortisol measurement. Long term assessments (using hair) and daily assessments haven't shown differences. Yes, there is some evidence for morning peaks being delayed, but this is not at all surprising given the fact that many people with ME/CFS get up later, and aren't routinely rushing around first thing in the morning.
 
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joshua leisk said:
Well, separate to that study, it’s a common marker I see in my clients.

Either really high cortisol or really low.
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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.
 
Snow Leopard said:
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.
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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.
 
Snow Leopard said:
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.
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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/
 
joshua leisk said:
That's not what I've seen at all. Seems to be a regular pattern.
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I still don't have a very good idea of how many people with ME/CFS you have worked with Joshua, or how solid their diagnoses are.

Go up to the top of this thread, on the left, and click on 'cortisol'. That will give you a list of some of the papers that have looked at cortisol levels. Hundreds of people with ME/CFS have been looked at, precisely for the reason that you give, because researchers feel that surely it must be part of the story. But, the evidence suggests cortisol levels aren't abnormal in people with ME/CFS.
 
Hutan said:
I still don't have a very good idea of how many people with ME/CFS you have worked with Joshua, or how solid their diagnoses are.

Go up to the top of this thread, on the left, and click on 'cortisol'. That will give you a list of some of the papers that have looked at cortisol levels. Hundreds of people with ME/CFS have been looked at, precisely for the reason that you give, because researchers feel that surely it must be part of the story. But, the evidence suggests cortisol levels aren't abnormal in people with ME/CFS.
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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. :)
 
Moderator note
Moderators have reviewed this thread in the context of our "No medical advice" rule and guidance notes which cover discussion of the diagnosis and treatment of individuals. Copies of individual clients' medical test results and discussion of these has been removed.
 
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Snow Leopard said:
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
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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... :thumbsdown:). 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/

Jonathan Edwards said:
If a group sets out to study mitochondria it has to find something that looks like a result in order to get another grant in. Forty years ago you could afford to get a negative result and publish.
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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. :)
 
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DMissa said:
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 (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.mdpi.com/1422-0067/22/4/2046/htm



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. :)
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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.
 
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joshua leisk said:
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. :)
Click to expand...

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.
 
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