[Health Rising] ME/CFS Autopsy Study Finds a Wrecked HPA Axis: The 2025 IACFS/ME Conference Report #3

[V.R.T.]

We were discussing on another thread the very real harms that are caused by the views of fringe doctors and the people with ME/CFS who promote them.

If further evidence were needed, see posts 7 – 11 on this thread. I wish the people who make a practice of this would read and reflect on them before hyping the next thing out of all proportion.

I have now edited my posts upthread so as not to distress anyone else but yes I agree. I saw neuron loss and thought alzheimers parkinsons permanent damage etc etc and got in a bit of a mental spiral.

Thankfully the sensible observations made on this thread have calmed me down significantly !

 

[Jonathan Edwards]

My sense at this point is that either these data are artefacts (and probably nothing to do with secondary effects from illness), which sadly is so often the case with histopathology, or that this is a key finding that tells us something important about very local hypothalamic pathology, maybe analogous to narcolepsy.

If it is the second, and it might well be, then drug replacement ought to be feasible, yes. But it also quite likely would mean that we have to rewrite the textbook physiology on the 'HPA axis', which is a much overused concept and maybe just wrong as it stands. ME/CFS is not associated with corticosteroid failure, so the one thing this does not show is a 'wrecked HPA axis'. And steroid treatment produces modest benefit if at all long term. Maybe CRH cells are not needed for maintaining cortisol levels after all. But maybe a lack of CRH feels really bad - bad enough to be known as PEM.

 

[jnmaciuch]

Or maybe just very poor sleep quality in general?

yeah possibly, I meant dysregulated circadian rhythm pretty generally

 

[Utsikt]

yeah possibly, I meant dysregulated circadian rhythm pretty generally

Ah, my English failed me there. Of course disrupted rhythm can refer to all kinds of deviations from the normal.

 

[V.R.T.]

then drug replacement ought to be feasible, yes

What would that look like in this context? And what in particular would be replaced by drugs? The neurons or something they produce? (I assume the latter as the former sounds highly experimental/impossible).

 

[Utsikt]

But maybe a lack of CRH feels really bad - bad enough to be known as PEM.

As in living with PEM in general or as in currently experiencing being in PEM?

 

[jnmaciuch]

Ah, my English failed me there. Of course disrupted rhythm can refer to all kinds of deviations from the normal.

all good, it can mean different things in different contexts anyways, I should’ve been more specific

 

[Kitty]

I saw neuron loss and thought alzheimers parkinsons permanent damage etc etc and got in a bit of a mental spiral.

Why wouldn't you, though? Anyone who isn't familiar with the author and his tendency to weave fantastical stories from fragments might well be scared by it. I don't understand why people who claim to be advocates fail to consider that.

 

[Utsikt]

With regards to reversibility:

If the findings are correct and relevant for ME/CFS, it should be noted that the mean disease duration of the six responders in the Dara pilot was 15 years, the shortest was 3 years, and the longest was 35 years.

That would indicate that it can be possible to get back to a high level of functioning even after decades of ME/CFS, if the disease is treated.

A possible speculative explanation would be that the reduction in a specific type of neuron is an adapted change, and that this can change back enough, or be worked around to function well enough when the conditions causing the adaptation is reversed.

 

[jnmaciuch]

But maybe a lack of CRH feels really bad - bad enough to be known as PEM.

That seems unlikely if all 5 narcolepsy participants from the autopsy study posted upthread also had significant depletion of these neurons. There might well be some mechanistic overlap between narcolepsy and ME/CFS, but the thing that causes PEM is the most likely thing to be differential between those two groups

 

[Verity]

This might be a silly question. I don’t have the background to understand these findings. Aren’t we all supposed to have an ACTH stimulation test for adrenal insufficiency before getting diagnosed with ME? Wouldn’t a lack of ACTH show up? Or is my assumption that this finding would cause an abnormal result on that test incorrect?

 

[Jonathan Edwards]

That seems unlikely if all 5 narcolepsy participants from the autopsy study posted upthread also had significant depletion of these neurons. There might well be some mechanistic overlap between narcolepsy and ME/CFS, but the thing that causes PEM is the most likely thing to be differential between those two groups

But the difference might be the failure of CRH in the presence of normal orexin. In other words a particular sort of out of kilter signal pattern. There are examples in this are of biology where it is worse to have one of two pathways knocked out than have both knocked out. It is too long since I knew about it to remember at present but strange things happen after radiotherapy for craniopharyngioma impacting on hypothalamus for instance.

So in a sense i agree that it cannot be as simple as just no CRH=PEM but if this finding is meaningful at all I think it may be part of the story. I find it hard to believe that CRH cells would just die off because of changes in sleep patterns.

 

[Jonathan Edwards]

This might be a silly question. I don’t have the background to understand these findings. Aren’t we all supposed to have an ACTH stimulation test for adrenal insufficiency before getting diagnosed with ME? Wouldn’t a lack of ACTH show up? Or is my assumption that this finding would cause an abnormal result on that test incorrect?

It isn't a silly question. It is exactly the right question, as far as I can see.

 

[jnmaciuch]

I find it hard to believe that CRH cells would just die off because of changes in sleep patterns.

They might not die at all. The only thing being measured in these studies is antibody binding to CRH. It might only be the proteins involved in producing or secreting CRH that drop off because their production is dependent on other signals involved in circadian rhythm

But the difference might be the failure of CRH in the presence of normal orexin

Fair enough. That could be disproven by finding clear cases of narcolepsy that also have PEM. Or a mouse model, I suppose

 

[Jonathan Edwards]

They might not die at all. The only thing being measured in these studies is antibody binding to CRH. It might only be the proteins involved in producing or secreting CRH that drop off because their production is dependent on other signals involved in circadian rhythm

That sounds unlikely to me. Cells that secrete hormones tend to produce and store them ready for release in response to signals. If anything cells depleted of CRH might suggest they have released it all.

I think it is quite likely that we are looking at an artefact. I also think that although apparent loss of CRH cells seems unlikely s secondary to sleep changes or whatever, it might reflect the mode of death. I have not looked into this further but I ownder if we now anything about how these people died? Death from inanition might be associated with CRH cell exhaustion for instance.

 

[RedFox]

Like every other research finding in ME/CFS, this one is perplexing. I imagine it's unlikely to be an artifact, but we still don't know if this is a cause of the illness or an effect. It's quite interesting that they found the same changes in narcolepsy. Maybe the actual cause of ME/CFS causes neurons that regular circadian rhythm to stop working? I doubt this is a main cause of ME/CFS but I wonder if it could explain some of the sleep or concentration issues.

 

[Utsikt]

This might be a silly question. I don’t have the background to understand these findings. Aren’t we all supposed to have an ACTH stimulation test for adrenal insufficiency before getting diagnosed with ME? Wouldn’t a lack of ACTH show up? Or is my assumption that this finding would cause an abnormal result on that test incorrect?

I don’t think I’ve ever heard about that test. As far as I can see, it’s not mentioned in the Norwegian guidelines, but it might have been under a different name that I didn’t search for.

 

[Verity]

I don’t think I’ve ever heard about that test. As far as I can see, it’s not mentioned in the Norwegian guidelines, but it might have been under a different name that I didn’t search for.

Do you mean the guidelines for diagnosing ME? The test is one of two tests given for diagnosing adrenal insufficiency, so it will probably not be listed separately from a general direction to rule out adrenal insufficiency. I think it is unlikely they’d list every necessary lab test for every potential ME mimic. I’ve never seen something like that. Correct me if I’m wrong!

If you mean guidelines for diagnosing adrenal insufficiency, I don’t know why it wouldn’t be there!

 

[StellariaGraminea]

I find the discussion re ? a relationship with narcolepsy fascinating from the point of view that I've a relative who developed narcolepsy (not sure what type & unfortunately they live abroad and not in touch or I'd ask them re PEM) & have always wondered could there be some related genetic predisposition in both of us that triggered these illnesses.

The other reason is remembering reading about a Dr who previously believed there was a relationship between ME & narcolepsy, that narcolepsy was a spectrum anyway and ME could be a manifestation of a previously unknown form of it. (I'm paraphrasing going on memory, I may have not quite got that right). The dr was apparently having a little success treating ME with narcolepsy treatments until they (the treatments) became more restricted. Does anyone else remember that?

I can't remember where I read about it, of course all speculation. But just interesting to see a possible connection come up again with this autopsy study. What @Jonathan Edwards says makes sense about the CRH being an issue but orexin not, & one stream being knocked out potentially worse than two. I would say if I were guessing that my orexin was in excess the first years of this illness - ha no way of measuring it. I would like to know whether there is any loss of inhibition of orexin implicated in reduced CRH (If that even makes sense).

 

[jnmaciuch]

That sounds unlikely to me. Cells that secrete hormones tend to produce and store them ready for release in response to signals. If anything cells depleted of CRH might suggest they have released it all.

Actually, transcription of CRH appears to require constitutive cAMP -> CREB signaling and can be suppressed by blocking that pathway. Insufficient stimulation of that signaling cascade means no activity at the promoter region to produce CRH for those cells to store.

And funnily enough cAMP/CREB is tied into the exact calcium and interferon-related pathways I’ve been theorizing about. Orexin signaling is another known required factor for CRH transcription, apparently.

https://www.sciencedirect.com/science/article/pii/S0021925817366930 cited in

https://www.sciencedirect.com/science/article/pii/S0091302211000707 (Section 6.2)

[edited for clarity]