Hypothalamic-Pituitary autoimmunity and related impairment of hormone secretions in chronic fatigue syndrome, 2021, De Bellis, Montoya et al

Abstract

Context
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe chronic illness which reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized.

Objective
To investigate the occurrence of anti-pituitary (APA) and anti-hypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients.

Design, Setting, Patients and Other Participants
This is a case-control study conducted in University Hospital setting (Stanford, Naples). Thirty women with ME/CSF (Group 1) diagnosed according to Fukuda, Canadian, and IOM criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls.

Main Outcome Measures
APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands and plasma and urinary osmolality. Both APA and AHA titers were assessed and the prevalence of pituitary hormone deficiencies was also investigated.

Results
Patients in Group 1 showed a high prevalence of AHA (33%) and APA (56%) and a significant lower levels of ACTH/cortisol, and GH peak/IGF1 vs controls (all AHA/APA negative). Patients in Group 1A (13 patients positive at high titers, ≥1:32) showed ACTH/cortisol and GH peak/ IGF1 levels significantly lower and more severe forms of ME/CFS with respect to patients in Group 1B (7 positive at middle/low titers,1:16-1:8) and 1C (10 Ab negative patients).

Conclusions
Both AHA and/or APA at high titers associated with hypothalamic/pituitary dysfunction suggest that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Paywall, https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgab429/6319899

 

Intriguing, to say the least. Another piece of the puzzle?

 

This is certainly curious, but I'd like to see independent replication by another lab before I get too excited.

 

I'd like to read the paper first before I suggest, and of course Dr Edwards will bring his honest opinion anytime now, providing he is not on a birdwatching trip

In anyone has access please let me know.

 

Sounds like this could be relevant for me as I have an empty sella (a flattened pituitary). One of the things I learned is that empty sella can be the outcome of autoimmune hypophysitis.

The radiology report says mine is primary empty sella which means inborn but it's not clear to me how it's determined that it's inborn as I don't have pre-ME/CFS images. If the assumption is that it's inborn because of an absence of evidence I ever had an illness known to cause empty sella then it could be incorrect, as there is the possibility that the illness eventually leading to empty sella wasn't diagnosed at the time it occurred.

As for my pituitary function it's somewhat affected but the important hormones are within the norm or I probably wouldn't have been diagnosed with ME/CFS.

 

There's an excellent post by @Jonathan Edwards here* I'm not optimistic about this holding up (although Jonathan's comments might be entertaining - I have visions of fur flying).I'd be happy to be proved wrong though!

I'm interested in @strategist comments - I wonder if the European Union established an European Reference Network for ME/CFS whether cases like this would give an insight into a mechanism which explains ME/CFS in a wider group of patients @Michiel Tack


*https://www.s4me.info/threads/reap-...eome-2021-wang-et-al.20747/page-2#post-348828

 

I have primary empty cellar due to gene PITX2 when the pituitary was forming it formed very flattened but there is still enough left to send out vital signalling to glands although I need to take 75mcg for not otherwise specified hypothyroidism
This was one of dr Hyde’s markers the thyroid not otherwise specified

 

The full paper:

 

Bump.

So they took patient samples at Stanford but the APA and AHA testing happened in Italy using bits of pituitary gland and hypothalamus from young baboons. I can sort of see why this sort of study hasn't happened before...

Those of you who actually understand this study, is it worth sacrificing more baboons for to replicate on a larger scale?

 

Not sure why you would think this has anything to do with the reasons this study hasn't been done before (I can assure you that it does not - JCEM has not published a single study with CFS as the primary patient group since 2008 - CFS has been dead to endocrinology). All use of animals, especially primates in medical research needs to be done judiciously. Baboons are THE primary source of many human studies in medicine as they share 94% of our genetics.

That is never an easy question, nor should it be taken lightly. The answer depends upon what you think the research may achieve (care to share your understanding of the goals/potential ramifications of this study?). I'm sure that if you'll simply share a truly workable alternative that the authors would welcome your constructive input.

 

ALL Thirteen subjects with severe ME were found to have high APA and/or AHA antibodies. Eleven of those 13 had stimulation tests that were positive for central ACTH or GH deficiencies. Two thirds of all MS/CFS subjects were positive for APA and/or AHA. Antibodies are not a sign of actual dysfunction. They suggest a process. That said, many of these processes have to have been underway for years before you see marked/florid deficiencies. For example, it is widely thought that you have to lose 80% of your Arginine Vasopressin Producing cells (AVPc's) before you develop florid Central Diabetes Insipidus. Before you hit that degree of cell lost, your fluid balance gradually gets less and less normal over time (but you are unlikely to get diagnosed with CDI via a water deprivation test or the newer co-peptin test). Now, imagine this happening to varying degrees at varying rates on a number of your pituitary axes. You can then toss in a significant degree of inflammation for good measure (are enlarged perivascular/Virchow-Robin spaces more than just an atypical finding in younger patients?).

With some luck and hard work, this may be just a start.

"In patients with ME/CFS, the onset of anterior pituitary deficiency could be the result of an autoimmune attack by APA at high titer to selective pituitary hormone-secreting cells or by AHA at high titer to hypothalamic-releasing hormone-secreting cells probably favored by mediators of inflammation triggered by viral infections. Even if the hypothalamic/pituitary cells targeted by AHA and APA have not been investigated, it can be hypothesized that in our patients the kind of pituitary dysfunction depends on the pituitary secreting cells targeted by APA and on the hypothalamic releasing factor–secreting cells targeted by AHA."
​

APA and AHA are broad categories of pituitary and hypothalamic cells. Similar tests exist for pituitary and hypothalamic cell sub-types. Imagine a day when people go in for a blood draw and 2/3's of people who are now diagnosed as ME/CFS are actually found to have TREATABLE secondary and tertiary endocrine deficiencies.

A lot of additional work needs to be done to confirm and possibly expand upon this study (and a lot of resistance to the idea that ME/CFS may be an endocrine disorder needs to be overcome - solid research is how that battle is won) but I can assure you that when this was in the planning stages, identifying 10% of CFS as misdiagnosed endocrine patients was considered a worthwhile goal.

 

I am not familiar with any suitable alternatives. Dr. De Bellis is the worlds expert on this topic (go take a look on pubmed and at JCEM). One obstacle would be trying to make this argument with a technology that lacks the weight of all the work she has done. You'd likely add at least another decade to this avenue of investigation.

The problem here is and likely always has been "noise." Assess CRH (or ACTH) production in a group of patients diagnosed with ME/CFS and half or more may not have a current CRH (or ACTH) deficit. As a group they may never reach the magical level of clinical significance (I prefer the label "Statistically reliable/stable"). I've always felt like the only way that we were ever going to make progress with CFS would be the very careful splitting of patients into the right sub-cohorts. What if they are largely a group of pituitary/hypothalamic patients with differing presentations because of the various axes are differently impacted. This is where this needs to start. Down the road we may have a very different view and a far more direct way to assess the status of individual patients. Right now, I'm thrilled to think that we may have a theoretical framework with very practical implications.

I suspect yes. The cell sub-types in the pit/hypothalamus can generally be mapped by location but I doubt that at that point the person isn't going to benefit from the mapping. My guess is that functional deficiencies (even those that are now considered "sub-clinical") will likely guide treatment (and perhaps attempts to mitigate of further damage).

 

For me it's really fascinating. When I went from moderate to severe I suddenly developed hypoglycemia where I needed to eat every 2 hours. Throughout the years it has stabilized a bit but it never left. I also had slightly elevated prolactin.

 

Suspected misunderstanding #1. The reason I thought it unsurprising that an APA/AHA study had not been done before is that I assumed the tests they did were highly specialised (something we don't get to play with as often as we should in ME). My assumption was based on the fact that they sent samples from Stanford - which must have fairly good laboratory facilities - to Italy. But maybe they just did that because some of the research team were in Italy. If that sort of APA/AHA testing is quite standard I stand corrected (and annoyed because in that case it would be frustrating this hasn't been studied before).

Suspected misunderstanding #2. Clarification: I don't object to animal studies where it makes sense to use them, i.e. where there is a reasonable base for assuming the study will provide useful data and where there's no other way to obtain such data. I do object to them when they're just done because we can and with the sort of poor study design that leaves little hope for useful findings (in the ME field certain stressed rodent studies come to mind).

So my question - because I don't have enough knowledge about endocrinology to judge for myself - really was just if the current study's findings are strong enough to justify continuing/replicating or not.

Your explanation in post 12 suggests you think this is worth pursuing. Thanks for explaining in detail, it helps me understand the study topic a little bit better.

Some more questions (directed at no one in particular):

Would it now make sense to treat group 1A for their deficiencies to see if that helps them, as in a good treatment effect would strengthen the hypothesis? Assuming there are treatments? Or do we first have to figure out more specifically the exact type of deficiency/deficiencies?

Is group 1B just an intermediary stage on the road to 1A? How would we find out? Longitudinal study or are there other options?

Are we more likely to be looking at misdiagnosis, i.e. a primary endocrine deficiency in a subset of people currently having an ME diagnosis, or is it more likely that any endocrine issues are secondary to ME and treating them would improve that part of a patient's symptom complex - always a plus - but they'd still have ME?

 

This may already be underway. Keep in mind that these ME patients were screened for no prior endocrine diagnoses. They didn't have endocrinologists they were seeing.
I know of patients who have made impressive gains when properly Dx'd and Tx'd.
There are excellent treatments that are not expensive once the proper Dx has been made (that said, these meds do require a lot of monitoring, especially early in their administration and if not prescribed/taken appropriately they can cause major life threatening/life-long issues). I would not encourage anyone to undertake treatment without proper testing or the close supervision of an endocrinologist who specializes in the pituitary/hypothalamus.

In order, some members of group 1b may be on their way to group 1a. Time will tell.
Regular monitoring for both Sx's worsening/changing, Abs and perhaps repeated stim. tests. I suspect that these subjects could be followed outside of a longitudinal study but documentation showing patients progressing through stages would be informative and unfortunate (I would hope that if it is shown that pts. get progressively worse that at some point we are able to stop disease progression).
I'm sure there are many smart people who would pursue this aggressively if the results are shown to apply to a larger group of pts.

Testing for (and missing) a primary deficiency is not likely to be what's happening here.
Secondary and tertiary endocrine deficiencies (central) are far more difficult to detect, testing itself often comes with significant risks for some populations, and it is not undertaken without a very high "index of suspicion."
The good news is that once one axis is shown to be centrally deficient, the index of suspicion increases dramatically for a central deficiency in other axes. The bad news is that a Dx of ME/CFS likely sends the message that someone else has likely already screened you for endocrine issues and stimulation tests aren't indicated. These Ab tests are not presently used outside of research. Your local endocrinologist is not likely to know what to make of them. A few might feel like they tip the balance between testing and not but I wouldn't count on that yet.
It is possible that some cases of ME could be pituitary/hypothalamic autoimmunity that has gone unrecognized.
This is an interesting start but there is a lot more work to be done.

 

I know this is speculative, but Abilify has definite known effects on endocrine function due to its binding on to dopamine and serotonin receptors in the hypothalamus, so maybe a possible mechanism as to why it seems to work very well in a subset of ME.

 

That sort of significant shift in some aspect of a pt's ME Sx's and/or the severity of a symptom seems to be more common that is widely discussed. I suspect that tracking those sorts of changes has been beyond the resources of ME/CFS researchers without a framework in which to understand what might be happening (big fan of relentlessly subjecting your schema to new data - and parsimony where you can find it). It would be nice to make some sense of what is going on.