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

Just wondering, but during these times have you accurately measured your blood glucose to confirm what you were experiencing was actually hypoglycemia? (not just feeling symptoms that correlate)

I never had this phenomenon and symptom, but have had a similar one that other pwME also report, when I overexert to the point of near crash and at the beginning of a crash I have pretty insane carb hunger. As I rest and recover through the crash days later one way I know I’m coming out of it is that symptom then goes away.

But I’ve checked my blood glucose and ketones with an accurate meter a couple of instances during those times and I did not actually have hypoglycemia, it just felt like the symptoms of it.

 

This list may be of use as background info in this thread :

List of autoimmune diseases from Wikipedia

Note that new autoimmune diseases are discovered from time to time. And the entries on the list may be tentative and more research will be required to confirm or reject the condition as being autoimmune.

 

I had bad hypoglycaemia when I did more. It was very frustrating to feel well enough to go shopping then collapse because of a sudden hypo. I was told it was panic attacks but a blood sugar machine confirmed it was low blood sugar (about 3)

Workwell said that the liver gets a signal to release more glucose to the blood stream in the same way temperature is controlled. Since I have very bad temperature control, to the point it takes about 5 hours to heat up if I get chilled, this made sense to me.

They did a study but the results were not particularly strong but that could have been because it is not a universal problem or that the patients were not active enough to need extra blood sugar.

leokitten, people talk about ME patients having increased adrenalin as the body releases that to keep them going. It seemed to fit what I experience when I have pushed myself to do something like seeing my grandchildren. Have read that increased adrenalin can make you crave sweet things and feel hungry.

The biology behind glucose and insulin and hunger and leptin and so on is very complicated but it will not be worked out for ME until the symptoms are more widely known.

Like you there are occasions when I feel hungry all the time which is not relieved by eating. It is like a pain gnawing away.

 

De Bellis, Montoya, et al. found that GH and IGF-1 were significantly lower in Group 1A. Four (of 13) severe ME/CFS subjects were Dx'd with GHD (1 in 3 to 4).

 

Makes a lot of sense, and this intense carb hunger as a crash nears is worse in the evening and it’s accompanied by that ME super wired feeling, so it really could be adrenaline. I think there is endocrine dysfunction going on at least in some of of us and it does contribute to symptoms and sleep issues at night.

 

It has taken me a while to form an opinion on this. I have had some input and I Amin a position to say:

My own assessment and that of a knowledgeable colleague suggest that the data are probably not enough to form any useful interpretation.

Immunohistochemistry is so subject to artifactual findings it is always difficult to interpret on its own. The hormonal findings tend, as others have said, to suggest some other coexistent problem rather than an explanation for ME.

 

I'm just wondering if this would be indicated/supported by the proposed GWAS study - OK that's now a standard reply from me! @Simon M

I have a family member who has a thyroid problem (hypothyroidism I think) and another with disabling fatigue of unknown cause, so yes thyroid issues are interesting.

Would this turn up in a GWAS study e.G. if the incidence of thyroid problems was significant in ME/CFS and/or if your (thyroid) genetic makeup predisposes you to ME?

 

Autoimmunity to hypothalamus or pituitary might be linked to immune response genes like MHC but is not particularly likely to link to genes actually involved in the thyroid (or pituitary).

 

1. Standard answer to "this is a main cause of ME/CFS".
In theory, a GWAS is likely to show a signal, e.g. for the metabolic trap hypothesis.
However, there is scale issue. To avoid false positives, GWAS use fierce statistical correction (instead of p<0.05 = 5 x 10^-2, GWAS use p<5 x 10^-8 (0.00000005). this means there will be false negatives, so if you don't find anything, it could be a false negative. That said, as GWAS become bigger (and you can combine results from different GWAS studies on the same illness), false positives become less of an issue.
Also, even in an initial GWAS like this, if there is NO signal around a proposed cause (as opposed to a signl that doesn't quite reach the high threshold for statistical significance), it would be a concern.

2.For this question, about endocrine misdiagnosis:
Probably not. If it's only a relatively small issue, a GWAS will struggle to find it. A GWAS is more likely to find evidence for the main causes(s), not minor ones or misdiagnoses.

 

I've only glanced at this and I'm not confident that I understand it but basically they took some blood samples and poured them onto slices of baboon pituitary gland?

As per @Ravn perhaps there are opportunities to limit the impact on baboons e.g. there's thread here on producing human proteins using genetically modified yeast
[https://www.s4me.info/threads/reap-...-the-human-exoproteome-2021-wang-et-al.20747/]
@Ron was in contact with one of the researchers [Aaron Ring at Yale University] so perhaps Ron could mention this study - the baboons in particular might be grateful. I assume that if the proteins identified, as possible targets for autoimmune antibodies, were produced (from yeast) then that might allow a diagnostic screening test - possible cash/intellectual property rights for Aaron (I'll take cash if it's going).

EDIT - just sent Aaron a brief email (found his email online) @Ron

 

Thirty subjects is a very small sample and thirteen severe ME/CFS patients even smaller. That said, identifiable and treatable hormonal deficiencies in 11 of those thirteen is a lot of previously unrecognized/untreated dysfunction in this small group.
At the least, I would hope that treating these deficiencies would help to "clean up" their clinical presentations and lead to significantly less morbidity for these people.
As for this being an "explanation" for ME, I've always struggled with the notion of ME itself due to it being a diagnosis of exclusion. In the case of these severe subjects (group 1a), what appears to have been excluded was not based on testing but at least to some degree, presumption ("ME isn't endocrine" and it's a waste of time and resources testing for secondary and tertiary dysfunction - it does need to be done with care and by experienced labs/practitioners).

 

It is possible, but since even complete ablation of the pituitary does not usually produce a symptom pattern suggestive of ME and hypothalamic disease also produces quite different pictures I think these findings are pretty hard to interpret.

 

Is the interpretation less challenging if you presume that the most severe pituitary/hypothalamic damage might occur over a period of years (with a lot of adaptation and compensation - ablation not so much) and that there could simultaneously be a significant amount of immune/inflammatory processes?

Also, I do not suspect or hypothesize (nor does this study suggest) the complete loss of function across all axes.

As just one example, it is estimated/widely accepted that a patient must lose 75-80% of their Arginine Vasopressin Producing cells (AVPc's) before they are symptomatic for central diabetes insipidus (CDI - "Presentation with HDI [Hypothalamic DI] implies destruction or loss of function of more than 80% of vasopressinergic magnocellular neurons" - The Neurohypophysis: Endocrinology of Vasopressin and Oxytocin, Ball - https://www.endotext.org/chapter/the-neurohypophysis-endocrinology-of-vasopressin-and-oxytocin/). CDI patients may not appreciate their increased compensatory fluid intake until their CDI becomes florid (bradycardia and hypo-tension are likely sporadic as well early on - when florid, eventually electrolyte imbalance and loss of vascular tone can have life altering/life threatening effects).

While 13 of the 30 ME/CFS patients had symptoms rated as severe, one of the "... inclusion criteria for these patients w[as] duration of fatigue 3 years or less"

 

Nit really.
I wonder if low growth hormone levels are just a manifestation of limited activity.

 

That's already been suggested regarding fatigue. I can assure you that is not the case.

 

On what basis? I thought that exercise generated a rise in GH normally and that prolonged inactivity blunted the GH rise in any subsequent activity.

 

First, with regards to GHD and this study, we are talking about four of eleven subjects/patients identified as hormonally deficient. Throw those four out and you still have a majority of severely ill subjects that were deficient for other hormones.

But why throw those four out? Of all the deficiencies, the symptom profile for GHD is probably as close to the symptom profile of severe ME/CFS as any hormone deficiency (an earlier complaint of yours – see below).

Take a look at Table 2

Group Hormone levels - GH peak (Glucagon Stim test),

1A(n = 13) Group - 2.3 (1.2) - P < .001 Statistically significant vs group 1B, 1C, and controls.

1B (n = 7) Group - 5.9 (0.7)

1C (n = 10) - 6.2 (0.7)

Normal controls (n = 25) 6.9 (2.5)


Group Hormone levels - IGF-1

1A(n = 13) Group - 160.2 (50.8) - P < .001 Statistically significant vs group 1B, 1C, and controls.

1B (n = 7) Group - 234.3 (20.3)

1C (n = 10) - 212.9 (33.6)

Normal controls (n = 25) 225 (26.3)



In the control group, GH peak was 6.9 with a SD of 2.5. In group 1A (thirteen subjects), GH Peak in response to stimulation was 2.3 with a SD of 1.2. Only four of those 13 were determined to be GHD (GH =< 1.18). The high Ab ME/CFS group (which was also the severe symptom group) had an AVERAGE GH peak that was 33% that of the controls and very close to 30% of the other two patient groups.

There is data to suggest the need for a lower cut-off in patients who are overweight/obese adults and in those with glucose intolerance but there is no evidence to suggest the need for a lower cut-off to account for activity levels (this was not a study measuring short-term GH response to exercise as that is not the diagnostic standard).

In this study, “GHD was diagnosed by the presence of low normal basal IGF-1 AND impaired GH response (< 1.18 mcg/L) to a glucagon stimulation test.” This is the recommended standard for suspicion of GHD and subsequent Glucagon Stimulation Testing/GHD diagnosis.



Direct comparisons to the data citing concerns about obesity glucose intolerance are impaired due to laboratory differences in standardization (a recognized issue across the field).



From the current version of EndoText (https://www.endotext.org/chapter/gr...in-assessing-adult-growth-hormone-deficiency/):

“Several recent retrospective studies have questioned the diagnostic accuracy of the GST when the GH cut-point of 3mg/L is applied to overweight/obese adults (26-29) and in those with glucose intolerance (28, 29), while Hamrahian et al. (30) demonstrated in a prospective study of 28 patients by comparing the GST to the ITT that a lower GH cut-point of 1 mg/L improved its diagnostic accuracy with a 92% sensitivity and 100% specificity.”



In conclusion, De Bellis, et al. write: “…our results show for the first time that the GH peak in response to glucagon was significantly lower in patients with severe ME/CFS than in controls and in those with moderate/mild disease. For this reason, we suggest that several of the main typical symptoms in severe ME/CFS, such as fatigue, myalgia, contractility, delaying muscle recovery and function, exertional malaise, neurocognitive dysfunction, and physical disability may be related to severe GHD.

This also considers the multifarious role played by GH/IGF-1 secretions and in particular the important IGF-1 role in many biological processes of neurons, including neuroprotective action, mitochondrial protection, antioxidant defense, and reduction of CNS inflammation by improving brain damage (42). In this regard, we hypothesize that autoimmune GHD may amplify the severe damage in ME/CFS determined by cytokines due to the absence of neuroprotective, antioxidant, and antineuronal functions normally exerted by IGF-1.”


Lastly, hormonal deficiencies, specifically in GH, as a response to infectious disease are not something with which De bellis is unfamiliar:


Tanriverdi, F., De Bellis, A., Teksahin, H. et al. Prospective investigation of pituitary functions in patients with acute infectious meningitis: is acute meningitis induced pituitary dysfunction associated with autoimmunity?. Pituitary 15, 579–588 (2012). https://doi.org/10.1007/s11102-011-0371-7


“The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months. In addition, the occurrence of AHA and APA positivity due to acute infectious meningitis was demonstrated for the first time.”

Remarkably similar results in a group with no history of reduced activity (presumably aside from those brought about by their current health issues).

In conclusion, at this point, no one is claiming that ME is GHD but given the results of the present study, there needs to be significantly more work to understand what is going on here.

 

I didn't raise the question about low activity levels causing low GH response to the GST. I provided the most up to date clinical guidance which does not mention anything about low activity and low GH (but does mention obesity and glucose intolerance - of which there is nothing suggesting it as an issue). Wouldn't it make more sense to substantiate that original claim (low activity causes low GH response?) first and to work from that?

 

I'm not entirely clear on how you differentiate and which studies to which you are referring. Perhaps much of what is being dismissed is more important than is thought but the schema is faulty.